Announcing an automatic patient savings program

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1 Pharmacy E change Volume 17, Number 3 August 2016 Web Version New from Mylan Generic for Doryx (doxycycline hyclate delayed-release tablets) 1,2 Now Available from Mylan in 50 mg and 200 mg dosage strengths Mylan Doxycycline Hyclate Delayed-release Tablets, USP, a therapeutic equivalent generic for Doryx, is now available in 50 mg and 200 mg dosage strengths. 1,2 Mylan Doxycycline Hyclate Delayed-release Tablets, USP Dosage Strength Mylan NDC 50 mg 120 tablets mg 60 tablets Dosage Form White, round unscored tablets containing yellow beads debossed with M on one side of the tablet and D36 on the other side White, capsule-shaped scored tablets containing yellow beads debossed with M on one side of the tablet and D to the left side of the score and 34 to the right side of the score on the other side Consider 50 mg and 200 mg Mylan Doxycycline Hyclate Delayed-release Tablets, USP for your patients For more information, call Mylan Customer Relations at To download full Prescribing Information, visit: Mylan.com/Products/Doxycycline Hyclate Delayed-release Click here for full Prescribing Information for Mylan Doxycycline Hyclate Delayed-release Tablets, USP 50 mg. Click here for full Prescribing Information for Mylan Doxycycline Hyclate Delayed-release Tablets, USP 200 mg. NOW eligible patients* with commercial insurance may save with $0 Co-pay on the 50 mg or pay only $10 per prescription on the 200 mg* Mylan offers an evoucherrx automatic patient saving program that may allow eligible patients to save on out-of-pocket costs for Mylan Doxycycline Hyclate Delayed-release Tablets, USP, 50 mg and 200 mg. No coupons, cards or forms required! Patients can take their prescriptions to one of more than 46,000 participating pharmacies nationwide. For a list of participating pharmacies, go to Eligible patients will get an automatic copay reduction at the pharmacy counter when they pick up their Mylan Doxycycline Hyclate Delayed-release Tablets, USP prescription. No coupons, cards or forms needed. Click here for Eligibility Requirements/Exclusions and Terms and Conditions. The color blue of the Mylan Blue Bottle is a registered trademark of Mylan Pharmaceuticals Inc. Announcing an automatic patient savings program SEE NEW PRODUCTS ONLINE Since the last edition of Pharmacy Exchange in June, Mylan has introduced a number of products. For a complete listing of products introduced since the last edition of Pharmacy Exchange, click here.

2 *Eligibility Requirements/Exclusions: The evoucherrx TM program will not offer copay savings for claims paid by government-sponsored insurance plans, including Medicare, Medicaid, TRICARE and federal and state programs; cash claims (see Terms and Conditions below). Terms and Conditions: 50 mg Offer applies to out-of-pocket expenses (copay) greater than $0. Out-of-pocket expenses greater than $0 will be covered up to $25 per prescription. If your total out-of-pocket cost exceeds $25, you will be responsible for a $0 copay plus any additional amount over $25. If your copay is already $0, this offer does not apply. 200 mg Offer applies to out-of-pocket expenses (copay) greater than $10. Out-of-pocket expenses greater than $10 will be covered up to $50 per prescription. If your total out-of-pocket cost exceeds $50, you will be responsible for a $10 copay plus any additional amount over $50. If your copay is already $10 or less, this offer does not apply. This offer is not valid for prescriptions paid in part or in full by any federally or state-funded program, including but not limited to Medicaid, Medicare, Department of Veterans Affairs, Department of Defense or TRICARE, and where prohibited by law. Offer good only in the USA at participating retail pharmacies and cannot be redeemed at government-subsidized clinics. Void where taxed, restricted or prohibited by law. Participation in this program must comply with all applicable laws and contractual or other obligations as a pharmacy provider. This is not an insurance program. Participating patients and pharmacists understand and agree to comply with the Terms and Conditions of this offer as set forth herein. Any step-edits or prior authorizations required by the insurance plan still apply. This offer is void where taxed, restricted or prohibited by law. Mylan reserves the right to modify or cancel this program at any time. evoucherrx is not extended on prescriptions for patients: Who are cash-paying customers Using mail-order or institution-based pharmacies to fill their prescriptions, or who are federal or state government employees Who are filling their prescriptions at nonparticipating pharmacies Click here for full Prescribing Information for Mylan Doxycycline Hyclate Delayed-release Tablets, USP 50 mg. Click here for full Prescribing Information for Mylan Doxycycline Hyclate Delayed-release Tablets, USP 200 mg. For more information, visit Mylan.com. *Some restrictions apply. Mylan reserves the right to modify or cancel this offer at any time. Participation status subject to change. For a current list of participating pharmacies in your area, go to Doryx is a registered trademark of Mayne Pharma. evoucherrx TM is a trademark of RelayHealth and/or its affiliates. References 1. Doxycycline Hyclate Delayed-release Tablets Prescribing Information. Morgantown, WV: Mylan Pharmaceuticals Inc. 2. Food and Drug Administration. Approval Letter for Doxycycline Hyclate Delayed-release Tablets, USP; 2016.

3 Exclusive Generic Strengths Introducing AB-rated generic to Nuvigil (armodafinil) tablets C lv from Mylan in 50 mg, 150 mg, and 250 mg dosage strengths 3,4 Mylan is the first and only manufacturer to offer an FDA-approved, AB-rated generic for Nuvigil (armodafinil) tablets in exclusive 50 mg, 150 mg, and 250 mg generic dosage strengths. 4 Mylan Armodafinil Tablets C lv Dosage Strength Mylan NDC Dosage Form 50 mg 30 tablets mg 30 tablets White to off-white round, unscored tablet Not actual size White to off-white round, unscored tablet Not actual size For more information, call Mylan Customer Relations at The Mylan Blue Bottle stands for Mylan quality 250 mg 30 tablets White to off-white capsule-shaped, unscored tablet Not actual size INDICATIONS AND USAGE Armodafinil tablets are indicated to improve wakefulness in adult patients with excessive sleepiness associated with obstructive sleep apnea (OSA), narcolepsy, or shift work disorder (SWD). Limitations of Use In OSA, Armodafinil tablets are indicated to treat excessive sleepiness and not as treatment for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating armodafinil tablets for excessive sleepiness. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS: Armodafinil tablets are contraindicated in patients with a known hypersensitivity to modafinil or armodafinil or its inactive ingredients. Click here for additional IMPORTANT SAFETY INFORMATION and click here for full Prescribing Information, including Patient Counseling Information and Medication Guide for Armodafinil Tablets. WARNINGS AND PRECAUTIONS Serious rash, including Stevens-Johnson Syndrome: Serious rash requiring hospitalization and discontinuation of treatment has been reported in association with the use of Armodafinil tablets or modafinil (the racemic mixture of S- and R-enantiomers). There are no factors, including duration of therapy, that are known to predict the risk of occurrence or the severity of rash. Although benign rashes also occur with Armodafinil tablets, it is not possible to reliably predict which rashes will prove to be serious. Armodafinil tablets should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring. Armodafinil has not been studied in pediatric patients in any setting and is not approved for use in pediatric patients for any indication.

4 IMPORTANT SAFETY INFORMATION FOR ARMODAFINIL TABLETS (CONT D) Angioedema and anaphylaxis reactions: Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm), were observed with armodafinil. Patients should be advised to discontinue therapy and immediately report to their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness). Multi-organ Hypersensitivity Reactions: Multi-organ hypersensitivity reactions, including at least one fatality in post-marketing experience, have occurred in close temporal association (median time to detection 13 days: range 4 to 33) to the initiation of modafinil. A similar risk of multi-organ hypersensitivity reactions with armodafinil cannot be ruled out. Although there have been a limited number of reports, multi-organ hypersensitivity reactions may result in hospitalization or be life-threatening. There are no factors that are known to predict the risk of occurrence or the severity of multi-organ hypersensitivity reactions. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included myocarditis, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multi-organ hypersensitivity is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If a multi-organ hypersensitivity reaction is suspected, armodafinil should be discontinued. Although there are no case reports to indicate cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. Persistent sleepiness and CNS effects: Patients with abnormal levels of sleepiness who take armodafinil should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking armodafinil, should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Prescribers should also be aware that patients may not acknowledge sleepiness or drowsiness until directly questioned about drowsiness or sleepiness during specific activities. Although Armodafinil tablets have not been shown to produce functional impairment, any drug affecting the CNS may alter judgment, thinking or motor skills. Patients should be cautioned about operating an automobile or other hazardous machinery until it is reasonably certain that armodafinil therapy will not adversely affect their ability to engage in such activities. Psychiatric symptoms: Psychiatric adverse reactions have been reported in patients treated with Armodafinil tablets and modafinil. In controlled trials in adults treated with Armodafinil tablets, psychiatric symptoms resulting in treatment discontinuation included anxiety, agitation, nervousness, irritability, and depression versus placebo (armodafinil 0.6% and placebo 0.2%). Cases of suicide ideation were observed in clinical trials. Postmarketing adverse reactions associated with the use of modafinil have included mania, delusions, hallucinations, suicidal ideation, and aggression, some resulting in hospitalization. Caution should be exercised when Armodafinil tablets is given to patients with a history of psychosis, depression, or mania. Consider discontinuing Armodafinil tablets if psychiatric symptoms develop. Cardiovascular events: Cardiovascular adverse reactions have been reported in patients treated with modafinil in association with mitral valve prolapse or left ventricular hypertrophy. Armodafinil tablets are not recommended in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced mitral valve prolapse syndrome when previously receiving CNS stimulants. If findings of mitral valve prolapse syndrome occur, consider cardiac evaluation. In clinical studies, a slightly greater proportion of patients on Armodafinil tablets required new or increased use of antihypertensive medications compared to patients on placebo. Increased monitoring of heart rate and blood pressure may be appropriate in patients on Armodafinil tablets. Caution should be exercised when prescribing Armodafinil tablets to patients with known cardiovascular disease. Common adverse reactions: In clinical trials, the most commonly reported adverse reactions ( 5%) associated with the use of Armodafinil tablets were headache, nausea, dizziness, and insomnia. Armodafinil tablets is a Schedule IV controlled substance because it has the potential to be abused or lead to dependence. Physicians should follow patients closely, especially those with a history of drug and/or stimulant (e.g., methylphenidate, amphetamine, or cocaine) abuse. Drug interactions: Armodafinil tablets may interact with drugs that are substrates for CYP3A4/5 (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) or CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine). Dose adjustment of these drugs may be required. The effectiveness of steroidal contraceptives may be reduced when used with Armodafinil tablets and for one month after discontinuation of therapy. Alternative or concomitant methods of contraception are recommended for patients taking steroidal contraceptives (e.g., ethinyl estradiol) when treated concomitantly with armodafinil and for 1 month after discontinuation of armodafinil treatment. Blood levels of cyclosporine may be reduced when used with armodafinil. More frequent monitoring of prothrombin times/inr should be considered whenever armodafinil is coadministered with warfarin. Caution should be used when concomitantly administering MAO inhibitors and armodafinil. Click here for full Prescribing Information, including Patient Counseling Information and Medication Guide. Nuvigil is a registered trademark of Cephalon, Inc. The color blue of the blue bottle is a registered trademark of Mylan Pharmaceuticals Inc. The Mylan logo is a registered trademark of Mylan Inc. References 3. Armodafinil Tablets Prescribing Information. Morgantown, WV: Mylan Pharmaceuticals Inc. 4. Food and Drug Administration. Approval Letter for Armodafinil Tablets; 2016.

5 Products Introduced Since April 1, 2016 (Products not actual size) AMOXICILLIN and CLAVULANATE POTASSIUM Tablets, USP 500 mg/125 mg and 875 mg/125 mg Generic for: Augmentin * Tablets (Product Images Unavailable at this Time.) Click here for full Prescribing Information for 500 mg/125 mg and 875 mg/125 mg tablets supplied in bottles of 20. Click here for full Prescribing Information for 875 mg/125 mg tablets supplied in bottles of 100. AMOXICILLIN and CLAVULANATE POTASSIUM for Oral Suspension, USP 200 mg/28.5 mg per 5 ml, 400 mg/57 mg per 5 ml and 600 mg/42.9 mg per 5 ml Generic for: Augmentin * for Oral Suspension (Product Images Unavailable at this Time.) Click here for full Prescribing Information for 200 mg/28.5 mg per 5 ml and 400 mg/57 mg per 5 ml oral suspension supplied in 100 ml bottles. Click here for full Prescribing Information for 400 mg/57 mg per 5 ml oral suspension supplied in 50 ml and 75 ml bottles. Click here for full Prescribing Information for 600 mg/42.9 mg per 5 ml oral suspension supplied in 75 ml, 125 ml and 200 ml bottles. CLINDAMYCIN PALMITATE HYDROCHLORIDE for Oral Solution, USP (Pediatric) 75 mg/5 ml Generic for: Cleocin * Solution (Product Images Unavailable at this Time.) Click here for full Prescribing Information, including Boxed WARNING regarding CLOSTRIDIUM DIFFICILE ASSOCIATED DIARRHEA (CDAD). DUTASTERIDE Capsules 0.5 mg Generic for: Avodart * Capsules Click here for full Prescribing Information and Patient Information. FENOFIBRATE Tablets 40 mg and 120 mg Generic for: Fenoglide * Tablets 0.5 mg Click here for full Prescribing Information. 40 mg 120 mg FROVATRIPTAN Succinate Tablets 2.5 mg Generic for: Frova * Tablets 2.5 mg Click here for full Prescribing Information and Patient Information. PROPAFENONE HYDROCHLORIDE Extended-release Capsules, USP 225 mg, 325 mg, and 425 mg Generic for: Rythmol SR * Capsules 225 mg 325 mg 425 mg Click here for full Prescribing Information, including Boxed WARNING regarding MORTALITY and Patient Information. TEMOZOLOMIDE Capsules 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg Generic for: Temodar * Capsules Click here for full Prescribing Information and Patient Information. 5 mg 20 mg 100 mg 140 mg 180 mg 250 mg *Brand names are the trademarks of the products manufacturers and/or owners. The Mylan logo is a registered trademark of Mylan Inc Mylan Pharmaceuticals Inc. All rights reserved. ARM MYNMKT599 (08/16)

6 SDZ:AXCLT:R2 Amoxicillin and Clavulanate Potassium Tablets, USP 500 mg/125 mg and 875 mg/125 mg HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use AMOXICILLIN AND CLAVULANATE POTASSIUM, USP safely and effectively. See full prescribing information for AMOXICILLIN AND CLAVULANATE POTASSIUM, USP. AMOXICILLIN and CLAVULANATE Potassium Tablets USP, for Oral Use Initial U.S. Approval: 1984 To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium and other antibacterial drugs, amoxicillin and clavulanate potassium should be used only to treat infections that are proven or strongly suspected to be caused by bacteria INDICATIONS AND USAGE Amoxicillin and clavulanate potassium tablets, USP, are a combination penicillin-class antibacterial and beta-lactamase inhibitor indicated for treatment of the following: Lower respiratory tract infections (1.1) Acute bacterial otitis media (1.2) Sinusitis (1.3) Skin and skin structure infections (1.4) Urinary tract infections (1.5) DOSAGE AND ADMINISTRATION Adults and Pediatric Patients > 40 kg: 500 or 875 mg every 12 hours or 250 or 500 mg every 8 hours. (2.1, 2.2) Pediatric patients aged 12 weeks (3 months) and older: 25 to 45 mg/kg/day every 12 hours or 20 to 40 mg/kg/day every 8 hours, up to the adult dose. (2.2) Neonates and infants < 12 weeks of age: 30 mg/kg/day divided every 12 hours, based on the amoxicillin component. Use of the 125 mg/5 ml oral suspension is recommended. (2.2) DOSAGE FORMS AND STRENGTHS Formulations and amoxicillin/clavulanate content are: Tablets: 500 mg/125 mg, 875 mg/125 mg; 875 mg/125 mg tablets are scored (3) CONTRAINDICATIONS History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin and clavulanate potassium or to other beta-lactams (e.g., penicillins or cephalosporins). (4) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Lower Respiratory Tract Infections 1.2 Acute Bacterial Otitis Media 1.3 Sinusitis 1.4 Skin and Skin Structure Infections 1.5 Urinary Tract Infections 1.6 Limitations of Use 2 DOSAGE AND ADMINISTRATION 2.1 Adults 2.2 Pediatric Patients 2.3 Patients with Renal Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Serious Hypersensitivity Reactions 4.2 Cholestatic Jaundice/Hepatic Dysfunction 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 5.2 Hepatic Dysfunction 5.3 Clostridium difficile Associated Diarrhea 5.4 Skin Rash in Patients with Mononucleosis 5.5 Potential for Microbial Overgrowth 5.7 Development of Drug-Resistant Bacteria 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Probenecid 7.2 Oral Anticoagulants 7.3 Allopurinol FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium and other antibacterial drugs, amoxicillin and clavulanate potassium should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Amoxicillin and clavulanate potassium tablets, USP are a combination penicillin-class antibacterial and beta-lactamase inhibitor indicated in the treatment of infections due to susceptible isolates of the designated bacteria in the conditions listed below: 1.1 Lower Respiratory Tract Infections Caused by beta-lactamase producing isolates of Haemophilus influenzae and Moraxella catarrhalis. 1.2 Acute Bacterial Otitis Media Caused by beta-lactamase producing isolates of H. influenzae and M. catarrhalis. 1.3 Sinusitis Caused by beta-lactamase producing isolates of H. influenzae and M. catarrhalis. 1.4 Skin and Skin Structure Infections Caused by beta-lactamase producing isolates of Staphylococcus aureus, Escherichia coli, and Klebsiella species. 1.5 Urinary Tract Infections Caused by beta-lactamase producing isolates of E. coli, Klebsiella species, and Enterobacter species. 1.6 Limitations of Use When susceptibility test results show susceptibility to amoxicillin, indicating no beta-lactamase production, amoxicillin and clavulanate potassium should not be used. 2 DOSAGE AND ADMINISTRATION Amoxicillin and clavulanate potassium may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when amoxicillin and clavulanate potassium is administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, amoxicillin and clavulanate potassium should be taken at the start of a meal. 2.1 Adults The usual adult dose is one 500-mg tablet of amoxicillin and clavulanate potassium every 12 hours or one 250 mg tablet of amoxicillin and clavulanate potassium every 8 hours. For more severe infections and infections of the respiratory tract, the dose should be one 875-mg tablet of amoxicillin and clavulanate potassium every 12 hours or one 500-mg tablet of amoxicillin and clavulanate potassium every 8 hours. Adults who have difficulty swallowing may be given the 125 mg/5 ml or 250 mg/5 ml suspension in place of the 500-mg tablet. The 200 mg/5 ml suspension or the 400 mg/5 ml suspension may be used in place of the 875-mg tablet. Two 250-mg tablets of amoxicillin and clavulanate potassium should not be substituted for one 500-mg tablet of amoxicillin and clavulanate potassium. Since both the 250-mg and 500-mg tablets of amoxicillin and clavulanate potassium contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250-mg tablets are not equivalent to one 500-mg tablet of amoxicillin and clavulanate potassium. The 250-mg tablet of amoxicillin and clavulanate potassium and the 250-mg History of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium. (4) WARNINGS AND PRECAUTIONS Serious (including fatal) hypersensitivity reactions: Discontinue amoxicillin and clavulanate potassium if a reaction occurs. (5.1) Hepatic dysfunction and cholestatic jaundice: Discontinue if signs/ symptoms of hepatitis occur. Monitor liver function tests in patients with hepatic impairment. (5.2) Clostridium difficile-associated diarrhea (CDAD): Evaluate patients if diarrhea occurs. (5.3) Patients with mononucleosis who receive amoxicillin and clavulanate potassium develop skin rash. Avoid amoxicillin and clavulanate potassium use in these patients. (5.4) Overgrowth: The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. (5.5) ADVERSE REACTIONS The most frequently reported adverse effects were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at ( INFO-RX) or FDA at FDA-1088 or DRUG INTERACTIONS Coadministration with probenecid is not recommended. (7.1) Concomitant use of amoxicillin and clavulanate potassium and oral anticoagulants may increase the prolongation of prothrombin time. (7.2) Coadministration with allopurinol increases the risk of rash. (7.3) Amoxicillin and clavulanate potassium may reduce efficacy of oral contraceptives. (7.4) USE IN SPECIFIC POPULATIONS Pediatric Use: Modify dose in patients 12 weeks or younger. (8.4) Renal impairment; Dosage adjustment is recommended for severe renal impairment (GFR < 30mL/min). (2.3, 8.6) See 17 for PATIENT COUNSELING INFORMATION REVISED FEBRUARY 2016 SDZ:AXCLT:R2 7.4 Oral Contraceptives 7.5 Effects on Laboratory Tests 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Dosing in Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Lower Respiratory Tract and Complicated Urinary Tract Infections 14.2 Acute Bacterial Otitis Media and Diarrhea in Pediatric Patients 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Information for Patients *Sections or subsections omitted from the full prescribing information are not listed. chewable tablet should not be substituted for each other, as they are not interchangeable. The 250-mg tablet of amoxicillin and clavulanate potassium and the 250-mg chewable tablet do not contain the same amount of clavulanic acid (as the potassium salt). The 250-mg tablet of amoxicillin and clavulanate potassium contains 125 mg of clavulanic acid, whereas the 250-mg chewable tablet contains 62.5 mg of clavulanic acid. 2.2 Pediatric Patients Based on the amoxicillin component, amoxicillin and clavulanate potassium should be dosed as follows: Neonates and Infants Aged < 12 weeks (< 3 months): The recommended dose of Amoxicillin and clavulanate potassium is 30 mg/kg/day divided every 12 hours, based on the amoxicillin component. Experience with the 200 mg/5 ml formulation in this age group is limited, and thus, use of the 125 mg/5 ml oral suspension is recommended. Patients Aged 12 weeks (3 months) and Older: See dosing regimens provided in Table 1. The every 12 hour regimen is recommended as it is associated with significantly less diarrhea [see Clinical Studies (14.2)]. However, the every 12 hour suspension (200 mg/5 ml and 400 mg/5 ml) and chewable tablets (200 mg and 400 mg) contain aspartame and should not be used by phenylketonurics. Table 1. Dosing in Patients Aged 12 weeks (3 months) and Older DOSING REGIMEN Every 12 hours Every 8 hours INFECTION Otitis media, sinusitis, lower respiratory tract infections, and more severe infections Less severe infections 200 mg/5 ml or 400 mg/5 ml oral suspension* 45 mg/kg/day every 12 hours 25 mg/kg/day every 12 hours 125 mg/5 ml or 250 mg/5 ml oral suspension* 40 mg/kg/day every 8 hours 20 mg/kg/day every 8 hours * Each strength of suspension of amoxicillin and clavulanate potassium is available as a chewable tablet for use by older children. Duration of therapy studied and recommended for acute otitis media is 10 days. Patients Weighing 40 kg or More: Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations. The 250-mg tablet of amoxicillin and clavulanate potassium should not be used until the child weighs at least 40 kg, due to the different amoxicillin to clavulanic acid ratios in the 250-mg tablet of amoxicillin and clavulanate potassium (250 mg/125 mg) versus the 250-mg chewable tablet of amoxicillin and clavulanate potassium (250 mg/62.5 mg). 2.3 Patients with Renal Impairment Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Renal impairment patients with a glomerular filtration rate of < 30 ml/min should not receive the 875-mg dose. Patients with a glomerular filtration rate of 10 to 30 ml/min should receive 500 mg or 250 mg every 12 hours, depending on the severity of the infection. Patients with a glomerular filtration rate less than 10 ml/min should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection. Hemodialysis patients should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection. They should receive an additional dose both during and at the end of dialysis. 3 DOSAGE FORMS AND STRENGTHS Tablets Amoxicillin and Clavulanate Potassium Tablets, USP, 500 mg/125 mg: Each film coated tablet, for oral administration, is white, oval-shaped, debossed GGN6 on one side and plain on the reverse side, and contains 500 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt. Amoxicillin and Clavulanate Potassium Tablets, USP, 875 mg/125 mg: Each film coated tablet, for oral administration, is white, capsule-shaped, scored and debossed GGN7 on one side and scored on the reverse side, and contains 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt. The 250-mg tablet of amoxicillin and clavulanate potassium and the 250-mg chewable tablet should NOT be substituted for each other, as they are not interchangeable and the 250-mg tablet should not be used in children weighing less than 40 kg. The 250-mg tablet of amoxicillin and clavulanate potassium and the 250-mg chewable tablet do not contain the same amount of clavulanic acid. The 250-mg tablet of amoxicillin and clavulanate potassium contains 125 mg of clavulanic acid whereas the 250-mg chewable tablet contains 62.5 mg of clavulanic acid. Two 250 mg tablets of amoxicillin and clavulanate potassium should NOT be substituted for one 500 mg tablet of amoxicillin and clavulanate potassium. Since both the 250 mg and 500 mg tablets of amoxicillin and clavulanate potassium contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250 mg tablets of amoxicillin and clavulanate potassium are not equivalent to one 500 mg tablet of amoxicillin and clavulanate potassium. 4 CONTRAINDICATIONS 4.1 Serious Hypersensitivity Reactions Amoxicillin and clavulanate potassium is contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin, clavulanate or to other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins). 4.2 Cholestatic Jaundice/Hepatic Dysfunction Amoxicillin and clavulanate potassium is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including amoxicillin and clavulanate potassium. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Before initiating therapy with amoxicillin and clavulanate potassium, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, amoxicillin and clavulanate potassium should be discontinued and appropriate therapy instituted. 5.2 Hepatic Dysfunction Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of amoxicillin and clavulanate potassium. Hepatic toxicity is usually reversible; however, deaths have been reported. Hepatic function should be monitored at regular intervals in patients with hepatic impairment. 5.3 Clostridium difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin and clavulanate potassium, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.4 Skin Rash in Patients with Mononucleosis A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus, amoxicillin and clavulanate potassium should not be administered to patients with mononucleosis. 5.5 Potential for Microbial Overgrowth The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfection occurs, amoxicillin/clavulanate potassium should be discontinued and appropriate therapy instituted. 5.7 Development of Drug-Resistant Bacteria Prescribing amoxicillin and clavulanate potassium in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient, and increases the risk of the development of drug-resistant bacteria. 6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Anaphylactic reactions [see Warnings and Precautions (5.1)] Hepatic Dysfunction [see Warnings and Precautions (5.2)] CDAD [see Warnings and Precautions (5.3)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most frequently reported adverse reactions were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). Less than 3% of patients discontinued therapy because of drug-related adverse reactions. The overall incidence of adverse reactions, and in particular diarrhea, increased with the higher recommended dose. Other less frequently reported adverse reactions (< 1%) include: Abdominal discomfort, flatulence, and headache. In pediatric patients (aged 2 months to 12 years), 1 US/Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of amoxicillin and clavulanate potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxicillin and clavulanate potassium for 10 days in the treatment of acute otitis media. A total of 575 patients were enrolled, and only the suspension formulations were used in this trial. Overall, the adverse reactions seen were comparable to that noted above; however, there were differences in the rates of diarrhea, skin rashes/urticaria, and diaper area rashes. [see Clinical Studies (14.2)] 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following have been identified during postmarketing use of amoxicillin and clavulanate potassium. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to amoxicillin and clavulanate potassium. Gastrointestinal: Indigestion, gastritis, stomatitis, glossitis, black hairy tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. [see Warnings and Precautions (5.3)] Hypersensitivity Reactions: Pruritus, angioedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), erythema multiforme, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and cases of exfoliative dermatitis (including toxic epidermal necrolysis) have been reported. [see Warnings and Precautions (5.1)] Liver: Hepatic dysfunction, including hepatitis and cholestatic jaundice, increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been reported with amoxicillin and clavulanate potassium. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued.

7 The hepatic dysfunction, which may be severe, is usually reversible. Deaths have been reported. [see Contraindications (4.2), Warnings and Precautions (5.2)] Renal: Interstitial nephritis, hematuria, and crystalluria have been reported. [see Overdosage (10)] Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Thrombocytosis was noted in less than 1% of the patients treated with amoxicillin and clavulanate potassium. There have been reports of increased prothrombin time in patients receiving amoxicillin and clavulanate potassium and anticoagulant therapy concomitantly. [see Drug Interactions (7.2)] Central Nervous System: Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported. Miscellaneous: Tooth discoloration (brown, yellow, or gray staining) has been reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases. 7 DRUG INTERACTIONS 7.1 Probenecid Probenecid decreases the renal tubular secretion of amoxicillin but does not delay renal excretion of clavulanic acid. Concurrent use with amoxicillin and clavulanate potassium may result in increased and prolonged blood concentrations of amoxicillin. Coadministration of probenecid is not recommended. 7.2 Oral Anticoagulants Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been reported in patients receiving amoxicillin and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently with amoxicillin and clavulanate potassium. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation. 7.3 Allopurinol The concurrent administration of allopurinol and amoxicillin increases the incidence of rashes in patients receiving both drugs as compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients. 7.4 Oral Contraceptives Amoxicillin and clavulanate potassium may affect intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives. 7.5 Effects on Laboratory Tests High urine concentrations of amoxicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST, Benedict s Solution, or Fehling s Solution. Since this effect may also occur with amoxicillin and clavulanate potassium, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. Following administration of amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects Pregnancy Category B Reproduction studies performed in pregnant rats and mice given amoxicillin and clavulanate potassium (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses up to 1200 mg/kg/day revealed no evidence of harm to the fetus due to amoxicillin and clavulanate potassium. The amoxicillin doses in rats and mice (based on body surface area) were approximately 4 and 2 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, these dose multiples were approximately 9 and 4 times the maximum recommended adult human oral dose (125 mg every 8 hours). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 8.2 Labor and Delivery Oral ampicillin-class antibiotics are poorly absorbed during labor. It is not known whether use of amoxicillin/clavulanate potassium in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood of the necessity for an obstetrical intervention. 8.3 Nursing Mothers Amoxicillin has been shown to be excreted in human milk. Amoxicillin/clavulanate potassium use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin/clavulanate potassium is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of amoxicillin and clavulanate potassium for oral suspension and chewable tablets have been established in pediatric patients. Use of amoxicillin and clavulanate potassium in pediatric patients is supported by evidence from studies of amoxicillin and clavulanate potassium tablets in adults with additional data from a study of amoxicillin and clavulanate potassium for oral suspension in pediatric patients aged 2 months to 12 years with acute otitis media. [see Clinical Studies (14.2)] Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed; clavulanate elimination is unaltered in this age group. Dosing of amoxicillin and clavulanate potassium should be modified in pediatric patients aged < 12 weeks (< 3 months). [see Dosage and Administration (2.2)] 8.5 Geriatric Use Of the 3,119 patients in an analysis of clinical studies of amoxicillin and clavulanate potassium, 32% were 65 years old, and 14% were 75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Dosing in Renal Impairment Amoxicillin is primarily eliminated by the kidney and dosage adjustment is usually required in patients with severe renal impairment (GFR < 30 ml/min). See Patients with Renal Impairment (2.3) for specific recommendations in patients with renal impairment. 10 OVERDOSAGE In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. A prospective study of 51 pediatric patients at a poison-control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms1. Interstitial nephritis resulting in oliguric renal failure has been reported in patients after overdosage with amoxicillin/clavulanate potassium. Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin/clavulanate potassium overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin/clavulanate potassium crystalluria. Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of amoxicillin/clavulanate potassium. Amoxicillin/clavulanate potassium may be removed from circulation by hemodialysis. [see Dosage and Administration (2.3)] 11 DESCRIPTION Amoxicillin and clavulanate potassium tablets, USP are an oral antibacterial combination consisting of amoxicillin and the beta-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is C 16 H 19 N 3 O 5 S 3H 2 O, and the molecular weight is Chemically, amoxicillin is (2S,5R,6R)-6-[(R)- (-)-2-Amino-2-(phydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate and may be represented structurally as: Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a beta-lactam structurally related to the penicillins and possesses the ability to inactivate some beta-lactamases by blocking the active sites of these enzymes. The clavulanate potassium molecular formula is C 8 H 8 KNO 5, and the molecular weight is Chemically, clavulanate potassium is potassium (Z)(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate and may be represented structurally as: Inactive Ingredients Tablets Colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, talc, titanium dioxide, triethyl citrate, ethylcellulose, cetyl alcohol and sodium lauryl sulfate. In addition, the 875 mg/125 mg tablet contains crospovidone. Each tablet of amoxicillin and clavulanate potassium contains 0.63 meq potassium. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Amoxicillin and clavulanate potassium is an antibacterial drug. [see Microbiology 12.4] 12.3 Pharmacokinetics Mean amoxicillin and clavulanate potassium pharmacokinetic parameters in normal adults following administration of amoxicillin and clavulanate potassium tablets are shown in Table 3 and following administration of amoxicillin and clavulanate potassium for oral suspension and chewable tablets are shown in Table 4. Table 3. Mean (± S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters*, with Amoxicillin and Clavulanate Potassium Tablets Dose and Regimen C max (mcg/ml) AUC 0-24 (mcg h/ml) Amoxicillin/ Clavulanate Clavulanate Clavulanate potassium Amoxicillin potassium Amoxicillin potassium 250 mg/125 mg 3.3 ± ± ± ± 3.25 every 8 hours 500 mg/125 mg 6.5 ± ± ± ± 1.95 every 12 hours 500 mg/125 mg 7.2 ± ± ± ± 3.86 every 8 hours 875 mg/125 mg 11.6 ± ± ± ± 3.04 every 12 hours * Mean (± standard deviation) values of 14 normal adults (N=15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose. Amoxicillin/clavulanate potassium administered at the start of a light meal. Table 4. Mean (± S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters*, with Amoxicillin and Clavulanate Potassium for Oral Suspension and Chewable Tablets Dose C max (mcg/ml) AUC 0-24 (mcg h/ml) Amoxicillin/ Clavulanate potassium 400 mg/57 mg (5 ml of suspension) 400 mg/57 mg (1 chewable tablet) Amoxicillin Clavulanate potassium Amoxicillin Clavulanate potassium 6.94 ± ± ± ± ± ± ± ± 0.73 * Mean (± standard deviation) values of 28 normal adults. Peak concentrations occurred approximately 1 hour after the dose. Amoxicillin/clavulanate potassium administered at the start of a light meal. Oral administration of 5 ml of 250 mg/5 ml suspension of amoxicillin and clavulanate potassium or the equivalent dose of 10 ml of 125 mg/5 ml suspension of amoxicillin and clavulanate potassium provides average peak serum concentrations approximately 1 hour after dosing of 6.9 mcg/ml for amoxicillin and 1.6 mcg/ml for clavulanic acid. The areas under the serum concentration curves obtained during the first 4 hours after dosing were 12.6 mcg h/ml for amoxicillin and 2.9 mcg h/ml for clavulanic acid when 5 ml of 250 mg/5 ml suspension of amoxicillin and clavulanate potassium or equivalent dose of 10 ml of 125 mg/5 ml suspension of amoxicillin and clavulanate potassium were administered to normal adults. One 250-mg chewable tablet of amoxicillin and clavulanate potassium or two 125-mg chewable tablets of amoxicillin and clavulanate potassium are equivalent to 5 ml of 250 mg/5 ml suspension of amoxicillin and clavulanate potassium and provide similar serum concentrations of amoxicillin and clavulanic acid. Amoxicillin serum concentrations achieved with amoxicillin and clavulanate potassium are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. Time above the minimum inhibitory concentration of 1 mcg/ml for amoxicillin has been shown to be similar after corresponding every 12 hour and every 8 hour dosing regimens of amoxicillin and clavulanate potassium in adults and children. Absorption: Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While amoxicillin and clavulanate potassium can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In one study, the relative bioavailability of clavulanate was reduced when amoxicillin and clavulanate potassium was dosed at 30 and 150 minutes after the start of a high-fat breakfast. Distribution: Neither component in amoxicillin and clavulanate potassium is highly protein-bound; clavulanic acid is approximately 25% bound to human serum and amoxicillin approximately 18% bound. Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. Two hours after oral administration of a single 35 mg/kg dose of suspension of amoxicillin and clavulanate potassium to fasting children, average concentrations of 3 mcg/ml of amoxicillin and 0.5 mcg/ml of clavulanic acid were detected in middle ear effusions. Metabolism and Excretion: The half-life of amoxicillin after the oral administration of amoxicillin and clavulanate potassium is 1.3 hours and that of clavulanic acid is 1 hour. Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single 250-mg or 500-mg tablet of amoxicillin and clavulanate potassium Microbiology Amoxicillin is a semisynthetic antibiotic with in vitro bactericidal activity against Gram-positive and Gram-negative bacteria. Amoxicillin is, however, susceptible to degradation by beta-lactamases, and therefore, the spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a beta-lactam, structurally related to the penicillins, which possesses the ability to inactivate some beta-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated beta-lactamases frequently responsible for transferred drug resistance. The formulation of amoxicillin and clavulanic acid in amoxicillin and clavulanate potassium protects amoxicillin from degradation by some beta-lactamase enzymes and extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin. Amoxicillin/clavulanic acid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive bacteria Staphylococcus aureus Gram-negative bacteria Enterobacter species Escherichia coli Haemophilus influenzae Klebsiella species Moraxella catarrhalis The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for amoxicillin/clavulanic acid. However, the efficacy of amoxicillin/ clavulanic acid in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials. Gram-positive bacteria Enterococcus faecalis Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus pneumoniae Streptococcus pyogenes Viridans group Streptococcus Gram-negative Bacteria Eikenella corrodens Proteus mirabilis Anaerobic Bacteria Bacteroides species including Bacteroides fragilis Fusobacterium species Peptostreptococcus species Susceptibility Test Methods When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment. Dilution techniques Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method2,3 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 5. Diffusion techniques Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method3,4 This procedure uses paper disks impregnated with 30 mcg amoxicillin/clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) to test the susceptibility of bacteria to amoxicillin/ clavulanic acid. The disc diffusion interpretive criteria are provided in Table 5. Table 5. Susceptibility Test Interpretive Criteria for QC Strain Escherichia coli ATCC Escherichia coli ATCC Haemophilus influenzae ATCC Staphylococcus aureus ATCC Staphylococcus aureus ATCC Amoxicillin/Clavulanic Acid Minimum Inhibitory Concentrations (mcg/ml) Disk Diffusion (zone diameters in mm) Pathogen S I R S I R Enterobacteriaceae 8/4 16/8 32/ Haemophilus influenzae 4/2 8/ and Staphylococcus aureus Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test2,3,4. Standard amoxicillin/clavulanic acid powder should provide the following range of MIC values noted in Table 6 for the diffusion technique using the 30 mcg amoxicillin/clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) disk, the criteria in Table 6 should be achieved. Table 6. Acceptable Quality Control Ranges for Amoxicillin/Clavulanic Acid Minimum Inhibitory Disk Diffusion Concentration (zone diameter (mcg/ml) in mm) 2/1 to 8/4 18 to 24 4/2 to 16/8 17 to 22 2/1 to 16/8 15 to /0.06 to 0.5/ to NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate carcinogenic potential. Amoxicillin and clavulanate potassium (4:1 ratio formulation of amoxicillin:clavulanate) was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and clavulanate potassium was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. Amoxicillin and clavulanate potassium was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. Amoxicillin and clavulanate potassium (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses of up to 1,200 mg/kg/day was found to have no effect on fertility and reproductive performance in rats. Based on body surface area, this dose of amoxicillin is approximately 4 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, the dose multiple is approximately 9 times higher than the maximum recommended adult human oral dose (125 mg every 8 hours), also based on body surface area. 14 CLINICAL STUDIES 14.1 Lower Respiratory Tract and Complicated Urinary Tract Infections Data from 2 pivotal trials in 1,191 patients treated for either lower respiratory tract infections or complicated urinary tract infections compared a regimen of 875-mg tablets of amoxicillin and clavulanate potassium every 12 hours to 500-mg tablets of amoxicillin and clavulanate potassium dosed every 8 hours (584 and 607 patients, respectively). Comparable efficacy was demonstrated between the every 12 hours and every 8 hours dosing regimens. There was no significant difference in the percentage of adverse events in each group. The most frequently reported adverse event was diarrhea; incidence rates were similar for the 875-mg every 12 hours and 500-mg every 8 hours dosing regimens (15% and 14%, respectively); however, there was a statistically significant difference (p < 0.05) in rates of severe diarrhea or withdrawals with diarrhea between the regimens: 1% for 875-mg every 12 hours regimen versus 2% for the 500-mg every 8 hours regimen. In one of these pivotal trials, patients with either pyelonephritis (n = 361) or a complicated urinary tract infection (i.e., patients with abnormalities of the urinary tract that predispose to relapse of bacteriuria following eradication, n = 268) were randomized (1:1) to receive either 875-mg tablets of amoxicillin and clavulanate potassium every 12 hours (n = 308) or 500-mg tablets of amoxicillin and clavulanate potassium every 8 hours (n = 321). The number of bacteriologically evaluable patients was comparable between the two dosing regimens. Amoxicillin and clavulanate potassium produced comparable bacteriological success rates in patients assessed 2 to 4 days immediately following end of therapy. The bacteriologic efficacy rates were comparable at one of the follow-up visits (5 to 9 days post-therapy) and at a late post-therapy visit (in the majority of cases, this was 2 to 4 weeks post-therapy), as seen in Table 7. Table 7. Bacteriologic efficacy rates for amoxicillin and clavulanate potassium 875 mg every 500 mg every Time Post Therapy 12 hours % (n) 8 hours % (n) 2 to 4 days 81% (58) 80% (54) 5 to 9 days 58% (41) 52% (52) 2 to 4 weeks 52% (101) 55% (104) As noted before, though there was no significant difference in the percentage of adverse events in each group, there was a statistically significant difference in rates of severe diarrhea or withdrawals with diarrhea between the regimens Acute Bacterial Otitis Media and Diarrhea in Pediatric Patients One US/Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of amoxicillin and clavulanate potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxicillin and clavulanate potassium for 10 days in the treatment of acute otitis media. Only the suspension formulations were used in this trial. A total of 575 pediatric patients (aged 2 months to 12 years) were enrolled, with an even distribution among the 2 treatment groups and a comparable number of patients were evaluable (i.e., 84%) per treatment group. Otitis media-specific criteria were required for eligibility and a strong correlation was found at the end of therapy and follow-up between these criteria and physician assessment of clinical response. The clinical efficacy rates at the end of therapy visit (defined as 2 to 4 days after the completion of therapy) and at the follow-up visit (defined as 22 to 28 days post-completion of therapy) were comparable for the 2 treatment groups, with the following cure rates obtained for the evaluable patients: At end of therapy, 87% (n = 265) and 82% (n = 260) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. At follow-up, 67% (n = 249) and 69% (n = 243) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. Diarrhea was defined as either: (a) 3 or more watery or 4 or more loose/watery stools in 1 day; OR (b) 2 watery stools per day or 3 loose/watery stools per day for 2 consecutive days. The incidence of diarrhea was significantly lower in patients who received the every 12 hours regimen compared to patients who received the every 8 hours regimen (14% and 34%, respectively). In addition, the number of patients with either severe diarrhea or who were withdrawn with diarrhea was significantly lower in the every 12 hours treatment group (3% and 8% for the every 12 hours/10 day and every 8 hours/10 day, respectively). In the every 12 hours treatment group, 3 patients (1%) were withdrawn with an allergic reaction, while 1 patient in the every 8 hours group was withdrawn for this reason. The number of patients with a candidal infection of the diaper area was 4% and 6% for the every 12 hours and every 8 hours groups, respectively. It is not known if the finding of a statistically significant reduction in diarrhea with the oral suspensions dosed every 12 hours, versus suspensions dosed every 8 hours, can be extrapolated to the chewable tablets. The presence of mannitol in the chewable tablets may contribute to a different diarrhea profile. The every 12 hour oral suspensions (200 mg/5 ml and 400 mg/5 ml) are sweetened with aspartame. 15 REFERENCES 1. Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol. 1988; 30: Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard 8th ed. CLSI Document M7-A9. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA, 19087, Clinical and Laboratory Standards Institute (CLSI). Performance Standard for Antimicrobial Disk Susceptibility Tests; Approved Standard 11th ed. CLSI Document M2-A11. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA, 19087, CLSI. Performance Standards for Antimicrobial Susceptibility Testing: 22nd Informational Supplement. CLSI document M100-S22. CLSI, Wayne, PA, HOW SUPPLIED/STORAGE AND HANDLING Tablets Amoxicillin and Clavulanate Potassium Tablets, USP, 500 mg/125 mg: Each film coated tablet, for oral administration, is white, oval-shaped, debossed GGN6 on one side and plain on the reverse side, and contains 500 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt. NDC bottles of 20 Amoxicillin and Clavulanate Potassium Tablets, USP, 875 mg/125 mg: Each film coated tablet, for oral administration, is white, capsule-shaped, scored and debossed GGN7 on one side and scored on the reverse side, and contains 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt. NDC bottles of 20 Store at 20 to 25 C (68 to 77 F) [see USP Controlled Room Temperature]. Dispense in original container; advise patient to keep in closed container. Keep out of reach of children. 17 PATIENT COUNSELING INFORMATION 17.1 Information for Patients Patients should be informed that amoxicillin and clavulanate potassium may be taken every 8 hours or every 12 hours, depending on the dose prescribed. Each dose should be taken with a meal or snack to reduce the possibility of gastrointestinal upset. Patients should be counseled that antibacterial drugs, including amoxicillin and clavulanate potassium, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When amoxicillin and clavulanate potassium is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by amoxicillin and clavulanate potassium or other antibacterial drugs in the future. Counsel patients that diarrhea is a common problem caused by antibacterials, and it usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken their last dose of the antibacterial. If diarrhea is severe or lasts more than 2 or 3 days, patients should contact their physician. Patients should be aware that amoxicillin and clavulanate potassium contains a penicillin class drug product that can cause allergic reactions in some individuals. CLINITEST is a registered trademark of Miles, Inc Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV U.S.A. Manufactured in Austria by: Sandoz GmbH Biochemiestrasse Kundl Austria REVISED FEBRUARY 2016 SDZ:AXCLT:R2

8 Rx only Amoxicillin and Clavulanate Potassium Tablets, USP 875 mg/125 mg LEK:AMCLT:R1 Rx only Amoxicillin and Clavulanate Potassium Tablets, USP 875 mg/125 mg LEK:AMCLT:R1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use amoxicillin and clavulanate potassium safely and effectively. See full prescribing information for amoxicillin and clavulanate potassium. AMOXICILLIN and CLAVULANATE Potassium Tablets, USP for oral use Initial U.S. Approval: 1984 To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium tablets, USP and other antibacterial drugs, amoxicillin and clavulanate potassium tablets, USP should be used only to treat infections that are proven or strongly suspected to be caused by bacteria INDICATIONS AND USAGE Amoxicillin and clavulanate potassium tablets, USP are a combination penicillin-class antibacterial and beta-lactamase inhibitor indicated for treatment of the following: Lower respiratory tract infections (1.1) Acute bacterial otitis media (1.2) Sinusitis (1.3) Skin and skin structure infections (1.4) Urinary tract infections (1.5) DOSAGE AND ADMINISTRATION Adults and Pediatric Patients > 40 kg: 500 or 875 mg every 12 hours or 250 or 500 mg every 8 hours. (2.1, 2.2) Pediatric patients aged 12 weeks (3 months) and older: 25 to 45 mg/kg/day every 12 hours or 20 to 40 mg/kg/day every 8 hours, up to the adult dose. (2.2) Neonates and infants < 12 weeks of age: 30 mg/kg/day divided every 12 hours, based on the amoxicillin component. Use of the 125 mg/5 ml oral suspension is recommended. (2.2) DOSAGE FORMS AND STRENGTHS Formulations and amoxicillin and clavulanate content are: Tablets: 875 mg/125 mg. (3) CONTRAINDICATIONS History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin and clavulanate potassium or to other beta-lactams (e.g., penicillins or cephalosporins). (4) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Lower Respiratory Tract Infections 1.2 Acute Bacterial Otitis Media 1.3 Sinusitis 1.4 Skin and Skin Structure Infections 1.5 Urinary Tract Infections 1.6 Limitations of Use 2 DOSAGE AND ADMINISTRATION 2.1 Adults 2.2 Pediatric Patients 2.3 Patients with Renal Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Serious Hypersensitivity Reactions 4.2 Cholestatic Jaundice/Hepatic Dysfunction 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 5.2 Hepatic Dysfunction 5.3 Clostridium difficile-associated Diarrhea (CDAD) 5.4 Skin Rash in Patients with Mononucleosis 5.5 Potential for Microbial Overgrowth 5.7 Development of Drug-Resistant Bacteria 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Probenecid FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium tablets, USP and other antibacterial drugs, amoxicillin and clavulanate potassium tablets, USP should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Amoxicillin and clavulanate potassium tablets, USP are a combination penicillin-class antibacterial and beta-lactamase inhibitor indicated in the treatment of infections due to susceptible isolates of the designated bacteria in the conditions listed below*: 1.1 Lower Respiratory Tract Infections caused by beta-lactamase-producing isolates of Haemophilus influenzae and Moraxella catarrhalis. 1.2 Acute Bacterial Otitis Media caused by beta-lactamase-producing isolates of H. influenzae and M. catarrhalis. 1.3 Sinusitis caused by beta-lactamase producing isolates of H. influenzae and M. catarrhalis. 1.4 Skin and Skin Structure Infections caused by beta-lactamase-producing isolates of Staphylococcus aureus, Escherichia coli, and Klebsiella species. 1.5 Urinary Tract Infections caused by beta-lactamase-producing isolates of E. coli, Klebsiella species, and Enterobacter species. 1.6 Limitations of Use When susceptibility test results show susceptibility to amoxicillin, indicating no beta-lactamase production, amoxicillin and clavulanate potassium tablets, USP should not be used. 2 DOSAGE AND ADMINISTRATION Amoxicillin and clavulanate potassium tablets, USP may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when amoxicillin and clavulanate potassium is administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, amoxicillin and clavulanate potassium tablets, USP should be taken at the start of a meal. 2.1 Adults The usual adult dose is one amoxicillin and clavulanate potassium tablet USP, 500 mg/125 mg every 12 hours or one amoxicillin and clavulanate potassium tablet USP, 250 mg/125 mg every 8 hours. For more severe infections and infections of the respiratory tract, the dose should be one amoxicillin and clavulanate potassium tablet USP, 875 mg/125 mg every 12 hours or one amoxicillin and clavulanate potassium tablet USP, 500 mg/125 mg every 8 hours. Adults who History of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium. (4) WARNINGS AND PRECAUTIONS Serious (including fatal) hypersensitivity reactions: Discontinue amoxicillin and clavulanate potassium if a reaction occurs. (5.1) Hepatic dysfunction and cholestatic jaundice: Discontinue if signs/symptoms of hepatitis occur. Monitor liver function tests in patients with hepatic impairment. (5.2) Clostridium difficile-associated diarrhea (CDAD): Evaluate patients if diarrhea occurs. (5.3) Patients with mononucleosis who receive amoxicillin and clavulanate potassium develop skin rash. Avoid amoxicillin and clavulanate potassium use in these patients. (5.4) Overgrowth: The possibility of superinfections with fun gal or bacterial pathogens should be considered during therapy. (5.5) ADVERSE REACTIONS The most frequently reported adverse effects were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at ( INFO-RX) or FDA at FDA-1088 or DRUG INTERACTIONS Coadministration with probenecid is not recommended. (7.1) Concomitant use of amoxicillin and clavulanate potassium and oral anticoagulants may increase the prolongation of prothrombin time. (7.2) Coadministration with allopurinol increases the risk of rash. (7.3) Amoxicillin and clavulanate potassium may reduce efficacy of oral contraceptives. (7.4) USE IN SPECIFIC POPULATIONS Pediatric Use: Modify dose in patients 12 weeks or younger. (8.4) Renal impairment: Dosage adjustment is recommended for severe renal impairment (GFR < 30mL/min). (2.3, 8.6) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. 7.2 Oral Anticoagulants 7.3 Allopurinol 7.4 Oral Contraceptives 7.5 Effects on Laboratory Tests 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Dosing in Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Rev. 09/ CLINICAL STUDIES 14.1 Lower Respiratory Tract and Complicated Urinary Tract Infections 14.2 Acute Bacterial Otitis Media and Diarrhea in Pediatric Patients 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Information for Patients *Sections or subsections omitted from the full prescribing information are not listed. have difficulty swallowing may be given the 125 mg/5 ml or 250 mg/5 ml suspension in place of the 500 mg/125 mg tablet. The 200 mg/5 ml suspension or the 400 mg/5 ml suspension may be used in place of the 875 mg/125 mg tablet. Two 250 mg/125 mg tablets of amoxicillin and clavulanate potassium tablets, USP should not be substituted for one 500 mg/125 mg tablet of amoxicillin and clavulanate potassium tablet, USP. Since both the 250 mg/125 mg and 500 mg/125 mg tablets of amoxicillin and clavulanate potas sium tablets, USP contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250 mg/125 mg tablets are not equivalent to one 500 mg/125 mg tablet of amoxicillin and clavulanate potassium tablets, USP. The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium tablets, USP and the 250 mg/62.5 mg chewable tablet should not be substituted for each other, as they are not interchangeable. The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium tablets, USP and the 250 mg/62.5 mg chewable tablet do not contain the same amount of clavulanic acid (as the potassium salt). The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium tablets, USP contains 125 mg of clavulanic acid, whereas the 250 mg/62.5 mg chewable tablet contains 62.5 mg of clavulanic acid. 2.2 Pediatric Patients Based on the amoxicillin component, amoxicillin and clavulanate potassium tablets, USP should be dosed as follows: Neonates and Infants Aged < 12 weeks (< 3 months) The recommended dose of amoxicillin and clavulanate potassium is 30 mg/kg/day divided every 12 hours, based on the amoxicillin component. Experience with the 200 mg/28.5 mg/5 ml formulation in this age group is limited, and thus, use of the 125 mg/31.25 mg/5 ml oral suspension is recommended. Patients Aged 12 weeks (3 months) and Older See dosing regimens provided in Table 1. The every 12 hour regimen is recommended as it is associated with significantly less diarrhea [see CLINICAL STUDIES (14.2)]. INFECTION Table 1: Dosing in Patients Aged 12 weeks (3 months) and Older Otitis media, sinusitis, lower respiratory tract infections, and more severe infections Less severe infections Every 12 hours 200 mg/28.5 mg/5 ml or 400 mg/57 mg/5 ml oral suspension* 45 mg/kg/day every 12 hours 25 mg/kg/day every 12 hours DOSING REGIMEN Every 8 hours 125 mg/31.25 mg/5 ml or 250 mg/62.5 mg/5 ml oral suspension * 40 mg/kg/day every 8 hours 20 mg/kg/day every 8 hours * Each strength of suspension of amoxicillin and clavulanate potassium is available as a chewable tablet for use by older children. Duration of therapy studied and recommended for acute otitis media is 10 days. Patients Weighing 40 kg or More Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations. The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium tablets, USP should not be used until the child weighs at least 40 kg, due to the different amoxicillin to clavulanic acid ratios in the 250 mg/125 mg tablet of amoxicillin and clavulanate potassium (250/125) versus the 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium tablets, USP (250/62.5). 2.3 Patients with Renal Impairment Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Renal impairment patients with a glomerular filtration rate of <30 ml/min should not receive the 875 mg/125 mg dose. Patients with a glomerular filtration rate of 10 to 30 ml/min should receive 500 mg/125 mg or 250 mg/125 mg every 12 hours, depending on the severity of the infection. Patients with a glomerular filtration rate less than 10 ml/min should receive 500 mg/125 mg or 250 mg/125 mg every 24 hours, depending on severity of the infection. Hemodialysis patients should receive 500 mg/125 mg or 250 mg/125 mg every 24 hours, depending on severity of the infection. They should receive an additional dose both during and at the end of dialysis. 3 DOSAGE FORMS AND STRENGTHS Tablets 875 mg/125 mg Tablets: Each white to off-white oblong film-coated tablet with beveled edges, scored and debossed with 875/125 on one side and AMC on the other side, contains 875 mg amoxicillin and 125 mg clavulanic acid as the potassium salt. The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium and the 250 mg/62.5 mg chewable tablet should NOT be substituted for each other, as they are not interchangeable and the 250 mg/125 mg tablet should not be used in children weighing less than 40 kg. The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium and the 250 mg/62.5 mg chewable tablet do not contain the same amount of clavulanic acid. The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium contains 125 mg of clavulanic acid whereas the 250 mg/62.5 mg chewable tablet contains 62.5 mg of clavulanic acid. Two 250 mg/125 mg tablets of amoxicillin and clavulanate potassium should NOT be substituted for one 500 mg/125 mg tablet of amoxicillin and clavulanate potassium. Since both the 250 mg/125 mg and 500 mg/125 mg tablets of amoxicillin and clavulanate potassium contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250 mg/125 mg tablets of amoxicillin and clavulanate potassium are not equivalent to one 500 mg/125 mg tablet of amoxicillin and clavulanate potassium. 4 CONTRAINDICATIONS 4.1 Serious Hypersensitivity Reactions Amoxicillin and clavulanate potassium is contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin, clavulanate or to other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins). 4.2 Cholestatic Jaundice/Hepatic Dysfunction Amoxicillin and clavulanate potassium is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including amoxicillin and clavulanate potassium. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Before initiating therapy with amoxicillin and clavulanate potassium, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, amoxicillin and clavulanate potassium should be discontinued and appropriate therapy instituted. 5.2 Hepatic Dysfunction Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of amoxicillin and clavulanate potassium. Hepatic toxicity is usually reversible; however, deaths have been reported. Hepatic function should be monitored at regular intervals in patients with hepatic impairment. 5.3 Clostridium difficile Associated Diarrhea (CDAD) Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin and clavulanate potassium, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.4 Skin Rash in Patients with Mononucleosis A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus, amoxicillin and clavulanate potassium should not be administered to patients with mononucleosis. 5.5 Potential for Microbial Overgrowth The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfection occurs, amoxicillin and clavulanate potassium should be discontinued and appropriate therapy instituted. 5.7 Development of Drug-Resistant Bacteria Prescribing amoxicillin and clavulanate potassium in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient, and increases the risk of the development of drug-resistant bacteria. 6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Anaphylactic reactions [see WARNINGS AND PRECAUTIONS (5.1)] Hepatic Dysfunction [see WARNINGS AND PRECAUTIONS (5.2)] CDAD [see WARNINGS AND PRECAUTIONS (5.3)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most frequently reported adverse reactions were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). Less than 3% of patients discontinued therapy because of drug-related adverse reactions. The overall incidence of adverse reactions, and in particular diarrhea, increased with the higher recommended dose. Other less frequently reported adverse reactions (< 1%) include: Abdominal discomfort, flatulence, and headache. In pediatric patients (aged 2 months to 12 years), 1 US/Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of amoxicillin and clavulanate potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxicillin and clavulanate potassium for 10 days in the treatment of acute otitis media. A total of 575 patients were enrolled, and only the suspension formulations were used in this trial. Overall, the adverse reactions seen were comparable to that noted above; however, there were differences in the rates of diarrhea, skin rashes/urticaria, and diaper area rashes [see CLINICAL STUDIES (14.2)]. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following have been identified during postmarketing use of amoxicillin and clavulanate potassium. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to amoxicillin and clavulanate potassium. Gastrointestinal Indigestion, gastritis, stomatitis, glossitis, black hairy tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment [see WARNINGS AND PRECAUTIONS (5.3)]. Hypersensitivity Reactions Pruritus, angioedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), erythema multiforme, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and cases of exfoliative dermatitis (including toxic epidermal necrolysis) have been reported [see WARNINGS AND PRECAUTIONS (5.1)]. Liver Hepatic dysfunction, including hepatitis and cholestatic jaundice, increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been reported with amoxicillin and clavulanate potassium. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, is usually reversible. Deaths have been reported [see CONTRAINDICATIONS (4.2), WARNINGS AND PRECAUTIONS (5.2)]. Renal Interstitial nephritis, hematuria, and crystalluria have been reported [see OVERDOSAGE (10)]. Hemic and Lymphatic Systems Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Thrombocytosis was noted in less than 1% of the patients treated with amoxicillin and clavulanate potassium. There have been reports of increased prothrombin time in patients receiving amoxicillin and clavulanate potassium and anticoagulant therapy concomitantly [see DRUG INTERACTIONS (7.2)]. Central Nervous System Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported. Miscellaneous Tooth discoloration (brown, yellow, or gray staining) has been reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases. 7 DRUG INTERACTIONS 7.1 Probenecid Probenecid decreases the renal tubular secretion of amoxicillin but does not delay renal excretion of clavulanic acid. Concurrent use with amoxicillin and clavulanate potassium may result in increased and prolonged blood concentrations of amoxicillin. Coadministration of probenecid is not recommended. 7.2 Oral Anticoagulants Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been reported in patients receiving amoxicillin and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently with amoxicillin and clavulanate potassium. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation. 7.3 Allopurinol The concurrent administration of allopurinol and amoxicillin increases the incidence of rashes in patients receiving both drugs as compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients. 7.4 Oral Contraceptives Amoxicillin and clavulanate potassium may affect intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives. 7.5 Effects on Laboratory Tests High urine concentrations of amoxicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST, Benedict s Solution, or Fehling s Solution. Since this effect may also occur with amoxicillin and clavulanate potassium, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. Following administration of amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects Pregnancy Category B. Reproduction studies performed in pregnant rats and mice given amoxicillin and clavulanate potassium (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses up to 1200 mg/kg/day revealed no evidence of harm to the fetus due to amoxicillin and clavulanate potassium. The amoxicillin doses in rats and mice (based on body surface area) were approximately 4 and 2 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, these dose multiples were approximately 9 and 4 times the maximum recommended adult human oral dose (125 mg every 8 hours). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 8.2 Labor and Delivery Oral ampicillin-class antibiotics are poorly absorbed during labor. It is not known whether use of amoxicillin and clavulanate potassium in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood of the necessity for an obstetrical intervention. 8.3 Nursing Mothers Amoxicillin has been shown to be excreted in human milk. Amoxicillin and clavulanate potassium use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin and clavulanate potassium is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of amoxicillin and clavulanate potassium powder for oral

9 suspension have been established in pediatric patients. Use of amoxicillin and clavulanate potassium in pediatric patients is supported by evidence from studies of amoxicillin and clavulanate potassium tablets in adults with additional data from a study of amoxicillin and clavulanate potassium powder for oral suspension in pediatric patients aged 2 months to 12 years with acute otitis media [see CLINICAL STUDIES (14.2)]. Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed; clavulanate elimination is unaltered in this age group. Dosing of amoxicillin and clavulanate potassium should be modified in pediatric patients aged < 12 weeks (< 3 months) [see DOSAGE AND ADMINISTRATION (2.2)]. 8.5 Geriatric Use Of the 3,119 patients in an analysis of clinical studies of amoxicillin and clavulanate potassium, 32% were 65 years old, and 14% were 75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Dosing in Renal Impairment Amoxicillin is primarily eliminated by the kidney and dosage adjustment is usually required in patients with severe renal impairment (GFR < 30 ml/min). See Patients with Renal Impairment (2.3) for specific recommendations in patients with renal impairment. 10 OVERDOSAGE In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. A prospective study of 51 pediatric patients at a poison-control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms 1. Interstitial nephritis resulting in oliguric renal failure has been reported in patients after overdosage with amoxicillin and clavulanate potassium. Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin and clavulanate potassium overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin and clavulanate potassium crystalluria. Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of amoxicillin and clavulanate potassium. Amoxicillin and clavulanate potassium may be removed from circulation by hemodialysis [see DOSAGE AND ADMINISTRATION (2.3)]. 11 DESCRIPTION Amoxicillin and clavulanate potassium is an oral antibacterial combination consisting of amoxicillin and the beta-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is C 16 H 19 N 3 O 5 S 3H 2 O, and the molecular weight is Chemically, amoxicillin is (2S,5R,6R)-6-[(R)-(-)-2-Amino-2- (p-hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2- carboxylic acid trihydrate and may be represented structurally as: Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a beta-lactam structurally related to the penicillins and possesses the ability to inactivate some beta-lactamases by blocking the active sites of these enzymes. The clavulanate potassium molecular formula is C 8 H 8 KNO 5, and the molecular weight is Chemically, clavulanate potassium is potassium (Z)(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1- azabicyclo[3.2.0]-heptane-2-carboxylate and may be represented structurally as: O N O COOK CH 2 OH Inactive Ingredients: Tablets - Colloidal silicon dioxide, croscarmellose sodium dried, crospovidone dried, ethylcellulose, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, microcrystalline cellulose dried, polysorbate 80, talc, titanium dioxide, triethyl citrate. Each tablet of amoxicillin and clavulanate potassium contains 0.63 meq potassium. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Amoxicillin and clavulanate potassium is an antibacterial drug [see MICROBIOLOGY (12.4)] Pharmacokinetics Mean amoxicillin and clavulanate potassium pharmacokinetic parameters in normal adults following administration of amoxicillin and clavulanate potassium tablets are shown in Table 3 and following administration of amoxicillin and clavulanate potassium for oral suspension and chewable tablets are shown in Table 4. Table 3: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters*, with Amoxicillin and Clavulanate Potassium Tablets Dose and Regimen C max (mcg/ml) AUC 0-24 (mcg h/ml) Amoxicillin and Clavulanate potassium Amoxicillin Clavulanate potassium H Amoxicillin Clavulanate potassium 250/125 mg every 8 hours 3.3 ± ± ± ± /125 mg every 12 hours 6.5 ± ± ± ± /125 mg every 8 hours 7.2 ± ± ± ± /125 mg every 12 hours 11.6 ± ± ± ± 3.04 * Mean (± standard deviation) values of 14 normal adults (N = 15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose. Amoxicillin and clavulanate potassium administered at the start of a light meal. Table 4: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters *, with Amoxicillin and Clavulanate Potassium Powder for Oral Suspension and Chewable Tablets Dose C max (mcg/ml) AUC 0-24 (mcg h/ml) Amoxicillin and Clavulanate potassium Amoxicillin Clavulanate potassium Amoxicillin Clavulanate potassium 400/57 mg (5 ml of suspension) 6.94 ± ± ± ± /57 mg (1 chewable tablet) 6.67 ± ± ± ± 0.73 * Mean (± standard deviation) values of 28 normal adults. Peak concentrations occurred approximately 1 hour after the dose. Amoxicillin and clavulanate potassium administered at the start of a light meal. Oral administration of 5 ml of 250 mg/62.5 mg/5 ml suspension of amoxicillin and clavulanate potassium or the equivalent dose of 10 ml of 125 mg/31.25 mg/5 ml suspension of amoxicillin and clavulanate potassium provides average peak serum concentrations approximately 1 hour after dosing of 6.9 mcg/ml for amoxicillin and 1.6 mcg/ml for clavulanic acid. The areas under the serum concentration curves obtained during the first 4 hours after dosing were 12.6 mcg h/ml for amoxicillin and 2.9 mcg h/ml for clavulanic acid when 5 ml of 250 mg/62.5 mg/5 ml suspension of amoxicillin and clavulanate potassium or equivalent dose of 10 ml of 125 mg/31.25 mg/5 ml suspension of amoxicillin and clavulanate potassium were administered to normal adults. One 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium or two 125 mg/31.25 mg chewable tablets of amoxicillin and clavulanate potassium are equivalent to 5 ml of 250 mg/62.5 mg/5 ml suspension of amoxicillin and clavulanate potassium and provide similar serum concentrations of amoxicillin and clavulanic acid. Amoxicillin serum concentrations achieved with amoxicillin and clavulanate potassium are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. Time above the minimum inhibitory concentration of 1 mcg/ml for amoxicillin has been shown to be similar after corresponding every 12 hour and every 8 hour dosing regimens of amoxicillin and clavulanate potassium in adults and children. Absorption Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While amoxicillin and clavulanate potassium can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In one study, the relative bioavailability of clavulanate was reduced when amoxicillin and clavulanate potassium was dosed at 30 and 150 minutes after the start of a high-fat breakfast. Distribution Neither component in amoxicillin and clavulanate potassium is highly protein-bound; clavulanic acid is approximately 25% bound to human serum and amoxicillin approximately 18% bound. Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. Two hours after oral administration of a single 35 mg/kg dose of suspension of amoxicillin and clavulanate potassium to fasting children, average concentrations of 3 mcg/ml of amoxicillin and 0.5 mcg/ml of clavulanic acid were detected in middle ear effusions. Metabolism and Excretion The half-life of amoxicillin after the oral administration of amoxicillin and clavulanate potassium is 1.3 hours and that of clavulanic acid is 1 hour. Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single 250 mg/125 mg or 500 mg/125 mg tablet of amoxicillin and clavulanate potassium Microbiology Amoxicillin is a semisynthetic antibiotic with in vitro bactericidal activity against Grampositive and Gram-negative bacteria. Amoxicillin is, however, susceptible to degradation by beta-lactamases, and therefore, the spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a beta-lactam, structurally related to the penicillins, which possesses the ability to inactivate some beta-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated beta-lactamases frequently responsible for transferred drug resistance. The formulation of amoxicillin and clavulanic acid in amoxicillin and clavulanate potassium protects amoxicillin from degradation by some beta-lactamase enzymes and extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin. Amoxicillin and clavulanic acid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive Bacteria Staphylococcus aureus Gram-negative Bacteria Enterobacter species Escherichia coli Haemophilus influenzae Klebsiella species Moraxella catarrhalis The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for amoxicillin and clavulanic acid. However, the efficacy of amoxicillin and clavulanic acid in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials. Gram-positive Bacteria Enterococcus faecalis Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus pneumoniae Streptococcus pyogenes Viridans group Streptococcus Gram-negative Bacteria Eikenella corrodens Proteus mirabilis Anaerobic Bacteria Bacteroides species including Bacteroides fragilis Fusobacterium species Peptostreptococcus species Susceptibility Test Methods When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment. Dilution techniques Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method 2,3 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 5. Diffusion techniques Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method 3,4. This procedure uses paper disks impregnated with 30 mcg amoxicillin and clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) to test the susceptibility of bacteria to amoxicillin and clavulanic acid. The disc diffusion interpretive criteria are provided in Table 5. Table 5: Susceptibility Test Interpretive Criteria for Amoxicillin Clavulanic Acid Minimum Inhibitory Concentrations (mcg/ml) Disk Diffusion (zone diameters in mm) Pathogen S I R S I R Enterobacteriaceae 8/4 16/8 32/ to Haemophilus influenzae and Staphylococcus aureus 4/2-8/ Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test 2,3,4. Standard amoxicillin and clavulanic acid powder should provide the following range of MIC values noted in Table 6 for the diffusion technique using the 30 mcg amoxicillin and clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) disk, the criteria in Table 6 should be achieved. Table 6: Acceptable Quality Control Ranges for Amoxicillin and Clavulanic Acid QC Strain Escherichia coli ATCC Escherichia coli ATCC Haemophilus influenzae ATCC Staphylococcus aureus ATCC Staphylococcus aureus ATCC Minimum Inhibitory Concentration (mcg/ml) Disk Diffusion (zone diameter in mm) 2/1 to 8/4 18 to 24 4/2 to 16/8 17 to 22 2/1 to 16/8 15 to /0.06 to 0.5/ to NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate carcinogenic potential. Amoxicillin and clavulanate potassium (4:1 ratio formulation of amoxicillin:clavulanate) was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and clavulanate potassium was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. Amoxicillin and clavulanate potassium was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. Amoxicillin and clavulanate potassium (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses of up to 1,200 mg/kg/day was found to have no effect on fertility and reproductive performance in rats. Based on body surface area, this dose of amoxicillin is approximately 4 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, the dose multiple is approximately 9 times higher than the maximum recommended adult human oral dose (125 mg every 8 hours), also based on body surface area. 14 CLINICAL STUDIES 14.1 Lower Respiratory Tract and Complicated Urinary Tract Infections Data from 2 pivotal trials in 1,191 patients treated for either lower respiratory tract infections or complicated urinary tract infections compared a regimen of 875 mg/125 mg tablets of amoxicillin and clavulanate potassium every 12 hours to 500 mg/125 mg tablets of amoxicillin and clavulanate potassium dosed every 8 hours (584 and 607 patients, respectively). Comparable efficacy was demonstrated between the every 12 hours and every 8 hours dosing regimens. There was no significant difference in the percentage of adverse events in each group. The most frequently reported adverse event was diarrhea; incidence rates were similar for the 875 mg/125 mg every 12 hours and 500 mg/125 mg every 8 hours dosing regimens (15% and 14%, respectively); however, there was a statistically significant difference (p < 0.05) in rates of severe diarrhea or withdrawals with diarrhea between the regimens: 1% for 875 mg/125 mg every 12 hours regimen versus 2% for the 500 mg/125 mg every 8 hours regimen. In one of these pivotal trials, patients with either pyelonephritis (n = 361) or a complicated urinary tract infection (i.e., patients with abnormalities of the urinary tract that predispose to relapse of bacteriuria following eradication, n = 268) were randomized (1:1) to receive either 875 mg/125 mg tablets of amoxicillin and clavulanate potassium every 12 hours (n = 308) or 500 mg/125 mg tablets of amoxicillin and clavulanate potassium every 8 hours (n = 321). The number of bacteriologically evaluable patients was comparable between the two dosing regimens. Amoxicillin and clavulanate potassium produced comparable bacteriological success rates in patients assessed 2 to 4 days immediately following end of therapy. The bacteriologic efficacy rates were comparable at one of the follow-up visits (5 to 9 days post-therapy) and at a late post-therapy visit (in the majority of cases, this was 2 to 4 weeks post-therapy), as seen in Table 7. Table 7: Bacteriologic efficacy rates for amoxicillin and clavulanate potassium Time Post Therapy 875 mg/125 mg every 12 hours % (n) mg/125 mg every 8 hours % (n) 2 to 4 days 81% (58) 80% (54) 5 to 9 days 58% (41) 52% (52) 2 to 4 weeks 52% (101) 55% (104) As noted before, though there was no significant difference in the percentage of adverse events in each group, there was a statistically significant difference in rates of severe diarrhea or withdrawals with diarrhea between the regimens Acute Bacterial Otitis Media and Diarrhea in Pediatric Patients One US/Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of amoxicillin and clavulanate potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxicillin and clavulanate potassium for 10 days in the treatment of acute otitis media. Only the suspension formulations were used in this trial. A total of 575 pediatric patients (aged 2 months to 12 years) were enrolled, with an even distribution among the 2 treatment groups and a comparable number of patients were evaluable (i.e., 84%) per treatment group. Otitis media-specific criteria were required for eligibility and a strong correlation was found at the end of therapy and follow-up between these criteria and physician assessment of clinical response. The clinical efficacy rates at the end of therapy visit (defined as 2 to 4 days after the completion of therapy) and at the follow-up visit (defined as 22 to 28 days post-completion of therapy) were comparable for the 2 treatment groups, with the following cure rates obtained for the evaluable patients: At end of therapy, 87% (n = 265) and 82% (n = 260) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. At follow-up, 67% (n = 249) and 69% (n = 243) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. Diarrhea was defined as either: (a) 3 or more watery or 4 or more loose/watery stools in 1 day; OR (b) 2 watery stools per day or 3 loose/watery stools per day for 2 consecutive days. The incidence of diarrhea was significantly lower in patients who received the every 12 hours regimen compared to patients who received the every 8 hours regimen (14% and 34%, respectively). In addition, the number of patients with either severe diarrhea or who were withdrawn with diarrhea was significantly lower in the every 12 hours treatment group (3% and 8% for the every 12 hours/10 day and every 8 hours/10 day, respectively). In the every 12 hours treatment group, 3 patients (1%) were withdrawn with an allergic reaction, while 1 patient in the every 8 hours group was withdrawn for this reason. The number of patients with a candidal infection of the diaper area was 4% and 6% for the every 12 hours and every 8 hours groups, respectively. 15 REFERENCES 1 Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol. 1988; 30: Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard 8th ed. CLSI Document M7-A9. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA, 19087, Clinical and Laboratory Standards Institute (CLSI). Performance Standard for Antimicrobial Disk Susceptibility Tests; Approved Standard 11th ed. CLSI Document M2-A11. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA, 19087, CLSI. Performance Standards for Antimicrobial Susceptibility Testing: 22nd Informational Supplement. CLSI Document M100-S22. CLSI, Wayne, PA, HOW SUPPLIED/STORAGE AND HANDLING Tablets Amoxicillin and clavulanate potassium tablets, USP 875 mg/125 mg are white to off-white oblong film coated tablets with beveled edges, scored and debossed with 875/125 on one side and AMC on the other side. They are supplied in plastic bottles of 100 (with desiccant) as under: NDC bottles of 100 tablets Store at 20 to 25 C (68 to 77 F) [See USP Controlled Room Temperature]. Dispense in tightly closed, moisture-proof containers. Keep out of the reach of children. 17 PATIENT COUNSELING INFORMATION 17.1 Information for Patients Patients should be informed that amoxicillin and clavulanate potassium may be taken every 8 hours or every 12 hours, depending on the dose prescribed. Each dose should be taken with a meal or snack to reduce the possibility of gastrointestinal upset. Patients should be counseled that antibacterial drugs, including amoxicillin and clavulanate potassium, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When amoxicillin and clavulanate potassium is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by amoxicillin and clavulanate potassium or other antibacterial drugs in the future. Counsel patients that diarrhea is a common problem caused by antibacterials, and it usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken their last dose of the antibacterial. If diarrhea is severe or lasts more than 2 or 3 days, patients should contact their physician. Patients should be aware that amoxicillin and clavulanate potassium contains a penicillin class drug product that can cause allergic reactions in some individuals. CLINITEST is a registered trademark of Miles, Inc. Manufactured in Slovenia by Lek Pharmaceuticals d.d. for Mylan Pharmaceuticals Inc., Morgantown, WV U.S.A. Revised: September 2015 LEK:AMCLT:R

10 SDZ:AXCLOS:R2 Amoxicillin and Clavulanate Potassium for Oral Suspension, USP 200 mg/28.5 mg per 5 ml 400 mg/57 mg per 5 ml HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use AMOXICILLIN AND CLAVULANATE POTASSIUM, USP safely and effectively. See full prescribing information for AMOXICILLIN AND CLAVULANATE POTASSIUM, USP. AMOXICILLIN and CLAVULANATE Potassium for Oral Suspension USP, for Oral Use Initial U.S. Approval: 1984 To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium and other antibacterial drugs, amoxicillin and clavulanate potassium should be used only to treat infections that are proven or strongly suspected to be caused by bacteria INDICATIONS AND USAGE Amoxicillin and clavulanate potassium for oral suspension, USP is a combination penicillin-class antibacterial and beta-lactamase inhibitor indicated for treatment of the following: Lower respiratory tract infections (1.1) Acute bacterial otitis media (1.2) Sinusitis (1.3) Skin and skin structure infections (1.4) Urinary tract infections (1.5) DOSAGE AND ADMINISTRATION Adults and Pediatric Patients > 40 kg: 500 or 875 mg every 12 hours or 250 or 500 mg every 8 hours. (2.1, 2.2) Pediatric patients aged 12 weeks (3 months) and older: 25 to 45 mg/kg/day every 12 hours or 20 to 40 mg/kg/day every 8 hours, up to the adult dose. (2.2) Neonates and infants < 12 weeks of age: 30 mg/kg/day divided every 12 hours, based on the amoxicillin component. Use of the 125 mg/5 ml oral suspension is recommended. (2.2) DOSAGE FORMS AND STRENGTHS Formulations and amoxicillin/clavulanate content are: For Oral Suspension: 200 mg/28.5 mg per 5 ml, 400 mg/57 mg per 5 ml (3) CONTRAINDICATIONS History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin and clavulanate potassium or FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Lower Respiratory Tract Infections 1.2 Acute Bacterial Otitis Media 1.3 Sinusitis 1.4 Skin and Skin Structure Infections 1.5 Urinary Tract Infections 1.6 Limitations of Use 2 DOSAGE AND ADMINISTRATION 2.1 Adults 2.2 Pediatric Patients 2.3 Patients with Renal Impairment 2.4 Directions for Mixing Oral Suspension 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Serious Hypersensitivity Reactions 4.2 Cholestatic Jaundice/Hepatic Dysfunction 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 5.2 Hepatic Dysfunction 5.3 Clostridium difficile Associated Diarrhea 5.4 Skin Rash in Patients with Mononucleosis 5.5 Potential for Microbial Overgrowth 5.6 Phenylketonurics 5.7 Development of Drug-Resistant Bacteria 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Probenecid to other beta-lactams (e.g., penicillins or cephalosporins). (4) History of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium. (4) WARNINGS AND PRECAUTIONS Serious (including fatal) hypersensitivity reactions: Discontinue amoxicillin and clavulanate potassium if a reaction occurs. (5.1) Hepatic dysfunction and cholestatic jaundice: Discontinue if signs/ symptoms of hepatitis occur. Monitor liver function tests in patients with hepatic impairment. (5.2) Clostridium difficile-associated diarrhea (CDAD): Evaluate patients if diarrhea occurs. (5.3) Patients with mononucleosis who receive amoxicillin and clavulanate potassium develop skin rash. Avoid amoxicillin and clavulanate potassium use in these patients. (5.4) Overgrowth: The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. (5.5) ADVERSE REACTIONS The most frequently reported adverse effects were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at ( INFO-RX) or FDA at FDA-1088 or DRUG INTERACTIONS Coadministration with probenecid is not recommended. (7.1) Concomitant use of amoxicillin and clavulanate potassium and oral anticoagulants may increase the prolongation of prothrombin time. (7.2) Coadministration with allopurinol increases the risk of rash. (7.3) Amoxicillin and clavulanate potassium may reduce efficacy of oral contraceptives. (7.4) USE IN SPECIFIC POPULATIONS Pediatric Use: Modify dose in patients 12 weeks or younger. (8.4) Renal impairment; Dosage adjustment is recommended for severe renal impairment (GFR < 30mL/min). (2.3, 8.6) See 17 for PATIENT COUNSELING INFORMATION REVISED FEBRUARY 2016 SDZ:AXCLOS:R2 7.2 Oral Anticoagulants 7.3 Allopurinol 7.4 Oral Contraceptives 7.5 Effects on Laboratory Tests 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Dosing in Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Lower Respiratory Tract and Complicated Urinary Tract Infections 14.2 Acute Bacterial Otitis Media and Diarrhea in Pediatric Patients 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Information for Patients *Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium and other antibacterial drugs, amoxicillin and clavulanate potassium should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Amoxicillin and clavulanate potassium for oral suspension, USP is a combination penicillin-class antibacterial and beta-lactamase inhibitor indicated in the treatment of infections due to susceptible isolates of the designated bacteria in the conditions listed below: 1.1 Lower Respiratory Tract Infections Caused by beta-lactamase producing isolates of Haemophilus influenzae and Moraxella catarrhalis. 1.2 Acute Bacterial Otitis Media Caused by beta-lactamase producing isolates of H. influenzae and M. catarrhalis. 1.3 Sinusitis Caused by beta-lactamase producing isolates of H. influenzae and M. catarrhalis. 1.4 Skin and Skin Structure Infections Caused by beta-lactamase producing isolates of Staphylococcus aureus, Escherichia coli, and Klebsiella species. 1.5 Urinary Tract Infections Caused by beta-lactamase producing isolates of E. coli, Klebsiella species, and Enterobacter species. 1.6 Limitations of Use When susceptibility test results show susceptibility to amoxicillin, indicating no beta-lactamase production, amoxicillin and clavulanate potassium should not be used. 2 DOSAGE AND ADMINISTRATION Amoxicillin and clavulanate potassium may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when amoxicillin and clavulanate potassium is administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, amoxicillin and clavulanate potassium should be taken at the start of a meal. 2.1 Adults The usual adult dose is one 500-mg tablet of amoxicillin and clavulanate potassium every 12 hours or one 250-mg tablet of amoxicillin and clavulanate potassium every 8 hours. For more severe infections and infections of the respiratory tract, the dose should be one 875-mg tablet of amoxicillin and clavulanate potassium every 12 hours or one 500-mg tablet of amoxicillin and clavulanate potassium every 8 hours. Adults who have difficulty swallowing may be given the 125 mg/5 ml or 250 mg/5 ml suspension in place of the 500-mg tablet. The 200 mg/5 ml suspension or the 400 mg/5 ml suspension may be used in place of the 875-mg tablet. Two 250-mg tablets of amoxicillin and clavulanate potassium should not be substituted for one 500-mg tablet of amoxicillin and clavulanate potassium. Since both the 250-mg and 500-mg tablets of amoxicillin and clavulanate potassium contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250-mg tablets are not equivalent to one 500-mg tablet of amoxicillin and clavulanate potassium. The 250-mg tablet of amoxicillin and clavulanate potassium and the 250-mg chewable tablet should not be substituted for each other, as they are not interchangeable. The 250-mg tablet of amoxicillin and clavulanate potassium and the 250-mg chewable tablet do not contain the same amount of clavulanic acid (as the potassium salt). The 250-mg tablet of amoxicillin and clavulanate potassium contains 125 mg of clavulanic acid, whereas the 250-mg chewable tablet contains 62.5 mg of clavulanic acid. 2.2 Pediatric Patients Based on the amoxicillin component, amoxicillin and clavulanate potassium should be dosed as follows: Neonates and Infants Aged < 12 weeks (< 3 months): The recommended dose of Amoxicillin and clavulanate potassium is 30 mg/kg/day divided every 12 hours, based on the amoxicillin component. Experience with the 200 mg/5 ml formulation in this age group is limited, and thus, use of the 125 mg/5 ml oral suspension is recommended. Patients Aged 12 weeks (3 months) and Older: See dosing regimens provided in Table 1. The every 12 hour regimen is recommended as it is associated with significantly less diarrhea [see Clinical Studies (14.2)]. However, the every 12 hour suspension (200 mg/5 ml and 400 mg/5 ml) and chewable tablets (200 mg and 400 mg) contain aspartame and should not be used by phenylketonurics. [see Warnings and Precautions (5.6)] Table 1. Dosing in Patients Aged 12 weeks (3 months) and Older DOSING REGIMEN Every 12 hours Every 8 hours INFECTION Otitis media, sinusitis, lower respiratory tract infections, and more severe infections Less severe infections 200 mg/5 ml or 400 mg/5 ml oral suspension* 45 mg/kg/day every 12 hours 25 mg/kg/day every 12 hours 125 mg/5 ml or 250 mg/5 ml oral suspension* 40 mg/kg/day every 8 hours 20 mg/kg/day every 8 hours * Each strength of suspension of amoxicillin and clavulanate potassium is available as a chewable tablet for use by older children. Duration of therapy studied and recommended for acute otitis media is 10 days. Patients Weighing 40 kg or More: Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations. The 250-mg tablet of amoxicillin and clavulanate potassium should not be used until the child weighs at least 40 kg, due to the different amoxicillin to clavulanic acid ratios in the 250-mg tablet of amoxicillin and clavulanate potassium (250 mg/125 mg) versus the 250-mg chewable tablet of amoxicillin and clavulanate potassium (250 mg/62.5 mg). 2.3 Patients with Renal Impairment Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Renal impairment patients with a glomerular filtration rate of < 30 ml/min should not receive the 875-mg dose. Patients with a glomerular filtration rate of 10 to 30 ml/min should receive 500 mg or 250 mg every 12 hours, depending on the severity of the infection. Patients with a glomerular filtration rate less than 10 ml/min should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection. Hemodialysis patients should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection. They should receive an additional dose both during and at the end of dialysis. 2.4 Directions for Mixing Oral Suspension Prepare a suspension at time of dispensing as follows: Tap bottle until all the powder flows freely. Add approximately 2/3 of the total amount of water for reconstitution (see Table 2 below) and shake vigorously to suspend powder. Add remainder of the water and again shake vigorously. Table 2. Amount of Water for Mixing Oral Suspension Amount of Water for Contents of Each Strength Bottle Size Reconstitution Teaspoonful (5 ml) 200 mg/5 ml 100 ml 88 ml 200 mg amoxicillin and 28.5 mg of clavulanic acid as the potassium salt 400 mg/5 ml 100 ml 84 ml 400 mg amoxicillin and 57 mg of clavulanic acid as the potassium salt Note: Shake oral suspension well before using. Reconstituted suspension must be stored under refrigeration and discarded after 10 days. 3 DOSAGE FORMS AND STRENGTHS For Oral Suspension Amoxicillin and Clavulanate Potassium for Oral Suspension, USP, 200 mg/28.5 mg per 5 ml: as a dry, white powder. Each 5 ml of reconstituted orange-flavored suspension contains 200 mg amoxicillin as the trihydrate and 28.5 mg clavulanic acid as the potassium salt. Amoxicillin and Clavulanate Potassium for Oral Suspension, USP, 400 mg/57 mg per 5 ml: as a dry, white powder. Each 5 ml of reconstituted orange-flavored suspension contains 400 mg amoxicillin as the trihydrate and 57 mg clavulanic acid as the potassium salt. The 250-mg tablet of amoxicillin and clavulanate potassium and the 250-mg chewable tablet should NOT be substituted for each other, as they are not interchangeable and the 250-mg tablet should not be used in children weighing less than 40 kg. The 250-mg tablet of amoxicillin and clavulanate potassium and the 250-mg chewable tablet do not contain the same amount of clavulanic acid. The 250-mg tablet of amoxicillin and clavulanate potassium contains 125 mg of clavulanic acid whereas the 250-mg chewable tablet contains 62.5 mg of clavulanic acid. Two 250 mg tablets of amoxicillin and clavulanate potassium should NOT be substituted for one 500 mg tablet of amoxicillin and clavulanate potassium. Since both the 250 mg and 500 mg tablets of amoxicillin and clavulanate potassium contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250 mg tablets of amoxicillin and clavulanate potassium are not equivalent to one 500 mg tablet of amoxicillin and clavulanate potassium. 4 CONTRAINDICATIONS 4.1 Serious Hypersensitivity Reactions Amoxicillin and clavulanate potassium is contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin, clavulanate or to other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins). 4.2 Cholestatic Jaundice/Hepatic Dysfunction Amoxicillin and clavulanate potassium is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including amoxicillin and clavulanate potassium. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Before initiating therapy with amoxicillin and clavulanate potassium, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, amoxicillin and clavulanate potassium should be discontinued and appropriate therapy instituted. 5.2 Hepatic Dysfunction Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of amoxicillin and clavulanate potassium. Hepatic toxicity is usually reversible; however, deaths have been reported. Hepatic function should be monitored at regular intervals in patients with hepatic impairment. 5.3 Clostridium difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin and clavulanate potassium, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.4 Skin Rash in Patients with Mononucleosis A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus, amoxicillin and clavulanate potassium should not be administered to patients with mononucleosis. 5.5 Potential for Microbial Overgrowth The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfection occurs, amoxicillin/clavulanate potassium should be discontinued and appropriate therapy instituted. 5.6 Phenylketonurics Amoxicillin and clavulanate potassium for oral suspension contains aspartame which contains phenylalanine. Each 5 ml of either the 200 mg/5 ml or 400 mg/5 ml oral suspension contains 7 mg phenylalanine. The other formulations of amoxicillin and clavulanate potassium do not contain phenylalanine. 5.7 Development of Drug-Resistant Bacteria Prescribing amoxicillin and clavulanate potassium in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient, and increases the risk of the development of drug-resistant bacteria. 6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Anaphylactic reactions [see Warnings and Precautions (5.1)] Hepatic Dysfunction [see Warnings and Precautions (5.2)] CDAD [see Warnings and Precautions (5.3)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most frequently reported adverse reactions were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). Less than 3% of patients discontinued therapy because of drug-related adverse reactions. The overall incidence of adverse reactions, and in particular diarrhea, increased with the higher recommended dose. Other less frequently reported adverse reactions (< 1%) include: Abdominal discomfort, flatulence, and headache. In pediatric patients (aged 2 months to 12 years), 1 US/Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of amoxicillin and clavulanate potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxicillin and clavulanate potassium for 10 days in the treatment of acute otitis media. A total of 575 patients were enrolled, and only the suspension formulations were used in this trial. Overall, the adverse reactions seen were comparable to that noted above; however, there were differences in the rates of diarrhea, skin rashes/urticaria, and diaper area rashes. [see Clinical Studies (14.2)] 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following have been identified during postmarketing use of amoxicillin and clavulanate potassium. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to amoxicillin and clavulanate potassium. Gastrointestinal: Indigestion, gastritis, stomatitis, glossitis, black hairy tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembra-

11 nous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. [see Warnings and Precautions (5.3)] Hypersensitivity Reactions: Pruritus, angioedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), erythema multiforme, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and cases of exfoliative dermatitis (including toxic epidermal necrolysis) have been reported. [see Warnings and Precautions (5.1)] Liver: Hepatic dysfunction, including hepatitis and cholestatic jaundice, increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been reported with amoxicillin and clavulanate potassium. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, is usually reversible. Deaths have been reported. [see Contraindications (4.2), Warnings and Precautions (5.2)] Renal: Interstitial nephritis, hematuria, and crystalluria have been reported. [see Overdosage (10)] Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Thrombocytosis was noted in less than 1% of the patients treated with amoxicillin and clavulanate potassium. There have been reports of increased prothrombin time in patients receiving amoxicillin and clavulanate potassium and anticoagulant therapy concomitantly. [see Drug Interactions (7.2)] Central Nervous System: Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported. Miscellaneous: Tooth discoloration (brown, yellow, or gray staining) has been reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases. 7 DRUG INTERACTIONS 7.1 Probenecid Probenecid decreases the renal tubular secretion of amoxicillin but does not delay renal excretion of clavulanic acid. Concurrent use with amoxicillin and clavulanate potassium may result in increased and prolonged blood concentrations of amoxicillin. Coadministration of probenecid is not recommended. 7.2 Oral Anticoagulants Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been reported in patients receiving amoxicillin and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently with amoxicillin and clavulanate potassium. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation. 7.3 Allopurinol The concurrent administration of allopurinol and amoxicillin increases the incidence of rashes in patients receiving both drugs as compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients. 7.4 Oral Contraceptives Amoxicillin and clavulanate potassium may affect intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives. 7.5 Effects on Laboratory Tests High urine concentrations of amoxicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST, Benedict s Solution, or Fehling s Solution. Since this effect may also occur with amoxicillin and clavulanate potassium, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. Following administration of amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects Pregnancy Category B Reproduction studies performed in pregnant rats and mice given amoxicillin and clavulanate potassium (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses up to 1200 mg/kg/day revealed no evidence of harm to the fetus due to amoxicillin and clavulanate potassium. The amoxicillin doses in rats and mice (based on body surface area) were approximately 4 and 2 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, these dose multiples were approximately 9 and 4 times the maximum recommended adult human oral dose (125 mg every 8 hours). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 8.2 Labor and Delivery Oral ampicillin-class antibiotics are poorly absorbed during labor. It is not known whether use of amoxicillin/clavulanate potassium in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood of the necessity for an obstetrical intervention. 8.3 Nursing Mothers Amoxicillin has been shown to be excreted in human milk. Amoxicillin/clavulanate potassium use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin/clavulanate potassium is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of amoxicillin and clavulanate potassium for oral suspension and chewable tablets have been established in pediatric patients. Use of amoxicillin and clavulanate potassium in pediatric patients is supported by evidence from studies of amoxicillin and clavulanate potassium tablets in adults with additional data from a study of amoxicillin and clavulanate potassium for oral suspension in pediatric patients aged 2 months to 12 years with acute otitis media. [see Clinical Studies (14.2)] Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed; clavulanate elimination is unaltered in this age group. Dosing of amoxicillin and clavulanate potassium should be modified in pediatric patients aged < 12 weeks (< 3 months). [see Dosage and Administration (2.2)] 8.5 Geriatric Use Of the 3,119 patients in an analysis of clinical studies of amoxicillin and clavulanate potassium, 32% were 65 years old, and 14% were 75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Dosing in Renal Impairment Amoxicillin is primarily eliminated by the kidney and dosage adjustment is usually required in patients with severe renal impairment (GFR < 30 ml/min). See Patients with Renal Impairment (2.3) for specific recommendations in patients with renal impairment. 10 OVERDOSAGE In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. A prospective study of 51 pediatric patients at a poison-control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms1. Interstitial nephritis resulting in oliguric renal failure has been reported in patients after overdosage with amoxicillin/clavulanate potassium. Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin/clavulanate potassium overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin/clavulanate potassium crystalluria. Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of amoxicillin/clavulanate potassium. Amoxicillin/clavulanate potassium may be removed from circulation by hemodialysis. [see Dosage and Administration (2.3)] 11 DESCRIPTION Amoxicillin and clavulanate potassium for oral suspension, USP is an oral antibacterial combination consisting of amoxicillin and the beta-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is C 16 H 19 N 3 O 5 S 3H 2 O, and the molecular weight is Chemically, amoxicillin is (2S,5R,6R)-6-[(R)-(-)-2-Amino- 2-(phydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylic acid trihydrate and may be represented structurally as: Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a beta-lactam structurally related to the penicillins and possesses the ability to inactivate some beta-lactamases by blocking the active sites of these enzymes. The clavulanate potassium molecular formula is C 8 H 8 KNO 5, and the molecular weight is Chemically, clavulanate potassium is potassium (Z)(2R,5R)-3- (2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate and may be represented structurally as: Inactive Ingredients For Oral Suspension Aspartame, colloidal silicon dioxide, hydroxypropyl methylcellulose, mannitol, orange flavoring, precipitated silicon dioxide, succinic acid, xanthan gum, and golden syrup flavoring (caramel). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Amoxicillin and clavulanate potassium is an antibacterial drug. [see Microbiology 12.4] 12.3 Pharmacokinetics Mean amoxicillin and clavulanate potassium pharmacokinetic parameters in normal adults following administration of amoxicillin and clavulanate potassium tablets are shown in Table 3 and following administration of amoxicillin and clavulanate potassium for oral suspension and chewable tablets are shown in Table 4. Table 3. Mean (± S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters*, with Amoxicillin and Clavulanate Potassium Tablets Dose and Regimen C max (mcg/ml) AUC 0-24 (mcg h/ml) Amoxicillin/ Clavulanate Clavulanate Clavulanate potassium Amoxicillin potassium Amoxicillin potassium 250 mg/125 mg 3.3 ± ± ± ± 3.25 every 8 hours 500 mg/125 mg 6.5 ± ± ± ± 1.95 every 12 hours 500 mg/125 mg 7.2 ± ± ± ± 3.86 every 8 hours 875 mg/125 mg every 12 hours 11.6 ± ± ± ± 3.04 * Mean (± standard deviation) values of 14 normal adults (N=15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose. Amoxicillin/clavulanate potassium administered at the start of a light meal. Table 4. Mean (± S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters*, with Amoxicillin and Clavulanate Potassium for Oral Suspension and Chewable Tablets Dose C max (mcg/ml) AUC 0-24 (mcg h/ml) Amoxicillin/ Clavulanate potassium 400 mg/57 mg (5 ml of suspension) 400 mg/57 mg (1 chewable tablet) Clavulanate Clavulanate Amoxicillin potassium Amoxicillin potassium 6.94 ± ± ± ± ± ± ± ± 0.73 * Mean (± standard deviation) values of 28 normal adults. Peak concentrations occurred approximately 1 hour after the dose. Amoxicillin/clavulanate potassium administered at the start of a light meal. Oral administration of 5 ml of 250 mg/5 ml suspension of amoxicillin and clavulanate potassium or the equivalent dose of 10 ml of 125 mg/5 ml suspension of amoxicillin and clavulanate potassium provides average peak serum concentrations approximately 1 hour after dosing of 6.9 mcg/ml for amoxicillin and 1.6 mcg/ml for clavulanic acid. The areas under the serum concentration curves obtained during the first 4 hours after dosing were 12.6 mcg h/ml for amoxicillin and 2.9 mcg h/ml for clavulanic acid when 5 ml of 250 mg/5 ml suspension of amoxicillin and clavulanate potassium or equivalent dose of 10 ml of 125 mg/5 ml suspension of amoxicillin and clavulanate potassium were administered to normal adults. One 250-mg chewable tablet of amoxicillin and clavulanate potassium or two 125-mg chewable tablets of amoxicillin and clavulanate potassium are equivalent to 5 ml of 250 mg/5 ml suspension of amoxicillin and clavulanate potassium and provide similar serum concentrations of amoxicillin and clavulanic acid. Amoxicillin serum concentrations achieved with amoxicillin and clavulanate potassium are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. Time above the minimum inhibitory concentration of 1 mcg/ml for amoxicillin has been shown to be similar after corresponding every 12 hour and every 8 hour dosing regimens of amoxicillin and clavulanate potassium in adults and children. Absorption: Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While amoxicillin and clavulanate potassium can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In one study, the relative bioavailability of clavulanate was reduced when amoxicillin and clavulanate potassium was dosed at 30 and 150 minutes after the start of a high-fat breakfast. Distribution: Neither component in amoxicillin and clavulanate potassium is highly protein-bound; clavulanic acid is approximately 25% bound to human serum and amoxicillin approximately 18% bound. Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. Two hours after oral administration of a single 35 mg/kg dose of suspension of amoxicillin and clavulanate potassium to fasting children, average concentrations of 3 mcg/ml of amoxicillin and 0.5 mcg/ml of clavulanic acid were detected in middle ear effusions. Metabolism and Excretion: The half-life of amoxicillin after the oral administration of amoxicillin and clavulanate potassium is 1.3 hours and that of clavulanic acid is 1 hour. Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single 250-mg or 500-mg tablet of amoxicillin and clavulanate potassium Microbiology Amoxicillin is a semisynthetic antibiotic with in vitro bactericidal activity against Gram-positive and Gram-negative bacteria. Amoxicillin is, however, susceptible to degradation by beta-lactamases, and therefore, the spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a beta-lactam, structurally related to the penicillins, which possesses the ability to inactivate some beta-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated beta-lactamases frequently responsible for transferred drug resistance. The formulation of amoxicillin and clavulanic acid in amoxicillin and clavulanate potassium protects amoxicillin from degradation by some beta-lactamase enzymes and extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin. Amoxicillin/clavulanic acid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive bacteria Staphylococcus aureus Gram-negative bacteria Enterobacter species Escherichia coli Haemophilus influenzae Klebsiella species Moraxella catarrhalis The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for amoxicillin/clavulanic acid. However, the efficacy of amoxicillin/clavulanic acid in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials. Gram-positive bacteria Enterococcus faecalis Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus pneumoniae Streptococcus pyogenes Viridans group Streptococcus Gram-negative Bacteria Eikenella corrodens Proteus mirabilis Anaerobic Bacteria Bacteroides species including Bacteroides fragilis Fusobacterium species Peptostreptococcus species Susceptibility Test Methods When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment. Dilution techniques Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method2,3 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 5. Diffusion techniques Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method3,4. This procedure uses paper disks impregnated with 30 mcg amoxicillin/clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) to test the susceptibility of bacteria to amoxicillin/clavulanic acid. The disc diffusion interpretive criteria are provided in Table 5. Table 5. Susceptibility Test Interpretive Criteria for QC Strain Escherichia coli ATCC Escherichia coli ATCC Haemophilus influenzae ATCC Staphylococcus aureus ATCC Staphylococcus aureus ATCC Amoxicillin/Clavulanic Acid Minimum Inhibitory Concentrations (mcg/ml) Disk Diffusion (zone diameters in mm) Pathogen S I R S I R Enterobacteriaceae 8/4 16/8 32/ Haemophilus influenzae 4/2 8/ and Staphylococcus aureus Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test2,3,4. Standard amoxicillin/clavulanic acid powder should provide the following range of MIC values noted in Table 6 for the diffusion technique using the 30 mcg amoxicillin/clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) disk, the criteria in Table 6 should be achieved. Table 6. Acceptable Quality Control Ranges for Amoxicillin/Clavulanic Acid Minimum Inhibitory Disk Diffusion Concentration (zone diameter (mcg/ml) in mm) 2/1 to 8/4 18 to 24 4/2 to 16/8 17 to 22 2/1 to 16/8 15 to /0.06 to 0.5/ to NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate carcinogenic potential. Amoxicillin and clavulanate potassium (4:1 ratio formulation of amoxicillin:clavulanate) was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and clavulanate potassium was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. Amoxicillin and clavulanate potassium was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. Amoxicillin and clavulanate potassium (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses of up to 1,200 mg/kg/day was found to have no effect on fertility and reproductive performance in rats. Based on body surface area, this dose of amoxicillin is approximately 4 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, the dose multiple is approximately 9 times higher than the maximum recommended adult human oral dose (125 mg every 8 hours), also based on body surface area. 14 CLINICAL STUDIES 14.1 Lower Respiratory Tract and Complicated Urinary Tract Infections Data from 2 pivotal trials in 1,191 patients treated for either lower respiratory tract infections or complicated urinary tract infections compared a regimen of 875-mg tablets of amoxicillin and clavulanate potassium every 12 hours to 500-mg tablets of amoxicillin and clavulanate potassium dosed every 8 hours (584 and 607 patients, respectively). Comparable efficacy was demonstrated between the every 12 hours and every 8 hours dosing regimens. There was no significant difference in the percentage of adverse events in each group. The most frequently reported adverse event was diarrhea; incidence rates were similar for the 875-mg every 12 hours and 500-mg every 8 hours dosing regimens (15% and 14%, respectively); however, there was a statistically significant difference (p < 0.05) in rates of severe diarrhea or withdrawals with diarrhea between the regimens: 1% for 875-mg every 12 hours regimen versus 2% for the 500-mg every 8 hours regimen. In one of these pivotal trials, patients with either pyelonephritis (n = 361) or a complicated urinary tract infection (i.e., patients with abnormalities of the urinary tract that predispose to relapse of bacteriuria following eradication, n = 268) were randomized (1:1) to receive either 875-mg tablets of amoxicillin and clavulanate potassium every 12 hours (n = 308) or 500-mg tablets of amoxicillin and clavulanate potassium every 8 hours (n = 321). The number of bacteriologically evaluable patients was comparable between the two dosing regimens. Amoxicillin and clavulanate potassium produced comparable bacteriological success rates in patients assessed 2 to 4 days immediately following end of therapy. The bacteriologic efficacy rates were comparable at one of the follow-up visits (5 to 9 days post-therapy) and at a late post-therapy visit (in the majority of cases, this was 2 to 4 weeks post-therapy), as seen in Table 7. Table 7. Bacteriologic efficacy rates for amoxicillin and clavulanate potassium 875 mg every 500 mg every Time Post Therapy 12 hours % (n) 8 hours % (n) 2 to 4 days 81% (58) 80% (54) 5 to 9 days 58% (41) 52% (52) 2 to 4 weeks 52% (101) 55% (104) As noted before, though there was no significant difference in the percentage of adverse events in each group, there was a statistically significant difference in rates of severe diarrhea or withdrawals with diarrhea between the regimens Acute Bacterial Otitis Media and Diarrhea in Pediatric Patients One US/Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of amoxicillin and clavulanate potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxicillin and clavulanate potassium for 10 days in the treatment of acute otitis media. Only the suspension formulations were used in this trial. A total of 575 pediatric patients (aged 2 months to 12 years) were enrolled, with an even distribution among the 2 treatment groups and a comparable number of patients were evaluable (i.e., 84%) per treatment group. Otitis media-specific criteria were required for eligibility and a strong correlation was found at the end of therapy and follow-up between these criteria and physician assessment of clinical response. The clinical efficacy rates at the end of therapy visit (defined as 2 to 4 days after the completion of therapy) and at the follow-up visit (defined as 22 to 28 days post-completion of therapy) were comparable for the 2 treatment groups, with the following cure rates obtained for the evaluable patients: At end of therapy, 87% (n = 265) and 82% (n = 260) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. At follow-up, 67% (n = 249) and 69% (n = 243) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. Diarrhea was defined as either: (a) 3 or more watery or 4 or more loose/watery stools in 1 day; OR (b) 2 watery stools per day or 3 loose/watery stools per day for 2 consecutive days. The incidence of diarrhea was significantly lower in patients who received the every 12 hours regimen compared to patients who received the every 8 hours regimen (14% and 34%, respectively). In addition, the number of patients with either severe diarrhea or who were withdrawn with diarrhea was significantly lower in the every 12 hours treatment group (3% and 8% for the every 12 hours/10 day and every 8 hours/10 day, respectively). In the every 12 hours treatment group, 3 patients (1%) were withdrawn with an allergic reaction, while 1 patient in the every 8 hours group was withdrawn for this reason. The number of patients with a candidal infection of the diaper area was 4% and 6% for the every 12 hours and every 8 hours groups, respectively. It is not known if the finding of a statistically significant reduction in diarrhea with the oral suspensions dosed every 12 hours, versus suspensions dosed every 8 hours, can be extrapolated to the chewable tablets. The presence of mannitol in the chewable tablets may contribute to a different diarrhea profile. The every 12 hour oral suspensions (200 mg/5 ml and 400 mg/5 ml) are sweetened with aspartame. 15 REFERENCES 1. Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol. 1988; 30: Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard 8th ed. CLSI Document M7-A9. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA, 19087, Clinical and Laboratory Standards Institute (CLSI). Performance Standard for Antimicrobial Disk Susceptibility Tests; Approved Standard 11th ed. CLSI Document M2-A11. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA, 19087, CLSI. Performance Standards for Antimicrobial Susceptibility Testing: 22nd Informational Supplement. CLSI document M100-S22. CLSI, Wayne, PA, HOW SUPPLIED/STORAGE AND HANDLING For Oral Suspension Amoxicillin and Clavulanate Potassium for Oral Suspension, USP 200 mg/28.5 mg per 5 ml: as a dry, white powder. Each 5 ml of reconstituted orange-flavored suspension contains 200 mg amoxicillin as the trihydrate and 28.5 mg clavulanic acid as the potassium salt. NDC ml bottle Amoxicillin and Clavulanate Potassium for Oral Suspension, USP 400 mg/57 mg per 5 ml: as a dry, white powder. Each 5 ml of reconstituted orange-flavored suspension contains 400 mg amoxicillin as the trihydrate and 57 mg clavulanic acid as the potassium salt. NDC ml bottle Store dry powder at 20 to 25 C (68 to 77 F) [see USP Controlled Room Temperature]. Dispense in original container; Store reconstituted suspension under refrigeration. Discard unused suspension after 10 days. Keep out of reach of children. 17 PATIENT COUNSELING INFORMATION 17.1 Information for Patients Patients should be informed that amoxicillin and clavulanate potassium may be taken every 8 hours or every 12 hours, depending on the dose prescribed. Each dose should be taken with a meal or snack to reduce the possibility of gastrointestinal upset. Patients should be counseled that antibacterial drugs, including amoxicillin and clavulanate potassium, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When amoxicillin and clavulanate potassium is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by amoxicillin and clavulanate potassium or other antibacterial drugs in the future. Counsel patients that diarrhea is a common problem caused by antibacterials, and it usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken their last dose of the antibacterial. If diarrhea is severe or lasts more than 2 or 3 days, patients should contact their physician. Patients should be advised to keep suspension refrigerated. Shake well before using. When dosing a child with the suspension (liquid) of amoxicillin and clavulanate potassium, use a dosing spoon or medicine dropper. Be sure to rinse the spoon or dropper after each use. Bottles of suspension of amoxicillin and clavulanate potassium may contain more liquid than required. Follow your doctor s instructions about the amount to use and the days of treatment your child requires. Discard any unused medicine. Patients should be aware that amoxicillin and clavulanate potassium contains a penicillin class drug product that can cause allergic reactions in some individuals. CLINITEST is a registered trademark of Miles, Inc Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV U.S.A. Manufactured in Austria by: Sandoz GmbH Biochemiestrasse Kundl Austria REVISED FEBRUARY 2016 SDZ:AXCLOS:R2

12 Rx only Amoxicillin and Clavulanate Potassium for Oral Suspension, USP 400 mg/57 mg LEK:AMXCLOS:R1 Rx only Amoxicillin and Clavulanate Potassium for Oral Suspension, USP 400 mg/57 mg LEK:AMXCLOS:R1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use amoxicillin and clavulanate potassium safely and effectively. See full prescribing information for amoxicillin and clavulanate potassium. AMOXICILLIN and CLAVULANATE Potassium For Oral Suspension USP, for Oral Use Initial U.S. Approval: 1984 To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium and other antibacterial drugs, amoxicillin and clavulanate potassium should be used only to treat infections that are proven or strongly suspected to be caused by bacteria INDICATIONS AND USAGE Amoxicillin and clavulanate potassium is a combination penicillin-class antibacterial and betalactamase inhibitor indicated for treatment of the following: Lower respiratory tract infections (1.1) Acute bacterial otitis media (1.2) Sinusitis (1.3) Skin and skin structure infections (1.4) Urinary tract infections (1.5) DOSAGE AND ADMINISTRATION Adults and Pediatric Patients > 40 kg: 500 or 875 mg every 12 hours or 250 or 500 mg every 8 hours. (2.1, 2.2) Pediatric patients aged 12 weeks (3 months) and older: 25 to 45 mg/kg/day every 12 hours or 20 to 40 mg/kg/day every 8 hours, up to the adult dose. (2.2) Neonates and infants < 12 weeks of age: 30 mg/kg/day divided every 12 hours, based on the amoxicillin component. Use of the 125 mg/5 ml oral suspension is recommended. (2.2) DOSAGE FORMS AND STRENGTHS Formulations and amoxicillin and clavulanate content are: Oral Suspension: 400 mg/57 mg per 5 ml (3) CONTRAINDICATIONS History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin and clavulanate potassium or to other beta-lactams (e.g., penicillins or cephalosporins). (4) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Lower Respiratory Tract Infections 1.2 Acute Bacterial Otitis Media 1.3 Sinusitis 1.4 Skin and Skin Structure Infections 1.5 Urinary Tract Infections 1.6 Limitations of Use 2 DOSAGE AND ADMINISTRATION 2.1 Adults 2.2 Pediatric Patients 2.3 Patients with Renal Impairment 2.4 Directions for Mixing Oral Suspension 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Serious Hypersensitivity Reactions 4.2 Cholestatic Jaundice/Hepatic Dysfunction 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 5.2 Hepatic Dysfunction 5.3 Clostridium difficile-associated Diarrhea 5.4 Skin Rash in Patients with Mononucleosis 5.5 Potential for Microbial Overgrowth 5.7 Development of Drug-Resistant Bacteria 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Probenecid FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium and other antibacterial drugs, amoxicillin and clavulanate potassium should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Amoxicillin and clavulanate potassium is a combination penicillin-class antibacterial and betalactamase inhibitor indicated in the treatment of infections due to susceptible isolates of the designated bacteria in the conditions listed below * : 1.1 Lower Respiratory Tract Infections caused by beta-lactamase-producing isolates of Haemophilus influenzae and Moraxella catarrhalis. 1.2 Acute Bacterial Otitis Media caused by beta-lactamase-producing isolates of H. influenzae and M. catarrhalis. 1.3 Sinusitis caused by beta-lactamase-producing isolates of H. influenzae and M. catarrhalis. 1.4 Skin and Skin Structure Infections caused by beta-lactamase-producing isolates of Staphylococcus aureus, Escherichia coli, and Klebsiella species. 1.5 Urinary Tract Infections caused by beta-lactamase-producing isolates of E. coli, Klebsiella species, and Enterobacter species. 1.6 Limitations of Use When susceptibility test results show susceptibility to amoxicillin, indicating no beta-lactamase production, amoxicillin and clavulanate potassium should not be used. 2 DOSAGE AND ADMINISTRATION Amoxicillin and clavulanate potassium may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when amoxicillin and clavulanate potassium is administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, amoxicillin and clavulanate potassium should be taken at the start of a meal. 2.1 Adults The usual adult dose is one amoxicillin and clavulanate potassium tablet, 500 mg/125 mg every 12 hours or one amoxicillin and clavulanate potassium tablet, 250 mg/125 mg every 8 hours. For more severe infections and infections of the respiratory tract, the dose should be one amoxicillin and clavulanate potassium tablet, 875 mg/125 mg every 12 hours or one amoxicillin and clavulanate potassium tablet, 500 mg/125 mg every 8 hours. Adults who have difficulty swallowing may be given the 125 mg/5 ml or 250 mg/5 ml suspension in place of the 500 mg/125 mg tablet. The 200 mg/5 ml suspension or the 400 mg/5 ml suspension may be used in place of the 875 mg/125 mg tablet. Two 250 mg/125 mg tablets of amoxicillin and clavulanate potassium should not be substituted for one 500 mg/125 mg tablet of amoxicillin and clavulanate potassium. Since both the 250 mg/125 mg and 500 mg/125 mg tablets of amoxicillin and clavulanate potassium contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250 mg/125 mg tablets are not equivalent to History of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium. (4) WARNINGS AND PRECAUTIONS Serious (including fatal) hypersensitivity reactions: Discontinue amoxicillin and clavulanate potassium if a reaction occurs. (5.1) Hepatic dysfunction and cholestatic jaundice: Discontinue if signs/symptoms of hepatitis occur. Monitor liver function tests in patients with hepatic impairment. (5.2) Clostridium difficile-associated diarrhea (CDAD): Evaluate patients if diarrhea occurs. (5.3) Patients with mononucleosis who receive amoxicillin and clavulanate potassium develop skin rash. Avoid amoxicillin and clavulanate potassium use in these patients. (5.4) Overgrowth: The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. (5.5) ADVERSE REACTIONS The most frequently reported adverse effects were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%) (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals, Inc. at ( INFO-RX) or FDA at FDA-1088 or DRUG INTERACTIONS Co-administration with probenecid is not recommended. (7.1) Concomitant use of amoxicillin and clavulanate potassium and oral anticoagulants may increase the prolongation of prothrombin time. (7.2) Coadministration with allopurinol increases the risk of rash. (7.3) Amoxicillin and clavulanate potassium may reduce efficacy of oral contraceptives. (7.4) USE IN SPECIFIC POPULATIONS Pediatric Use: Modify dose in patients 12 weeks or younger. (8.4) Renal impairment: Dosage adjustment is recommended for severe renal impairment (GFR < 30 ml/min). (2.3, 8.6) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Rev. 12/ Oral Anticoagulants 7.3 Allopurinol 7.4 Oral Contraceptives 7.5 Effects on Laboratory Tests 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Dosing in Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Lower Respiratory Tract and Complicated Urinary Tract Infections 14.2 Acute Bacterial Otitis Media and Diarrhea in Pediatric Patients 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Information for Patients *Sections or subsections omitted from the full prescribing information are not listed. one 500 mg/125 mg tablet of amoxicillin and clavulanate potassium. The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium and the 250 mg/62.5 mg chewable tablet should not be substituted for each other, as they are not interchangeable. The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium and the 250 mg/125 mg chewable tablet do not contain the same amount of clavulanic acid (as the potassium salt). The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium contains 125 mg of clavulanic acid, whereas the 250 mg/62.5 mg chewable tablet contains 62.5 mg of clavulanic acid. 2.2 Pediatric Patients Based on the amoxicillin component, amoxicillin and clavulanate potassium should be dosed as follows: Neonates and Infants Aged < 12 weeks (< 3 months) The recommended dose of amoxicillin and clavulanate potassium is 30 mg/kg/day divided every 12 hours, based on the amoxicillin component. Experience with the 200 mg/28.5 mg/5 ml formulation in this age group is limited, and thus, use of the 125 mg/31.25 mg/5 ml oral suspension is recommended. Patients Aged 12 weeks (3 months) and Older See dosing regimens provided in Table 1. The every 12 hour regimen is recommended as it is associated with significantly less diarrhea [see CLINICAL STUDIES (14.2)]. Table 1: Dosing in Patients Aged 12 weeks (3 months) and Older INFECTION Otitis media, sinusitis, lower respiratory tract infections, and more severe infections Every 12 hours 200 mg/28.5 mg/5 ml or 400 mg/57 mg/5 ml oral suspension * DOSING REGIMEN Every 8 hours 125 mg/31.25 mg/5 ml or 250 mg/62.5 mg/5 ml oral suspension * 45 mg/kg/day every 12 hours 40 mg/kg/day every 8 hours Less severe infections 25 mg/kg/day every 12 hours 20 mg/kg/day every 8 hours * Each strength of suspension of amoxicillin and clavulanate potassium is available as a chewable tablet for use by older children. Duration of therapy studied and recommended for acute otitis media is 10 days. Patients Weighing 40 kg or More Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations. The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium should not be used until the child weighs at least 40 kg, due to the different amoxicillin to clavulanic acid ratios in the 250 mg/125 mg tablet of amoxicillin and clavulanate potassium (250/125) versus the 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium (250/62.5). 2.3 Patients with Renal Impairment Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Renal impairment patients with a glomerular filtration rate of < 30 ml/min should not receive the 875 mg/125 mg dose. Patients with a glomerular filtration rate of 10 to 30 ml/min should receive 500 mg/125 mg or 250 mg/125 mg every 12 hours, depending on the severity of the infection. Patients with a glomerular filtration rate less than 10 ml/min should receive 500 mg/125 mg or 250 mg/125 mg every 24 hours, depending on severity of the infection. Hemodialysis patients should receive 500 mg/125 mg or 250 mg/125 mg every 24 hours, depending on severity of the infection. They should receive an additional dose both during and at the end of dialysis. 2.4 Directions for Mixing Oral Suspension Prepare a suspension at time of dispensing as follows: Tap bottle until all the powder flows freely. Add approximately 2/3 of the total amount of water for reconstitution (see Table 2 below) and shake vigorously to suspend powder. Add remainder of the water and again shake vigorously. Table 2: Amount of Water for Mixing Oral Suspension Strength Bottle Size 400 mg/57 mg/ 5 ml 50 ml 75 ml Amount of Water for Reconstitution 45 ml 67 ml Contents of Each Teaspoonful (5 ml) 400 mg amoxicillin and 57 mg of clavulanic acid as the potassium salt Note: Shake oral suspension well before using. Reconstituted suspension must be stored under refrigeration and discarded after 10 days. 3 DOSAGE FORMS AND STRENGTHS Oral Suspension: 400 mg/57 mg per 5 ml: Caramel-orange-raspberry-flavored powder for oral suspension (each 5 ml of reconstituted suspension contains 400 mg amoxicillin and 57 mg of clavulanic acid as the potassium salt). The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium and the 250 mg/62.5 mg chewable tablet should NOT be substituted for each other, as they are not interchangeable and the 250 mg/125 mg tablet should not be used in children weighing less than 40 kg. The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium and the 250 mg/62.5 mg chewable tablet do not contain the same amount of clavulanic acid. The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium contains 125 mg of clavulanic acid whereas the 250 mg/62.5 mg chewable tablet contains 62.5 mg of clavulanic acid. Two 250 mg/125 mg tablets of amoxicillin and clavulanate potassium should NOT be substituted for one 500 mg/125 mg tablet of amoxicillin and clavulanate potassium. Since both the 250 mg/125 mg and 500 mg/125 mg tablets of amoxicillin and clavulanate potassium contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250 mg/125 mg tablets of amoxicillin and clavulanate potassium are not equivalent to one 500 mg/125 mg tablet of amoxicillin and clavulanate potassium. 4 CONTRAINDICATIONS 4.1 Serious Hypersensitivity Reactions Amoxicillin and clavulanate potassium is contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin, clavulanate or to other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins). 4.2 Cholestatic Jaundice/Hepatic Dysfunction Amoxicillin and clavulanate potassium is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including amoxicillin and clavulanate potassium. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Before initiating therapy with amoxicillin and clavulanate potassium, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, amoxicillin and clavulanate potassium should be discontinued and appropriate therapy instituted. 5.2 Hepatic Dysfunction Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of amoxicillin and clavulanate potassium. Hepatic toxicity is usually reversible; however, deaths have been reported. Hepatic function should be monitored at regular intervals in patients with hepatic impairment. 5.3 Clostridium difficile Associated Diarrhea (CDAD) Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin and clavulanate potassium, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxinproducing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.4 Skin Rash in Patients with Mononucleosis A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus, amoxicillin and clavulanate potassium should not be administered to patients with mononucleosis. 5.5 Potential for Microbial Overgrowth The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfection occurs, amoxicillin and clavulanate potassium should be discontinued and appropriate therapy instituted. 5.7 Development of Drug-Resistant Bacteria Prescribing amoxicillin and clavulanate potassium in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient, and increases the risk of the development of drug-resistant bacteria. 6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Anaphylactic reactions [see WARNINGS AND PRECAUTIONS (5.1)] Hepatic Dysfunction [see WARNINGS AND PRECAUTIONS (5.2)] CDAD [see WARNINGS AND PRECAUTIONS (5.3)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most frequently reported adverse reactions were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). Less than 3% of patients discontinued therapy because of drug-related adverse reactions. The overall incidence of adverse reactions, and in particular diarrhea, increased with the higher recommended dose. Other less frequently reported adverse reactions (< 1%) include: Abdominal discomfort, flatulence, and headache. In pediatric patients (aged 2 months to 12 years), 1 US/Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of amoxicillin and clavulanate potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxicillin and clavulanate potassium for 10 days in the treatment of acute otitis media. A total of 575 patients were enrolled, and only the suspension formulations were used in this trial. Overall, the adverse reactions seen were comparable to that noted above; however, there were differences in the rates of diarrhea, skin rashes/urticaria, and diaper area rashes [see CLINICAL STUDIES (14.2)]. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following have been identified during postmarketing use of amoxicillin and clavulanate potassium. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to amoxicillin and clavulanate potassium. Gastrointestinal: Indigestion, gastritis, stomatitis, glossitis, black hairy tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment [see WARNINGS AND PRECAUTIONS (5.3)]. Hypersensitivity Reactions: Pruritus, angioedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), erythema multiforme, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and cases of exfoliative dermatitis (including toxic epidermal necrolysis) have been reported [see WARNINGS AND PRECAUTIONS (5.1)]. Liver: Hepatic dysfunction, including hepatitis and cholestatic jaundice, increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been reported with amoxicillin and clavulanate potassium. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, is usually reversible. Deaths have been reported [see CONTRAINDICATIONS (4.2), WARNINGS AND PRECAUTIONS (5.2)]. Renal: Interstitial nephritis, hematuria, and crystalluria have been reported [see OVERDOSAGE (10)]. Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Thrombocytosis was noted in less than 1% of the patients treated with amoxicillin and clavulanate potassium. There have been reports of increased prothrombin time in patients receiving amoxicillin and clavulanate potassium and anticoagulant therapy concomitantly [see DRUG INTERACTIONS (7.2)]. Central Nervous System: Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported. Miscellaneous: Tooth discoloration (brown, yellow, or gray staining) has been reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases. 7 DRUG INTERACTIONS 7.1 Probenecid Probenecid decreases the renal tubular secretion of amoxicillin but does not delay renal excretion of clavulanic acid. Concurrent use with amoxicillin and clavulanate potassium may result in increased and prolonged blood concentrations of amoxicillin. Coadministration of probenecid is not recommended. 7.2 Oral Anticoagulants Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been reported in patients receiving amoxicillin and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently with amoxicillin and clavulanate potassium. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation. 7.3 Allopurinol The concurrent administration of allopurinol and amoxicillin increases the incidence of rashes in patients receiving both drugs as compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients. 7.4 Oral Contraceptives Amoxicillin and clavulanate potassium may affect intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives. 7.5 Effects on Laboratory Tests High urine concentrations of amoxicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST, Benedict s Solution, or Fehling s Solution. Since this effect may also occur with amoxicillin and clavulanate potassium, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. Following administration of amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category B. Reproduction studies performed in pregnant rats and mice given amoxicillin and clavulanate potassium (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses up to 1200 mg/kg/day revealed no evidence of harm to the fetus due to amoxicillin and clavulanate potassium. The amoxicillin doses in rats and mice (based on body surface area) were approximately 4 and 2 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, these dose multiples were approximately 9 and 4 times the maximum recommended adult human oral dose (125 mg every 8 hours). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 8.2 Labor and Delivery Oral ampicillin-class antibiotics are poorly absorbed during labor. It is not known whether use of amoxicillin and clavulanate potassium in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood of the necessity for an obstetrical intervention. 8.3 Nursing Mothers Amoxicillin has been shown to be excreted in human milk. Amoxicillin and clavulanate potassium use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin and clavulanate potassium is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of amoxicillin and clavulanate potassium for oral suspension have been established in pediatric patients. Use of amoxicillin and clavulanate potassium in pediatric patients is supported by evidence from studies of amoxicillin and clavulanate potassium tablets in adults with additional data from a study of amoxicillin and clavulanate potassium for oral suspension in pediatric patients aged 2 months to 12 years with acute otitis media [see CLINICAL STUDIES (14.2)].

13 Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed; clavulanate elimination is unaltered in this age group. Dosing of amoxicillin and clavulanate potassium should be modified in pediatric patients aged < 12 weeks (< 3 months) [see DOSAGE AND ADMINISTRATION (2.2)]. 8.5 Geriatric Use Of the 3,119 patients in an analysis of clinical studies of amoxicillin and clavulanate potassium, 32% were 65 years old, and 14% were 75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Dosing in Renal Impairment Amoxicillin is primarily eliminated by the kidney and dosage adjustment is usually required in patients with severe renal impairment (GFR < 30 ml/min). See Patients with Renal Impairment (2.3) for specific recommendations in patients with renal impairment. 10 OVERDOSAGE In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. A prospective study of 51 pediatric patients at a poison-control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms 1. Interstitial nephritis resulting in oliguric renal failure has been reported in patients after overdosage with amoxicillin and clavulanate potassium. Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin and clavulanate potassium overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin and clavulanate potassium crystalluria. Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of amoxicillin and clavulanate potassium. Amoxicillin and clavulanate potassium may be removed from circulation by hemodialysis [see DOSAGE AND ADMINISTRATION (2.3)]. 11 DESCRIPTION Amoxicillin and clavulanate potassium is an oral antibacterial combination consisting of amoxicillin and the beta-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is C 16 H 19 N 3 O 5 S 3H 2 O, and the molecular weight is Chemically, amoxicillin is (2S,5R,6R)-6-[(R)-(-)-2-Amino-2-(p-hydroxyphenyl)acetamido]- 3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate and may be represented structurally as: Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a beta-lactam structurally related to the penicillins and possesses the ability to inactivate some beta-lactamases by blocking the active sites of these enzymes. The clavulanate potassium molecular formula is C 8 H 8 KNO 5, and the molecular weight is Chemically, clavulanate potassium is potassium (Z) (2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate and may be represented structurally as: O CH 2 OH O N COOK Inactive Ingredients: Oral Suspension - citric acid (anhydrous), colloidal silicon dioxide, flavorings caramel, orange and raspberry, microcrystalline cellulose (dried), microcrystalline cellulose and carboxymethylcellulose sodium (dried), saccharin sodium (dried), silicon dioxide, sodium citrate (anhydrous), xanthan gum. Each 5 ml of reconstituted suspension contains: amoxicillin, 400 mg, as the trihydrate and clavulanic acid, 57 mg, as clavulanate potassium. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Amoxicillin and clavulanate potassium is an antibacterial drug [see MICROBIOLOGY (12.4)] Pharmacokinetics Mean amoxicillin and clavulanate potassium pharmacokinetic parameters in normal adults following administration of amoxicillin and clavulanate potassium tablets are shown in Table 3 and following administration of amoxicillin and clavulanate potassium for oral suspension and chewable tablets are shown in Table 4. Table 3: Mean (± S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters a,b with Amoxicillin and Clavulanate Potassium Tablets Dose and Regimen C max (mcg/ml) AUC 0-24 (mcg * h/ml) Amoxicillin and Clavulanate potassium 250/125 mg every 8 hours 500/125 mg every 12 hours 500/125 mg every 8 hours 875/125 mg every 12 hours Amoxicillin Clavulanate potassium H Amoxicillin Clavulanate potassium 3.3 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 3.04 a Mean (± standard deviation) values of 14 normal adults (N = 15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose. b Amoxicillin and clavulanate potassium administered at the start of a light meal. Table 4: Mean (± S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters a,b with Amoxicillin and Clavulanate Potassium for Oral Suspension and Chewable Tablets Dose C max (mcg/ml) AUC 0-24 (mcg * h/ml) Amoxicillin and Clavulanate potassium Amoxicillin Clavulanate potassium Amoxicillin Clavulanate potassium 400/57 mg (5 ml of suspension) 400/57 mg (1 chewable tablet) 6.94 ± ± ± ± ± ± ± ± 0.73 a Mean (± standard deviation) values of 28 normal adults. Peak concentrations occurred approximately 1 hour after the dose. b Amoxicillin and clavulanate potassium administered at the start of a light meal. Oral administration of 5 ml of 250 mg/62.5 mg/5 ml suspension of amoxicillin and clavulanate potassium or the equivalent dose of 10 ml of 125 mg/31.25 mg/5 ml suspension of amoxicillin and clavulanate potassium provides average peak serum concentrations approximately 1 hour after dosing of 6.9 mcg/ml for amoxicillin and 1.6 mcg/ml for clavulanic acid. The areas under the serum concentration curves obtained during the first 4 hours after dosing were 12.6 mcg*h/ml for amoxicillin and 2.9 mcg*h/ml for clavulanic acid when 5 ml of 250 mg/62.5 mg/5 ml suspension of amoxicillin and clavulanate potassium or equivalent dose of 10 ml of 125 mg/31.25 mg/5 ml suspension of amoxicillin and clavulanate potassium were administered to normal adults. One 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium or two 125 mg/31.25 mg chewable tablets of amoxicillin and clavulanate potassium are equivalent to 5 ml of 250 mg/62.5 mg/5 ml suspension of amoxicillin and clavulanate potassium and provide similar serum concentrations of amoxicillin and clavulanic acid. Amoxicillin serum concentrations achieved with amoxicillin and clavulanate potassium are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. Time above the minimum inhibitory concentration of 1 mcg/ml for amoxicillin has been shown to be similar after corresponding every 12 hour and every 8 hour dosing regimens of amoxicillin and clavulanate potassium in adults and children. Absorption Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While amoxicillin and clavulanate potassium can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In one study, the relative bioavailability of clavulanate was reduced when amoxicillin and clavulanate potassium was dosed at 30 and 150 minutes after the start of a high-fat breakfast. Distribution Neither component in amoxicillin and clavulanate potassium is highly protein-bound; clavulanic acid is approximately 25% bound to human serum and amoxicillin approximately 18% bound. Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. Two hours after oral administration of a single 35 mg/kg dose of suspension of amoxicillin and clavulanate potassium to fasting children, average concentrations of 3 mcg/ml of amoxicillin and 0.5 mcg/ml of clavulanic acid were detected in middle ear effusions. Metabolism and Excretion The half-life of amoxicillin after the oral administration of amoxicillin and clavulanate potassium is 1.3 hours and that of clavulanic acid is 1 hour. Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single 250 mg/125 mg or 500 mg/125 mg tablet of amoxicillin and clavulanate potassium Microbiology Amoxicillin is a semisynthetic antibiotic with in vitro bactericidal activity against Gram-positive and Gram-negative bacteria. Amoxicillin is, however, susceptible to degradation by beta-lactamases, and therefore, the spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a beta-lactam, structurally related to the penicillins, which possesses the ability to inactivate some beta-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmidmediated beta-lactamases frequently responsible for transferred drug resistance. The formulation of amoxicillin and clavulanic acid in amoxicillin and clavulanate potassium protects amoxicillin from degradation by some beta-lactamase enzymes and extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin. Amoxicillin and clavulanic acid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive bacteria Staphylococcus aureus Gram-negative bacteria Enterobacter species Escherichia coli Haemophilus influenzae Klebsiella species Moraxella catarrhalis The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for amoxicillin and clavulanic acid. However, the efficacy of amoxicillin and clavulanic acid in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials. Gram-positive bacteria Enterococcus faecalis Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus pneumoniae Streptococcus pyogenes Viridans group Streptococcus Gram-negative bacteria Eikenella corrodens Proteus mirabilis Anaerobic bacteria Bacteroides species including Bacteroides fragilis Fusobacterium species Peptostreptococcus species Susceptibility Test Methods When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment. Dilution techniques Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method2,3 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 5. Diffusion techniques Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method3,4. This procedure uses paper disks impregnated with 30 mcg amoxicillin and clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) to test the susceptibility of bacteria to amoxicillin and clavulanic acid. The disc diffusion interpretive criteria are provided in Table 5. Table 5: Susceptibility Test Interpretive Criteria for Amoxicillin Clavulanic Acid Minimum Inhibitory Concentrations (mcg/ml) Disk Diffusion (zone diameters in mm) Pathogen S I R S I I R Enterobacteriaceae 8/4 16/8 32/ to Haemophilus influenzae and Staphylococcus aureus 4/2-8/ Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test 2,3,4. Standard amoxicillin and clavulanic acid powder should provide the following range of MIC values noted in Table 6 for the diffusion technique using the 30 mcg amoxicillin and clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) disk, the criteria in Table 6 should be achieved. Table 6: Acceptable Quality Control Ranges for Amoxicillin and Clavulanic Acid QC Strain Escherichia coli ATCC Escherichia coli ATCC Minimum Inhibitory Concentration (mcg/ml) Disk Diffusion (zone diameter in mm) 2/1 to 8/4 18 to 24 4/2 to 16/8 17 to 22 Haemophilus influenzae ATCC /1 to 16/8 15 to 23 Staphylococcus aureus ATCC /0.06 to 0.5/ Staphylococcus aureus ATCC to NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate carcinogenic potential. Amoxicillin and clavulanate potassium (4:1 ratio formulation of amoxicillin:clavulanate) was nonmutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and clavulanate potassium was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. Amoxicillin and clavulanate potassium was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. Amoxicillin and clavulanate potassium (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses of up to 1,200 mg/kg/day was found to have no effect on fertility and reproductive performance in rats. Based on body surface area, this dose of amoxicillin is approximately 4 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, the dose multiple is approximately 9 times higher than the maximum recommended adult human oral dose (125 mg every 8 hours), also based on body surface area. 14 CLINICAL STUDIES 14.1 Lower Respiratory Tract and Complicated Urinary Tract Infections Data from 2 pivotal trials in 1,191 patients treated for either lower respiratory tract infections or complicated urinary tract infections compared a regimen of 875 mg/125 mg tablets of amoxicillin and clavulanate potassium every 12 hours to 500 mg/125 mg tablets of amoxicillin and clavulanate potassium dosed every 8 hours (584 and 607 patients, respectively). Comparable efficacy was demonstrated between the every 12 hours and every 8 hours dosing regimens. There was no significant difference in the percentage of adverse events in each group. The most frequently reported adverse event was diarrhea; incidence rates were similar for the 875 mg/125 mg every 12 hours and 500 mg/125 mg every 8 hours dosing regimens (15% and 14%, respectively); however, there was a statistically significant difference (p < 0.05) in rates of severe diarrhea or withdrawals with diarrhea between the regimens: 1% for 875 mg/125 mg every 12 hours regimen versus 2% for the 500 mg/125 mg every 8 hours regimen. In one of these pivotal trials, patients with either pyelonephritis (n = 361) or a complicated urinary tract infection (i.e., patients with abnormalities of the urinary tract that predispose to relapse of bacteriuria following eradication, n = 268) were randomized (1:1) to receive either 875 mg/125 mg tablets of amoxicillin and clavulanate potassium every 12 hours (n = 308) or 500 mg/125 mg tablets of amoxicillin and clavulanate potassium every 8 hours (n = 321). The number of bacteriologically evaluable patients was comparable between the two dosing regimens. Amoxicillin and clavulanate potassium produced comparable bacteriological success rates in patients assessed 2 to 4 days immediately following end of therapy. The bacteriologic efficacy rates were comparable at one of the follow-up visits (5 to 9 days post-therapy) and at a late post-therapy visit (in the majority of cases, this was 2 to 4 weeks post-therapy), as seen in Table 7. Table 7: Bacteriologic efficacy rates for amoxicillin and clavulanate potassium Time Post Therapy 875 mg/125 mg every 12 hours % (n) 500 mg/125 mg every 8 hours % (n) 2 to 4 days 81% (58) 80% (54) 5 to 9 days 58% (41) 52% (52) 2 to 4 weeks 52% (101) 55% (104) As noted before, though there was no significant difference in the percentage of adverse events in each group, there was a statistically significant difference in rates of severe diarrhea or withdrawals with diarrhea between the regimens Acute Bacterial Otitis Media and Diarrhea in Pediatric Patients One US/Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of amoxicillin and clavulanate potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxicillin and clavulanate potassium for 10 days in the treatment of acute otitis media. Only the suspension formulations were used in this trial. A total of 575 pediatric patients (aged 2 months to 12 years) were enrolled, with an even distribution among the 2 treatment groups and a comparable number of patients were evaluable (i.e., 84%) per treatment group. Otitis mediaspecific criteria were required for eligibility and a strong correlation was found at the end of therapy and follow-up between these criteria and physician assessment of clinical response. The clinical efficacy rates at the end of therapy visit (defined as 2 to 4 days after the completion of therapy) and at the follow-up visit (defined as 22 to 28 days post-completion of therapy) were comparable for the 2 treatment groups, with the following cure rates obtained for the evaluable patients: At end of therapy, 87% (n = 265) and 82% (n = 260) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. At follow-up, 67% (n = 249) and 69% (n = 243) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. Diarrhea was defined as either: (a) 3 or more watery or 4 or more loose/watery stools in 1 day; OR (b) 2 watery stools per day or 3 loose/watery stools per day for 2 consecutive days. The incidence of diarrhea was significantly lower in patients who received the every 12 hours regimen compared to patients who received the every 8 hours regimen (14% and 34%, respectively). In addition, the number of patients with either severe diarrhea or who were withdrawn with diarrhea was significantly lower in the every 12 hours treatment group (3% and 8% for the every 12 hours/10 day and every 8 hours/10 day, respectively). In the every 12 hours treatment group, 3 patients (1%) were withdrawn with an allergic reaction, while 1 patient in the every 8 hours group was withdrawn for this reason. The number of patients with a candidal infection of the diaper area was 4% and 6% for the every 12 hours and every 8 hours groups, respectively. 15 REFERENCES 1 Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol. 1988; 30: Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard 8 th ed. CLSI Document M7-A9. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA, 19087, Clinical and Laboratory Standards Institute (CLSI). Performance Standard for Antimicrobial Disk Susceptibility Tests; Approved Standard 11th ed. CLSI Document M2-A11. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA, 19087, CLSI. Performance Standards for Antimicrobial Susceptibility Testing: 22nd Informational Supplement. CLSI Document M100-S22. CLSI, Wayne, PA, HOW SUPPLIED/STORAGE AND HANDLING Oral Suspension Amoxicillin and clavulanate potassium for oral suspension, USP 400 mg/57 mg per 5 ml (each 5 ml of reconstituted caramel-orange-raspberry-flavored suspension contains 400 mg amoxicillin and 57 mg clavulanic acid as the potassium salt) are supplied as under: NDC ml bottle NDC ml bottle Store at 20 to 25 C (68 to 77 F) [See USP Controlled Room Temperature]. Dispense in tightly closed, moisture-proof containers. Store reconstituted suspension under refrigeration. Discard unused suspension after 10 days. Keep out of the reach of children. 17 PATIENT COUNSELING INFORMATION 17.1 Information for Patients Patients should be informed that amoxicillin and clavulanate potassium may be taken every 8 hours or every 12 hours, depending on the dose prescribed. Each dose should be taken with a meal or snack to reduce the possibility of gastrointestinal upset. Patients should be counseled that antibacterial drugs, including amoxicillin and clavulanate potassium, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When amoxicillin and clavulanate potassium is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by amoxicillin and clavulanate potassium or other antibacterial drugs in the future. Counsel patients that diarrhea is a common problem caused by antibacterials, and it usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken their last dose of the antibacterial. If diarrhea is severe or lasts more than 2 or 3 days, patients should contact their physician. Patients should be advised to keep suspension refrigerated. Shake well before using. When dosing a child with the suspension (liquid) of amoxicillin and clavulanate potassium, use a dosing spoon or medicine dropper. Be sure to rinse the spoon or dropper after each use. Bottles of suspension of amoxicillin and clavulanate potassium may contain more liquid than required. Follow your doctor s instructions about the amount to use and the days of treatment your child requires. Discard any unused medicine. Patients should be aware that amoxicillin and clavulanate potassium contains a penicillin class drug product that can cause allergic reactions in some individuals. CLINITEST is a registered trademark of Miles, Inc. Manufactured in Slovenia by Lek Pharmaceuticals d.d. for Mylan Pharmaceuticals Inc., Morgantown, WV U.S.A. Revised: December 2015 LEK:AMXCLOS:R

14 Rx only Amoxicillin and Clavulanate Potassium for Oral Suspension, USP *600 mg/42.9 mg LEK:AMCLOS:R1 Rx only Amoxicillin and Clavulanate Potassium for Oral Suspension, USP *600 mg/42.9 mg LEK:AMCLOS:R1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use amoxicillin and clavulanate potassium for oral suspension, USP safely and effectively. See full prescribing information for amoxicillin and clavulanate potassium for oral suspension, USP. AMOXICILLIN and CLAVULANATE potassium for oral suspension, USP Initial U.S. Approval: 1984 To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium for oral suspension, USP and other antibacterial drugs, amoxicillin and clavulanate potassium for oral suspension, USP should be used only to treat infections that are proven or strongly suspected to be caused by bacteria. (1) INDICATIONS AND USAGE Amoxicillin and clavulanate potassium for oral suspension, USP is indicated for the treatment of pediatric patients with recurrent or persistent acute otitis media due to S. pneumoniae (penicillin MICs 2 mcg/ml), H. influenzae (including beta-lactamase-producing strains), or M. catarrhalis (including beta-lactamase-producing strains) characterized by the following risk factors. (1) antibacterial drug exposure for acute otitis media within the preceding 3 months, and either of the following: 1) age 2 years or younger 2) daycare attendance DOSAGE AND ADMINISTRATION Pediatric Patients less than 40 kg: 90 mg/kg/day divided every 12 hours, administered for 10 days. (2) DOSAGE FORMS AND STRENGTHS mg/42.9 mg per 5 ml. (3) CONTRAINDICATIONS History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin and clavulanate potassium or to other beta-lactams (e.g., penicillins or cephalosporins). (4.1) History of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium. (4.2) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Serious Hypersensitivity Reactions 4.2 Cholestatic Jaundice/Hepatic Dysfunction 5 WARNINGS AND PRECAUTIONS 5.1 Serious Allergic Reactions, Including Anaphylaxis 5.2 Hepatic Dysfunction 5.3 Clostridium difficile-associated Diarrhea 5.4 Skin Rash in Patients with Mononucleosis 5.5 Potential for Microbial Overgrowth 5.7 Development of Drug-Resistant Bacteria 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Probenecid 7.2 Oral Anticoagulants 7.3 Allopurinol FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium for oral suspension, USP and other antibacterial drugs, amoxicillin and clavulanate potassium for oral suspension, USP should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Amoxicillin and clavulanate potassium for oral suspension, USP is indicated for the treatment of pediatric patients with recurrent or persistent acute otitis media due to S. pneumoniae (penicillin MICs 2 mcg/ml), H. influenzae (including beta-lactamase-producing strains), or M. catarrhalis (including beta-lactamase-producing strains) characterized by the following risk factors: antibacterial drug exposure for acute otitis media within the preceding 3 months, and either of the following: age 2 years or younger daycare attendance [see CLINICAL PHARMACOLOGY, Microbiology (12.4)] NOTE: Acute otitis media due to S. pneumoniae alone can be treated with amoxicillin. Amoxicillin and clavulanate potassium for oral suspension, USP is not indicated for the treatment of acute otitis media due to S. pneumoniae with penicillin MIC 4 mcg/ml. Therapy may be instituted prior to obtaining the results from bacteriological studies when there is reason to believe the infection may involve both S. pneumoniae (penicillin MIC 2 mcg/ml) and the beta-lactamase-producing organisms listed above. 2 DOSAGE AND ADMINISTRATION Amoxicillin and clavulanate potassium for oral suspension, USP does not contain the same amount of clavulanic acid (as the potassium salt) as any of the other suspensions of amoxicillin and clavulanate potassium. Amoxicillin and clavulanate potassium for oral suspension, USP contains 42.9 mg of clavulanic acid per 5 ml, whereas the 200 mg/5 ml suspension of amoxicillin and clavulanate potassium contains 28.5 mg of clavulanic acid per 5 ml and the 400 mg/5 ml suspension contains 57 mg of clavulanic acid per 5 ml. Therefore, the 200 mg/28.5 mg/5 ml and 400 mg/57 mg/5 ml suspensions of amoxicillin and clavulanate potassium should not be substituted for amoxicillin and clavulanate potassium for oral suspension, USP as they are not interchangeable. Dosage Pediatric patients 3 months and older Based on the amoxicillin component (600 mg/5 ml), the recommended dose of amoxicillin and clavulanate potassium for oral suspension, USP is 90 mg/kg/day divided every 12 hours, administered for 10 days (see chart below). This dose provides 6.4 mg/kg/day of the clavulanic acid component. Volume of amoxicillin and clavulanate potassium for oral Body Weight (kg) suspension, USP providing 90 mg/kg/day 8 3 ml twice daily ml twice daily 16 6 ml twice daily ml twice daily 24 9 ml twice daily ml twice daily ml twice daily ml twice daily WARNINGS AND PRECAUTIONS Serious (including fatal) hypersensitivity reactions: Discontinue amoxicillin and clavulanate potassium if a reaction occurs. (5.1) Hepatic dysfunction and cholestatic jaundice: Discontinue if signs/symptoms of hepatitis occur. Monitor liver function tests in patients with hepatic impairment. (5.2) Clostridium difficile-associated diarrhea (CDAD): Evaluate patients if diarrhea occurs. (5.3) Patients with mononucleosis who receive amoxicillin and clavulanate potassium develop skin rash. Avoid amoxicillin and clavulanate potassium use in these patients. (5.4) ADVERSE REACTIONS The most frequently reported adverse reactions were diaper rash (4%), diarrhea (3%), vomiting (2%), candidiasis (1%), and rash (1%). (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at ( INFO-RX) or FDA at FDA-1088 or DRUG INTERACTIONS Co-administration with probenecid is not recommended. (7.1) Concomitant use of amoxicillin and clavulanate potassium with oral anticoagulants may increase the prolongation of prothrombin time. (7.2) Co-administration with allopurinol increases the risk of rash. (7.3) Amoxicillin and clavulanate potassium may reduce efficacy of oral contraceptives. (7.4) USE IN SPECIFIC POPULATIONS Pediatric 3 months to 12 years old: Modify dose according to weight. (2, 8.4) Adults and pediatric patients weighing more than 40 kg: The safety and effectiveness of amoxicillin and clavulanate potassium for oral suspension has not been established. (8) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. 7.4 Oral Contraception 7.5 Effects on Laboratory Tests 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the Full Prescribing Information are not listed. Rev. 08/2015 Pediatric patients weighing 40 kg and more Experience with amoxicillin and clavulanate potassium for oral suspension, USP in this group is not available. Adults Experience with amoxicillin and clavulanate potassium for oral suspension, USP in adults is not available and adults who have difficulty swallowing should not be given amoxicillin and clavulanate potassium for oral suspension, USP in place of the 500-mg or 875-mg tablet of amoxicillin and clavulanate potassium. Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals [see WARNINGS AND PRECAUTIONS (5)]. Directions for Mixing Oral Suspension Prepare a suspension at time of dispensing as follows: Tap bottle until all the powder flows freely. Add approximately 2/3 of the total amount of water for reconstitution (see table below) and shake vigorously to suspend powder. Add remainder of the water and again shake vigorously. Bottle Size Amoxicillin and Clavulanate Potassium for Oral Suspension Amount of Water Required for Reconstitution 75 ml 62 ml 125 ml 103 ml 200 ml 165 ml Each teaspoonful (5 ml) will contain 600 mg amoxicillin as the trihydrate and 42.9 mg of clavulanic acid as the potassium salt. NOTE: SHAKE ORAL SUSPENSION WELL BEFORE USING. Administration To minimize the potential for gastrointestinal intolerance, amoxicillin and clavulanate potassium for oral suspension, USP should be taken at the start of a meal. Absorption of clavulanate potassium may be enhanced when amoxicillin and clavulanate potassium for oral suspension, USP is administered at the start of a meal. 3 DOSAGE FORMS AND STRENGTHS Oral Suspension 600 mg/42.9 mg per 5 ml Caramel-orange-raspberry-flavored powder for oral suspension (each 5 ml of reconstituted suspension contains 600 mg amoxicillin and 42.9 mg of clavulanic acid as the potassium salt). 4 CONTRAINDICATIONS 4.1 Serious Hypersensitivity Reactions Amoxicillin and clavulanate potassium is contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin, clavulanate or to other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins). 4.2 Cholestatic Jaundice/Hepatic Dysfunction Amoxicillin and clavulanate potassium is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with treatment with amoxicillin/clavulanate potassium. 5 WARNINGS AND PRECAUTIONS 5.1 Serious Allergic Reactions, Including Anaphylaxis Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving amoxicillin and clavulanate potassium. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Before initiating therapy with amoxicillin and clavulanate potassium, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, discontinue amoxicillin and clavulanate potassium and institute appropriate therapy. 5.2 Hepatic Dysfunction Use amoxicillin and clavulanate potassium with caution in patients with evidence of hepatic dysfunction. Hepatic toxicity associated with the use of amoxicillin/clavulanate potassium is usually reversible. Deaths have been reported (fewer than one death reported per estimated four million prescriptions worldwide). These have generally been cases associated with serious underlying diseases or concomitant medications [see CONTRAINDICATIONS (4.2) and ADVERSE REACTIONS (6.2)]. 5.3 Clostridium difficile-associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin and clavulanate potassium, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.4 Skin Rash in Patients with Mononucleosis A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus, amoxicillin and clavulanate potassium should not be administered to patients with mononucleosis. 5.5 Potential for Microbial Overgrowth The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur (usually involving Pseudomonas spp. or Candida spp.), the drug should be discontinued and/or appropriate therapy instituted. 5.7 Development of Drug-Resistant Bacteria Prescribing amoxicillin and clavulanate potassium in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Two clinical trials evaluated the safety of a 10 day treatment course of amoxicillin and clavulanate potassium for oral suspension (90/6.4 mg/kg/day, divided every 12 hours), in pediatric patients with acute otitis media [see CLINICAL STUDIES (14)]. The first trial involved 521 pediatric patients (3 months to 50 months) and the second trial involved 450 pediatric patients (3 months to 12 years). In the intent-to-treat population of the first trial of 521 patients, the most frequently reported adverse events were vomiting (7%), fever (6%), contact dermatitis (i.e., diaper rash) (6%), upper respiratory tract infection (4%), and diarrhea (4%). Protocol-defined diarrhea (i.e., 3 or more watery stools in one day or 2 watery stools per day for 2 consecutive days as recorded on diary cards) occurred in 13% of patients. The primary objective of the second study was to compare the safety of amoxicillin and clavulanate potassium for oral suspension (90/6.4 mg/kg/day, divided every 12 hours) to amoxicillin and clavulanate potassium (45/6.4 mg/kg/day, divided every 12 hours) for ten days. There was no statistically significant difference between treatments in the proportion of patients with 1 or more adverse events. The most frequently reported adverse reactions for amoxicillin and clavulanate potassium for oral suspension and the comparator of amoxicillin and clavulanate potassium were coughing (12% versus 7%), vomiting (7% versus 8%), contact dermatitis (i.e., diaper rash, 6% versus 5%), fever (6% versus 4%), and upper respiratory infection (3% versus 9%), respectively. The frequencies of protocol-defined diarrhea with amoxicillin and clavulanate potassium for oral suspension (11%) and amoxicillin and clavulanate potassium (9%) were not statistically different. Two patients in the group treated with amoxicillin and clavulanate potassium for oral suspension and one patient in the group treated with amoxicillin and clavulanate potassium were withdrawn due to diarrhea. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following have been identified during postmarketing use of amoxicillin and clavulanate potassium products, including amoxicillin and clavulanate potassium for oral suspension. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to amoxicillin and clavulanate potassium. Gastrointestinal Nausea, indigestion, gastritis, stomatitis, glossitis, black hairy tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial drug treatment. Hypersensitivity Reactions Skin rashes, pruritus, urticaria, angioedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), erythema multiforme, Stevens- Johnson syndrome, acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and an occasional case of exfoliative dermatitis (including toxic epidermal necrolysis) have been reported [see WARNINGS AND PRECAUTIONS (5.1)]. Liver A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted in patients treated with ampicillinclass antibacterial drugs. Hepatic dysfunction, including hepatitis and cholestatic jaundice, increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been reported with amoxicillin and clavulanate potassium or amoxicillin and clavulanate potassium for oral suspension. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, is usually reversible. Deaths have been reported [see CONTRAINDICATIONS (4.2), WARNINGS AND PRECAUTIONS (5.2)]. Renal Interstitial nephritis, hematuria, and crystalluria have been reported [see OVERDOSAGE (10)]. Hemic and Lymphatic Systems Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. There have been reports of increased prothrombin time in patients receiving amoxicillin and clavulanate potassium and anticoagulant therapy concomitantly. Central Nervous System Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, headache, insomnia, and reversible hyperactivity have been reported. Miscellaneous Tooth discoloration (brown, yellow, or gray staining) has been reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases. 7 DRUG INTERACTIONS 7.1 Probenecid Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with amoxicillin and clavulanate potassium for oral suspension may result in increased and prolonged blood levels of amoxicillin. Co-administration of probenecid is not recommended. 7.2 Oral Anticoagulants Abnormal prolongation of prothrombin time (increased international normalized ratio [INRI]) has been reported in patients receiving amoxicillin and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation. 7.3 Allopurinol The concurrent administration of allopurinol and amoxicillin increases substantially the incidence of rashes in patients receiving both drugs as compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients. There are no data with amoxicillin and clavulanate potassium for oral suspension and allopurinol administered concurrently. 7.4 Oral Contraceptives Amoxicillin and clavulanate potassium for oral suspension may affect intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives. 7.5 Effects on Laboratory Test High urine concentrations of amoxicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST, Benedict s Solution, or Fehling s Solution. Since this effect may also occur with amoxicillin and clavulanate potassium for oral suspension, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. Following administration of amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies of amoxicillin and clavulanate potassium in pregnant women. Because animal reproduction studies are not always predictive of human response, use this drug during pregnancy only if clearly needed. Reproduction studies performed in pregnant rats and mice given amoxicillin and clavulanate potassium (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses up to 1200 mg/kg/day revealed no evidence of harm to the fetus due to amoxicillin and clavulanate potassium. The amoxicillin doses in rodents (based on body surface area and assuming a 20 kg child) were approximately 2 times (rats) or equal to (mice) the recommended clinical amoxicillin and clavulanate potassium for oral suspension dose of 90/6.4 mg/kg/day. For clavulanate, these dose multiples were approximately 15 times and 7.5 times the recommended daily dose of amoxicillin and clavulanate potassium for oral suspension. 8.2 Labor and Delivery Oral ampicillin-class antibacterial drugs are generally poorly absorbed during labor. Studies in guinea pigs have shown that intravenous administration of ampicillin decreased the uterine tone, frequency of contractions, height of contractions, and duration of contractions. However, it is not known whether the use of amoxicillin and clavulanate potassium in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary. In a single study in women with premature rupture of fetal membranes, it was reported that prophylactic treatment with amoxicillin and clavulanate potassium may be associated with an increased risk of necrotizing enterocolitis in neonates. 8.3 Nursing Mothers Ampicillin-class antibacterial drugs are excreted in human milk; therefore, caution should be exercised when amoxicillin and clavulanate potassium is administered to a nursing woman. 8.4 Pediatric Use Safety and efficacy of amoxicillin and clavulanate potassium for oral suspension in infants younger than 3 months have not been established. Safety and efficacy of amoxicillin and clavulanate potassium for oral suspension have been demonstrated for treatment of acute otitis media in infants and children 3 months to 12 years [see Description of CLINICAL STUDIES (14)]. The safety and effectiveness of amoxicillin and clavulanate potassium for oral suspension have been established for the treatment of pediatric patients (3 months to 12 years) with acute bacterial sinusitis. This use is supported by evidence from adequate and well-controlled studies of amoxicillin and clavulanate potassium extended-release tablets in adults with acute bacterial sinusitis, studies of amoxicillin and clavulanate potassium for oral suspension in pediatric patients with acute otitis media, and by similar pharmacokinetics of amoxicillin and clavulanate in pediatric patients taking amoxicillin and clavulanate potassium for oral suspension [see CLINICAL PHARMACOLOGY (12)] and adults taking amoxicillin and clavulanate potassium extended-release tablets. 10 OVERDOSAGE Following overdosage, patients have experienced primarily gastrointestinal symptoms including stomach and abdominal pain, vomiting, and diarrhea. Rash, hyperactivity, or drowsiness has also been observed in a small number of patients. In the case of overdosage, discontinue amoxicillin and clavulanate potassium for oral suspension, treat symptomatically, and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison control center suggested that overdosage of less than 250 mg/kg of amoxicillin is not associated with significant clinical symptoms and does not require gastric emptying. 4 Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin. Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin crystalluria. Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of both amoxicillin and clavulanate. Both amoxicillin and clavulanate are removed from the circulation by hemodialysis. 11 DESCRIPTION Amoxicillin and clavulanate potassium for oral suspension, USP is an oral antibacterial combination consisting of the semisynthetic antibacterial amoxicillin and the beta-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is C 16 H 19 N S 3H 2 O, and the molecular weight is Chemically, amoxicillin is (2S,5R,6R)-6- [(R)-(-)-2-Amino-2-(p-hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid trihydrate and may be represented structurally as:

15 Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a beta-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of beta-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid-mediated beta-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. The clavulanate potassium molecular formula is C 8 H 8 KNO 5 and the molecular weight is Chemically, clavulanate potassium is potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate and may be represented structurally as: O CH 2 OH O N COOK Inactive Ingredients Powder for Oral Suspension Caramel flavor, carboxymethyl cellulose sodium, citric acid, colloidal silicon dioxide, microcrystalline cellulose, orange flavor, raspberry flavor, saccharin sodium, silicon dioxide, sodium citrate, and xanthan gum. Each 5 ml of reconstituted Amoxicillin and Clavulanate Potassium for Oral Suspension 600 mg/42.9 mg per 5 ml contains 600 mg amoxicillin as the trihydrate and 42.9 mg clavulanic acid as the potassium salt (clavulanate potassium). The potassium content per 5 ml is 0.23 meq (equivalent to 9 mg). Color and appearance of the dry powder White to yellowish white crystalline powder. Color and appearance of the suspension Almost white to yellow, homogeneous suspension. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Amoxicillin and clavulanate potassium is an antibacterial drug [see Microbiology (12.4)] Pharmacokinetics The pharmacokinetics of amoxicillin and clavulanate were determined in a study of 19 pediatric patients, 8 months to 11 years, given amoxicillin and clavulanate potassium for oral suspension at an amoxicillin dose of 45 mg/kg q12h with a snack or meal. The mean plasma amoxicillin and clavulanate for oral suspension pharmacokinetic parameter values are listed in the following table. Table 1 Mean (± SD) Plasma Amoxicillin and Clavulanate Pharmacokinetic Parameter Values Following Administration of 45 mg/kg of Amoxicillin and Clavulanate Potassium for Oral Suspension Every 12 Hours to Pediatric Patients Parameter Amoxicillin Clavulanate C max (mcg/ml) 15.7 ± ± 0.9 T max (hour) 2 (1 4) 1.1 (1 4) AUC 0-T (mcg*hour/ml) 59.8 ± 20 4 ± 1.9 T ½ (hour) 1.4 ± ± 0.3 CL/F (L/hour/kg) 0.9 ± ± 1.1 *Arithmetic mean ± standard deviation, except T max values which are medians (ranges). The effect of food on the oral absorption of amoxicillin and clavulanate potassium for oral suspension has not been studied. Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of 10 ml of 250 mg/5 ml suspension of amoxicillin and clavulanate potassium. Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid. Neither component in amoxicillin and clavulanate potassium for oral suspension is highly proteinbound; clavulanic acid has been found to be approximately 25% bound to human serum and amoxicillin approximately 18% bound. Oral administration of a single dose of amoxicillin and clavulanate potassium for oral suspension at 45 mg/kg (based on the amoxicillin component) to pediatric patients, 9 months to 8 years, yielded the following pharmacokinetic data for amoxicillin in plasma and middle ear fluid (MEF): Table 2 Amoxicillin Concentrations in Plasma and Middle Ear Fluid Following Administration of 45 mg/kg of Amoxicillin and Clavulanate Potassium for Oral Suspension to Pediatric Patients 1 hour 2 hour 3 hour Timepoint Mean median range Mean median range Mean median range Dose administered immediately prior to eating. Amoxicillin concentration in plasma (mcg/ml) H Amoxicillin concentration in MEF (mcg/ml) (n = 5) (n = 4) (n = 7) (n = 5) (n = 5) (n = 5) Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like amoxicillin, is well distributed in body tissues Microbiology Mechanism of Action Amoxicillin binds to penicillin-binding proteins within the bacterial cell wall and inhibits bacterial cell wall synthesis. Clavulanic acid is a beta-lactam, structurally related to penicillin, that may inactivate certain beta-lactamase enzymes. Mechanism of Resistance Resistance to penicillins may be mediated by destruction of the beta-lactam ring by a beta-lactamase, altered affinity of penicillin for target, or decreased penetration of the antimicrobial drug to reach the target site. Amoxicillin alone is susceptible to degradation by beta-lactamases, and therefore its spectrum of activity does not include bacteria that produce these enzymes. Amoxicillin/clavulanic acid has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see INDICATIONS AND USAGE (1)]. Gram-positive bacteria Streptococcus pneumoniae (including isolates with penicillin MICs 2 mcg/ml) Gram-negative bacteria Haemophilus influenzae (including beta-lactamase-producing isolates) Moraxella catarrhalis (including beta-lactamase-producing isolates) The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoint for amoxicillin/clavulanic acid. However, the safety and efficacy of amoxicillin/clavulanic acid in treating infections due to these microorganisms have not been established in adequate and well-controlled trials. Gram-positive bacteria Staphylococcus aureus (including beta-lactamase-producing isolates) Streptococcus pyogenes Susceptibility Test Methods When available, the clinical microbiology laboratory should provide cumulative results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and communityacquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial. Dilution Technique Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standard test method1,2 (broth for S. pneumoniae and H. influenzae). The recommended dilution pattern utilizes a constant amoxicillin/clavulanate potassium ratio of 2 to 1 in all tubes with varying amounts of amoxicillin. MICs are expressed in terms of the amoxicillin concentration in the presence of clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid. The MIC values should be interpreted according to criteria provided in Table 3. Diffusion Technique Quantitative methods that require measurement of zone diameters also provides reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method2,3. This procedure uses paper disks impregnated with 30 mcg amoxicillin/clavulanate potassium (20 mcg amoxicillin plus 10 mcg clavulanate potassium) to test susceptibility of microorganisms to amoxicillin/clavulanate potassium. Disk diffusion zone sizes should be interpreted according to criteria provided in Table 3. Table 3 Susceptibility Test Result Interpretive Criteria for Amoxicillin/Clavulanate Potassium Minimum Inhibitory Concentration (mcg/ml) Disk Diffusion (Zone Diameter in mm) Pathogen S I R S I R Streptococcus pneumoniae (non-meningitis isolates) 2/1 4/2 8/4 Not Applicable (NA) Haemophilus influenzae 4/2 N/A 8/4 20 N/A 19 S = Susceptible, I = Intermediate, R = Resistant NOTE: Susceptibility of S. pneumoniae should be determined using a 1-mcg oxacillin disk. NOTE: For nonmeningitis isolates, a penicillin MIC of 0.06 mcg/ml (or oxacillin zone 20 mm) can predict susceptibility to amoxicillin/clavulanic acid 2. NOTE: Beta-lactamase-negative, ampicillin-resistant (BLNAR) H. influenzae isolates should be considered resistant to amoxicillin/clavulanic acid despite apparent in vitro susceptibility of some BLNAR isolates to these agents. A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the microorganism if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible antimicrobials, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high doses of antimicrobial can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. 1-3 Standard amoxicillin/clavulanate potassium powder should provide the following range of MIC noted in Table 4. For the disk diffusion technique using the 30 mcg amoxicillin/clavulanate potassium disk, the criteria in Table 4 should be achieved. Table 4 Acceptable Quality Control Ranges for Amoxicillin/Clavulanate Potassium Quality Control Organism Enterococcus faecalis ATCC * Escherichia coli ATCC Minimum Inhibitory Concentration (mcg/ml) Disk Diffusion (Zone Diameter in mm) 0.25/0.12 1/0.5 N/A 2/1 8/ Escherichia coli ATCC 35218, 4/2 16/ Haemophilus influenzae ATCC Staphylococcus aureus ATCC Staphylococcus aureus ATCC /1 16/ N/A / /0.25 N/A Streptococcus pneumonia 0.03/ /0.06 N/A ATCC *ATCC = American Type Culture Collection QC strain recommended when testing beta-lactam/beta-lactamase inhibitors2. This strain may lose its plasmid and develop susceptibility to beta-lactam antimicrobial agents after repeated transfers onto culture media. Minimize by removing new culture from storage at least monthly or whenever the strain begins to show decreased MICs to ampicillin, piperacillin, or ticarcillin2. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate carcinogenic potential. Amoxicillin and clavulanate potassium (4:1 ratio formulation of amoxicillin:clavulanate) was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and clavulanate potassium was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at concentrations that were also associated with decreased cell survival. Amoxicillin and clavulanate potassium was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. Amoxicillin and clavulanate potassium (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses of up to 1,200 mg/kg/day was found to have no effect on fertility and reproductive performance in rats. Based on body surface area (assuming a 20 kg child), this dose of amoxicillin is approximately 2 times the recommended clinical amoxicillin and clavulanate potassium for oral suspension dose of 90/6.4 mg/kg/day. For clavulanate, the dose multiple is approximately 15 times higher than the recommended clinical daily dose, also based on body surface area. 14 CLINICAL STUDIES Two clinical studies were conducted in pediatric patients with acute otitis media. A non-comparative, open-label study assessed the bacteriologic and clinical efficacy of amoxicillin and clavulanate potassium for oral suspension (90/6.4 mg/kg/day, divided every 12 hours) for 10 days in 521 pediatric patients (3 to 50 months) with acute otitis media. The primary objective was to assess bacteriological response in children with acute otitis media due to S. pneumoniae with amoxicillin/clavulanic acid MICs of 4 mcg/ml. The study sought the enrollment of patients with the following risk factors: Failure of antibacterial therapy for acute otitis media in the previous 3 months, history of recurrent episodes of acute otitis media, 2 years or younger, or daycare attendance. Prior to receiving amoxicillin and clavulanate potassium for oral suspension, all patients had tympanocentesis to obtain middle ear fluid for bacteriological evaluation. Patients from whom S. pneumoniae (alone or in combination with other bacteria) was isolated had a second tympanocentesis 4 to 6 days after the start of therapy. Clinical assessments were planned for all patients during treatment (4 to 6 days after starting therapy), as well as 2 to 4 days post-treatment and 15 to 18 days post-treatment. Bacteriological success was defined as the absence of the pretreatment pathogen from the on-therapy tympanocentesis specimen. Clinical success was defined as improvement or resolution of signs and symptoms. Clinical failure was defined as lack of improvement or worsening of signs and/or symptoms at any time following at least 72 hours of amoxicillin and clavulanate potassium for oral suspension; patients who received an additional systemic antibacterial drug for otitis media after 3 days of therapy were considered clinical failures. Bacteriological eradication on therapy (day 4 to 6 visit) in the per protocol population is summarized in the following table: Table 5 Bacteriologic Eradication Rates in the Per Protocol Population Bacteriologic Eradication on Therapy Pathogen n/n % 95% CI All S. pneumoniae 121/ (94.3, 99.8) S. pneumoniae with penicillin MIC = 2 mcg/ml 19/ (82.4, 100) S. pneumoniae with penicillin MIC = 4 mcg/ml 12/14 86 (57.2, 98.2) H. influenzae 75/81 93 (84.6, 97.2) M. catarrhalis 11/ (71.5, 100) CI = confidence intervals; 95% CIs are not adjusted for multiple comparisons. Clinical assessments were made in the per protocol population 2 to 4 days post-therapy and 15 to 18 days post-therapy. Patients who responded to therapy 2 to 4 days post-therapy were followed for 15 to 18 days post-therapy to assess them for acute otitis media. Nonresponders at 2 to 4 days post-therapy were considered failures at the latter timepoint. Table 6 Clinical Assessments in the Per Protocol Population (Includes S. pneumoniae Patients With Penicillin MICs = 2 mcg/ml or 4 mcg/ml*) 2 to 4 Days Post-Therapy (Primary Endpoint) Clinical Response Pathogen n/n % 95% CI All S. pneumoniae 122/ (82.6, 93.7) S. pneumoniae with penicillin MIC = 2 mcg/ml 17/20 85 (62.1, 96.8) S. pneumoniae with penicillin MIC = 4 mcg/ml 11/14 79 (49.2, 95.3) H. influenzae 141/ (80.9, 91.8) M. catarrhalis 22/26 85 (65.1, 95.6) 15 to 18 Days Post-Therapy (Secondary Endpoint) Clinical Response Pathogen n/n % 95% CI* All S. pneumoniae 95/ (61.4, 77.4) S. pneumoniae with penicillin MIC = 2 mcg/ml 11/20 55 (31.5, 76.9) S. pneumoniae with penicillin MIC = 4 mcg/ml 5/14 36 (12.8, 64.9) H. influenzae 106/ (60, 75.2) M. catarrhalis 14/25 56 (34.9, 75.6) * S. pneumoniae strains with penicillin MICs of 2 mcg/ml or 4 mcg/ml are considered resistant to penicillin. CI = confidence intervals; 95% CIs are not adjusted for multiple comparisons. Clinical assessments at 15 to 18 days post-therapy may have been confounded by viral infections and new episodes of acute otitis media with time elapsed post-treatment. In the intent-to-treat analysis, overall clinical outcomes at 2 to 4 days and 15 to 18 days post treatment in patients with S. pneumoniae with penicillin MIC = 2 mcg/ml and 4 mcg/ml were 29/41 (71%) and 17/41 (42%), respectively. 15 REFERENCES 1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fourth Informational Supplement, CLSI document M100-S24, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard Eleventh Edition. CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol. 1988;30: HOW SUPPLIED/STORAGE AND HANDLING How Supplied Amoxicillin and Clavulanate Potassium for Oral Suspension, USP Each 5 ml of reconstituted suspension contains 600 mg amoxicillin and 42.9 mg clavulanic acid as the potassium salt. NDC , 75 ml bottle NDC , 125 ml bottle NDC , 200 ml bottle Storage Store reconstituted suspension under refrigeration. Discard unused suspension after 10 days. Store dry powder for oral suspension at 20 to 25 C (68 to 77 F) [see USP Controlled Room Temperature]. Dispense in original container. 17 PATIENT COUNSELING INFORMATION Take amoxicillin and clavulanate potassium for oral suspension every 12 hours with a meal or snack to reduce the possibility of gastrointestinal upset. If diarrhea develops and is severe or lasts more than 2 or 3 days, call your doctor. Counsel patients that antibacterial drugs, including amoxicillin and clavulanate potassium for oral suspension should only be used to treat bacterial infections. Antibacterial drugs do not treat viral infections (e.g., the common cold). When amoxicillin and clavulanate potassium for oral suspension is prescribed to treat a bacterial infection, tell patients that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by amoxicillin and clavulanate potassium for oral suspension or other antibacterial drugs in the future. Counsel patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patient can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible. Keep suspension refrigerated. Shake well before using. When dosing a child with the suspension (liquid) of amoxicillin and clavulanate potassium for oral suspension, use a dosing spoon or medicine dropper. Be sure to rinse the spoon or dropper after each use. Bottles of suspension of amoxicillin and clavulanate potassium for oral suspension may contain more liquid than required. Follow your doctor s instructions about the amount to use and the days of treatment your child requires. Discard any unused medicine. Counsel patients that amoxicillin and clavulanate potassium for oral suspension contains a penicillin class drug product that can cause allergic reactions in some individuals. The brands listed are the registered trademarks of their respective owners and are not trademarks of Mylan Pharmaceuticals Inc. Manufactured in Slovenia by Lek Pharmaceuticals d.d. for Mylan Pharmaceuticals Inc., Morgantown, WV U.S.A. Revised: August 2015 LEK:AMCLOS:R

16 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use armodafinil tablets safely and effectively. See full prescribing information for armodafinil tablets. ARMODAFINIL tablets, for oral use Initial U.S. Approval: INDICATIONS AND USAGE Armodafinil tablets are indicated to improve wakefulness in adult patients with excessive sleepiness associated with obstructive sleep apnea (OSA), narcolepsy, or shift work disorder (SWD). (1) Limitations of Use In OSA, armodafinil tablets are indicated to treat excessive sleepiness and not as treatment for the underlying obstruction DOSAGE AND ADMINISTRATION The recommended dosage of armodafinil for each indication is as follows: OSA or Narcolepsy: 150 mg to 250 mg once a day in the morning. (2.1) SWD: 150 mg once a day taken approximately one hour prior to start of the work shift. (2.2) Hepatic Impairment: reduced dose in patients with severe hepatic impairment. (2.3, 12.3) Geriatric Patients: consider lower dose. (2.4, 12.3) DOSAGE FORMS AND STRENGTHS Tablets: 50 mg, 150 mg, and 250 mg. (3) CONTRAINDICATIONS Armodafinil tablets are contraindicated in patients with known hypersensitivity to modafinil or armodafinil. (4) WARNINGS AND PRECAUTIONS Serious Rash, including Stevens-Johnson Syndrome: Discontinue armodafinil at the first sign of rash, unless the rash is clearly not drug-related. (5.1) Angioedema and Anaphylaxis Reactions: If suspected, discontinue armodafinil. (5.2) Multi-organ Hypersensitivity Reactions: If suspected, discontinue armodafinil. (5.3) Persistent Sleepiness: Assess patients frequently for degree of sleepiness and, if appropriate, advise patients to avoid driving or engaging in any other potentially dangerous activity. (5.4) Psychiatric Symptoms: Use particular caution in treating patients with a history of psychosis, depression, or mania. Consider discontinuing armodafinil if psychiatric symptoms develop. (5.5) Known Cardiovascular Disease: Consider increased monitoring. (5.7) ADVERSE REACTIONS Most common adverse reactions ( 5%): headache, nausea, dizziness, and insomnia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at ( INFO-RX) or FDA at FDA-1088 or DRUG INTERACTIONS Steroidal contraceptives (e.g., ethinyl estradiol): Use alternative or concomitant methods of contraception while taking armodafinil and for 1 month after discontinuation of armodafinil treatment. (7) Cyclosporine: Blood concentrations of cyclosporine may be reduced. (7) CYP2C19 substrates, such as omeprazole, phenytoin, and diazepam: Exposure of these medications may be increased. (7) USE IN SPECIFIC POPULATIONS Pregnancy: based on animal data, may cause fetal harm. (8.1) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. REVISED MAY 2015 MX:ARDFL:R5mmh/MX:MG:ARDFL:R4m/MX:MG:ARDFL:R4mh FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosage in Obstructive Sleep Apnea (OSA) and Narcolepsy 2.2 Dosage in Shift Work Disorder (SWD) 2.3 Dosage Modification in Patients with Severe Hepatic Impairment 2.4 Use in Geriatric Patients 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Serious Rash, including Stevens-Johnson Syndrome 5.2 Angioedema and Anaphylaxis Reactions 5.3 Multi-organ Hypersensitivity Reactions 5.4 Persistent Sleepiness 5.5 Psychiatric Symptoms 5.6 Effects on Ability to Drive and Use Machinery 5.7 Cardiovascular Events 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Obstructive Sleep Apnea (OSA) 14.2 Narcolepsy 14.3 Shift Work Disorder (SWD) 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1

17 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Armodafinil tablets are indicated to improve wakefulness in adult patients with excessive sleepiness associated with obstructive sleep apnea (OSA), narcolepsy, or shift work disorder (SWD). Limitations of Use In OSA, armodafinil tablets are indicated to treat excessive sleepiness and not as treatment for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating armodafinil tablets for excessive sleepiness. 2 DOSAGE AND ADMINISTRATION 2.1 Dosage in Obstructive Sleep Apnea (OSA) and Narcolepsy The recommended dosage of armodafinil tablets for patients with OSA or narcolepsy is 150 mg to 250 mg taken orally once a day as a single dose in the morning. In patients with OSA, doses up to 250 mg/day, given as a single dose, have been well tolerated, but there is no consistent evidence that these doses confer additional benefit beyond that of the 150 mg/day dose [see Clinical Pharmacology (12.3) and Clinical Studies (14.1, 14.2)]. 2.2 Dosage in Shift Work Disorder (SWD) The recommended dosage of armodafinil tablets for patients with SWD is 150 mg taken orally once a day as a single dose approximately 1 hour prior to the start of their work shift. 2.3 Dosage Modification in Patients with Severe Hepatic Impairment In patients with severe hepatic impairment, the dosage of armodafinil tablets should be reduced [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 2.4 Use in Geriatric Patients Consideration should be given to the use of lower doses and close monitoring in geriatric patients [see Use in Specific Populations (8.5)]. 3 DOSAGE FORMS AND STRENGTHS The 50 mg tablets are white to off-white round, unscored tablets debossed with M on one side of the tablet and A31 on the other side. The 150 mg tablets are white to off-white round, unscored tablets debossed with M on one side of the tablet and A32 on the other side. The 250 mg tablets are white to off-white capsule shaped, unscored tablets debossed with M on one side of the tablet and A33 on the other side. 4 CONTRAINDICATIONS Armodafinil tablets are contraindicated in patients with known hypersensitivity to modafinil or armodafinil or its inactive ingredients [see Warnings and Precautions (5.1, 5.2, 5.3)]. 5 WARNINGS AND PRECAUTIONS 5.1 Serious Rash, including Stevens-Johnson Syndrome Serious rash requiring hospitalization and discontinuation of treatment has been reported in association with the use of armodafinil or modafinil (the racemic mixture of S- and R-enantiomers). Armodafinil has not been studied in pediatric patients in any setting and is not approved for use in pediatric patients for any indication. In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age < 17 years); these rashes included one case of possible Stevens-Johnson Syndrome (SJS) and one case of apparent multi-organ hypersensitivity reaction. Several of the cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia). The median time to rash that resulted in discontinuation was 13 days. No such cases were observed among 380 pediatric patients who received placebo. Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults and children in worldwide post-marketing experience. The reporting rate of TEN and SJS associated with modafinil use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate. Estimates of the background incidence rate for these serious skin reactions in the general population range between one to two cases per million-person years. Cases of serious rash similar to those observed with modafinil including skin and mouth blistering have been reported in adults in post-marketing experience with armodafinil. There are no factors that are known to predict the risk of occurrence or the severity of rash associated with modafinil or armodafinil. Nearly all cases of serious rash associated with these drugs occurred within 1 to 5 weeks after treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 3 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash. Although benign rashes also occur with armodafinil, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, armodafinil should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring. 5.2 Angioedema and Anaphylaxis Reactions Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm), were observed with armodafinil. Patients should be advised to discontinue therapy and immediately report to their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness). 5.3 Multi-organ Hypersensitivity Reactions Multi-organ hypersensitivity reactions, including at least one fatality in post-marketing experience, have occurred in close temporal association (median time to detection 13 days: range 4 to 33) to the initiation of modafinil. A similar risk of multi-organ hypersensitivity reactions with armodafinil cannot be ruled out. 2 Although there have been a limited number of reports, multi-organ hypersensitivity reactions may result in hospitalization or be life-threatening. There are no factors that are known to predict the risk of occurrence or the severity of multi-organ hypersensitivity reactions. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included myocarditis, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multi-organ hypersensitivity is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If a multi-organ hypersensitivity reaction is suspected, armodafinil should be discontinued. Although there are no case reports to indicate cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. 5.4 Persistent Sleepiness Patients with abnormal levels of sleepiness who take armodafinil should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking armodafinil, should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Prescribers should also be aware that patients may not acknowledge sleepiness or drowsiness until directly questioned about drowsiness or sleepiness during specific activities. 5.5 Psychiatric Symptoms In pre-approval narcolepsy, OSA and SWD controlled trials of armodafinil, anxiety, agitation, nervousness, and irritability were reasons for treatment discontinuation more often in patients on armodafinil compared to placebo (armodafinil 1.2% and placebo 0.3%). Depression was also a reason for treatment discontinuation more often in patients on armodafinil compared to placebo (armodafinil 0.6% and placebo 0.2%). Cases of suicide ideation were observed in clinical trials. Caution should be exercised when armodafinil is given to patients with a history of psychosis, depression, or mania. If psychiatric symptoms develop in association with armodafinil administration, consider discontinuing armodafinil tablets. Psychiatric adverse reactions have been reported in patients treated with modafinil. Modafinil and armodafinil are very closely related. Therefore, the incidence and type of psychiatric symptoms associated with armodafinil are expected to be similar to the incidence and type of these events with modafinil. Post-marketing adverse reactions associated with the use of modafinil have included mania, delusions, hallucinations, suicidal ideation, and aggression, some resulting in hospitalization. Many, but not all, patients had a prior psychiatric history. One healthy male volunteer developed ideas of reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600 mg doses of modafinil and sleep deprivation. There was no evidence of psychosis 36 hours after drug discontinuation. 5.6 Effects on Ability to Drive and Use Machinery Although armodafinil has not been shown to produce functional impairment, any drug affecting the CNS may alter judgment, thinking or motor skills. Patients should be cautioned about operating an automobile or other hazardous machinery until it is reasonably certain that armodafinil therapy will not adversely affect their ability to engage in such activities. 5.7 Cardiovascular Events In clinical studies of modafinil, cardiovascular adverse reactions, including chest pain, palpitations, dyspnea and transient ischemic T-wave changes on ECG were observed in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. It is recommended that armodafinil tablets not be used in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants. Findings suggestive of mitral valve prolapse syndrome include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these findings occurs, consider cardiac evaluation. Blood pressure monitoring in short term ( 3 months) pre-approval controlled trials of OSA, SWD, and narcolepsy showed small average increases in mean systolic and diastolic blood pressure in patients receiving armodafinil as compared to placebo (1.2 mmhg to 4.3 mmhg in the various experimental groups). There was also a slightly greater proportion of patients on armodafinil requiring new or increased use of antihypertensive medications (2.9%) compared to patients on placebo (1.8%). There was a small, but consistent, average increase in pulse rate over placebo in pre-approval controlled trials. This increase varied from 0.9 BPM to 3.5 BPM. Increased monitoring of heart rate and blood pressure may be appropriate in patients on armodafinil. Caution should be exercised when prescribing armodafinil to patients with known cardiovascular disease. 6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Serious Rash, including Stevens-Johnson Syndrome [see Warnings and Precautions (5.1)] Angioedema and Anaphylaxis Reactions [see Warnings and Precautions (5.2)] Multi-organ Hypersensitivity Reactions [see Warnings and Precautions (5.3)] Persistent Sleepiness [see Warnings and Precautions (5.4)] Psychiatric Symptoms [see Warnings and Precautions (5.5)] Effects on Ability to Drive and Use Machinery [see Warnings and Precautions (5.6)] Cardiovascular Events [see Warnings and Precautions (5.7)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

18 Armodafinil has been evaluated for safety in over 1,100 patients with excessive sleepiness associated with OSA, SWD, and narcolepsy. Most Common Adverse Reactions: In the placebo-controlled clinical trials, the most common adverse reactions ( 5%) associated with the use of armodafinil more frequently than in placebo-treated patients were headache, nausea, dizziness, and insomnia. The adverse reaction profile was similar across the studies. Table 1 presents the adverse reactions that occurred at a rate of 1% or more and were more frequent in armodafinil-treated patients than in placebo-treated patients in the placebo-controlled clinical trials. Table 1. Adverse Reactions in Pooled Placebo-controlled Clinical Trials* in OSA, Narcolepsy, and SWD with Armodafinil (150 mg and 250 mg) Armodafinil Placebo (%) (%) N = 645 N = 445 Headache 17 9 Nausea 7 3 Dizziness 5 2 Insomnia 5 1 Anxiety 4 1 Diarrhea 4 2 Dry Mouth 4 1 Depression 2 0 Dyspepsia 2 0 Fatigue 2 1 Palpitations 2 1 Rash 2 0 Upper Abdominal Pain 2 1 Agitation 1 0 Anorexia 1 0 Constipation 1 0 Contact Dermatitis 1 0 Decreased Appetite 1 0 Depressed Mood 1 0 Disturbance In Attention 1 0 Dyspnea 1 0 Hyperhydrosis 1 0 Increased Gamma-Glutamyltransferase 1 0 Increased Heart Rate 1 0 Influenza-like Illness 1 0 Loose Stools 1 0 Migraine 1 0 Nervousness 1 0 Pain 1 0 Paresthesia 1 0 Polyuria 1 0 Pyrexia 1 0 Seasonal Allergy 1 0 Thirst 1 0 Tremor 1 0 Vomiting 1 0 * Adverse reactions that occurred in 1% of armodafinil-treated patients and greater incidence than that of placebo. Dose-dependent Adverse Reactions: In the placebo-controlled clinical trials which compared doses of 150 mg/day and 250 mg/day of armodafinil and placebo, the following adverse reactions were dose-related: headache, rash, depression, dry mouth, insomnia, and nausea. See Table 2 for additional information. Table 2. Dose-dependent Adverse Reactions in Pooled Placebo-controlled Clinical Trials in OSA, Narcolepsy and SWD Armodafinil Armodafinil Armodafinil 250 mg 150 mg Combined Placebo (%) (%) (%) (%) N = 198 N = 447 N = 645 N = 445 Headache Nausea Insomnia Dry Mouth < 1 Rash < 1 Depression < 1 Adverse Reactions Resulting in Discontinuation of Treatment: In placebo-controlled clinical trials, 44 of the 645 patients (7%) who received armodafinil discontinued due to an adverse reaction compared to 16 of the 445 (4%) of patients that received placebo. The most frequent reason for discontinuation was headache (1%). Laboratory Abnormalities: Clinical chemistry, hematology, and urinalysis parameters were 3 monitored in the studies. Mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of armodafinil, but not placebo. Few patients, however, had GGT or AP elevations outside of the normal range. No differences were apparent in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin, although there were rare cases of isolated elevations of AST and/or ALT. A single case of mild pancytopenia was observed after 35 days of treatment and resolved with drug discontinuation. A small mean decrease from baseline in serum uric acid compared to placebo was seen in clinical trials. The clinical significance of this finding is unknown. 7 DRUG INTERACTIONS Effects of Armodafinil on CYP3A4/5 Substrates: The clearance of drugs that are substrates for CYP3A4/5 (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be increased by armodafinil via induction of metabolic enzymes, which results in lower systemic exposure. Dosage adjustment of these drugs should be considered when these drugs are used concomitantly with armodafinil [see Clinical Pharmacology (12.3)]. The effectiveness of steroidal contraceptives may be reduced when used with armodafinil and for 1 month after discontinuation of therapy. Alternative or concomitant methods of contraception are recommended for patients taking steroidal contraceptives (e.g., ethinyl estradiol) when treated concomitantly with armodafinil and for 1 month after discontinuation of armodafinil treatment. Blood levels of cyclosporine may be reduced when used with armodafinil. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with armodafinil. Effects of Armodafinil on CYP2C19 Substrates: Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by armodafinil via inhibition of metabolic enzymes, with resultant higher systemic exposure. Dose reduction of these drugs may be required when these drugs are used concomitantly with armodafinil. Warfarin: More frequent monitoring of prothrombin times/inr should be considered whenever armodafinil is coadministered with warfarin [see Clinical Pharmacology (12.3)]. Monoamine Oxidase (MAO) Inhibitors: Caution should be used when concomitantly administering MAO inhibitors and armodafinil. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled studies of armodafinil in pregnant women. Intrauterine growth restriction and spontaneous abortion have been reported in association with armodafinil and modafinil. Although the pharmacology of armodafinil is not identical to that of the sympathomimetic amines, it does share some pharmacologic properties with this class. Certain of these drugs have been associated with intrauterine growth restriction and spontaneous abortions. Whether the cases reported with armodafinil are drug-related is unknown. In studies of armodafinil (R-modafinil) and modafinil (a mixture of R- and S-modafinil) conducted in rats (armodafinil, modafinil) and rabbits (modafinil), developmental toxicity was observed at clinically relevant plasma exposures. Armodafinil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral administration of armodafinil (60, 200, or 600 mg/kg/day) to pregnant rats throughout organogenesis resulted in increased incidences of fetal visceral and skeletal variations and decreased fetal body weight at the highest dose. The highest no-effect dose for embryofetal developmental toxicity in rat (200 mg/kg/day) was associated with a plasma armodafinil exposure (AUC) less than that in humans at the maximum recommended human dose (MRHD) of armodafinil (250 mg/day). Modafinil (50, 100, or 200 mg/kg/day) administered orally to pregnant rats throughout organogenesis caused, in the absence of maternal toxicity, an increase in resorptions and an increased incidence of visceral and skeletal variations in the offspring at the highest dose tested. The higher no-effect dose for embryofetal developmental toxicity in rat (100 mg/kg/day) was associated with a plasma armodafinil AUC less than that in humans at the MRHD of armodafinil. However, in a subsequent study of up to 480 mg/kg/day of modafinil, no adverse effects on embryofetal development were observed. Modafinil administered orally to pregnant rabbits throughout organogenesis at doses of up to 100 mg/kg/day had no effect on embryofetal development; however, the doses used were too low to adequately assess the effects of modafinil on embryofetal development. In a subsequent developmental toxicity study evaluating doses of 45, 90, and 180 mg/kg/day in pregnant rabbits, the incidences of fetal structural alterations and embryofetal death were increased at the highest dose. The highest no-effect dose for developmental toxicity (100 mg/kg/day) was associated with a plasma armodafinil AUC less than that in humans at the MRHD of armodafinil. Modafinil administration to rats throughout gestation and lactation at oral doses of up to 200 mg/kg/day resulted in decreased viability in the offspring at doses greater than 20 mg/kg/day, a dose resulting in a plasma armodafinil AUC less than that in humans at the MRHD of armodafinil. No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring. 8.3 Nursing Mothers It is not known whether armodafinil or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when armodafinil is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Serious rash has been seen in pediatric patients receiving modafinil [see Warnings and Precautions (5.1)].

19 8.5 Geriatric Use In elderly patients, elimination of armodafinil and its metabolites may be reduced as a consequence of aging. Therefore, consideration should be given to the use of lower doses and close monitoring in this population [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. 8.6 Hepatic Impairment The dosage of armodafinil should be reduced in patients with severe hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Armodafinil tablets contain armodafinil, a Schedule IV controlled substance. 9.2 Abuse Although the abuse potential of armodafinil has not been specifically studied, its abuse potential is likely to be similar to that of modafinil. In humans, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking and feelings typical of other CNS stimulants. In in vitro binding studies, modafinil binds to the dopamine reuptake site and causes an increase in extracellular dopamine, but no increase in dopamine release. Modafinil is reinforcing, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine. In some studies, modafinil was also partially discriminated as stimulant-like. Physicians should follow patients closely, especially those with a history of drug and/or stimulant (e.g., methylphenidate, amphetamine, or cocaine) abuse. Patients should be observed for signs of misuse or abuse (e.g., incrementation of doses or drug-seeking behavior). The abuse potential of modafinil (200 mg, 400 mg, and 800 mg) was assessed relative to methylphenidate (45 mg and 90 mg) in an inpatient study in individuals experienced with drugs of abuse. Results from this clinical study demonstrated that modafinil produced psychoactive and euphoric effects and feelings consistent with other scheduled CNS stimulants (methylphenidate). 10 OVERDOSAGE There were no overdoses reported in the armodafinil clinical studies. Symptoms of armodafinil overdose are likely to be similar to those of modafinil. Symptoms of overdose in modafinil clinical trials included excitation or agitation, insomnia, and slight or moderate elevations in hemodynamic parameters. From post-marketing experience with modafinil, there have been reports of fatal overdoses involving modafinil alone or in combination with other drugs. Symptoms most often accompanying modafinil overdose, alone or in combination with other drugs have included insomnia; central nervous system symptoms such as restlessness, disorientation, confusion, excitation and hallucination; digestive changes such as nausea and diarrhea; and cardiovascular changes such as tachycardia, bradycardia, hypertension and chest pain. No specific antidote exists for the toxic effects of an armodafinil overdose. Such overdoses should be managed with primarily supportive care, including cardiovascular monitoring. 11 DESCRIPTION Armodafinil is a wakefulness-promoting agent for oral administration. Armodafinil is the R- enantiomer of modafinil which is a 1:1 mixture of the R and S-enantiomers. The chemical name for armodafinil is R-(-)-2-[(Diphenylmethyl)sulfinyl]acetamide. The molecular formula is C 15 H 15 NO 2 S and the molecular weight is The chemical structure is: O S Armodafinil is a white to off-white powder that is sparingly soluble in methanol and acetone, very slightly soluble or insoluble in water and insoluble in cyclohexane. At least 90% of the armodafinil particles used in armodafinil have a diameter of less than 200 microns. Armodafinil tablets contain 50 mg, 150 mg, or 250 mg of armodafinil and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate and povidone. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism(s) through which armodafinil promotes wakefulness is unknown. Armodafinil (R-modafinil) has pharmacological properties similar to those of modafinil (a mixture of R- and S-modafinil), to the extent tested in animal and in vitro studies. The R- and S-enantiomers have similar pharmacological actions in animals. Armodafinil and modafinil have wake-promoting actions similar to sympathomimetic agents including amphetamine and methylphenidate, although their pharmacologic profile is not identical to that of the sympathomimetic amines. Modafinil-induced wakefulness can be attenuated by the α1-adrenergic receptor antagonist, prazosin; however, modafinil is inactive in other in vitro assay systems known to be responsive to α-adrenergic agonists such as the rat vas deferens preparation. Armodafinil is an indirect dopamine receptor agonist; both armodafinil and modafinil bind in vitro to the dopamine transporter and inhibit dopamine reuptake. For modafinil, this activity has been associated in vivo with increased extracellular dopamine levels in some brain regions of O NH 2 4 animals. In genetically engineered mice lacking the dopamine transporter (DAT), modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the wake-promoting effects of modafinil, unlike those of amphetamine, were not antagonized by the dopamine receptor antagonist haloperidol in rats. In addition, alpha-methyl-p-tyrosine, a dopamine synthesis inhibitor, blocks the action of amphetamine, but does not block locomotor activity induced by modafinil. In addition to its wake-promoting effects and ability to increase locomotor activity in animals, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of other CNS stimulants in humans. Modafinil has reinforcing properties, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine; modafinil was also partially discriminated as stimulant-like. Based on nonclinical studies, two major metabolites, acid and sulfone, of modafinil or armodafinil, do not appear to contribute to the CNS-activating properties of the parent compounds Pharmacokinetics Armodafinil exhibits linear time-independent kinetics following single and multiple oral dose administration. Increase in systemic exposure is proportional over the dose range of 50 mg to 400 mg. No time-dependent change in kinetics was observed through 12 weeks of dosing. Apparent steady state for armodafinil was reached within 7 days of dosing. At steady state, the systemic exposure for armodafinil is 1.8 times the exposure observed after a single dose. The concentration-time profiles of the R-enantiomer following administration of a single-dose of 50 mg armodafinil or 100 mg PROVIGIL (modafinil, a 1:1 mixture of R- and S-enantiomers) are nearly superimposable. However, the C max and AUC 0-, of armodafinil at steady-state were approximately 37% and 70% higher, respectively, following administration of 200 mg armodafinil than the corresponding values of modafinil following administration of 200 mg PROVIGIL due to the more rapid clearance of the S-enantiomer (elimination half-life approximately 4 hours) as compared to the R-enantiomer. Absorption: Armodafinil is readily absorbed after oral administration. The absolute oral bioavailability was not determined due to the aqueous insolubility of armodafinil, which precluded intravenous administration. Peak plasma concentrations are attained at approximately 2 hours in the fasted state. Food effect on the overall bioavailability of armodafinil is considered minimal; however, time to reach peak concentration (t max ) may be delayed by approximately 2 to 4 hours in the fed state. Since the delay in t max is also associated with elevated plasma concentrations later in time, food can potentially affect the onset and time course of pharmacologic action for armodafinil. Distribution: Armodafinil has an apparent volume of distribution of approximately 42 L. Data specific to armodafinil protein binding are not available. However, modafinil is moderately bound to plasma protein (approximately 60%), mainly to albumin. The potential for interactions of armodafinil with highly protein-bound drugs is considered to be minimal. Metabolism: In vitro and in vivo data show that armodafinil undergoes hydrolytic deamidation, S-oxidation, and aromatic ring hydroxylation, with subsequent glucuronide conjugation of the hydroxylated products. Amide hydrolysis is the single most prominent metabolic pathway, with sulfone formation by cytochrome P450 (CYP) 3A4/5 being next in importance. The other oxidative products are formed too slowly in vitro to enable identification of the enzyme(s) responsible. Only two metabolites reach appreciable concentrations in plasma (i.e., R-modafinil acid and modafinil sulfone). Data specific to armodafinil disposition are not available. However, modafinil is mainly eliminated via metabolism, predominantly in the liver, with less than 10% of the parent compound excreted in the urine. A total of 81% of the administered radioactivity was recovered in 11 days post-dose, predominantly in the urine (80% vs. 1% in the feces). Elimination: After oral administration of armodafinil, armodafinil exhibits an apparent monoexponential decline from the peak plasma concentration. The apparent terminal t ½ is approximately 15 hours. The oral clearance of armodafinil is approximately 33 ml/min. Specific Populations: Age: In a clinical study, systemic exposure of armodafinil was approximately 15% higher in elderly subjects ( 65 years of age, N = 24), corresponding to approximately 12% lower oral clearance (CL/F), as compared to young subjects (18 to 45 years of age, N = 25). Systemic exposure of armodafinil acid (metabolite) was approximately 61% and 73% greater for C max and AUC 0-τ, respectively, compared to young subjects. Systemic exposure of the sulfone metabolite was approximately 20% lower for elderly subjects compared with young subjects. A subgroup analysis of elderly subjects demonstrated elderly subjects 75 and 65 to 74 years of age had approximately 21% and 9% lower oral clearance, respectively, compared to young subjects. Systemic exposure was approximately 10% greater in subjects 65 to 74 years of age (N = 17) and 27% greater in subjects 75 years of age (N = 7), respectively, when compared to young subjects. The change is considered not likely to be clinically significant for elderly patients, however, because some elderly patients have greater exposure to armodafinil, consideration should be given to the use of lower doses. Gender: Population pharmacokinetic analysis suggests no gender effect on the pharmacokinetics of armodafinil. Race: The influence of race on the pharmacokinetics of armodafinil has not been studied. Hepatic Impairment: The pharmacokinetics and metabolism of modafinil were examined in patients with cirrhosis of the liver (six men and three women). Three patients had stage B or B+ cirrhosis and six patients had stage C or C+ cirrhosis (per the Child-Pugh score criteria). Clinically eight of nine patients were icteric and all had ascites. In these patients, the oral clearance of modafinil was decreased by about 60% and the steady state concentration was doubled compared to normal patients [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)]. Renal Impairment: In a single dose 200 mg modafinil study, severe chronic renal failure (creatinine clearance 20 ml/min) did not significantly influence the pharmacokinetics of modafinil, but exposure to modafinil acid (metabolite) was increased 9-fold.

20 Drug Interactions: In vitro data demonstrated that armodafinil weakly induces CYP1A2 and possibly CYP3A activities in a concentration-related manner and that CYP2C19 activity is reversibly inhibited by armodafinil. Other CYP activities did not appear to be affected by armodafinil. An in vitro study demonstrated that armodafinil is a substrate of P-glycoprotein. Potential Interactions with Drugs That Inhibit, Induce, or Are Metabolized by Cytochrome P450 Isoenzymes and Other Hepatic Enzymes: The existence of multiple pathways for armodafinil metabolism, as well as the fact that a non-cyp-related pathway is the most rapid in metabolizing armodafinil, suggest that there is a low probability of substantive effects on the overall pharmacokinetic profile of armodafinil due to CYP inhibition by concomitant medications. However, due to the partial involvement of CYP3A enzymes in the metabolic elimination of armodafinil, coadministration of potent inducers of CYP3A4/5 (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4/5 (e.g., ketoconazole, erythromycin) could alter the plasma concentrations of armodafinil. The Potential of Armodafinil Tablets to Alter the Metabolism of Other Drugs by Enzyme Induction or Inhibition: Drugs Metabolized by CYP3A4/5 In vitro data demonstrated that armodafinil is a weak inducer of CYP3A activity in a concentration-related manner. In a clinical study, concomitant administration of armodafinil 250 mg resulted in a reduction in systemic exposure to midazolam by 32% after a single oral dose (5 mg) and 17% after a single intravenous dose (2 mg). Therefore, the blood levels and effectiveness of drugs that are substrates for CYP3A enzymes (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be reduced after initiation of concomitant treatment with armodafinil [see Drug Interactions (7)]. In a separate clinical study, concomitant administration of armodafinil 250 mg with quetiapine (300 mg to 600 mg daily doses) resulted in a reduction in the mean systemic exposure of quetiapine by approximately 29%. No dose adjustment is required. Drugs Metabolized by CYP1A2 In vitro data demonstrated that armodafinil is a weak inducer of CYP1A2 in a concentrationrelated manner. However, in a clinical study using caffeine as a probe substrate, no significant effect on CYP1A2 activity was observed. Drugs Metabolized by CYP2C19 In vitro data demonstrated that armodafinil is a reversible inhibitor of CYP2C19 activity. In a clinical study, concomitant administration of armodafinil 400 mg resulted in a 40% increase in exposure to omeprazole after a single oral dose (40 mg), as a result of moderate inhibition of CYP2C19 activity [see Drug Interactions (7)]. Interactions with CNS Active Drugs Concomitant administration of armodafinil with quetiapine reduced the systemic exposure of quetiapine. Data specific to armodafinil drug-drug interaction potential with other CNS active drugs are not available. However, the following available drug-drug interaction information on modafinil should be applicable to armodafinil. Concomitant administration of modafinil with methylphenidate or dextroamphetamine produced no significant alterations on the pharmacokinetic profile of modafinil or either stimulant, even though the absorption of modafinil was delayed for approximately 1 hour. Concomitant modafinil or clomipramine did not alter the pharmacokinetic profile of either drug; however, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine was reported in a patient with narcolepsy during treatment with modafinil. Data specific to armodafinil or modafinil drug-drug interaction potential with monoamine oxidase (MAO) inhibitors are not available [see Drug Interactions (7)]. Interaction with P-Glycoprotein An in vitro study demonstrated that armodafinil is a substrate of P-glycoprotein. The impact of inhibition of P-glycoprotein is not known. Interactions with Other Drugs Data specific to armodafinil drug-drug interaction potential for additional other drugs are not available. However, the following available drug-drug interaction information on modafinil should be applicable to armodafinil. Warfarin: Concomitant administration of modafinil with warfarin did not produce significant changes in the pharmacokinetic profiles of R- and S-warfarin. However, since only a single dose of warfarin was tested in this study, an interaction cannot be ruled out [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: In a mouse carcinogenicity study, armodafinil (R-modafinil) was administered at oral doses of up to 300 mg/kg/day in males and 100 mg/kg/day in females for approximately 2 years, no tumorigenic effects were observed. In a rat carcinogenicity study modafinil (a mixture of R- and S-modafinil) was administered at oral doses of up to 60 mg/kg/day for 2 years; no tumorigenic effects were observed. At the highest doses studied in mouse and rat, the plasma armodafinil exposures (AUC) were less than that in humans at the MRHD of armodafinil (250 mg/day). Mutagenesis: Armodafinil was negative in an in vitro bacterial reverse mutation assay and in an in vitro chromosomal aberration assay in human lymphocytes. Modafinil was negative in a series of in vitro (i.e., bacterial reverse mutation, mouse lymphoma tk, chromosomal aberration in human lymphocytes, cell transformation in BALB/3T3 mouse embryo cells) or in vivo (mouse bone marrow micronucleus) assays. 5 Impairment of Fertility: A fertility and early embryonic development (to implantation) study was not conducted with armodafinil alone. Oral administration of modafinil (doses of up to 480 mg/kg/day) to male and female rats prior to and throughout mating, and continuing in females through day 7 of gestation produced an increase in the time to mate at the highest dose; no effects were observed on other fertility or reproductive parameters. The no-effect dose of 240 mg/kg/day was associated with a plasma armodafinil AUC less than that in humans at the MRHD of armodafinil. 14 CLINICAL STUDIES 14.1 Obstructive Sleep Apnea (OSA) The effectiveness of armodafinil in improving wakefulness in patients with excessive sleepiness associated with OSA was established in two 12-week, multi-center, placebo-controlled, parallel-group, double-blind clinical studies of outpatients who met the criteria for OSA. The criteria include either: 1) excessive sleepiness or insomnia, plus frequent episodes of impaired breathing during sleep, and associated features such as loud snoring, morning headaches or dry mouth upon awakening; or 2) excessive sleepiness or insomnia; and polysomnography demonstrating one of the following: more than five obstructive apneas, each greater than 10 seconds in duration, per hour of sleep; and one or more of the following: frequent arousals from sleep associated with the apneas, bradytachycardia, or arterial oxygen desaturation in association with the apneas. In addition, for entry into these studies, all patients were required to have excessive sleepiness as demonstrated by a score 10 on the Epworth Sleepiness Scale (ESS), despite treatment with continuous positive airway pressure (CPAP). Evidence that CPAP was effective in reducing episodes of apnea/hypopnea was required along with documentation of CPAP use. Patients were required to be compliant with CPAP, defined as CPAP use 4 hours/night on 70% of nights. CPAP use continued throughout the study. In both studies, the primary measures of effectiveness were 1) sleep latency, as assessed by the Maintenance of Wakefulness Test (MWT) and 2) the change in the patient s overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at the final visit. For a successful trial both measures had to show statistically significant improvement. The MWT measures latency (in minutes) to sleep onset. An extended MWT was performed with test sessions at 2-hour intervals between 9AM and 7PM. The primary analysis was the average of the sleep latencies from the first four test sessions (9AM to 3PM). For each test session, the subject was asked to attempt to remain awake without using extraordinary measures. Each test session was terminated after 30 minutes if no sleep occurred or immediately after sleep onset. The CGI-C is a 7-point scale, centered at No Change, and ranging from Very Much Worse to Very Much Improved. Evaluators were not given any specific guidance about the criteria they were to apply when rating patients. In the first study, a total of 395 patients with OSA were randomized to receive armodafinil 150 mg/day, armodafinil 250 mg/day or matching placebo. Patients treated with armodafinil showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT at final visit. A statistically significant greater number of patients treated with armodafinil showed improvement in overall clinical condition as rated by the CGI-C scale at final visit. The average sleep latencies (in minutes) in the MWT at baseline for the trials are shown in Table 3 below, along with the average change from baseline on the MWT at final visit. The percentages of patients who showed any degree of improvement on the CGI-C in the clinical trials are shown in Table 4 below. The two doses of armodafinil produced statistically significant effects of similar magnitudes on the MWT, and also on the CGI-C. In the second study, 263 patients with OSA were randomized to either armodafinil 150 mg/day or placebo. Patients treated with armodafinil showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT (Table 3). A statistically significant greater number of patients treated with armodafinil showed improvement in overall clinical condition as rated by the CGI-C scale (Table 4). Nighttime sleep measured with polysomnography was not affected by the use of armodafinil in either study Narcolepsy The effectiveness of armodafinil in improving wakefulness in patients with excessive sleepiness associated with narcolepsy was established in one 12-week, multi-center, placebo-controlled, parallel-group, double-blind study of outpatients who met the criteria for narcolepsy. A total of 196 patients were randomized to receive armodafinil 150 or 250 mg/day, or matching placebo. The criteria for narcolepsy include either: 1) recurrent daytime naps or lapses into sleep that occur almost daily for at least 3 months, plus sudden bilateral loss of postural muscle tone in association with intense emotion (cataplexy); or 2) a complaint of excessive sleepiness or sudden muscle weakness with associated features: sleep paralysis, hypnagogic hallucinations, automatic behaviors, disrupted major sleep episode; and polysomnography demonstrating one of the following: sleep latency less than 10 minutes or rapid eye movement (REM) sleep latency less than 20 minutes and a Multiple Sleep Latency Test (MSLT) that demonstrates a mean sleep latency of less than 5 minutes and two or more sleep onset REM periods and no medical or mental disorder accounts for the symptoms. For entry into these studies, all patients were required to have objectively documented excessive daytime sleepiness, via MSLT with a sleep latency of 6 minutes or less and the absence of any other clinically significant active medical or psychiatric disorder. The MSLT, an objective polysomnographic assessment of the patient s ability to fall asleep in an unstimulating environment, measured latency (in minutes) to sleep onset averaged over four test sessions at 2-hour intervals. For each test session, the subject was told to lie quietly and attempt to sleep. Each test session was terminated after 20 minutes if no sleep occurred or immediately after sleep onset. The primary measures of effectiveness were: 1) sleep latency as assessed by the Maintenance of Wakefulness Test (MWT); and 2) the change in the patient s overall disease status, as measured by the CGI-C at the final visit [see Clinical Studies (14.1) for a description of these

21 measures]. Each MWT test session was terminated after 20 minutes if no sleep occurred or immediately after sleep onset in this study. Patients treated with armodafinil showed a statistically significantly enhanced ability to remain awake on the MWT at each dose compared to placebo at final visit [Table 3]. A statistically significant greater number of patients treated with armodafinil at each dose showed improvement in overall clinical condition as rated by the CGI-C scale at final visit [Table 4]. The two doses of armodafinil produced statistically significant effects of similar magnitudes on the CGI-C. Although a statistically significant effect on the MWT was observed for each dose, the magnitude of effect was observed to be greater for the higher dose. Nighttime sleep measured with polysomnography was not affected by the use of armodafinil Shift Work Disorder (SWD) The effectiveness of armodafinil in improving wakefulness in patients with excessive sleepiness associated with SWD was demonstrated in a 12-week, multi-center, double-blind, placebocontrolled, parallel-group clinical trial. A total of 254 patients with chronic SWD were randomized to receive armodafinil 150 mg/day or placebo. All patients met the criteria for chronic SWD. The criteria include: 1) either, a) a primary complaint of excessive sleepiness or insomnia which is temporally associated with a work period (usually night work) that occurs during the habitual sleep phase, or b) polysomnography and the MSLT demonstrate loss of a normal sleep-wake pattern (i.e., disturbed chronobiological rhythmicity); and 2) no other medical or mental disorder accounts for the symptoms; and 3) the symptoms do not meet criteria for any other sleep disorder producing insomnia or excessive sleepiness (e.g., time zone change [jet lag] syndrome). It should be noted that not all patients with a complaint of sleepiness who are also engaged in shift work meet the criteria for the diagnosis of SWD. In the clinical trial, only patients who were symptomatic for at least 3 months were enrolled. Enrolled patients were also required to work a minimum of five night shifts per month, have excessive sleepiness at the time of their night shifts (MSLT score 6 minutes), and have daytime insomnia documented by a daytime polysomnogram. The primary measures of effectiveness were: 1) sleep latency, as assessed by the Multiple Sleep Latency Test (MSLT) performed during a simulated night shift at the final visit; and 2) the change in the patient s overall disease status, as measured by the CGI-C at the final visit [see Clinical Studies (14.1) for a description of these measures]. Patients treated with armodafinil showed a statistically significant prolongation in the time to sleep onset compared to placebo-treated patients, as measured by the nighttime MSLT at final visit (Table 3). A statistically significant greater number of patients treated with armodafinil showed improvement in overall clinical condition as rated by the CGI-C scale at final visit (Table 4). Daytime sleep measured with polysomnography was not affected by the use of armodafinil. Table 3. Average Baseline Sleep Latency and Change from Baseline at Final Visit (MWT and MSLT in minutes) Disorder Measure Armodafinil Armodafinil Placebo 150 mg* 250 mg* Change Change Change from from from Baseline Baseline Baseline Baseline Baseline Baseline OSA I MWT OSA II MWT Narcolepsy MWT SWD MSLT * Significantly different than placebo for all trials (p < 0.05) Table 4. Clinical Global Impression of Change (CGI-C) (Percent of Patients Who Improved at Final Visit) Disorder Armodafinil Armodafinil Placebo 150 mg* 250 mg* OSA I 71% 74% 37% OSA II 71% - 53% Narcolepsy 69% 73% 33% SWD 79% - 59% * Significantly different than placebo for all trials (p < 0.05) 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Armodafinil Tablets are available containing 50 mg, 150 mg or 250 mg of armodafinil. The 50 mg tablets are white to off-white round, unscored tablets debossed with M on one side of the tablet and A31 on the other side. They are available as follows: NDC bottles of 30 tablets NDC bottles of 60 tablets NDC bottles of 500 tablets The 150 mg tablets are white to off-white round, unscored tablets debossed with M on one side of the tablet and A32 on the other side. They are available as follows: NDC bottles of 30 tablets NDC bottles of 60 tablets NDC bottles of 500 tablets The 250 mg tablets are white to off-white capsule shaped, unscored tablets debossed with M on one side of the tablet and A33 on the other side. They are available as follows: NDC bottles of 30 tablets NDC bottles of 60 tablets NDC bottles of 500 tablets 16.2 Storage Store at 20 to 25 C (68 to 77 F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Dispense a Medication Guide with each prescription. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Wakefulness: Armodafinil tablets are indicated for patients who have abnormal levels of sleepiness. Armodafinil tablets have been shown to improve, but not eliminate, this abnormal tendency to fall asleep. Therefore, patients should not alter their previous behavior with regard to potentially dangerous activities (e.g., driving, operating machinery) or other activities requiring appropriate levels of wakefulness, until and unless treatment with armodafinil tablets has been shown to produce levels of wakefulness that permit such activities. Advise patients that armodafinil tablets are not a replacement for sleep. Continuing Previously Prescribed Treatments: Inform patients that it may be critical that they continue to take their previously prescribed treatments (e.g., patients with OSA receiving CPAP should continue to do so). Discontinuing Drug Due to Adverse Reactions: Advise patients to stop taking armodafinil tablets and contact their physician right away if they experience rash, depression, anxiety, or signs of psychosis or mania. Pregnancy: Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy. Caution patients regarding the potential increased risk of pregnancy when using steroidal contraceptives (including depot or implantable contraceptives) with armodafinil tablets and for 1 month after discontinuation of therapy. Nursing: Advise patients to notify their physician if they are breastfeeding an infant. Concomitant Medication: Advise patients to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, because of the potential for interactions between armodafinil tablets and other drugs. Alcohol: Advise patients that the use of armodafinil tablets in combination with alcohol has not been studied. Advise patients that it is prudent to avoid alcohol while taking armodafinil tablets. Allergic Reactions: Advise patients to stop taking armodafinil tablets and to notify their physician right away if they develop a rash, hives, mouth sores, blisters, peeling skin, trouble swallowing or breathing or a related allergic phenomenon. MEDICATION GUIDE ARMODAFINIL TABLETS (ar moe daf' i nil) 50 mg, 150 mg and 250 mg Read the Medication Guide that comes with armodafinil tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your condition or treatment. What is the most important information I should know about armodafinil tablets? Armodafinil tablets may cause serious side effects including a serious rash or a serious allergic reaction that may affect parts of your body such as your liver or blood cells. Any of these may need to be treated in a hospital and may be life-threatening. Stop taking armodafinil tablets and call your doctor right away or get emergency help if you have any of these symptoms: skin rash, hives, sores in your mouth, or your skin blisters and peels swelling of your face, eyes, lips, tongue, or throat trouble swallowing or breathing fever, shortness of breath, swelling of the legs, yellowing of the skin or whites of the eyes, or dark urine. If you have a severe rash with armodafinil tablets, stopping the medicine 6

22 may not keep the rash from becoming life-threatening or causing you to be permanently disabled or disfigured. Armodafinil tablets are not approved for use in children for any medical condition. It is not known if armodafinil tablets are safe or if it works in children under the age of 17. What are armodafinil tablets? Armodafinil tablets are a prescription medicine used to improve wakefulness in adults who are very sleepy due to one of the following diagnosed sleep disorders: narcolepsy obstructive sleep apnea (OSA). Armodafinil tablets are used with other medical treatments for this sleep disorder. Armodafinil tablets do not take the place of using your CPAP machine or other treatments that your doctor has prescribed for this condition. It is important that you continue to use these treatments as prescribed by your doctor. shift work disorder (SWD) Armodafinil tablets will not cure these sleep disorders. Armodafinil tablets may help the sleepiness caused by these conditions, but it may not stop all your sleepiness. Armodafinil tablets do not take the place of getting enough sleep. Follow your doctor s advice about good sleep habits and using other treatments. Armodafinil tablets are a federally controlled substance (C-IV) because it can be abused or lead to dependence. Keep armodafinil tablets in a safe place to prevent misuse and abuse. Selling or giving away armodafinil tablets may harm others, and is against the law. Tell your doctor if you have ever abused or been dependent on alcohol, prescription medicines or street drugs. Who should not take armodafinil tablets? Do not take armodafinil tablets if you: are allergic to any of its ingredients. See the end of this Medication Guide for a complete list of ingredients in armodafinil tablets. have had a rash or allergic reaction to either armodafinil (armodafinil tablets) or modafinil (PROVIGIL ). These medicines are very similar. What should I tell my doctor before taking armodafinil tablets? Tell your doctor about all of your medical conditions including, if you: have a history of mental health problems, including psychosis have heart problems or had a heart attack have high blood pressure. Your blood pressure may need to be checked more often while taking armodafinil tablets. have liver or kidney problems have a history of drug or alcohol abuse or addiction are pregnant or planning to become pregnant. It is not known if armodafinil tablets will harm your unborn baby. are breastfeeding. It is not known if armodafinil passes into your milk. Talk to your doctor about the best way to feed your baby if you take armodafinil tablets. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Armodafinil tablets and many other medicines can interact with each other, sometimes causing side effects. Armodafinil tablets may affect the way other medicines work, and other medicines may affect how armodafinil tablets work. Your dose of armodafinil tablets or certain other medicines may need to be changed. Especially, tell your doctor if you use or take: a hormonal birth control method, such as birth control pills, shots, implants, patches, vaginal rings, and intrauterine devices (IUDs). Hormonal birth control methods may not work while you take armodafinil tablets. Women who use one of these methods of birth control may have a higher chance for getting pregnant while taking armodafinil tablets, and for 1 month after stopping armodafinil tablets. Talk to your doctor about birth control choices that are right for you while taking armodafinil tablets. 7 Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine. Your doctor or pharmacist will tell you if it is safe to take armodafinil tablets and other medicines together. Do not start any new medicines with armodafinil tablets unless your doctor has told you it is okay. How should I take armodafinil tablets? Take armodafinil tablets exactly as prescribed by your doctor. Your doctor will prescribe the dose of armodafinil tablets that is right for you. Do not change your dose of armodafinil tablets without talking to your doctor. Your doctor will tell you the right time of day to take armodafinil tablets. People with narcolepsy or OSA usually take armodafinil tablets one time each day in the morning. People with SWD usually take armodafinil tablets about 1 hour before their work shift. Do not change the time of day you take armodafinil tablets unless you have talked to your doctor. If you take armodafinil tablets too close to your bedtime, you may find it harder to go to sleep. You can take armodafinil tablets with or without food. If you take more than your prescribed dose or if you take an overdose of armodafinil tablets, call your doctor or poison control center right away. Symptoms of an overdose of armodafinil tablets may include: Trouble sleeping Restlessness Confusion Feeling disoriented Feeling excited Hearing, seeing, feeling, or sensing things that are not really there (hallucinations) Nausea and diarrhea A fast or slow heartbeat Chest pain Increased blood pressure What should I avoid while taking armodafinil tablets? Do not drive a car or do other dangerous activities until you know how armodafinil tablets affect you. People with sleep disorders should always be careful about doing things that could be dangerous. Do not change your daily habits until your doctor tells you it is okay. You should avoid drinking alcohol. It is not known how drinking alcohol will affect you when taking armodafinil tablets. What are possible side effects of armodafinil tablets? Armodafinil tablets may cause serious side effects. Stop taking armodafinil tablets and call your doctor right away or get emergency help if you get any of the following: a serious rash or serious allergic reaction. (See What is the most important information I should know about armodafinil tablets? ) mental (psychiatric) symptoms, including: depression feeling anxious hearing, seeing, feeling, or sensing things that are not really there (hallucinations) an extreme increase in activity and talking (mania) thoughts of suicide aggressive behavior other mental problems symptoms of a heart problem, including chest pain, abnormal heart beats, and trouble breathing. Common side effects that can happen in anyone who takes armodafinil tablets include: headache nausea

23 dizziness trouble sleeping Tell your doctor if you get any side effect that bothers you or that does not go away while taking armodafinil tablets. These are not all the side effects of armodafinil tablets. For more information, ask your doctor or pharmacist. Some effects of armodafinil tablets on the brain are the same as other medicines called stimulants. These effects may lead to abuse or dependence on armodafinil tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at FDA How should I store armodafinil tablets? Store armodafinil tablets at 20 to 25 C (68 to 77 F). Keep armodafinil tablets and all medicines out of the reach of children. General information about armodafinil tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use armodafinil tablets for a condition for which it was not prescribed. Do not give armodafinil tablets to other people, even if they have the same symptoms you have. It may harm them and it is against the law. This Medication Guide summarizes the most important information about armodafinil tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about armodafinil tablets that is written for health professionals. For more information, call Mylan Pharmaceuticals Inc. at ( INFO-RX). What are the ingredients in armodafinil tablets? Active Ingredient: armodafinil Inactive Ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate and povidone. The brands listed are trademarks of their respective owners. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV U.S.A. Manufactured in India by: Mylan Laboratories Limited Hyderabad , India Code No.: MH/DRUGS/25/NKD/89 REVISED MAY MX:ARDFL:R5mmh 8

24 CLINDAMYCIN PALMITATE HYDROCHLORIDE FOR ORAL SOLUTION, USP (PEDIATRIC) To reduce the development of drug-resistant bacteria and maintain the effectiveness of clindamycin palmitate hydrochloride for oral solution (pediatric) and other antibacterial drugs, clindamycin palmitate hydrochloride for oral solution (pediatric) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. Not for Injection WARNING Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clindamycin and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. Because clindamycin therapy has been associated with severe colitis which may end fatally, it should be reserved for serious infections where less toxic antimicrobial agents are inappropriate, as described in the INDICATIONS AND USAGE section. It should not be used in patients with nonbacterial infections such as most upper respiratory tract infections. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may re - quire colectomy. CDAD must be considered in all patients who present with diarrhea following anti biotic use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. DESCRIPTION: Clindamycin palmitate hydrochloride is a water soluble hydrochloride salt of the ester of clindamycin and palmitic acid. Clindamycin is a semisynthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent compound lincomycin. The structural formula is represented below: The chemical name for clindamycin palmitate hydrochloride is Methyl 7-chloro-6,7,8- trideoxy-6-(1-methyl-trans-4-propyl-l-2-pyrrolidinecarboxamido)-1-thio-l-threo-α-d-galactooctopyranoside 2-palmitate monohydrochloride. Clindamycin palmitate hydrochloride for oral solution, USP (pediatric) contains clindamycin palmitate hydrochloride for reconstitution. Each 5 ml contains the equivalent of 75 mg of clindamycin. Inactive ingredients: cherry flavor, dextrin, ethylparaben, poloxamer, sucrose and simethicone. CLINICAL PHARMACOLOGY: Microbiology: Clin da mycin inhibits bacterial protein synthesis by binding to the 50S subunit of the ribosome. It has activity against Gram-positive aerobes and anaerobes, as well as some Gram-negative anaerobes. Clindamycin is bacteriostatic. Cross-resistance between clindamycin and lincomycin is complete. Antagonism in vitro has been demonstrated between clindamycin and erythromycin. Clindamycin inducible resistance has been identified in macrolide-resistant staphylococci and beta-hemolytic streptococci. Macrolide-resistant isolates of these organisms should be screened for clindamycin inducible resistance using the D-zone test. Clindamycin has been shown to be active against most of the isolates of the following microorganisms, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section. Gram-positive Aerobes Staphylococcus aureus (methicillin-susceptible strains) Streptococcus pneumoniae (penicillin-susceptible strains) Streptococcus pyogenes Anaerobes Prevotella melaninogenica Fusobacterium necrophorum Fusobacterium nucleatum Peptostreptococcus anaerobius Clostridium perfringens At least 90% of the microorganisms listed below exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the clindamycin susceptible MIC breakpoint for organisms of a similar type to those shown in Table 1. However, the efficacy of clindamycin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials. Gram-positive Aerobes Staphylococcus epidermidis (methicillin-susceptible strains) Streptococcus agalactiae Streptococcus anginosus Streptococcus oralis Streptococcus mitis Anaerobes Prevotella intermedia Prevotella bivia Propionibacterium acnes Micromonas ( Peptostreptococcus ) micros Finegoldia ( Peptostreptococcus ) magna Actinomyces israelii Clostridium clostridioforme Eubacterium lentum Susceptibility Testing Methods: When available, the clinical microbiology laboratory should provide cumulative in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial. Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure based on dilution methods (broth, agar or microdilution) 2,3 or equivalent using standardized inoculum and concentrations of clindamycin. The MIC values should be interpreted according to the criteria provided in Table 1. Diffusion Techniques: Quantitative methods that require the measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The standardized procedure 2,4 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 2 mcg of clindamycin to test the susceptibility of microorganisms to clindamycin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 2 mcg clindamycin disk should be interpreted according to the criteria in Table 1. Table 1. Susceptibility Interpretive Criteria for Clindamycin Susceptibility Interpretive Criteria Minimal Disk Inhibitory Diffusion Pathogen Concentrations (Zone Diameters (MIC in mcg/ml) in mm) S I R S I R Staphylococcus spp to to Streptococcus pneumoniae and to other Streptococcus spp. Anaerobic Bacteria NA NA NA NA = not applicable A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of Intermediate indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small, uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Quality Control: Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test. 2,3,4,5 Standard clindamycin powder should provide the MIC ranges in Table 2. For the disk diffusion technique using the 2 mcg clindamycin disk the criteria provided in Table 1 should be achieved. 1

25 Table 2. Acceptable Quality Control Ranges for Clindamycin to be Used in Validation of Susceptibility Test Results Acceptable Quality Control Ranges Minimum Inhibitory Disk Diffusion QC Strain Concentration Range Range (Zone Diameters (mcg/ml) in mm) Enterococcus faecalis ATCC to 16 NA Staphylococcus aureus ATCC to 0.25 NA Staphylococcus aureus ATCC NA 24 to 30 Streptococcus pneumoniae ATCC to to 25 Bacteroides fragilis ATCC to 2 NA Bacteroides thetaiotaomicron 2 to 8 NA ATCC Clostridium difficile ATCC to 8 Eggerthella lenta ATCC to 0.25 NA 1 Quality control for C. difficile is performed using the agar dilution method only, all other obligate anaerobes may be tested by either broth microdilution or agar diffusion methods NA = Not applicable ATCC is a registered trademark of the American Type Culture Collection Human Pharmacology: Blood level studies comparing clindamycin palmitate hydrochloride with clindamycin hydrochloride show that both drugs reach their peak active serum levels at the same time, indicating a rapid hydrolysis of the palmitate to the clindamycin. Clindamycin is widely distributed in body fluids and tissues (including bones). Approximately 10% of the biological activity is excreted in the urine. The average serum half-life after doses of clindamycin palmitate hydrochloride for oral solution (pediatric) is approximately 2 hours in pediatric patients. Serum half-life of clindamycin is increased slightly in patients with markedly reduced renal function. Hemo dialysis and peritoneal dialysis are not effective in removing clindamycin from the serum. Serum level studies with clindamycin palmitate hydrochloride in normal pediatric patients weighing 50 lbs to 100 lbs given 2, 3 or 4 mg/kg every 6 hours (8, 12 or 16 mg/kg/day) demonstrated mean peak clindamycin serum levels of 1.24, 2.25 and 2.44 mcg/ml respectively, one hour after the first dose. By the fifth dose, the 6-hour serum concentration had reached equilibrium. Peak serum concentrations after this time would be about 2.46, 2.98 and 3.79 mcg/ml with doses of 8, 12 and 16 mg/kg/day, respectively. Serum levels have been uniform and predictable from person to person and dose to dose. Multiple-dose studies in neonates and infants up to 6 months of age show that the drug does not accumulate in the serum and is excreted rapidly. Serum levels exceed the MICs for most indicated organisms for at least 6 hours following administration of the usually recommended doses of clindamycin palmitate hydrochloride for oral solution in adults and pediatric patients. No significant levels of clindamycin are attained in the cerebrospinal fluid, even in the presence of inflamed meninges. Pharmacokinetic studies in elderly volunteers (61 to 79 years) and younger adults (18 to 39 years) indicate that age alone does not alter clindamycin pharmacokinetics (clearance, elimination half-life, volume of distribution, and area under the serum concentration-time curve) after IV administration of clindamycin phosphate. After oral administration of clindamycin hydrochloride, elimination half-life is increased to approximately 4 hours (range 3.4 h to 5.1 h) in the elderly compared to 3.2 hours (range 2.1 h to 4.2 h) in younger adults; administration of clindamycin palmitate hydrochloride resulted in a similar elimination halflife value of about 4.5 hours in elderly subjects. However, the extent of absorption is not different between age groups and no dosage alteration is necessary for the elderly with normal hepatic function and normal (age-adjusted) renal function 1. INDICATIONS AND USAGE: Clindamycin palmitate hydrochloride for oral solution, USP (pediatric) is indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. Clindamycin is also indicated in the treatment of serious infections due to susceptible strains of streptococci, pneumococci and staphylococci. Its use should be re served for penicillin-allergic patients or other patients for whom, in the judgment of the physician, a penicillin is inappropriate. Because of the risk of colitis, as described in the WARNING box, before selecting clindamycin the physician should consider the nature of the infection and the suitability of less toxic alternatives (e.g., erythromycin). Anaerobes: Serious respiratory tract infections such as empyema, anaerobic pneumonitis and lung abscess; serious skin and soft tissue infections; septicemia; intra-abdominal infections such as peritonitis and intra-abdominal abscess (typically resulting from anaerobic organisms resident in the normal gastrointestinal tract); infections of the female pelvis and genital tract such as endometritis, nongonococcal tubo-ovarian abscess, pelvic cellulitis and 2 postsurgical vaginal cuff infection. Streptococci: Serious respiratory tract infections; serious skin and soft tissue infections. Staphylococci: Serious respiratory tract infections; serious skin and soft tissue infections. Pneumococci: Serious respiratory tract infections. Bacteriologic studies should be performed to determine the causative organisms and their susceptibility to clindamycin. In Vitro Susceptibility Testing: A standardized disk testing procedure 2 is recommended for determining susceptibility of aerobic bacteria to clindamycin. A description is contained in the CLEOCIN Susceptibility Disk (clindamycin) insert. Using this method, the laboratory can designate isolates as resistant, intermediate, or susceptible. Tube or agar dilution methods may be used for both anaerobic and aerobic bacteria. When the directions in the CLEOCIN Susceptibility Powder insert are followed, an MIC (minimal inhibitory concentration) of 1.6 mcg/ml may be considered susceptible; MICs of 1.6 to 4.8 mcg/ml may be considered intermediate and MICs greater than 4.8 mcg/ml may be considered resistant. CLEOCIN Susceptibility Disks 2 mcg. See package insert for use. CLEOCIN Susceptibility Powder 20 mg. See package insert for use. For anaerobic bacteria the minimal inhibitory concentration (MIC) of clindamycin can be determined by agar dilution and broth dilution (including microdilution) techniques. If MICs are not determined routinely, the disk broth method is recommended for routine use. THE KIRBY- BAUER DISK DIFFUSION METHOD AND ITS INTERPRETIVE STANDARDS ARE NOT RECOMMENDED FOR ANAEROBES. To reduce the development of drug-resistant bacteria and maintain the effectiveness of clindamycin palmitate hydrochloride for oral solution, USP (pediatric) and other antibacterial drugs, clindamycin palmitate hydrochloride for oral solution, USP (pediatric) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. CONTRAINDICATIONS: This drug is contraindicated in individuals with a history of hypersensitivity to preparations containing clindamycin or lincomycin. WARNINGS: See WARNING box. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clindamycin palmitate hydrochloride for oral solution (pediatric), and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. A careful inquiry should be made concerning previous sensitivities to drugs and other allergens. Usage in Meningitis: Since clindamycin does not diffuse adequately into the cerebrospinal fluid, the drug should not be used in the treatment of meningitis. PRECAUTIONS: General: Review of experience to date suggests that a subgroup of older patients with associated severe illness may tolerate diarrhea less well. When clindamycin is indicated in these patients, they should be carefully monitored for change in bowel frequency. Clindamycin palmitate hydrochloride for oral solution (pediatric) should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. Clindamycin palmitate hydrochloride for oral solution (pediatric) should be prescribed with caution in atopic individuals. Indicated surgical procedures should be performed in conjunction with antibiotic therapy. The use of clindamycin palmitate hydrochloride for oral solution (pediatric) occasionally results in overgrowth of nonsusceptible organisms-particularly yeasts. Should superinfections occur, appropriate measures should be taken as indicated by the clinical situation. Clindamycin dosage modification may not be necessary in patients with renal disease. In patients with moderate to severe liver disease, prolongation of clindamycin half-life has been found. However, it was postulated from studies that when given every 8 hours, accumulation should rarely occur. Therefore, dosage modification in patients with liver disease may not be necessary. How ever, periodic liver enzyme determinations should be made when treating patients with severe liver disease. Prescribing clindamycin palmitate hydrochloride for oral solution (pediatric) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients: Patients should be counseled that antibacterial drugs including clindamycin palmitate hydrochloride for oral solution (pediatric) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When clindamycin palmitate hydrochloride for oral solution (pediatric) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course

26 of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by clindamycin palmitate hydrochloride for oral solution (pediatric) or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Laboratory Tests: During prolonged therapy, periodic liver and kidney function tests and blood counts should be performed. Drug Interactions: Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents. Antagonism has been demonstrated between clindamycin and erythromycin in vitro. Because of possible clinical significance, these two drugs should not be administered concurrently. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed with clindamycin to evaluate carcinogenic potential. Genotoxicity tests performed included a rat micronucleus test and an Ames Salmonella reversion test. Both tests were negative. Fertility studies in rats treated orally with up to 300 mg/kg/day (approximately 1.6 times the highest recommended adult human oral dose based on mg/m 2 ) revealed no effects on fertility or mating ability. In oral embryo fetal development studies in rats and subcutaneous embryo fetal development studies in rats and rabbits, no developmental toxicity was observed except at doses that produced maternal toxicity. Pregnancy: Teratogenic Effects. Pregnancy Category B: Oral and subcutaneous reproductive toxicity studies in rats and rabbits revealed no evidence of impaired fertility or harm to the fetus due to clindamycin, except at doses that caused maternal toxicity. Animal reproduction studies are not always predictive of human response. In clinical trials with pregnant women, the systemic administration of clindamycin during the second and third trimesters, has not been associated with an increased frequency of congenital abnormalities. Clindamycin should be used during the first trimester of pregnancy only if clearly needed. There are no adequate and well-controlled studies in pregnant women during the first trimester of pregnancy. Nursing Mothers: Clindamycin has been reported to appear in breast milk in the range of 0.7 to 3.8 mcg/ml. Because of the potential for serious adverse reactions in nursing infants, clindamycin should not be taken by nursing mothers. Pediatric Use: When clindamycin hydrochloride is administered to the pediatric population (birth to 16 years), appropriate monitoring of organ system functions is desirable. Geriatric Use: Clinical studies of clindamycin did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience indicates that antibiotic-associated colitis and diarrhea (due to Clostridium difficile) seen in association with most antibiotics occur more frequently in the elderly (> 60 years) and may be more severe. These patients should be carefully monitored for the development of diarrhea. Pharmacokinetic studies with clindamycin have shown no clinically important differences between young subjects (18 to 39 years) and elderly subjects (61 to 79 years) with normal hepatic function and normal (age-adjusted) renal function after oral or intravenous administration. ADVERSE REACTIONS: The following reactions have been reported with the use of clindamycin. Gastrointestinal: Abdominal pain, pseudomembranous colitis, esophagitis, nausea, vomiting and diarrhea (see WARNING box). The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS). Hypersensitivity Reactions: Generalized mild to moderate morbilliform-like (maculopapular) skin rashes are the most frequently reported adverse reactions. Vesiculo bullous rashes, as well as urticaria, have been observed during drug therapy. Rare instances of erythema multiforme, some resembling Stevens-Johnson Syndrome, and a few cases of anaphylactoid reactions have also been reported. Skin and Mucous Membranes: Pruritus, vaginitis, and rare instances of exfoliative dermatitis have been reported. (See Hypersensitivity Reactions.) Liver: Jaundice and abnormalities in liver function tests have been observed during clindamycin therapy. Renal: Although no direct relationship of clindamycin to renal damage has been established, renal dysfunction as evidenced by azotemia, oliguria, and/or proteinuria has been observed in rare instances. Hematopoietic: Transient neutropenia (leukopenia) and eosinophilia have been reported. Reports of agranulocytosis and thrombocytopenia have been made. No direct etiologic relationship to concurrent clindamycin therapy could be made in any of the foregoing. Musculoskeletal: Rare instances of polyarthritis have been reported. OVERDOSAGE: Significant mortality was observed in mice at an intravenous dose of 855 mg/kg and in rats at an oral or subcutaneous dose of approximately 2618 mg/kg. In the mice, convulsions and depression were observed. Hemodialysis and peritoneal dialy- 3 sis are not effective in removing clindamycin from the serum. DOSAGE AND ADMINISTRATION: If significant diarrhea occurs during therapy, this antibiotic should be discontinued (see WARNING box). Concomitant administration of food does not adversely affect the absorption of clindamycin palmitate hydrochloride contained in clindamycin palmitate hydrochloride for oral solution (pediatric). Serious infections: 8 to 12 mg/kg/day (4 to 6 mg/lb/day) divided into 3 or 4 equal doses. Severe infections: 13 to 16 mg/kg/day (6.5 to 8 mg/lb/day) divided into 3 or 4 equal doses. More severe infections: 17 to 25 mg/kg/day (8.5 to 12.5 mg/lb/day) divided into 3 or 4 equal doses. In pediatric patients weighing 10 kg or less, ½ teaspoon (37.5 mg) 3 times a day should be considered the minimum recommended dose. Serious infections due to anaerobic bacteria are usually treated with clindamycin injection. However, in clinically appropriate circumstances, the physician may elect to initiate treatment or continue treatment with clindamycin palmitate hydrochloride for oral solution (pediatric). NOTE: In cases of ß-hemolytic streptococcal infections, treatment should be continued for at least 10 days. Reconstitution Instructions: When reconstituted with water as follows, each 5 ml (teaspoonful) of solution contains clindamycin palmitate hydrochloride equivalent to 75 mg of clindamycin. Reconstitute bottles of 100 ml with 75 ml of water. Add a large portion of the water and shake vigorously; add the remainder of the water and shake until the solution is uniform. Storage Conditions: Store at 20 to 25 C (68 to 77 F). [See USP Controlled Room Temperature.] Do NOT refrigerate the reconstituted solution; when chilled, the solution may thicken and be difficult to pour. The solution is stable for 2 weeks at room temperature. HOW SUPPLIED: Clindamycin Palmitate Hydrochloride for Oral Solution, USP (Pediatric) is available as a white to off-white granular powder. When reconstituted with water as directed, each bottle will contain 100 ml of a solution providing clindamycin palmitate hydrochloride, USP equivalent to 75 mg of clindamycin per each 5 ml. Clindamycin palmitate hydrochloride for oral solution, USP (pediatric) is supplied as follows: NDC mg/5 ml in 100 ml amber, glass bottles Storage Conditions: Store at 20 to 25 C (68 to 77 F). [See USP Controlled Room Temperature.] Do NOT refrigerate the reconstituted solution; when chilled, the solution may thicken and be difficult to pour. The solution is stable for 2 weeks at room temperature. ANIMAL TOXICOLOGY: One year oral toxicity studies in Spartan Sprague-Dawley rats and beagle dogs at dose levels up to 300 mg/kg/day (approximately 1.6 and 5.4 times the highest recommended adult human oral dose based on mg/m 2, respectively) have shown clindamycin to be well tolerated. No appreciable difference in pathological findings has been observed between groups of animals treated with clindamycin and comparable control groups. Rats receiving clindamycin hydrochloride at 600 mg/kg/day (approximately 3.2 times the highest recommended adult human oral dose based on mg/m 2 ) for 6 months tolerated the drug well; however, dogs dosed at this level (approximately 10.8 times the highest recommended adult human oral dose based on mg/m 2 ) vomited, would not eat, and lost weight. REFERENCES: 1. Smith RB, Phillips JP: Evaluation of CLEOCIN HCl and CLEOCIN Phosphate in an Aged Population. Upjohn TR , December CLSI. Performance Standards for Antimicrobial Susceptibility Testing: Twenty-fifth Informational Supplement. CLSI document M 100-S25. Wayne, PA: Clinical and Laboratory Standards Institute; CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition. CLSI document M07-A10. Wayne, PA: Clinical and Laboratory Standards Institute; CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard - Twelfth Edition. CLSI document M02-A12. Wayne, PA: Clinical and Laboratory Standards Institute; CLSI. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eighth Edition. CLSI document M11-A8. Wayne, PA: Clinical and Laboratory Standards Institute; The brands listed are trademarks of their respective owners. Mylan Pharmaceuticals Inc. Morgantown, WV U.S.A. REVISED JANUARY 2016 CLINOS:R2

27 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DOXYCYCLINE HYCLATE DELAYED- RELEASE TABLETS safely and effectively. See full prescribing information for DOXYCYCLINE HYCLATE DELAYED-RELEASE TABLETS. DOXYCYCLINE HYCLATE delayed-release tablets, for oral use Initial U.S. Approval: 1967 To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline hyclate and other antibacterial drugs, doxycycline hyclate delayed-release tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1) RECENT MAJOR CHANGES Warnings and Precautions (5.5) 12/ INDICATIONS AND USAGE Doxycycline hyclate delayed-release tablets are a tetracycline-class anti bacterial indicated for: Rickettsial infections (1.1) Sexually transmitted infections (1.2) Respiratory tract infections (1.3) Specific bacterial infections (1.4) Ophthalmic infections (1.5) Anthrax, including inhalational anthrax (post-exposure) (1.6) Alternative treatment for selected infections when penicillin is contraindicated (1.7) Adjunctive therapy in acute intestinal amebiasis and severe acne (1.8) Prophylaxis of malaria (1.9) DOSAGE AND ADMINISTRATION Adults: the usual dose of oral doxycycline is 200 mg on the first day of treatment (administered 100 mg every 12 hours) followed by a maintenance dose of 100 mg daily. In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended. (2.1) For children above 8 years of age: The recommended dosage schedule for children weighing 45 kg or less is 4.4 mg/kg of body weight divided into two doses on the first day of treatment, followed by 2.2 mg/kg of body weight given as a single daily dose or divided into two doses on subsequent days. For more severe infections up to 4.4 mg/kg of body weight may be used. For children over 45 kg, the usual adult dose should be used. (2.1) DOSAGE FORMS AND STRENGTHS Tablets: 50 mg CONTRAINDICATIONS Doxycycline is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. (4) WARNINGS AND PRECAUTIONS The use of drugs of the tetracycline-class during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). (5.1) Clostridium difficile-associated diarrhea. Evaluate patients if diarrhea occurs. (5.2) Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Limit sun exposure. (5.3) Overgrowth of non-susceptible organisms, including fungi, may occur. Re-eval uate therapy if superinfection occurs. (5.4) ADVERSE REACTIONS Adverse reactions observed in patients receiving tetracyclines include anorexia, nausea, vomiting, diarrhea, rash, photosensitivity, urticaria, and hemolytic anemia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at ( INFO-RX) or FDA at FDA-1088 or DRUG INTERACTIONS Patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage (7.1) Avoid co-administration of tetracyclines with penicillin (7.2) Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate and iron-containing preparations (7.3) Concurrent use of tetracycline may render oral contraceptives less effective (7.4) Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline (7.5) USE IN SPECIFIC POPULATIONS Pregnancy Category D (8.1) Tetracyclines are excreted in human milk; however, the extent of absorption of doxycycline in the breastfed infant is not known. Doxycycline use during nursing should be avoided if possible. (8.3) See 17 for PATIENT COUNSELING INFORMATION Revised: 4/2016 DXYDR50:R1 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Rickettsial Infections 1.2 Sexually Transmitted Infections 1.3 Respiratory Tract Infections 1.4 Specific Bacterial Infections 1.5 Ophthalmic Infections 1.6 Anthrax Including Inhalational Anthrax (Post-Exposure) 1.7 Alternative Treatment for Selected Infections when Penicillin is Con traindicated 1.8 Adjunctive Therapy for Acute Intestinal Amebiasis and Severe Acne 1.9 Prophylaxis of Malaria 2 DOSAGE AND ADMINISTRATION 2.1 Usual Dosage and Administration 2.2 For Prophylaxis of Malaria 2.3 Inhalational Anthrax (Post-Exposure) 2.4 Sprinkling the Tablet over Applesauce 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Tooth Development 5.2 Clostridium difficile Associated Diarrhea 5.3 Photosensitivity 5.4 Superinfection 5.5 Intracranial Hypertension 5.6 Skeletal Development 5.7 Antianabolic Action 5.8 Malaria 5.9 Development of Drug-Resistant Bacteria 5.10 Laboratory Monitoring for Long-Term Therapy 6 ADVERSE REACTIONS 6.1 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Anticoagulant Drugs 7.2 Penicillin 7.3 Antacids and Iron Preparations 7.4 Oral Contraceptives 7.5 Barbiturates and Anti-Epileptics 7.6 Penthrane 7.7 Drug/Laboratory Test Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. 1

28 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline hyclate delayed-release tablets and other antibacterial drugs, doxycycline hyclate delayed-release tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Doxycycline is a tetracycline-class antibacterial indicated in the following conditions or diseases: 1.1 Rickettsial Infections Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae. 1.2 Sexually Transmitted Infections Uncomplicated urethral, endocervical or rectal infections in adults caused by Chlamydia trachomatis. Nongonococcal urethritis caused by Ureaplasma urealyticum. Lymphogranuloma venereum caused by Chlamydia trachomatis. Granuloma inguinale caused by Klebsiella granulomatis. Uncomplicated gonorrhea caused by Neisseria gonorrhoeae. Chancroid caused by Haemophilus ducreyi. 1.3 Respiratory Tract Infections Respiratory tract infections caused by Mycoplasma pneumoniae. Psittacosis (ornithosis) caused by Chlamydophila psittaci. Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug: Respiratory tract infections caused by Haemophilus influenzae. Respiratory tract infections caused by Klebsiella species. Upper respiratory infections caused by Streptococcus pneumoniae. 1.4 Specific Bacterial Infections Relapsing fever due to Borrelia recurrentis. Plague due to Yersinia pestis. Tularemia due to Francisella tularensis. Cholera caused by Vibrio cholerae. Campylobacter fetus infections caused by Campylobacter fetus. Brucellosis due to Brucella species (in conjunction with streptomycin). Bartonellosis due to Bartonella bacilliformis. Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following gram-negative microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug: Escherichia coli Enterobacter aerogenes Shigella species Acinetobacter species Urinary tract infections caused by Klebsiella species. 1.5 Ophthalmic Infections Trachoma caused by Chlamydia trachomatis, although the infectious agent is not always eliminated as judged by immunofluorescence. Inclusion conjunctivitis caused by Chlamydia trachomatis. 1.6 Anthrax Including Inhalational Anthrax (Post-Exposure) Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. 1.7 Alternative Treatment for Selected Infections when Penicillin is Con traindicated When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of the following infections: Syphilis caused by Treponema pallidum. Yaws caused by Treponema pallidum subspecies pertenue. Vincent s infection caused by Fusobacterium fusiforme. Actinomycosis caused by Actinomyces israelii. Infections caused by Clostridium species. 1.8 Adjunctive Therapy for Acute Intestinal Amebiasis and Severe Acne In acute intestinal amebiasis, doxycycline may be a useful adjunct to amebicides. In severe acne, doxycycline may be useful adjunctive therapy. 1.9 Prophylaxis of Malaria Doxycycline is indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (less than 4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains [see Dosage and Admin istration (2.2) and Patient Counseling Information (17)]. 2 DOSAGE AND ADMINISTRATION 2.1 Usual Dosage and Administration THE USUAL DOSAGE AND FREQUENCY OF ADMINISTRATION OF DOXYCYCLINE DIFFERS FROM THAT OF 2 THE OTHER TETRACYCLINES. EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS. Adults: The usual dose of oral doxycycline is 200 mg on the first day of treatment (administered 100 mg every 12 hours), followed by a maintenance dose of 100 mg daily. The maintenance dose may be administered as a single dose or as 50 mg every 12 hours. In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended. For Pediatric Patients Above 8 Years of Age: The recommended dosage schedule for children weighing 45 kg or less is 4.4 mg/kg of body weight divided into two doses on the first day of treatment, followed by 2.2 mg/kg of body weight given as a single daily dose or divided into two doses on subsequent days. For more severe infections up to 4.4 mg/kg of body weight may be used. For children over 45 kg, the usual adult dose should be used. Administration of adequate amounts of fluid along with capsule and tablet forms of drugs in the tetracycline-class is recommended to wash down the drugs and reduce the risk of esophageal irritation and ulceration [see Adverse Reactions (6.1)]. If gastric irritation occurs, doxycycline may be given with food or milk [see Clinical Pharmacology (12)]. When used in streptococcal infections, therapy should be continued for 10 days. Uncomplicated Urethral, Endocervical, or Rectal Infection in Adults Caused by Chlamydia Trachomatis: 100 mg by mouth twice a day for 7 days. Uncomplicated Gonococcal Infections in Adults (Except Anorectal Infections in Men): 100 mg, by mouth, twice-a-day for 7 days. As an alternative single visit dose, administer 300 mg stat followed in an hour by a second 300 mg dose. Nongonococcal Urethritis (NGU) Caused by U. Urealyticum: 100 mg by mouth twice-a-day for 7 days. Syphilis Early: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice-a-day for 2 weeks. Syphilis of More Than One Year s Duration: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice-a-day for 4 weeks. Acute Epididymo-Orchitis Caused by C. Trachomatis: 100 mg, by mouth, twice-a-day for at least 10 days. 2.2 For Prophylaxis of Malaria For adults, the recommended dose is 100 mg daily. For children over 8 years of age, the recommended dose is 2 mg/kg given once daily up to the adult dose. Prophylaxis should begin 1 or 2 days before travel to the malarious area. Prophylaxis should be continued daily during travel in the malarious area and for 4 weeks after the traveler leaves the malarious area. 2.3 Inhalational Anthrax (Post-Exposure) Adults: 100 mg, of doxycycline, by mouth, twice-a-day for 60 days. Children: weighing less than 45 kg, 2.2 mg/kg of body weight, by mouth, twice-a-day for 60 days. Children weighing 45 kg or more should receive the adult dose. 2.4 Sprinkling the Tablet over Applesauce Doxycycline hyclate delayed-release tablets may also be administered by carefully breaking up the tablet and sprinkling the tablet contents (delayed-release beads) on a spoonful of applesauce. The delayed-release beads must not be crushed or damaged when breaking up the tablet. Any loss of beads in the transfer would prevent using the dose. The applesauce/doxycycline mixture should be swallowed immediately without chewing and may be followed by a glass of water if desired. The applesauce should not be hot, and it should be soft enough to be swallowed without chewing. In the event that a prepared dose of applesauce/doxycycline cannot be taken immediately, the mixture should be discarded and not stored for later use. 3 DOSAGE FORMS AND STRENGTHS Doxycycline Hyclate Delayed-Release Tablets, USP are available containing delayed-release beads of doxycycline hyclate, USP equivalent to 50 mg of doxycycline. Doxycycline Hyclate Delayed-Release Tablets USP, 50 mg are white, round, unscored tablets containing yellow beads debossed with M on one side of the tablet and D36 on the other side. Each tablet contains specially coated beads of doxycycline hyclate, USP equivalent to 50 mg of doxycycline. 4 CONTRAINDICATIONS The drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. 5 WARNINGS AND PRECAUTIONS 5.1 Tooth Development The use of drugs of the tetracycline-class during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drugs but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Doxy cycline should not be used in this age group, except for anthrax, including inhalational anthrax (post-exposure), unless other drugs are not likely to be effective or are contraindicated. 5.2 Clostridium difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including doxycycline hyclate delayed-release tablets, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has

29 been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.3 Photosensitivity Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema. 5.4 Superinfection As with other antibacterial preparations, use of doxycycline may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, the antibacterial should be discontinued and appropriate therapy instituted. 5.5 Intracranial Hypertension Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline including doxycycline. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Avoid concomitant use of isotretinoin and doxycycline because isotretinoin is also known to cause pseudotumor cerebri. Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize. 5.6 Skeletal Development All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the fetus. 5.7 Antianabolic Action The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function. 5.8 Malaria Doxycycline offers substantial but not complete suppression of the asexual blood stages of Plasmodium strains. Doxycycline does not suppress P. falciparum s sexual blood stage gametocytes. Subjects completing this prophylactic regimen may still transmit the infection to mosquitoes outside endemic areas. 5.9 Development of Drug-Resistant Bacteria Prescribing doxycycline hyclate delayed-release tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria Laboratory Monitoring for Long-Term Therapy In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic studies should be performed. 6 ADVERSE REACTIONS 6.1 Postmarketing Experience The following adverse reactions have been identified during post-approval use of doxycycline. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Due to oral doxycycline s virtually complete absorption, side effects to the lower bowel, particularly diarrhea, have been infrequent. The following adverse reactions have been observed in patients receiving tetracyclines: Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region. Hepatotoxicity has been reported. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline-class. Most of these patients took medications immediately before going to bed [see Dosage and Administration (2.1)]. Skin: Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, and erythema multiforme have been reported. Photosensitivity is discussed above [see Warnings and Precautions (5.3)]. Renal: Rise in BUN has been reported and is apparently dose-related [see Warnings and Precautions (5.7)]. Hypersensitivity Reactions: Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus. Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported. Intracranial Hypertension: Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline [see Warnings and Pre cautions (5.5)]. Thyroid Gland Changes: When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function are known to occur. 3 7 DRUG INTERACTIONS 7.1 Anticoagulant Drugs Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. 7.2 Penicillin Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin. 7.3 Antacids and Iron Preparations Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron-containing preparations. 7.4 Oral Contraceptives Concurrent use of tetracycline may render oral contraceptives less effective. 7.5 Barbiturates and Anti-Epileptics Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. 7.6 Penthrane The concurrent use of tetracycline and Penthrane (methoxyflurane) has been reported to result in fatal renal toxicity. 7.7 Drug/Laboratory Test Interactions False elevations of urinary catecholamines may occur due to interference with the fluorescence test. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category D: There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for the treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS - the Teratogen Information System - concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk.1 A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. Sixty-three (0.19%) of the controls and 56 (0.30%) of the cases were treated with doxycycline. This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e., in the second and third months of gestation), with the exception of a marginal relationship with neural tube defect based on only two-exposed cases.2 A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of age.3 Nonteratogenic Effects: [See Warnings and Precautions (5.1, 5.6).] 8.3 Nursing Mothers Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not necessarily contraindicated. The effects of prolonged exposure to doxycycline in breast milk are unknown.4 Because of the potential for serious adverse reactions in nursing infants from doxycycline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother [see Warnings and Precautions (5.1, 5.6)]. 8.4 Pediatric Use Because of the effects of drugs of the tetracycline-class on tooth development and growth, doxycycline should not be used in pediatric patients to the age of 8 years, unless the potential benefits are expected to outweigh the risks such as for anthrax, or when other drugs are not likely to be effective or are contraindicated [see Warnings and Precautions (5.1, 5.6) and Dosage and Ad ministration (2.1, 2.3)]. 8.5 Geriatric Use Clinical studies of doxycycline did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Doxycycline hyclate delayed-release 50 mg tablets contain 1.43 mg (0.06 meq) of sodium. 10 OVERDOSAGE In case of overdosage, discontinue medication, treat symptomatically and in stitute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage. 11 DESCRIPTION Doxycycline hyclate delayed-release tablets, USP, for oral administration, contain specially coated beads of doxycycline hyclate, a broad-spectrum antibacterial synthetically derived from oxytetracycline, in a delayed-release formulation for oral administration. The structural formula for doxycycline hyclate is: with a molecular formula of (C 22 H 24 N 2 O 8 HCl) 2 C 2 H 6 O H 2 O and a molecular weight of The

30 chemical designation for doxycycline hyclate is 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. Doxycycline hyclate, USP is a yellow to light yellow crystalline powder soluble in water and in solutions of alkali hydroxides and carbonates. Doxycycline has a high degree of lipid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form. Inactive ingredients in the tablet formulation are: anhydrous lactose, colloidal silicon dioxide, crospovidone, hypromellose phthalate, lactose monohydrate, povidone, pregelatinized starch (corn), sodium chloride, sodium lauryl sulfate, stearic acid, talc, and triethyl citrate. USP Dissolution Test Pending CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Doxycycline is an antibacterial drug [see Microbiology (12.4)] Pharmacokinetics Doxycycline is virtually completely absorbed after oral administration. Following administration of a single 200 mg dose to adult volunteers, average serum doxycycline levels were 2.6 mcg/ml at 2 hours decreasing to 1.45 mcg/ml at 24 hours. The mean C max and AUC 0- of doxycycline are 24% and 13% lower, respectively, following single dose administration of doxycycline hyclate delayed-release tablets, 100 mg with a high fat meal (including milk) compared to fasted conditions. The mean C max of doxycycline is 19% lower and the AUC 0- is unchanged following single dose administration of doxycycline hyclate tablets, 150 mg with a high fat meal (including milk) compared to fasted conditions. The clinical significance of these differences is unknown. When doxycycline hyclate delayed-release tablets are sprinkled over applesauce and taken with or without water, the extent of doxycycline absorption is unchanged, but the rate of absorption is increased slightly. Tetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with a creatinine clearance of about 75 ml/min. This percentage may fall as low as 1% to 5%/72 hours in individuals with a creatinine clearance below 10 ml/min. Studies have shown no significant difference in the serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the serum half-life Microbiology Mechanism of Action: Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against a broad range of Gram-positive and Gramnegative bacteria. Cross-resistance between tetracyclines is common. Doxycycline has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for doxycycline hyclate delayed-release tablets [see Indications and Usage (1)]. Gram-Negative Bacteria Acinetobacter species Bartonella bacilliformis Brucella species Campylobacter fetus Enterobacter aerogenes Escherichia coli Francisella tularensis Haemophilus ducreyi Haemophilus influenzae Klebsiella granulomatis Klebsiella species Neisseria gonorrhoeae Shigella species Vibrio cholerae Yersinia pestis Gram-Positive Bacteria Bacillus anthracis Streptococcus pneumoniae Anaerobic Bacteria Clostridium species Fusobacterium fusiforme Propionibacterium acnes Other Bacteria Norcardiae and other aerobic Actinomyces species Borrelia recurrentis Chlamydophila psittaci Chlamydia trachomatis Mycoplasma pneumoniae Rickettsiae Treponema pallidum Treponema pallidum subspecies pertenue Ureaplasma urealyticum Parasites Balantidium coli Entamoeba species Plasmodium falciparum* *Doxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum but not against the gametocytes of P. falciparum. The precise mechanism of action of the drug is not known. Susceptibility Test Methods: When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired path ogens. These reports should aid the physician in selecting the most effective antimicrobial. Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth and/or agar).5,6,8 The MIC values should be interpreted according to the criteria provided in Table 1. Diffusion Techniques: Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. Zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standard test method.5,7,8 This procedure uses paper disks impregnated with 30 mcg doxycycline to test the susceptibility of bacteria to doxycycline. The disk diffusion interpretive criteria are provided in Table 1. Anaerobic Techniques: For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method.9 The MIC values obtained should be interpreted according to the criteria provided in Table 1. Table 1: Susceptibility Test Interpretive Criteria for Doxycycline and Tetracycline Minimal Inhibitory Zone Agar Bacteria a Concentration Diameter Dilution (mcg/ml) (mm) (mcg/ml) S I R S I R S I R Acinetobacter spp. Doxycycline to Tetracycline to Anaerobes Tetracycline Bacillus anthracis ab Doxycycline Tetracycline Brucella species ab Doxycycline Tetracycline Enterobacteriacea Doxycycline to Tetracycline to Franciscella tularensis ab Doxycycline Tetracycline Haemophilus influenzae Tetracycline to Mycoplasma pneumoniae Tetracycline Norcardiae and other aerobic Actinomyces species ab Doxycycline 1 2 to Neisseria gonorrhoeae c Tetracycline to to 1 2 Streptococcus pneumoniae Doxycycline > 1 > to 27 < Tetracycline 1 2 > 4 > to 27 < Vibrio cholerae Doxycycline Tetracycline Yersinia pestis Doxycycline Tetracycline Ureaplasma urealyticum Tetracycline a Organisms susceptible to tetracycline are also considered susceptible to doxycycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to doxycycline. b The current absence of resistance isolates precludes defining any results other than Susceptible. If isolates yielding MIC results other than susceptible, they should be submitted to a reference laboratory for further testing. c Gonococci with 30 mcg tetracycline disk zone diameters of less than 19 mm usually indicate a plasmid-mediated tetracycline resistant Neisseria gonorrhoeae isolate. Resistance in these strains should be confirmed by a dilution test (MIC greater than or equal to 16 mcg/ml). A report of Susceptible (S) indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of Intermediate (I) indicates that the result should be considered

31 equivocal, and, if the bacteria is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected. Quality Control: Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test.5,6,7,8,9,10,11 Standard doxycycline and tetracycline powders should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg doxycycline disk the criteria noted in Table 2 should be achieved. Table 2: Acceptable Quality Control Ranges for Susceptibility Testing for Doxycycline and Tetracycline Minimal Inhibitory Zone Agar QC Strain Concentration Diameter Dilution (mcg/ml) (mm) (mcg/ml) Enterococcus faecalis ATCC Doxycycline 2 to Tetracycline 8 to Escherichia coli ATCC Doxycycline 0.5 to 2 18 to 24 - Tetracycline 0.5 to 2 18 to 25 - Eubacterium lentum ATCC Doxycycline 2 to Haemophilus influenzae ATCC Tetracycline 4 to to 22 - Neisseria gonorrhoeae ATCC Tetracycline - 30 to to 1 Staphylococcus aureus ATCC Doxycycline - 23 to 29 - Tetracycline - 24 to 30 - Staphylococcus aureus ATCC Doxycycline 0.12 to Tetracycline 0.12 to Streptococcus pneumoniae ATCC Doxycycline to to 34 - Tetracycline 0.06 to to 31 - Bacteroides fragilis ATCC Tetracycline to 0.5 Bacteroides thetaiotaomicron ATCC Doxycycline 2 to Tetracycline to 32 Mycoplasma pneumoniae ATCC Tetracycline 0.06 to to 0.5 Ureaplasma urealyticum ATCC Tetracycline NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibiotics, oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors). Likewise, although mutagenicity studies of doxycycline have not been conducted, positive results in in vitro mammalian cell assays have been reported for related antibacterials (tetracycline, oxytetracycline). Doxycycline administered orally at dosage levels as high as 250 mg/kg/day had no apparent effect on the fertility of female rats. Effect on male fertility has not been studied Animal Toxicology and/or Pharmacology Hyperpigmentation of the thyroid has been produced by members of the tetracycline-class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO 4, and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO 4, and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline. Minocycline, tetracycline PO 4, methacycline, doxycycline, tetracycline base, oxytetracycline hydrochloride, and tetracycline hydrochloride, were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet. Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs (minocycline); in chickens (chlortetracycline); and in rats and mice (oxytetracycline). Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline. Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues. 15 REFERENCES 1. Friedman JM, Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press: 2000: Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997; 89: Horne HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 1980; 25: Hale T. Medications and Mothers Milk. 9th edition. Amarillo, TX: Pharmasoft Publishing 2000; Clinical and Laboratory Standards Institute (CLSI). Performance Stand ards for Antimicrobial Susceptibility Testing; Twenty-fourth Informational Supplement. CLSI document M100-S24, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard Ninth Edition. CLSI document M07-A9, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Anti - microbial Disk Diffusion Susceptibility Tests; Approved Standard Eleventh Edition. CLSI document M02-A11, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline Second Edition. CLSI document M45-A2, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard Eighth Edition. CLSI document M11-A8, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute (CLSI). Methods for Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard Second Edition. CLSI document M24-A2, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing for Human Mycoplasmas; Approved Guideline. CLSI document M43-A, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, HOW SUPPLIED/STORAGE AND HANDLING Doxycycline Hyclate Delayed-Release Tablets, USP are available containing delayed-release beads of doxycycline hyclate, USP equivalent to 50 mg of doxycycline. The 50 mg tablets are white, round, unscored tablets containing yellow beads debossed with M on one side of the tablet and D36 on the other side. They are available as follows: NDC bottles of 60 tablets NDC bottles of 120 tablets NDC bottles of 500 tablets Store at 20 to 25 C (68 to 77 F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. 17 PATIENT COUNSELING INFORMATION Patients taking doxycycline for malaria prophylaxis should be advised: that no present-day antimalarial agent, including doxycycline, guarantees protection against malaria. to avoid being bitten by mosquitoes by using personal protective measures that help avoid contact with mosquitoes, especially from dusk to dawn (for example, staying in well-screened areas, using mosquito nets, covering the body with clothing, and using an effective insect repellent). that doxycycline prophylaxis: should begin 1 to 2 days before travel to the malarious area, should be continued daily while in the malarious area and after leaving the malarious area, should be continued for 4 further weeks to avoid development of malaria after returning from an endemic area, should not exceed 4 months. All patients taking doxycycline should be advised: to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (for example, skin eruptions, etc.) occurs. Sunscreen or sunblock should be considered [see Warnings and Precautions (5.3)]. to drink fluids liberally along with doxycycline to reduce the risk of esophageal irritation and ulceration [see Adverse Reactions (6.1)]. that the absorption of tetracyclines is reduced when taken with foods, especially those that contain calcium. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk [see Drug Interactions (7.3)]. that the absorption of tetracyclines is reduced when taken with antacids containing aluminum, calcium or magnesium, bismuth subsalicylate, and iron-containing preparations [see Drug Interactions (7.3)]. that the use of doxycycline might increase the incidence of vaginal candidiasis. Diarrhea is a common problem caused by antibacterials which usually ends when the antibacterial is

32 discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of antibacterial. If this occurs, patients should contact their physician as soon as possible. Patients should be counseled that antibacterial drugs including doxycycline hyclate delayed-release tablets should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When doxycycline hyclate delayed-release tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by doxycycline hyclate delayed-release tablets or other antibacterial drugs in the future. The brands listed are trademarks of their respective owners. Mylan Pharmaceuticals Inc. Morgantown, WV U.S.A. Revised: 4/2016 DXYDR50:R1 6

33 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DOXYCYCLINE HYCLATE DELAYED- RELEASE TABLETS safely and effectively. See full prescribing information for DOXYCYCLINE HYCLATE DELAYED-RELEASE TABLETS. DOXYCYCLINE HYCLATE delayed-release tablets, for oral use Initial U.S. Approval: 1967 To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline hyclate and other antibacterial drugs, doxycycline hyclate delayed-release tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1) RECENT MAJOR CHANGES Warnings and Precautions (5.5) 12/ INDICATIONS AND USAGE Doxycycline hyclate delayed-release tablets are a tetracycline-class anti bacterial indicated for: Rickettsial infections (1.1) Sexually transmitted infections (1.2) Respiratory tract infections (1.3) Specific bacterial infections (1.4) Ophthalmic infections (1.5) Anthrax, including inhalational anthrax (post-exposure) (1.6) Alternative treatment for selected infections when penicillin is contraindicated (1.7) Adjunctive therapy in acute intestinal amebiasis and severe acne (1.8) Prophylaxis of malaria (1.9) DOSAGE AND ADMINISTRATION Adults: the usual dose of oral doxycycline is 200 mg on the first day of treatment (administered 100 mg every 12 hours) followed by a maintenance dose of 100 mg daily. In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended. (2.1) For children above 8 years of age: The recommended dosage schedule for children weighing 45 kg or less is 4.4 mg/kg of body weight divided into two doses on the first day of treatment, followed by 2.2 mg/kg of body weight given as a single daily dose or divided into two doses on subsequent days. For more severe infections up to 4.4 mg/kg of body weight may be used. For children over 45 kg, the usual adult dose should be used. (2.1) DOSAGE FORMS AND STRENGTHS Tablets: 50 mg CONTRAINDICATIONS Doxycycline is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. (4) WARNINGS AND PRECAUTIONS The use of drugs of the tetracycline-class during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). (5.1) Clostridium difficile-associated diarrhea. Evaluate patients if diarrhea occurs. (5.2) Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Limit sun exposure. (5.3) Overgrowth of non-susceptible organisms, including fungi, may occur. Re-eval uate therapy if superinfection occurs. (5.4) ADVERSE REACTIONS Adverse reactions observed in patients receiving tetracyclines include anorexia, nausea, vomiting, diarrhea, rash, photosensitivity, urticaria, and hemolytic anemia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at ( INFO-RX) or FDA at FDA-1088 or DRUG INTERACTIONS Patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage (7.1) Avoid co-administration of tetracyclines with penicillin (7.2) Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate and iron-containing preparations (7.3) Concurrent use of tetracycline may render oral contraceptives less effective (7.4) Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline (7.5) USE IN SPECIFIC POPULATIONS Pregnancy Category D (8.1) Tetracyclines are excreted in human milk; however, the extent of absorption of doxycycline in the breastfed infant is not known. Doxycycline use during nursing should be avoided if possible. (8.3) See 17 for PATIENT COUNSELING INFORMATION Revised: 4/2016 DXYDR50:R1 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Rickettsial Infections 1.2 Sexually Transmitted Infections 1.3 Respiratory Tract Infections 1.4 Specific Bacterial Infections 1.5 Ophthalmic Infections 1.6 Anthrax Including Inhalational Anthrax (Post-Exposure) 1.7 Alternative Treatment for Selected Infections when Penicillin is Con traindicated 1.8 Adjunctive Therapy for Acute Intestinal Amebiasis and Severe Acne 1.9 Prophylaxis of Malaria 2 DOSAGE AND ADMINISTRATION 2.1 Usual Dosage and Administration 2.2 For Prophylaxis of Malaria 2.3 Inhalational Anthrax (Post-Exposure) 2.4 Sprinkling the Tablet over Applesauce 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Tooth Development 5.2 Clostridium difficile Associated Diarrhea 5.3 Photosensitivity 5.4 Superinfection 5.5 Intracranial Hypertension 5.6 Skeletal Development 5.7 Antianabolic Action 5.8 Malaria 5.9 Development of Drug-Resistant Bacteria 5.10 Laboratory Monitoring for Long-Term Therapy 6 ADVERSE REACTIONS 6.1 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Anticoagulant Drugs 7.2 Penicillin 7.3 Antacids and Iron Preparations 7.4 Oral Contraceptives 7.5 Barbiturates and Anti-Epileptics 7.6 Penthrane 7.7 Drug/Laboratory Test Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed. 1

34 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline hyclate delayed-release tablets and other antibacterial drugs, doxycycline hyclate delayed-release tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Doxycycline is a tetracycline-class antibacterial indicated in the following conditions or diseases: 1.1 Rickettsial Infections Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae. 1.2 Sexually Transmitted Infections Uncomplicated urethral, endocervical or rectal infections in adults caused by Chlamydia trachomatis. Nongonococcal urethritis caused by Ureaplasma urealyticum. Lymphogranuloma venereum caused by Chlamydia trachomatis. Granuloma inguinale caused by Klebsiella granulomatis. Uncomplicated gonorrhea caused by Neisseria gonorrhoeae. Chancroid caused by Haemophilus ducreyi. 1.3 Respiratory Tract Infections Respiratory tract infections caused by Mycoplasma pneumoniae. Psittacosis (ornithosis) caused by Chlamydophila psittaci. Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug: Respiratory tract infections caused by Haemophilus influenzae. Respiratory tract infections caused by Klebsiella species. Upper respiratory infections caused by Streptococcus pneumoniae. 1.4 Specific Bacterial Infections Relapsing fever due to Borrelia recurrentis. Plague due to Yersinia pestis. Tularemia due to Francisella tularensis. Cholera caused by Vibrio cholerae. Campylobacter fetus infections caused by Campylobacter fetus. Brucellosis due to Brucella species (in conjunction with streptomycin). Bartonellosis due to Bartonella bacilliformis. Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following gram-negative microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug: Escherichia coli Enterobacter aerogenes Shigella species Acinetobacter species Urinary tract infections caused by Klebsiella species. 1.5 Ophthalmic Infections Trachoma caused by Chlamydia trachomatis, although the infectious agent is not always eliminated as judged by immunofluorescence. Inclusion conjunctivitis caused by Chlamydia trachomatis. 1.6 Anthrax Including Inhalational Anthrax (Post-Exposure) Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. 1.7 Alternative Treatment for Selected Infections when Penicillin is Con traindicated When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of the following infections: Syphilis caused by Treponema pallidum. Yaws caused by Treponema pallidum subspecies pertenue. Vincent s infection caused by Fusobacterium fusiforme. Actinomycosis caused by Actinomyces israelii. Infections caused by Clostridium species. 1.8 Adjunctive Therapy for Acute Intestinal Amebiasis and Severe Acne In acute intestinal amebiasis, doxycycline may be a useful adjunct to amebicides. In severe acne, doxycycline may be useful adjunctive therapy. 1.9 Prophylaxis of Malaria Doxycycline is indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (less than 4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains [see Dosage and Admin istration (2.2) and Patient Counseling Information (17)]. 2 DOSAGE AND ADMINISTRATION 2.1 Usual Dosage and Administration THE USUAL DOSAGE AND FREQUENCY OF ADMINISTRATION OF DOXYCYCLINE DIFFERS FROM THAT OF 2 THE OTHER TETRACYCLINES. EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS. Adults: The usual dose of oral doxycycline is 200 mg on the first day of treatment (administered 100 mg every 12 hours), followed by a maintenance dose of 100 mg daily. The maintenance dose may be administered as a single dose or as 50 mg every 12 hours. In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended. For Pediatric Patients Above 8 Years of Age: The recommended dosage schedule for children weighing 45 kg or less is 4.4 mg/kg of body weight divided into two doses on the first day of treatment, followed by 2.2 mg/kg of body weight given as a single daily dose or divided into two doses on subsequent days. For more severe infections up to 4.4 mg/kg of body weight may be used. For children over 45 kg, the usual adult dose should be used. Administration of adequate amounts of fluid along with capsule and tablet forms of drugs in the tetracycline-class is recommended to wash down the drugs and reduce the risk of esophageal irritation and ulceration [see Adverse Reactions (6.1)]. If gastric irritation occurs, doxycycline may be given with food or milk [see Clinical Pharmacology (12)]. When used in streptococcal infections, therapy should be continued for 10 days. Uncomplicated Urethral, Endocervical, or Rectal Infection in Adults Caused by Chlamydia Trachomatis: 100 mg by mouth twice a day for 7 days. Uncomplicated Gonococcal Infections in Adults (Except Anorectal Infections in Men): 100 mg, by mouth, twice-a-day for 7 days. As an alternative single visit dose, administer 300 mg stat followed in an hour by a second 300 mg dose. Nongonococcal Urethritis (NGU) Caused by U. Urealyticum: 100 mg by mouth twice-a-day for 7 days. Syphilis Early: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice-a-day for 2 weeks. Syphilis of More Than One Year s Duration: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice-a-day for 4 weeks. Acute Epididymo-Orchitis Caused by C. Trachomatis: 100 mg, by mouth, twice-a-day for at least 10 days. 2.2 For Prophylaxis of Malaria For adults, the recommended dose is 100 mg daily. For children over 8 years of age, the recommended dose is 2 mg/kg given once daily up to the adult dose. Prophylaxis should begin 1 or 2 days before travel to the malarious area. Prophylaxis should be continued daily during travel in the malarious area and for 4 weeks after the traveler leaves the malarious area. 2.3 Inhalational Anthrax (Post-Exposure) Adults: 100 mg, of doxycycline, by mouth, twice-a-day for 60 days. Children: weighing less than 45 kg, 2.2 mg/kg of body weight, by mouth, twice-a-day for 60 days. Children weighing 45 kg or more should receive the adult dose. 2.4 Sprinkling the Tablet over Applesauce Doxycycline hyclate delayed-release tablets may also be administered by carefully breaking up the tablet and sprinkling the tablet contents (delayed-release beads) on a spoonful of applesauce. The delayed-release beads must not be crushed or damaged when breaking up the tablet. Any loss of beads in the transfer would prevent using the dose. The applesauce/doxycycline mixture should be swallowed immediately without chewing and may be followed by a glass of water if desired. The applesauce should not be hot, and it should be soft enough to be swallowed without chewing. In the event that a prepared dose of applesauce/doxycycline cannot be taken immediately, the mixture should be discarded and not stored for later use. 3 DOSAGE FORMS AND STRENGTHS Doxycycline Hyclate Delayed-Release Tablets, USP are available containing delayed-release beads of doxycycline hyclate, USP equivalent to 50 mg of doxycycline. Doxycycline Hyclate Delayed-Release Tablets USP, 50 mg are white, round, unscored tablets containing yellow beads debossed with M on one side of the tablet and D36 on the other side. Each tablet contains specially coated beads of doxycycline hyclate, USP equivalent to 50 mg of doxycycline. 4 CONTRAINDICATIONS The drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. 5 WARNINGS AND PRECAUTIONS 5.1 Tooth Development The use of drugs of the tetracycline-class during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drugs but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Doxy cycline should not be used in this age group, except for anthrax, including inhalational anthrax (post-exposure), unless other drugs are not likely to be effective or are contraindicated. 5.2 Clostridium difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including doxycycline hyclate delayed-release tablets, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has

35 been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.3 Photosensitivity Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema. 5.4 Superinfection As with other antibacterial preparations, use of doxycycline may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, the antibacterial should be discontinued and appropriate therapy instituted. 5.5 Intracranial Hypertension Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline including doxycycline. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Avoid concomitant use of isotretinoin and doxycycline because isotretinoin is also known to cause pseudotumor cerebri. Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize. 5.6 Skeletal Development All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the fetus. 5.7 Antianabolic Action The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function. 5.8 Malaria Doxycycline offers substantial but not complete suppression of the asexual blood stages of Plasmodium strains. Doxycycline does not suppress P. falciparum s sexual blood stage gametocytes. Subjects completing this prophylactic regimen may still transmit the infection to mosquitoes outside endemic areas. 5.9 Development of Drug-Resistant Bacteria Prescribing doxycycline hyclate delayed-release tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria Laboratory Monitoring for Long-Term Therapy In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic studies should be performed. 6 ADVERSE REACTIONS 6.1 Postmarketing Experience The following adverse reactions have been identified during post-approval use of doxycycline. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Due to oral doxycycline s virtually complete absorption, side effects to the lower bowel, particularly diarrhea, have been infrequent. The following adverse reactions have been observed in patients receiving tetracyclines: Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region. Hepatotoxicity has been reported. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline-class. Most of these patients took medications immediately before going to bed [see Dosage and Administration (2.1)]. Skin: Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, and erythema multiforme have been reported. Photosensitivity is discussed above [see Warnings and Precautions (5.3)]. Renal: Rise in BUN has been reported and is apparently dose-related [see Warnings and Precautions (5.7)]. Hypersensitivity Reactions: Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus. Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported. Intracranial Hypertension: Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline [see Warnings and Pre cautions (5.5)]. Thyroid Gland Changes: When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function are known to occur. 3 7 DRUG INTERACTIONS 7.1 Anticoagulant Drugs Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. 7.2 Penicillin Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin. 7.3 Antacids and Iron Preparations Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron-containing preparations. 7.4 Oral Contraceptives Concurrent use of tetracycline may render oral contraceptives less effective. 7.5 Barbiturates and Anti-Epileptics Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. 7.6 Penthrane The concurrent use of tetracycline and Penthrane (methoxyflurane) has been reported to result in fatal renal toxicity. 7.7 Drug/Laboratory Test Interactions False elevations of urinary catecholamines may occur due to interference with the fluorescence test. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category D: There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for the treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS - the Teratogen Information System - concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk.1 A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. Sixty-three (0.19%) of the controls and 56 (0.30%) of the cases were treated with doxycycline. This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e., in the second and third months of gestation), with the exception of a marginal relationship with neural tube defect based on only two-exposed cases.2 A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of age.3 Nonteratogenic Effects: [See Warnings and Precautions (5.1, 5.6).] 8.3 Nursing Mothers Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not necessarily contraindicated. The effects of prolonged exposure to doxycycline in breast milk are unknown.4 Because of the potential for serious adverse reactions in nursing infants from doxycycline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother [see Warnings and Precautions (5.1, 5.6)]. 8.4 Pediatric Use Because of the effects of drugs of the tetracycline-class on tooth development and growth, doxycycline should not be used in pediatric patients to the age of 8 years, unless the potential benefits are expected to outweigh the risks such as for anthrax, or when other drugs are not likely to be effective or are contraindicated [see Warnings and Precautions (5.1, 5.6) and Dosage and Ad ministration (2.1, 2.3)]. 8.5 Geriatric Use Clinical studies of doxycycline did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Doxycycline hyclate delayed-release 50 mg tablets contain 1.43 mg (0.06 meq) of sodium. 10 OVERDOSAGE In case of overdosage, discontinue medication, treat symptomatically and in stitute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage. 11 DESCRIPTION Doxycycline hyclate delayed-release tablets, USP, for oral administration, contain specially coated beads of doxycycline hyclate, a broad-spectrum antibacterial synthetically derived from oxytetracycline, in a delayed-release formulation for oral administration. The structural formula for doxycycline hyclate is: with a molecular formula of (C 22 H 24 N 2 O 8 HCl) 2 C 2 H 6 O H 2 O and a molecular weight of The

36 chemical designation for doxycycline hyclate is 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. Doxycycline hyclate, USP is a yellow to light yellow crystalline powder soluble in water and in solutions of alkali hydroxides and carbonates. Doxycycline has a high degree of lipid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form. Inactive ingredients in the tablet formulation are: anhydrous lactose, colloidal silicon dioxide, crospovidone, hypromellose phthalate, lactose monohydrate, povidone, pregelatinized starch (corn), sodium chloride, sodium lauryl sulfate, stearic acid, talc, and triethyl citrate. USP Dissolution Test Pending CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Doxycycline is an antibacterial drug [see Microbiology (12.4)] Pharmacokinetics Doxycycline is virtually completely absorbed after oral administration. Following administration of a single 200 mg dose to adult volunteers, average serum doxycycline levels were 2.6 mcg/ml at 2 hours decreasing to 1.45 mcg/ml at 24 hours. The mean C max and AUC 0- of doxycycline are 24% and 13% lower, respectively, following single dose administration of doxycycline hyclate delayed-release tablets, 100 mg with a high fat meal (including milk) compared to fasted conditions. The mean C max of doxycycline is 19% lower and the AUC 0- is unchanged following single dose administration of doxycycline hyclate tablets, 150 mg with a high fat meal (including milk) compared to fasted conditions. The clinical significance of these differences is unknown. When doxycycline hyclate delayed-release tablets are sprinkled over applesauce and taken with or without water, the extent of doxycycline absorption is unchanged, but the rate of absorption is increased slightly. Tetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with a creatinine clearance of about 75 ml/min. This percentage may fall as low as 1% to 5%/72 hours in individuals with a creatinine clearance below 10 ml/min. Studies have shown no significant difference in the serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the serum half-life Microbiology Mechanism of Action: Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against a broad range of Gram-positive and Gramnegative bacteria. Cross-resistance between tetracyclines is common. Doxycycline has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for doxycycline hyclate delayed-release tablets [see Indications and Usage (1)]. Gram-Negative Bacteria Acinetobacter species Bartonella bacilliformis Brucella species Campylobacter fetus Enterobacter aerogenes Escherichia coli Francisella tularensis Haemophilus ducreyi Haemophilus influenzae Klebsiella granulomatis Klebsiella species Neisseria gonorrhoeae Shigella species Vibrio cholerae Yersinia pestis Gram-Positive Bacteria Bacillus anthracis Streptococcus pneumoniae Anaerobic Bacteria Clostridium species Fusobacterium fusiforme Propionibacterium acnes Other Bacteria Norcardiae and other aerobic Actinomyces species Borrelia recurrentis Chlamydophila psittaci Chlamydia trachomatis Mycoplasma pneumoniae Rickettsiae Treponema pallidum Treponema pallidum subspecies pertenue Ureaplasma urealyticum Parasites Balantidium coli Entamoeba species Plasmodium falciparum* *Doxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum but not against the gametocytes of P. falciparum. The precise mechanism of action of the drug is not known. Susceptibility Test Methods: When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired path ogens. These reports should aid the physician in selecting the most effective antimicrobial. Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth and/or agar).5,6,8 The MIC values should be interpreted according to the criteria provided in Table 1. Diffusion Techniques: Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. Zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standard test method.5,7,8 This procedure uses paper disks impregnated with 30 mcg doxycycline to test the susceptibility of bacteria to doxycycline. The disk diffusion interpretive criteria are provided in Table 1. Anaerobic Techniques: For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method.9 The MIC values obtained should be interpreted according to the criteria provided in Table 1. Table 1: Susceptibility Test Interpretive Criteria for Doxycycline and Tetracycline Minimal Inhibitory Zone Agar Bacteria a Concentration Diameter Dilution (mcg/ml) (mm) (mcg/ml) S I R S I R S I R Acinetobacter spp. Doxycycline to Tetracycline to Anaerobes Tetracycline Bacillus anthracis ab Doxycycline Tetracycline Brucella species ab Doxycycline Tetracycline Enterobacteriacea Doxycycline to Tetracycline to Franciscella tularensis ab Doxycycline Tetracycline Haemophilus influenzae Tetracycline to Mycoplasma pneumoniae Tetracycline Norcardiae and other aerobic Actinomyces species ab Doxycycline 1 2 to Neisseria gonorrhoeae c Tetracycline to to 1 2 Streptococcus pneumoniae Doxycycline > 1 > to 27 < Tetracycline 1 2 > 4 > to 27 < Vibrio cholerae Doxycycline Tetracycline Yersinia pestis Doxycycline Tetracycline Ureaplasma urealyticum Tetracycline a Organisms susceptible to tetracycline are also considered susceptible to doxycycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to doxycycline. b The current absence of resistance isolates precludes defining any results other than Susceptible. If isolates yielding MIC results other than susceptible, they should be submitted to a reference laboratory for further testing. c Gonococci with 30 mcg tetracycline disk zone diameters of less than 19 mm usually indicate a plasmid-mediated tetracycline resistant Neisseria gonorrhoeae isolate. Resistance in these strains should be confirmed by a dilution test (MIC greater than or equal to 16 mcg/ml). A report of Susceptible (S) indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of Intermediate (I) indicates that the result should be considered

37 equivocal, and, if the bacteria is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected. Quality Control: Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test.5,6,7,8,9,10,11 Standard doxycycline and tetracycline powders should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg doxycycline disk the criteria noted in Table 2 should be achieved. Table 2: Acceptable Quality Control Ranges for Susceptibility Testing for Doxycycline and Tetracycline Minimal Inhibitory Zone Agar QC Strain Concentration Diameter Dilution (mcg/ml) (mm) (mcg/ml) Enterococcus faecalis ATCC Doxycycline 2 to Tetracycline 8 to Escherichia coli ATCC Doxycycline 0.5 to 2 18 to 24 - Tetracycline 0.5 to 2 18 to 25 - Eubacterium lentum ATCC Doxycycline 2 to Haemophilus influenzae ATCC Tetracycline 4 to to 22 - Neisseria gonorrhoeae ATCC Tetracycline - 30 to to 1 Staphylococcus aureus ATCC Doxycycline - 23 to 29 - Tetracycline - 24 to 30 - Staphylococcus aureus ATCC Doxycycline 0.12 to Tetracycline 0.12 to Streptococcus pneumoniae ATCC Doxycycline to to 34 - Tetracycline 0.06 to to 31 - Bacteroides fragilis ATCC Tetracycline to 0.5 Bacteroides thetaiotaomicron ATCC Doxycycline 2 to Tetracycline to 32 Mycoplasma pneumoniae ATCC Tetracycline 0.06 to to 0.5 Ureaplasma urealyticum ATCC Tetracycline NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibiotics, oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors). Likewise, although mutagenicity studies of doxycycline have not been conducted, positive results in in vitro mammalian cell assays have been reported for related antibacterials (tetracycline, oxytetracycline). Doxycycline administered orally at dosage levels as high as 250 mg/kg/day had no apparent effect on the fertility of female rats. Effect on male fertility has not been studied Animal Toxicology and/or Pharmacology Hyperpigmentation of the thyroid has been produced by members of the tetracycline-class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO 4, and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO 4, and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline. Minocycline, tetracycline PO 4, methacycline, doxycycline, tetracycline base, oxytetracycline hydrochloride, and tetracycline hydrochloride, were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet. Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs (minocycline); in chickens (chlortetracycline); and in rats and mice (oxytetracycline). Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline. Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues. 15 REFERENCES 1. Friedman JM, Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press: 2000: Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997; 89: Horne HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 1980; 25: Hale T. Medications and Mothers Milk. 9th edition. Amarillo, TX: Pharmasoft Publishing 2000; Clinical and Laboratory Standards Institute (CLSI). Performance Stand ards for Antimicrobial Susceptibility Testing; Twenty-fourth Informational Supplement. CLSI document M100-S24, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard Ninth Edition. CLSI document M07-A9, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Anti - microbial Disk Diffusion Susceptibility Tests; Approved Standard Eleventh Edition. CLSI document M02-A11, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline Second Edition. CLSI document M45-A2, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard Eighth Edition. CLSI document M11-A8, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute (CLSI). Methods for Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard Second Edition. CLSI document M24-A2, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing for Human Mycoplasmas; Approved Guideline. CLSI document M43-A, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, HOW SUPPLIED/STORAGE AND HANDLING Doxycycline Hyclate Delayed-Release Tablets, USP are available containing delayed-release beads of doxycycline hyclate, USP equivalent to 50 mg of doxycycline. The 50 mg tablets are white, round, unscored tablets containing yellow beads debossed with M on one side of the tablet and D36 on the other side. They are available as follows: NDC bottles of 60 tablets NDC bottles of 120 tablets NDC bottles of 500 tablets Store at 20 to 25 C (68 to 77 F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. 17 PATIENT COUNSELING INFORMATION Patients taking doxycycline for malaria prophylaxis should be advised: that no present-day antimalarial agent, including doxycycline, guarantees protection against malaria. to avoid being bitten by mosquitoes by using personal protective measures that help avoid contact with mosquitoes, especially from dusk to dawn (for example, staying in well-screened areas, using mosquito nets, covering the body with clothing, and using an effective insect repellent). that doxycycline prophylaxis: should begin 1 to 2 days before travel to the malarious area, should be continued daily while in the malarious area and after leaving the malarious area, should be continued for 4 further weeks to avoid development of malaria after returning from an endemic area, should not exceed 4 months. All patients taking doxycycline should be advised: to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (for example, skin eruptions, etc.) occurs. Sunscreen or sunblock should be considered [see Warnings and Precautions (5.3)]. to drink fluids liberally along with doxycycline to reduce the risk of esophageal irritation and ulceration [see Adverse Reactions (6.1)]. that the absorption of tetracyclines is reduced when taken with foods, especially those that contain calcium. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk [see Drug Interactions (7.3)]. that the absorption of tetracyclines is reduced when taken with antacids containing aluminum, calcium or magnesium, bismuth subsalicylate, and iron-containing preparations [see Drug Interactions (7.3)]. that the use of doxycycline might increase the incidence of vaginal candidiasis. Diarrhea is a common problem caused by antibacterials which usually ends when the antibacterial is

38 discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of antibacterial. If this occurs, patients should contact their physician as soon as possible. Patients should be counseled that antibacterial drugs including doxycycline hyclate delayed-release tablets should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When doxycycline hyclate delayed-release tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by doxycycline hyclate delayed-release tablets or other antibacterial drugs in the future. The brands listed are trademarks of their respective owners. Mylan Pharmaceuticals Inc. Morgantown, WV U.S.A. Revised: 4/2016 DXYDR50:R1 6

39 DXYDR:R19 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DOXYCYCLINE HYCLATE DELAYED-RELEASE TABLETS safely and effectively. See Full Prescribing Information for DOXYCYCLINE HYCLATE DELAYED-RELEASE TABLETS. DOXYCYCLINE HYCLATE delayed-release tablets, for oral use. Initial U.S. Approval: RECENT MAJOR CHANGES Dosage and Administration (2.1) 04/2016 Warnings and Precautions (5.1) 04/ INDICATIONS AND USAGE Doxycycline hyclate delayed-release tablets are a tetracycline-class drug indicated for: Rickettsial infections (1.1) Sexually transmitted infections (1.2) Respiratory tract infections (1.3) Specific bacterial infections (1.4) Ophthalmic infections (1.5) Anthrax, including inhalational anthrax (post-exposure) (1.6) Alternative treatment for selected infections when penicillin is contraindicated (1.7) Adjunctive therapy in acute intestinal amebiasis and severe acne (1.8) Prophylaxis of malaria (1.9) To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline hyclate and other antibacterial drugs, doxycycline hyclate delayed-release tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1) DOSAGE AND ADMINISTRATION Adults: Doxycycline hyclate delayed-release tablets The usual dosage is 200 mg on the first day of treatment (administered 100 mg every 12 hours) followed by a maintenance dose of 100 mg daily. (2.1) In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended. (2.1) Pediatric Patients: Doxycycline hyclate delayed-release tablets For all pediatric patients weighing less than 45 kg with severe or lifethreatening infections (e.g., anthrax, Rocky Mountain spotted fever), the recommended dose is 2.2 mg per kg of body weight administered every 12 hours. Pediatric patients weighing 45 kg or more should receive the adult dose. (2.1) For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dose is 4.4 mg per kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.2 mg per kg of body weight (given as a single daily dose or divided into two doses. For pediatric patients weighing over 45 kg, the usual adult dose should be used. (2.1) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Rickettsial Infections 1.2 Sexually Transmitted Infections 1.3 Respiratory Tract Infections 1.4 Specific Bacterial Infections 1.5 Ophthalmic Infections 1.6 Anthrax Including Inhalational Anthrax (Post-Exposure) 1.7 Alternative Treatment for Selected Infections when Penicillin is Contraindicated 1.8 Adjunctive Therapy for Acute Intestinal Amebiasis and Severe Acne 1.9 Prophylaxis of Malaria 2 DOSAGE AND ADMINISTRATION 2.1 Usual Dosage and Administration 2.2 For Prophylaxis of Malaria 2.3 Inhalational Anthrax (Post-Exposure) 2.4 Sprinkling the Tablet over Applesauce 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Tooth Development 5.2 Clostridium difficile Associated Diarrhea 5.3 Photosensitivity 5.4 Superinfection 5.5 Intracranial Hypertension 5.6 Skeletal Development 5.7 Antianabolic Action 5.8 Malaria 5.9 Development of Drug-Resistant Bacteria 5.10 Laboratory Monitoring for Long-Term Therapy 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline hyclate delayed-release tablets and other antibacterial drugs, doxycycline hyclate delayed-release tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Doxycycline is a tetracycline-class antibacterial indicated in the following conditions or diseases: 1.1 Rickettsial Infections Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae. 1.2 Sexually Transmitted Infections Uncomplicated urethral, endocervical or rectal infections caused by Chlamydia trachomatis. Nongonococcal urethritis caused by Ureaplasma urealyticum. Lymphogranuloma venereum caused by Chlamydia trachomatis. Granuloma inguinale caused by Klebsiella granulomatis. Uncomplicated gonorrhea caused by Neisseria gonorrhoeae. Chancroid caused by Haemophilus ducreyi. 1.3 Respiratory Tract Infections Respiratory tract infections caused by Mycoplasma pneumoniae. Psittacosis (ornithosis) caused by Chlamydophila psittaci. Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug: Respiratory tract infections caused by Haemophilus influenzae. Respiratory tract infections caused by Klebsiella species. Upper respiratory infections caused by Streptococcus pneumoniae. 1.4 Specific Bacterial Infections Relapsing fever due to Borrelia recurrentis. Plague due to Yersinia pestis. Tularemia due to Francisella tularensis. Cholera caused by Vibrio cholerae. Campylobacter fetus infections caused by Campylobacter fetus. Brucellosis due to Brucella species (in conjunction with streptomycin) DOSAGE FORMS AND STRENGTHS Doxycycline Hyclate Delayed-Release Tablets: 75 mg, 100 mg and 200 mg (3) CONTRAINDICATIONS Doxycycline is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. (4) WARNINGS AND PRECAUTIONS The use of drugs of the tetracycline-class during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). (2.2, 5.1) Clostridium difficile-associated diarrhea (CDAD) has been reported: Evaluate patients if diarrhea occurs. (5.2) Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Limit sun exposure. (5.3) Overgrowth of non-susceptible organisms, including fungi, may occur. If such infections occur, discontinue use and institute appropriate therapy. (5.4) ADVERSE REACTIONS Adverse reactions observed in patients receiving tetracyclines include anorexia, nausea, vomiting, diarrhea, rash, photosensitivity, urticaria, and hemolytic anemia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at ( INFO-RX) or FDA at FDA-1088 or DRUG INTERACTIONS Patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. (7.1) Avoid co-administration of tetracyclines with penicillin. (7.2) Absorption of tetracyclines, including doxycycline hyclate delayed-release tablets, is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate and iron-containing preparations. (7.3) Concurrent use of tetracycline, including doxycycline hyclate delayed-release tablets, may render oral contraceptives less effective. (7.4) Barbiturates, carbamazepine and phenytoin decrease the half-life of doxy - cycline. (7.5) USE IN SPECIFIC POPULATIONS Tetracycline-class drugs can cause fetal harm when administered to a pregnant woman, but data for doxycycline are limited. (5.6, 8.1) Tetracyclines are excreted in human milk; however, the extent of absorption of doxycycline in the breastfed infant is not known. Doxycycline use during nursing should be avoided if possible. (8.3) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 7/2016 DXYDR:R Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Anticoagulant Drugs 7.2 Penicillin 7.3 Antacids and Iron Preparations 7.4 Oral Contraceptives 7.5 Barbiturates and Anti-Epileptics 7.6 Penthrane 7.7 Drug/Laboratory Test Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the Full Prescribing Information are not listed. Bartonellosis due to Bartonella bacilliformis. Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following gram-negative microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug: Escherichia coli Enterobacter aerogenes Shigella species Acinetobacter species Urinary tract infections caused by Klebsiella species. 1.5 Ophthalmic Infections Trachoma caused by Chlamydia trachomatis, although the infectious agent is not always eliminated as judged by immunofluorescence. Inclusion conjunctivitis caused by Chlamydia trachomatis. 1.6 Anthrax Including Inhalational Anthrax (Post-Exposure) Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. 1.7 Alternative Treatment for Selected Infections when Penicillin is Con - traindicated When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of the following infections: Syphilis caused by Treponema pallidum. Yaws caused by Treponema pallidum subspecies pertenue. Vincent s infection caused by Fusobacterium fusiforme. Actinomycosis caused by Actinomyces israelii. Infections caused by Clostridium species. 1.8 Adjunctive Therapy for Acute Intestinal Amebiasis and Severe Acne In acute intestinal amebiasis, doxycycline may be a useful adjunct to amebicides. In severe acne, doxycycline may be useful adjunctive therapy. 1.9 Prophylaxis of Malaria Doxycycline is indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (less than 4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains [see Dosage and Admin - istration (2.2) and Patient Counseling Information (17)]. 2 DOSAGE AND ADMINISTRATION 2.1 Usual Dosage and Administration The usual dosage and frequency of administration of doxycycline differs from that of the other tetracyclines. Exceeding the recommended dosage may result in an increased incidence of side effects. Adults: The usual dose of oral doxycycline is 200 mg on the first day of treatment (administered 100 mg every 12 hours), followed by a maintenance dose of 100 mg daily. The maintenance dose may be administered as a single dose or as 50 mg every 12 hours. In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended. Pediatric Patients: For all pediatric patients weighing less than 45 kg with severe or lifethreatening infections (e.g., anthrax, Rocky Mountain spotted fever), the recommended dosage of doxycycline is 2.2 mg per kg of body weight administered every 12 hours. Pediatric patients weighing 45 kg or more should receive the adult dose [see Warnings and Precautions (5.1)]. For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dosage schedule of doxycycline is 4.4 mg per kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.2 mg per kg of body weight (given as a single daily dose or divided into twice daily doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used. Administration of adequate amounts of fluid along with capsule and tablet forms of drugs in the tetracycline-class is recommended to wash down the drugs and reduce the risk of esophageal irritation and ulceration [see Adverse Reactions (6.1)]. If gastric irritation occurs, doxycycline may be given with food or milk [see Clinical Pharmacology (12)]. When used in streptococcal infections, therapy should be continued for 10 days. Uncomplicated Urethral, Endocervical, or Rectal Infection Caused by Chlamydia Trachomatis: 100 mg by mouth twice a day for 7 days. As an alternate dosing regimen for uncomplicated urethral or endocervical infection caused by Chlamydia trachomatis, administer 200 mg by mouth once-a-day for 7 days. Uncomplicated Gonococcal Infections in Adults (Except Anorectal Infections in Men): 100 mg, by mouth, twice-a-day for 7 days. As an alternate single visit dose, administer 300 mg stat followed in one hour by a second 300 mg dose. Nongonococcal Urethritis (NGU) Caused by U. Urealyticum: 100 mg by mouth twice-a-day for 7 days. Syphilis Early: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice-a-day for 2 weeks. Syphilis of More Than One Year s Duration: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice-a-day for 4 weeks. Acute Epididymo-Orchitis Caused by C. Trachomatis: 100 mg, by mouth, twice-a-day for at least 10 days. 2.2 For Prophylaxis of Malaria For adults, the recommended dose is 100 mg daily. For children over 8 years of age, the recommended dose is 2 mg/kg given once daily up to the adult dose. Prophylaxis should begin 1 or 2 days before travel to the malarious area. Prophylaxis should be continued daily during travel in the malarious area and for 4 weeks after the traveler leaves the malarious area. 2.3 Inhalational Anthrax (Post-Exposure) Adults: 100 mg, of doxycycline, by mouth, twice-a-day for 60 days. Children: weighing less than 45 kg, 2.2 mg/kg of body weight, by mouth, twicea-day for 60 days. Children weighing 45 kg or more should receive the adult dose. 2.4 Sprinkling the Tablet over Applesauce Doxycycline hyclate delayed-release tablets may also be administered by carefully breaking up the tablet and sprinkling the tablet contents (delayed-release beads) on a spoonful of applesauce. The delayed-release beads must not be crushed or damaged when breaking up the tablet. Any loss of beads in the transfer would prevent using the dose. The applesauce/doxycycline hyclate delayed-release tablets mixture should be swallowed immediately without chewing and may be followed by a glass of water if desired. The applesauce should not be hot, and it should be soft enough to be swallowed without chewing. In the event that a prepared dose of applesauce/doxycycline hyclate delayed-release tablets cannot be taken immediately, the mixture should be discarded and not stored for later use. 3 DOSAGE FORMS AND STRENGTHS Doxycycline Hyclate Delayed-Release Tablets, USP are available containing delayed-release beads of doxycycline hyclate, USP equivalent to 75 mg, 100 mg or 200 mg of doxycycline. The 75 mg tablets are white, round, scored tablets containing yellow beads debossed with M on one side of the tablet and D to the left of the score and 31 to the right of the score on the other side. Each tablet contains specially coated beads of doxycycline hyclate, USP equivalent to 75 mg of doxycycline. The 100 mg tablets are white, round, scored tablets containing yellow beads debossed with M on one side of the tablet and D to the left of the score and 32 to the right of the score on the other side. Each tablet contains specially coated beads of doxycycline hyclate, USP equivalent to 100 mg of doxycycline. The 200 mg tablets are white, capsule shaped, scored tablets containing yellow beads debossed with M on one side of the tablet and D to the left of the score and 34 to the right of the score on the other side. Each tablet contains specially coated beads of doxycycline hyclate, USP equivalent to 200 mg of doxycycline. 4 CONTRAINDICATIONS The drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. 5 WARNINGS AND PRECAUTIONS 5.1 Tooth Development The use of drugs of the tetracycline-class during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drugs but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use doxycycline hyclate delayed-release tablets in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies. 5.2 Clostridium difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including doxycycline hyclate delayed-release tablets, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.3 Photosensitivity Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema. 5.4 Superinfection As with other antibacterial preparations, use of doxycycline hyclate delayedrelease tablets may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, the antibacterial should be discontinued and appropriate therapy instituted. 5.5 Intracranial Hypertension Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline including doxycycline hyclate delayed-release tablets. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Avoid concomitant use of isotretinoin and doxycycline hyclate delayed-release tablets because isotretinoin is also known to cause pseudotumor cerebri. Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize. 5.6 Skeletal Development All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the fetus. 5.7 Antianabolic Action The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function. 5.8 Malaria Doxycycline offers substantial but not complete suppression of the asexual blood stages of Plasmodium strains. Doxycycline does not suppress P. falciparum s sexual blood stage gametocytes. Subjects completing this prophylactic regimen may still transmit the infection to mosquitoes outside endemic areas. 5.9 Development of Drug-Resistant Bacteria Prescribing doxycycline hyclate delayed-release tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria Laboratory Monitoring for Long-Term Therapy In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic studies should be performed. 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience The safety and efficacy of doxycycline hyclate delayed-release tablets, 200 mg as a single daily dose was evaluated in a multicenter, randomized, doubleblind, active-controlled study. Doxycycline hyclate delayed-release tablets, 200 mg was given orally once-a-day for 7 days and compared to doxycycline hyclate capsules 100 mg given orally twice daily for 7 days for the treatment of men and women with uncomplicated urogenital C. trachomatis infection. Adverse events in the Safety Population were reported by 99 (40.2%) subjects in the doxycycline hyclate delayed-release tablets, 200 mg treatment group and 132 (53.2%) subjects in the doxycycline hyclate capsules reference treatment group. Most AEs were mild in intensity. The most commonly reported adverse events in both treatment groups were nausea, vomiting, diarrhea, and bacterial vaginitis, Table 1. Table 1: Adverse Reactions Reported in Greater Than or Equal to 2% of Subjects Doxycycline Hyclate Delayed-Release Tablets, 200 mg N = 246 Preferred Term n (%) Subjects with any AE 99 (40.2) Nausea 33 (13.4) Vomiting 20 (8.1) Headache 5 (2.0) Diarrhea 8 (3.3) Abdominal Pain Upper 5 (2.0) Vaginitis Bacterial 8 (3.3) Vulvovaginal Mycotic Infection 5 (2.0) Because clinical trials are conducted under prescribed conditions, adverse reaction rates observed in the clinical trial may not always reflect the rates observed in practice. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of doxycycline. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate a causal relationship to drug exposure. Due to oral doxycycline s virtually complete absorption, side effects to the lower bowel, particularly diarrhea, have been infrequent. The following adverse reactions have been observed in patients receiving tetracyclines: Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, en - terocolitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region. Hepatotoxicity has been reported. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline-class. Most of these patients took medications immediately before going to bed [see Dosage and Administration (2.1)]. Skin: Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, and erythema multiforme have been reported. Photosensitivity is discussed above [see Warnings and Precautions (5.3)]. Renal: Rise in BUN has been reported and is apparently dose-related [see Warnings and Precautions (5.7)]. Hypersensitivity Reactions: Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus. Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported. Intracranial Hypertension: Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline [see Warnings and Pre cautions (5.5)]. Thyroid Gland Changes: When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function are known to occur. 7 DRUG INTERACTIONS 7.1 Anticoagulant Drugs Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. 7.2 Penicillin Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin. 7.3 Antacids and Iron Preparations Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron-containing preparations.

40 7.4 Oral Contraceptives Concurrent use of tetracycline may render oral contraceptives less effective. 7.5 Barbiturates and Anti-Epileptics Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. 7.6 Penthrane The concurrent use of tetracycline and Penthrane (methoxyflurane) has been reported to result in fatal renal toxicity. 7.7 Drug/Laboratory Test Interactions False elevations of urinary catecholamines may occur due to interference with the fluorescence test. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category D: There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for the treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS - the Teratogen Information System - concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk. 1 A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. Sixty-three (0.19%) of the controls and 56 (0.30%) of the cases were treated with doxycycline. This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (that is, in the second and third months of gestation), with the exception of a marginal relationship with neural tube defect based on only two-exposed cases. 2 A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of age. 3 Nonteratogenic Effects: [See Warnings and Precautions (5.1, 5.6).] 8.3 Nursing Mothers Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines including doxycycline, by the breastfed infant is not known. Shortterm use by lactating women is not necessarily contraindicated. The effects of prolonged exposure to doxycycline in breast milk are unknown. 4 Because of the potential for serious adverse reactions in nursing infants from doxycycline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother [see Warnings and Precautions (5.1, 5.6)]. 8.4 Pediatric Use Because of the effects of drugs of the tetracycline-class on tooth development and growth, use doxycycline hyclate delayed-release tablets in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly, when there are no alternative therapies doxycycline hyclate delayed-release tablets [see Warnings and Precautions (5.1, 5.6) and Dosage and Administration (2.1, 2.3)]. 8.5 Geriatric Use Clinical studies of doxycycline hyclate delayed-release tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Doxycycline hyclate delayed-release 75 mg tablets contain 2.15 mg (0.09 meq) of sodium. Doxycycline hyclate delayed-release 100 mg tablets contain 2.86 mg (0.12 meq) of sodium. Doxycycline hyclate delayed-release 200 mg tablets contain 5.72 mg (0.24 meq) of sodium. 10 OVERDOSAGE In case of overdosage, discontinue medication, treat symptomatically and in - stitute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage. 11 DESCRIPTION Doxycycline hyclate delayed-release tablets, USP, for oral administration, contain specially coated beads of doxycycline hyclate, a broad-spectrum antibacterial synthetically derived from oxytetracycline, in a delayed-release formulation for oral administration. The structural formula for doxycycline hyclate is: with a molecular formula of (C 22 H 24 N 2 O 8 HCl) 2 C 2 H 6 O H 2 O and a molecular weight of The chemical designation for doxycycline hyclate is 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. Doxycycline hyclate, USP is a yellow to light yellow crystalline powder soluble in water and in solutions of alkali hydroxides and carbonates. Doxycycline has a high degree of lipid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form. Inactive ingredients in the tablet formulation are: anhydrous lactose, colloidal silicon dioxide, crospovidone, hypromellose phthalate, lactose monohydrate, povidone, pregelatinized starch (corn), sodium chloride, sodium lauryl sulfate, stearic acid, talc, and triethyl citrate. Meets USP Dissolution Test CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Doxycycline is an antibacterial drug [see Microbiology (12.4)] Pharmacokinetics Doxycycline is virtually completely absorbed after oral administration. Following single and multiple-dose administration of doxycycline hyclate delayed-release tablets, 200 mg to adult volunteers, average peak plasma doxycycline concentration (C max ) was 4.6 mcg/ml and 6.3 mcg/ml, respectively with median t max of 3 hours; the corresponding mean plasma concentration values 24 hours after single and multiple doses were 1.5 mcg/ml and 2.3 mcg/ml, respectively. The mean C max and AUC 0- of doxycycline are 24% and 13% lower, respectively, following single dose administration of doxycycline hyclate delayed-release tablets, 100 mg with a high fat meal (including milk) compared to fasted conditions. The mean C max of doxycycline is 19% lower and the AUC 0- is unchanged following single dose administration of doxycycline hyclate delayed-release tablets, 150 mg with a high fat meal (including milk) compared to fasted conditions. The clinical significance of these decreases is unknown. Doxycycline bioavailability from doxycycline hyclate delayed-release tablets, 200 mg was not affected by food, but the incidence of nausea was higher in fasted subjects. The 200 mg tablets may be administered without regard to meals. When doxycycline hyclate delayed-release tablets are sprinkled over applesauce and taken with or without water, the extent of doxycycline absorption is unchanged, but the rate of absorption is increased slightly. Tetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with a creatinine clearance of about 75 ml/min. This percentage may fall as low as 1% to 5%/72 hours in individuals with a creatinine clearance below 10 ml/min. Studies have shown no significant difference in the serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the serum half-life Microbiology Mechanism of Action: Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against a broad range of Gram-positive and Gram-negative bacteria. Cross resistance with other tetracyclines is common. Doxycycline has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert. Gram-Negative Bacteria Acinetobacter species Bartonella bacilliformis Brucella species Enterobacter aerogenes Escherichia coli Francisella tularensis Haemophilus ducreyi Haemophilus influenzae Klebsiella granulomatis Klebsiella species Neisseria gonorrhoeae Shigella species Vibrio cholerae Vibrio fetus Yersinia pestis Gram-Positive Bacteria Bacillus anthracis Streptococcus pneumoniae Anaerobes Clostridium species Fusobacterium fusiforme Propionibacterium acnes Other Bacteria Norcardiae and other aerobic Actinomyces species Borrelia recurrentis Chlamydophila psittaci Chlamydia trachomatis Mycoplasma pneumoniae Rickettsiae Treponema pallidum Treponema pallidum subspecies pertenue Ureaplasma urealyticum Parasites Balantidium coli Entamoeba species Plasmodium falciparum* *Doxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum, but not against the gametocytes of P. falciparum. The precise mechanism of action of the drug is not known. Susceptibility Testing Methods: When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and communityacquired path ogens. These reports should aid the physician in selecting the most effective antimicrobial. Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth and/or agar). 5,6,8,10,11 The MIC values should be interpreted according to the criteria provided in Table 2. Diffusion Techniques: Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standard test method. 5,7,8 This procedure uses paper disks impregnated with 30 mcg doxycycline to test the susceptibility of bacteria to doxycycline. The disk diffusion interpretive criteria are provided in Table 2. Anaerobic Techniques: For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method. 9 The MIC values obtained should be interpreted according to the criteria provided in Table 2. Table 2: Susceptibility Test Interpretive Criteria for Doxycycline and Tetracycline Minimal Inhibitory Zone Agar Bacteria a Concentration Diameter Dilution (mcg/ml) (mm) (mcg/ml) S I R S I R S I R Acinetobacter spp. Doxycycline to Tetracycline to Anaerobes Tetracycline Bacillus anthracis b Doxycycline Tetracycline Brucella species b Doxycycline Tetracycline Enterobacteriaceae Doxycycline to Tetracycline to Franciscella tularensis b Doxycycline Tetracycline Haemophilus influenzae Tetracycline to Mycoplasma pneumoniae b Tetracycline Neisseria gonorrhoeae c Tetracycline to to 1 2 Norcardiae and other aerobic Actinomyces species Doxycycline 1 2 to Streptococcus pneumoniae Doxycycline > 1 > to 27 < Tetracycline 1 2 > 4 > to 27 < Vibrio cholerae Doxycycline Tetracycline Yersinia pestis Doxycycline Tetracycline Ureaplasma urealyticum Tetracycline a Organisms susceptible to tetracycline are also considered susceptible to doxycycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to doxycycline. b The current absence of resistance isolates precludes defining any results other than Susceptible. If isolates yielding MIC results other than susceptible, they should be submitted to a reference laboratory for further testing. c Gonococci with 30 mcg tetracycline disk zone diameters of < 19 mm usually indicate a plasmid-mediated tetracycline resistant Neisseria gonorrhoeae isolate. Resistance in these strains should be confirmed by a dilution test (MIC 16 mcg/ml). A report of Susceptible (S) indicates that antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the bacteria is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug product is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the pathogen is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected. Quality Control: Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. 5,6,7,8,9,10,11 Standard doxycycline and tetracycline powders should provide the following range of MIC values noted in Table 3. For the diffusion technique using the 30 mcg doxycycline disk the criteria in Table 3 should be achieved. Table 3: Acceptable Quality Control Ranges for Susceptibility Testing for Doxycycline and Tetracycline QC Strain Minimal Inhibitory Zone Agar Concentration Diameter Dilution (mcg/ml) (mm) (mcg/ml) Enterococcus faecalis ATCC Doxycycline 2 to Tetracycline 8 to Escherichia coli ATCC Doxycycline 0.5 to 2 18 to 24 - Tetracycline 0.5 to 2 18 to 25 - Eggerthella lenta ATCC Doxycycline 2 to Haemophilus influenzae ATCC Tetracycline 4 to to 22 - Neisseria gonorrhoeae ATCC Tetracycline - 30 to to 1 Staphylococcus aureus ATCC Doxycycline - 23 to 29 - Tetracycline - 24 to 30 - Staphylococcus aureus ATCC Doxycycline 0.12 to Tetracycline 0.12 to Streptococcus pneumoniae ATCC Doxycycline to to 34 - Tetracycline 0.06 to to 31 - Bacteroides fragilis ATCC Tetracycline to 0.5 Bacteroides thetaiotaomicron ATCC Doxycycline 2 to Tetracycline to 32 Mycoplasma pneumoniae ATCC Tetracycline 0.06 to to 0.5 Ureaplasma urealyticum ATCC Tetracycline NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibacterials, oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors). Likewise, although mutagenicity studies of doxycycline have not been conducted, positive results in in vitro mammalian cell assays have been reported for related antibacterials (tetracycline, oxytetracycline). Doxycycline administered orally at dosage levels as high as 250 mg/kg/day had no apparent effect on the fertility of female rats. Effect on male fertility has not been studied Animal Toxicology and/or Pharmacology Hyperpigmentation of the thyroid has been produced by members of the tetracycline-class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO 4, and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO 4, and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline. Minocycline, tetracycline PO 4, methacycline, doxycycline, tetracycline base, oxytetracycline hydrochloride, and tetracycline hydrochloride, were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet. Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs (minocycline); in chickens (chlortetracycline); and in rats and mice (oxytetracycline). Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline. Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues. 14 CLINICAL STUDIES This was a randomized, double-blind, active-controlled, multicenter trial which enrolled 495 subjects, between 19 to 45 years of age with a confirmed diagnosis of urogenital C. trachomatis infection less than 14 days prior to enrollment, or partner(s) of a subject with a known positive test for urogenital C. trachomatis infection. The primary purpose of this study was to evaluate the efficacy and safety of doxycycline hyclate delayed-release tablets, 200 mg once daily versus doxycycline hyclate capsules, 100 mg twice daily for 7 days for the treatment of uncomplicated urogenital C. trachomatis infection. The primary efficacy objective was to demonstrate non-inferiority of the doxycycline hyclate delayed-release tablets, 200 mg once daily treatment regimen versus the doxycycline 100 mg twice daily treatment regimen for the indication using a negative nucleic acid amplification test (NAAT) at the test of cure visit (day 28) in the mitt population (subjects who were positive at baseline and took at least one day of study drug). Table 4: Primary Efficacy Outcome Microbiological Cure of C. trachomatis at Day 28 Doxycycline Hyclate Doxycycline Hyclate Delayed-Release Tablets, Capsules, 100 mg mitt Population 200 mg twice daily Difference once daily Cure Rate (%) Cure Rate (%) (%) N Microbiological Cure, n (%) 163 (86.7) 171 (90.0) -3.3% 95% Confidence Interval for Cure Rate -10.3, REFERENCES 1. Friedman JM, Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press: 2000: Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997; 89: Horne HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 1980; 25: Hale T. Medications and Mothers Milk. 9 th edition. Amarillo, TX: Pharmasoft Publishing 2000; Clinical and Laboratory Standards Institute (CLSI). Performance Stand - ards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement, CLSI document M100-S25. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard 10 th ed. CLSI document M07-A10. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard 11 th ed. CLSI document M02-A12. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute. Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline Second Edition. CLSI document M45-A2. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard Eighth Edition. CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA, Clinical and Laboratory Standards Institute. Susceptibility Testing of Mycobacteria, Norcardiae, and Other Aerobic Actinomycetes; Approved Standard Second Edition. CLSI document M24-A2. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA Clinical and Laboratory Standards Institute. Methods for Antimicrobial Susceptibility Testing for Human Mycoplasmas; Approved Guideline. CLSI document M43-A. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA HOW SUPPLIED/STORAGE AND HANDLING Doxycycline Hyclate Delayed-Release Tablets, USP are available containing delayed-release beads of doxycycline hyclate, USP equivalent to 75 mg, 100 mg or 200 mg of doxycycline. The 75 mg tablets are white, round, scored tablets containing yellow beads debossed with M on one side of the tablet and D to the left of the score and 31 to the right of the score on the other side. They are available as follows: NDC bottles of 60 tablets The 100 mg tablets are white, round, scored tablets containing yellow beads debossed with M on one side of the tablet and D to the left of the score and 32 to the right of the score on the other side. They are available as follows: NDC bottles of 100 tablets The 200 mg tablets are white, capsule shaped, scored tablets containing yellow beads debossed with M on one side of the tablet and D to the left of the score and 34 to the right of the score on the other side. They are available as follows: NDC bottles of 30 tablets NDC bottles of 60 tablets NDC bottles of 90 tablets NDC bottles of 500 tablets Store at 20 to 25 C (68 to 77 F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. 17 PATIENT COUNSELING INFORMATION Patients taking doxycycline for malaria prophylaxis should be advised: that no present-day antimalarial agent, including doxycycline, guarantees protection against malaria. to avoid being bitten by mosquitoes by using personal protective measures that help avoid contact with mosquitoes, especially from dusk to dawn (for example, staying in well-screened areas, using mosquito nets, covering the body with clothing, and using an effective insect repellent). that doxycycline prophylaxis: should begin 1 to 2 days before travel to the malarious area, should be continued daily while in the malarious area and after leaving the malarious area, should be continued for 4 further weeks to avoid development of malaria after returning from an endemic area, should not exceed 4 months. All patients taking doxycycline should be advised: to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (for example, skin eruptions, etc.) occurs. Sunscreen or sunblock should be considered [see Warnings and Precautions (5.3)]. to drink fluids liberally along with doxycycline to reduce the risk of esophageal irritation and ulceration [see Adverse Reactions (6.1)]. that the absorption of tetracyclines is reduced when taken with foods, especially those that contain calcium. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk [see Drug Interactions (7.3)]. that the absorption of tetracyclines is reduced when taken with antacids containing aluminum, calcium or magnesium, bismuth subsalicylate, and iron-containing preparations [see Drug Interactions (7.3)]. that the use of doxycycline might increase the incidence of vaginal candidiasis. Diarrhea is a common problem caused by antibacterials which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of antibacterial. If this occurs, patients should contact their physician as soon as possible. Patients should be counseled that antibacterial drugs including doxycycline hyclate delayed-release tablets should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When doxycycline hyclate delayed-release tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by doxycycline hyclate delayed-release tablets or other antibacterial drugs in the future. The brands listed are trademarks of their respective owners. Mylan Pharmaceuticals Inc. Morgantown, WV U.S.A. Revised: 7/2016 DXYDR:R19

41 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Monotherapy Dutasteride capsules are indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: improve symptoms, reduce the risk of acute urinary retention (AUR) and reduce the risk of the need for BPH-related surgery. 1.2 Combination with Alpha Adrenergic Antagonist Dutasteride capsules in combination with alpha adrenergic antagonist, tamsulosin, are indicated for the treatment of symptomatic BPH in men with an enlarged prostate. 1.3 Limitations of Use Dutasteride capsules are not approved for the prevention of prostate cancer. 2 DOSAGE AND ADMINISTRATION The capsules should be swallowed whole and not chewed or opened, as contact with the capsule contents may result in irritation of the oropharyngeal mucosa. Dutasteride capsules may be administered with or without food. 2.1 Monotherapy The recommended dose of dutasteride is one capsule (0.5 mg) taken once daily. 2.2 Combination with Alpha Adrenergic Antagonist The recommended dose of dutasteride is one capsule (0.5 mg) taken once daily and tamsulosin 0.4 mg taken once daily. 3 DOSAGE FORMS AND STRENGTHS 0.5 mg, buff opaque cap and buff opaque body, with a blue gelatin band that is radially printed with MYLAN on the cap and DU 0.5 on the body in black ink. 4 CONTRAINDICATIONS Dutasteride capsules are contraindicated for use in: Pregnancy. In animal reproduction and developmental toxicity studies, dutasteride inhibited development of male fetus external genitalia. Therefore, dutasteride may cause fetal harm when administered to a pregnant woman. If dutasteride is used during pregnancy or if the patient becomes pregnant while taking dutasteride, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)]. Women of childbearing potential [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)]. Pediatric patients [see Use in Specific Populations (8.4)]. Patients with previously demonstrated clinically significant hypersensitivity (e.g., serious skin reactions, angioedema) to dutasteride or other 5 alpha-reductase inhibitors [see Adverse Reactions (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Effects on Prostate-Specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection In clinical trials, dutasteride reduced serum PSA concentration by approximately 50% within 3 to 6 months of treatment. This decrease was predictable over the entire range of PSA values in subjects with symptomatic BPH, although it may vary in individuals. Dutasteride may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men taking dutasteride, a new PSA baseline should be established at least 3 months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on dutasteride may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5 alpha-reductase inhibitor. Noncompliance with dutasteride may also affect PSA test results. To interpret an isolated PSA value in a man treated with dutasteride for 3 months or more, the PSA value should be doubled for comparison with normal values in untreated men. The free-to-total PSA ratio (percent free PSA) remains constant, even under the influence of dutasteride. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving dutasteride, no adjustment to its value appears necessary. Coadministration of dutasteride and tamsulosin resulted in similar changes to serum PSA as dutasteride monotherapy. 5.2 Increased Risk of High-Grade Prostate Cancer In men aged 50 to 75 years with a prior negative biopsy for prostate cancer and a baseline PSA between 2.5 ng/ml and 10 ng/ml taking dutasteride in the 4-year Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, there was an increased incidence of Gleason score 8 to 10 prostate cancer compared with men taking placebo (dutasteride 1% versus placebo 0.5%) [see Indications and Usage (1.3), Adverse Reactions (6.1)]. In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR), similar results for Gleason score 8 to 10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%). 5 alpha-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5 alpha-reductase inhibitors to reduce prostate volume or trialrelated factors impacted the results of these trials has not been established. 5.3 Evaluation for Other Urological Diseases Prior to initiating treatment with dutasteride, consideration should be given to other urological conditions that may cause similar symptoms. In addition, BPH and prostate cancer may coexist. 5.4 Exposure of Women Risk to Male Fetus Dutasteride capsules should not be handled by a woman who is pregnant or who could become pregnant. Dutasteride is absorbed through the skin and could result in unintended fetal exposure. If a woman who is pregnant or who could become pregnant comes in contact with leaking dutasteride capsules, the contact area should be washed immediately with soap and water [see Use in Specific Populations (8.1)]. 5.5 Blood Donation Men being treated with dutasteride should not donate blood until at least 6 months have passed following their last dose. The purpose of this deferred period is to prevent administration of dutasteride to a pregnant female transfusion recipient. 5.6 Effect on Semen Characteristics The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in normal volunteers aged 18 to 52 (n = 27 dutasteride, n = 23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, the mean percent reductions from baseline in total sperm count, semen volume and sperm motility were 23%, 26% and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. Sperm concentration and sperm morphology were unaffected. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower than baseline. While mean values for all semen parameters at all timepoints remained within the normal ranges and did not meet predefined criteria for a clinically significant change (30%), two subjects in the dutasteride group had decreases in sperm count of greater than 90% from baseline at 52 weeks, with partial recovery at the 24-week follow-up. The clinical significance of dutasteride s effect on semen characteristics for an individual patient s fertility is not known. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trial of another drug and may not reflect the rates observed in practice. From clinical trials with dutasteride as monotherapy or in combination with tamsulosin: The most common adverse reactions reported in subjects receiving dutasteride were impotence, decreased libido, breast disorders (including breast enlargement and tenderness) and ejaculation disorders. The most common adverse reactions reported in subjects receiving combination therapy (dutasteride plus tamsulosin) were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders, and dizziness. Ejaculation disorders occurred significantly more in subjects receiving combination therapy (11%) compared with those receiving dutasteride (2%) or tamsulosin (4%) as monotherapy. Trial withdrawal due to adverse reactions occurred in 4% of subjects receiving dutasteride and 3% of subjects receiving placebo in placebo-controlled trials with dutasteride. The most common adverse reaction leading to trial withdrawal was impotence (1%). In the clinical trial evaluating the combination therapy, trial withdrawal due to adverse reactions occurred in 6% of subjects receiving combination therapy (dutasteride plus tamsulosin) and 4% of subjects receiving dutasteride or tamsulosin as monotherapy. The most common adverse reaction in all treatment arms leading to trial withdrawal was erectile dysfunction (1% to 1.5%). Monotherapy: Over 4,300 male subjects with BPH were randomly assigned to receive placebo or 0.5 mg daily doses of dutasteride in three identical 2-year, placebo-controlled, doubleblind, Phase 3 treatment trials, each followed by a 2-year open-label extension. During the double-blind treatment period, 2,167 male subjects were exposed to dutasteride, including 1,772 exposed for one year and 1,510 exposed for 2 years. When including the open-label extensions, 1,009 male subjects were exposed to dutasteride for 3 years and 812 were exposed for 4 years. The population was aged 47 to 94 years (mean age: 66 years) and greater than 90% were Caucasian. Table 1 summarizes clinical adverse reactions reported in at least 1% of subjects receiving dutasteride and at a higher incidence than subjects receiving placebo. Table 1. Adverse Reactions Reported in 1% of Subjects Over a 24-Month Period and More Frequently in the Group Receiving Dutasteride than the Placebo Group (Randomized, Double-Blind, Placebo-Controlled Trials Pooled) by Time of Onset a These sexual adverse reactions are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse reactions may persist after treatment discontinuation. The role of dutasteride in this persistence is unknown. b Includes breast tenderness and breast enlargement. Long-Term Treatment (Up to 4 Years): High-Grade Prostate Cancer: The REDUCE trial was a randomized, double-blind, placebo-controlled trial that enrolled 8,231 men aged 50 to 75 years with a serum PSA of 2.5 ng/ml to 10 ng/ml and a negative prostate biopsy within the previous 6 months. Subjects were randomized to receive placebo (n = 4,126) or 0.5 mg daily doses of dutasteride (n = 4,105) for up to 4 years. The mean age was 63 years and 91% were Caucasian. Subjects underwent protocol-mandated scheduled prostate biopsies at 2 and 4 years of treatment or had for-cause biopsies at non-scheduled times if clinically indicated. There was a higher incidence of Gleason score 8 to 10 prostate cancer in men receiving dutasteride (1%) compared with men on placebo (0.5%) [see Indications and Usage (1.3), Warnings and Precautions (5.2)]. In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR), similar results for Gleason score 8 to 10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%). No clinical benefit has been demonstrated in patients with prostate cancer treated with dutasteride. Reproductive and Breast Disorders: In the three pivotal placebo-controlled BPH trials with dutasteride, each 4 years in duration, there was no evidence of increased sexual adverse reactions (impotence, decreased libido, and ejaculation disorder) or breast disorders with increased duration of treatment. Among these three trials, there was one case of breast cancer in the dutasteride group and one case in the placebo group. No cases of breast cancer were reported in any treatment group in the 4-year CombAT trial or the 4-year REDUCE trial. The relationship between long-term use of dutasteride and male breast neoplasia is currently unknown. Combination with Alpha-Blocker Therapy (CombAT): Over 4,800 male subjects with BPH were randomly assigned to receive 0.5 mg dutasteride, 0.4 mg tamsulosin or combination therapy (0.5 mg dutasteride plus 0.4 mg tamsulosin) administered once daily in a 4-year double-blind trial. Overall, 1,623 subjects received monotherapy with dutasteride, 1,611 subjects received monotherapy with tamsulosin; and 1,610 subjects received combination therapy. The population was aged 49 to 88 years (mean age: 66 years) and 88% were Caucasian. Table 2 summarizes adverse reactions reported in at least 1% of subjects in the combination group and at a higher incidence than subjects receiving monotherapy with dutasteride or tamsulosin. Table 2. Adverse Reactions Reported Over a 48-Month Period in 1% of Subjects and More Frequently in the Coadministration Therapy Group than the Groups Receiving Monotherapy with Dutasteride or Tamsulosin (CombAT) by Time of Onset a Combination = Dutasteride 0.5 mg once daily plus tamsulosin 0.4 mg once daily. b Includes anorgasmia, retrograde ejaculation, semen volume decreased, orgasmic sensation decreased, orgasm abnormal, ejaculation delayed, ejaculation disorder, ejaculation failure, and premature ejaculation. c These sexual adverse reactions are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse reactions may persist after treatment discontinuation. The role of dutasteride in this persistence is unknown. d Includes erectile dysfunction and disturbance in sexual arousal. e Includes libido decreased, libido disorder, loss of libido, sexual dysfunction, and male sexual dysfunction. f Includes breast enlargement, gynecomastia, breast swelling, breast pain, breast tenderness, nipple pain, and nipple swelling. Cardiac Failure: In CombAT, after 4 years of treatment, the incidence of the composite term cardiac failure in the combination therapy group (12/1,610; 0.7%) was higher than in either monotherapy group: dutasteride, 2/1,623 (0.1%) and tamsulosin, 9/1,611 (0.6%). Composite cardiac failure was also examined in a separate 4-year placebo-controlled trial evaluating dutasteride in men at risk for development of prostate cancer. The incidence of cardiac failure in subjects taking dutasteride was 0.6% (26/4,105) compared with 0.4% (15/4,126) in subjects on placebo. A majority of subjects with cardiac failure in both trials had comorbidities associated with an increased risk of cardiac failure. Therefore, the clinical significance of the numerical imbalances in cardiac failure is unknown. No causal relationship between dutasteride alone or in combination with tamsulosin and cardiac failure has been established. No imbalance was observed in the incidence of overall cardiovascular adverse events in either trial. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of dutasteride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting or potential causal connection to dutasteride. Immune System Disorders: Hypersensitivity reactions, including rash, pruritus, urticaria, localized edema, serious skin reactions and angioedema. Neoplasms: Male breast cancer. Psychiatric Disorders: Depressed mood. Reproductive System and Breast Disorders: Testicular pain and testicular swelling. 7 DRUG INTERACTIONS 7.1 Cytochrome P450 3A Inhibitors Dutasteride is extensively metabolized in humans by the CYP3A4 and CYP3A5 isoenzymes. The effect of potent CYP3A4 inhibitors on dutasteride has not been studied. Because of the potential for drug-drug interactions, use caution when prescribing dutasteride to patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir) [see Clinical Pharmacology (12.3)]. 7.2 Alpha Adrenergic Antagonists The administration of dutasteride in combination with tamsulosin or terazosin has no effect on the steady-state pharmacokinetics of either alpha adrenergic antagonist. The effect of administration of tamsulosin or terazosin on dutasteride pharmacokinetic parameters has not been evaluated. 7.3 Calcium Channel Antagonists Coadministration of verapamil or diltiazem decreases dutasteride clearance and leads to increased exposure to dutasteride. The change in dutasteride exposure is not considered to be clinically significant. No dose adjustment is recommended [see Clinical Pharmacology (12.3)]. 7.4 Cholestyramine Administration of a single 5 mg dose of dutasteride followed one hour later by 12 g of cholestyramine does not affect the relative bioavailability of dutasteride [see Clinical Pharmacology (12.3)]. 7.5 Digoxin Dutasteride does not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at a dose of 0.5 mg/day for 3 weeks [see Clinical Pharmacology (12.3)]. 7.6 Warfarin Concomitant administration of dutasteride 0.5 mg/day for 3 weeks with warfarin does not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects. Pregnancy Category X: Dutasteride is contraindicated for use in women of childbearing potential and during pregnancy. Dutasteride is a 5 alpha-reductase inhibitor that prevents conversion of testosterone to dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. In animal reproduction and developmental toxicity studies, dutasteride inhibited normal development of external genitalia in male fetuses. Therefore, dutasteride may cause fetal harm when administered to a pregnant woman. If dutasteride is used during pregnancy or if the patient becomes pregnant while taking dutasteride, the patient should be apprised of the potential hazard to the fetus. Abnormalities in the genitalia of male fetuses is an expected physiological consequence of inhibition of the conversion of testosterone to DHT by 5 alpha-reductase inhibitors. These results are similar to observations in male infants with genetic 5 alpha-reductase deficiency. Dutasteride is absorbed through the skin. To avoid potential fetal exposure, women who are pregnant or could become pregnant should not handle dutasteride capsules. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water [see Warnings and Precautions (5.4)]. Dutasteride is secreted into semen. The highest measured semen concentration of dutasteride in treated men was 14 ng/ml. Assuming exposure of a 50 kg woman to 5 ml of semen and 100% absorption, the woman s dutasteride concentration would be about ng/ml. This concentration is more than 100 times less than concentrations producing abnormalities of male genitalia in animal studies. Dutasteride is highly protein bound in human semen (greater than 96%), which may reduce the amount of dutasteride available for vaginal absorption. In an embryo-fetal development study in female rats, oral administration of dutasteride at doses 10 times less than the maximum recommended human dose (MRHD) of 0.5 mg daily resulted in abnormalities of male genitalia in the fetus (decreased anogenital distance at 0.05 mg/kg/day), nipple development, hypospadias and distended preputial glands in male offspring (at all doses of 0.05, 2.5, 12.5, and 30 mg/kg/day). An increase in stillborn pups was observed at 111 times the MRHD and reduced fetal body weight was observed at doses of about 15 times the MRHD (animal dose of 2.5 mg/kg/day). Increased incidences of skeletal variations considered to be delays in ossification associated with reduced body weight were observed at doses about 56 times the MRHD (animal dose of 12.5 mg/kg/day). In a rabbit embryo-fetal study, doses 28- to 93-fold the MRHD (animal doses of 30, 100, and 200 mg/kg/day) were administered orally during the period of major organogenesis (gestation days 7 to 29) to encompass the late period of external genitalia development. Histological evaluation of the genital papilla of fetuses revealed evidence of feminization of the male fetus at all doses. A second embryo-fetal study in rabbits at 0.3- to 53-fold the expected clinical exposure (animal doses of 0.05, 0.4, 3, and 30 mg/kg/day) also produced evidence of feminization of the genitalia in male fetuses at all doses. In an oral pre- and post-natal development study in rats, dutasteride doses of 0.05, 2.5, 12.5, or 30 mg/kg/day were administered. Unequivocal evidence of feminization of the genitalia (i.e., decreased anogenital distance, increased incidence of hypospadias, nipple development) of male offspring occurred at 14- to 90-fold the MRHD (animal doses of 2.5 mg/kg/day or greater). At 0.05-fold the expected clinical exposure (animal dose of 0.05 mg/kg/day), evidence of feminization was limited to a small, but statistically significant, decrease in anogenital distance. Animal doses of 2.5 to 30 mg/kg/day resulted in prolonged gestation in the parental females and a decrease in time to vaginal patency for female offspring and a decrease in prostate and seminal vesicle weights in male offspring. Effects on newborn startle response were noted at doses greater than or equal to 12.5 mg/kg/day. Increased stillbirths were noted at 30 mg/kg/day. In an embryo-fetal development study, pregnant rhesus monkeys were exposed intravenously to a dutasteride blood level comparable to the dutasteride concentration found in human semen. Dutasteride was administered on gestation days 20 to 100 at doses of 400, 780, 1,325, or 2,010 ng/day (12 monkeys/group). The development of male external genitalia of monkey offspring was not adversely affected. Reduction of fetal adrenal weights, reduction in fetal prostate weights and increases in fetal ovarian and testis weights were observed at the highest dose tested in monkeys. Based on the highest measured semen concentration of dutasteride in treated men (14 ng/ml), these doses represent 0.8 to 16 times the potential maximum exposure of a 50 kg human female to 5 ml semen daily from a dutasteride-treated man, assuming 100% absorption. (These calculations are based on blood levels of parent drug which are achieved at 32 to 186 times the daily doses administered to pregnant monkeys on a ng/kg basis). Dutasteride is highly bound to proteins in human semen (greater than 96%), potentially reducing the amount of dutasteride available for vaginal absorption. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites. Estimates of exposure multiples comparing animal studies to the MRHD for dutasteride are based on clinical serum concentration at steady state. 8.3 Nursing Mothers Dutasteride is contraindicated for use in women of childbearing potential, including nursing women. It is not known whether dutasteride is excreted in human milk. 8.4 Pediatric Use Dutasteride is contraindicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of 2,167 male subjects treated with dutasteride in three clinical trials, 60% were aged 65 years and older and 15% were aged 75 years and older. No overall differences in safety or efficacy were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)]. 8.6 Renal Impairment No dose adjustment is necessary for dutasteride in patients with renal impairment [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients. However, in a clinical trial where 60 subjects received 5 mg (10 times the therapeutic dose) daily for 24 weeks, no additional adverse events were observed compared with those observed at the therapeutic dose of 0.5 mg [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE In volunteer trials, single doses of dutasteride up to 40 mg (80 times the therapeutic dose) for 7 days have been administered without significant safety concerns. In a clinical trial, daily doses of 5 mg (10 times the therapeutic dose) were administered to 60 subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg. There is no specific antidote for dutasteride. Therefore, in cases of suspected overdosage, symptomatic and supportive treatment should be given as appropriate, taking the long halflife of dutasteride into consideration. 11 DESCRIPTION Dutasteride is a synthetic 4-azasteroid compound that is a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5 alpha-reductase, an intracellular enzyme that converts testosterone to DHT. Dutasteride is chemically designated as α,α,α,α,α,α -Hexafluoro-3-oxo-4-aza-5α-androst- 1-ene-17β-carboxy-2,5 -xylidide. The molecular formula of dutasteride is C 27 H 30 F 6 N 2 O 2, representing a molecular weight of with the following structural formula: Dutasteride is a white to off white powder with a melting point of 242 to 250 C. It is soluble in ethanol (44 mg/ml), methanol (64 mg/ml) and polyethylene glycol 400 (3 mg/ml), but it is insoluble in water. Each dutasteride capsule, administered orally, contains 0.5 mg of dutasteride dissolved in a mixture of glycerol monocaprylocaprate, EP Type I, medium chain triglyceride and butylated hydroxytoluene. The inactive excipients in the capsule shell are FD&C Blue No. 1, gelatin, polysorbate 80, red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. The gelatin capsules are printed with edible black ink that contains the following inactive ingredients: black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Dutasteride inhibits the conversion of testosterone to dihydrotestosterone (DHT). DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme 5 alpha-reductase, which exists as two isoforms, type 1 and type 2. The type 2 isoenzyme is primarily active in the reproductive tissues, while the type 1 isoenzyme is also responsible for testosterone conversion in the skin and liver. Dutasteride is a competitive and specific inhibitor of both type 1 and type 2 5 alpha-reductase isoenzymes, with which it forms a stable enzyme complex. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride does not bind to the human androgen receptor Pharmacodynamics Effect on 5 Alpha-Dihydrotestosterone and Testosterone: The maximum effect of daily doses of dutasteride on the reduction of DHT is dose dependent and is observed within 1 to 2 weeks. After 1 and 2 weeks of daily dosing with dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. In patients with BPH treated with dutasteride 0.5 mg/day for 4 years, the median decrease in serum DHT was 94% at 1 year, 93% at 2 years and 95% at both 3 and 4 years. The median increase in serum testosterone was 19% at both 1 and 2 years, 26% at 3 years and 22% at 4 years, but the mean and median levels remained within the physiologic range. In patients with BPH treated with 5 mg/day of dutasteride or placebo for up to 12 weeks prior to transurethral resection of the prostate, mean DHT concentrations in prostatic tissue were significantly lower in the dutasteride group compared with placebo (784 and 5,793 pg/g, respectively, P < 0.001). Mean prostatic tissue concentrations of testosterone were significantly higher in the dutasteride group compared with placebo (2,073 and 93 pg/g, respectively, P < 0.001). Adult males with genetically inherited type 2 5 alpha-reductase deficiency also have decreased DHT levels. These 5 alpha-reductase-deficient males have a small prostate gland throughout life and do not develop BPH. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to 5 alpha-reductase deficiency have been observed in these individuals. Effects on Other Hormones: In healthy volunteers, 52 weeks of treatment with dutasteride 0.5 mg/day (n = 26) resulted in no clinically significant change compared with placebo (n = 23) in sex hormone-binding globulin, estradiol, luteinizing hormone, follicle-stimulating hormone, thyroxine (free T4) and dehydroepiandrosterone. Statistically significant, baseline-adjusted mean increases compared with placebo were observed for total testosterone at 8 weeks (97.1 ng/dl, P < 0.003) and thyroid-stimulating hormone at 52 weeks (0.4 mciu/ml, P < 0.05). The median percentage changes from baseline within the dutasteride group were 17.9% for testosterone at 8 weeks and 12.4% for thyroid-stimulating hormone at 52 weeks. After stopping dutasteride for 24 weeks, the mean levels of testosterone and thyroid-stimulating hormone had returned to baseline in the group of subjects with available data at the visit. In subjects with BPH treated with dutasteride in a large randomized, double-blind, placebo-controlled trial, there was a median percent increase in lu teini - zing hormone of 12% at 6 months and 19% at both 12 and 24 months. Other Effects: Plasma lipid panel and bone mineral density were evaluated following 52 weeks of dutasteride 0.5 mg once daily in healthy volunteers. There was no change in bone mineral density as measured by dual energy x-ray absorptiometry compared with either placebo or baseline. In addition, the plasma lipid profile (i.e., total cholesterol, low density lipoproteins, high density lipoproteins and triglycerides) was unaffected by dutasteride. No clinically significant changes in adrenal hormone responses to adrenocorticotropic hormone (ACTH) stimulation were observed in a subset population (n = 13) of the 1-year healthy volunteer trial Pharmacokinetics Absorption: Following administration of a single 0.5 mg dose of a soft gelatin capsule, time to peak serum concentrations (T max ) of dutasteride occurs within 2 to 3 hours. Absolute bioavailability in five healthy subjects is approximately 60% (range: 40% to 94%). When the drug is administered with food, the maximum serum concentrations were reduced by 10% to 15%. This reduction is of no clinical significance. Distribution: Pharmacokinetic data following single and repeat oral doses show that dutasteride has a large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma albumin (99%) and alpha-1 acid glycoprotein (96.6%). In a trial of healthy subjects (n = 26) receiving dutasteride 0.5 mg/day for 12 months, semen dutasteride concentrations averaged 3.4 ng/ml (range: 0.4 to 14 ng/ml) at 12 months and similar to serum, achieved steady-state concentrations at 6 months. On average, at 12 months 11.5% of serum dutasteride concentrations partitioned into semen. Metabolism and Elimination: Dutasteride is extensively metabolized in humans. In vitro studies showed that dutasteride is metabolized by the CYP3A4 and CYP3A5 isoenzymes. Both of these isoenzymes produced the 4 -hydroxydutasteride, 6-hydroxydutasteride and the 6,4 - dihydroxydutasteride metabolites. In addition, the 15-hydroxydutasteride metabolite was formed by CYP3A4. Dutasteride is not metabolized in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. In human serum following dosing to steady-state, unchanged dutasteride, three major metabolites (4 -hydroxydutasteride, 1,2-dihydrodutasteride and 6-hydroxydutasteride) and two minor metabolites (6,4 -dihydroxydutasteride and 15-hydroxydutasteride), as assessed by mass spectrometric response, have been detected. The absolute stereochemistry of the hydroxyl additions in the 6 and 15 positions is not known. In vitro, the 4 -hydroxydutasteride and 1,2-dihydrodutasteride metabolites are much less potent than dutasteride against both isoforms of human 5 alpha-reductase. The activity of 6β-hydroxydutasteride is comparable to that of dutasteride. Dutasteride and its metabolites were excreted mainly in feces. As a percent of dose, there was approximately 5% unchanged dutasteride (~1% to ~15%) and 40% as dutasteriderelated metabolites (~2% to ~90%). Only trace amounts of unchanged dutasteride were found in urine (< 1%). Therefore, on average, the dose unaccounted for approximated 55% (range: 5% to 97%). The terminal elimination half-life of dutasteride is approximately 5 weeks at steady-state. The average steady-state serum dutasteride concentration was 40 ng/ml following 0.5 mg/day for one year. Following daily dosing, dutasteride serum concentrations achieve 65% of steadystate concentration after one month and approximately 90% after 3 months. Due to the long half-life of dutasteride, serum concentrations remain detectable (greater than 0.1 ng/ml) for up to 4 to 6 months after discontinuation of treatment. Specific Populations: Pediatric: Dutasteride pharmacokinetics have not been investigated in subjects younger than 18 years. Geriatric: No dose adjustment is necessary in the elderly. The pharmacokinetics and pharmacodynamics of dutasteride were evaluated in 36 healthy male subjects aged between 24 and 87 years following administration of a single 5 mg dose of dutasteride. In this singledose trial, dutasteride half-life increased with age (approximately 170 hours in men aged 20 to 49 years, approximately 260 hours in men aged 50 to 69 years and approximately 300 hours in men older than 70 years). Of 2,167 men treated with dutasteride in the three pivotal trials, 60% were age 65 and over and 15% were age 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients. Gender: Dutasteride is contraindicated in pregnancy and women of childbearing potential and is not indicated for use in other women [see Contraindications (4), Warnings and Precautions (5.1)]. The pharmacokinetics of dutasteride in women have not been studied. Race: The effect of race on dutasteride pharmacokinetics has not been studied. Renal Impairment: The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a steady-state 0.5 mg dose of dutasteride is recovered in human urine, so no adjustment in dosage is anticipated for patients with renal impairment. Hepatic Impairment: The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients. Drug Interactions: Cytochrome P450 Inhibitors: No clinical drug interaction trials have been performed to evaluate the impact of CYP3A enzyme inhibitors on dutasteride pharmacokinetics. However, based on in vitro data, blood concentrations of dutasteride may increase in the presence of inhibitors of CYP3A4/5 such as ritonavir, ketoconazole, verapamil, diltiazem, cimetidine, troleandomycin and ciprofloxacin. Adverse Reaction Time of Onset Adverse Reaction Months 0 to 6 Months 7 to 12 Months 13 to 18 Months 19 to 24 Dutasteride (n) (n = 2,167) (n = 1,901) (n = 1,725) (n = 1,605) Placebo (n) (n = 2,158) (n = 1,922) (n = 1,714) (n = 1,555) Impotence a Dutasteride 4.7% 1.4% 1% 0.8% Placebo 1.7% 1.5% 0.5% 0.9% Decreased libido a Dutasteride 3% 0.7% 0.3% 0.3% Placebo 1.4% 0.6% 0.2% 0.1% Ejaculation disorders a Dutasteride 1.4% 0.5% 0.5% 0.1% Placebo 0.5% 0.3% 0.1% 0% Breast disorders b Dutasteride 0.5% 0.8% 1.1% 0.6% Placebo 0.2% 0.3% 0.3% 0.1% Adverse Reaction Time of Onset Year 1 Months Months Adverse Reaction 0 to 6 7 to 12 Year 2 Year 3 Year 4 Combination a (n = 1,610) (n = 1,527) (n = 1,428) (n = 1,283) (n = 1,200) Dutasteride (n = 1,623) (n = 1,548) (n = 1,464) (n = 1,325) (n = 1,200) Tamsulosin (n = 1,611) (n = 1,545) (n = 1,468) (n = 1,281) (n = 1,112) Ejaculation disorders b,c Combination 7.8% 1.6% 1% 0.5% < 0.1% Dutasteride 1% 0.5% 0.5% 0.2% 0.3% Tamsulosin 2.2% 0.5% 0.5% 0.2% 0.3% Impotence c,d Combination 5.4% 1.1% 1.8% 0.9% 0.4% Dutasteride 4% 1.1% 1.6% 0.6% 0.3% Tamsulosin 2.6% 0.8% 1% 0.6% 1.1% Decreased libido c,e Combination 4.5% 0.9% 0.8% 0.2% 0% Dutasteride 3.1% 0.7% 1% 0.2% 0% Tamsulosin 2% 0.6% 0.7% 0.2% < 0.1% Breast disorders f Combination 1.1% 1.1% 0.8% 0.9% 0.6% Dutasteride 0.9% 0.9% 1.2% 0.5% 0.7% Tamsulosin 0.4% 0.4% 0.4% 0.2% 0% Dizziness Combination 1.1% 0.4% 0.1% < 0.1% 0.2% Dutasteride 0.5% 0.3% 0.1% < 0.1% < 0.1% Tamsulosin 0.9% 0.5% 0.4% < 0.1% 0% DUTA:R1p FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Monotherapy 1.2 Combination with Alpha Adrenergic Antagonist 1.3 Limitations of Use 2 DOSAGE AND ADMINISTRATION 2.1 Monotherapy 2.2 Combination with Alpha Adrenergic Antagonist 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Effects on Prostate-Specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection 5.2 Increased Risk of High-Grade Prostate Cancer 5.3 Evaluation for Other Urological Diseases 5.4 Exposure of Women Risk to Male Fetus 5.5 Blood Donation 5.6 Effect on Semen Characteristics 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Post-Marketing Experience 7 DRUG INTERACTIONS 7.1 Cytochrome P450 3A Inhibitors 7.2 Alpha Adrenergic Antagonists 7.3 Calcium Channel Antagonists 7.4 Cholestyramine 7.5 Digoxin 7.6 Warfarin 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Monotherapy 14.2 Combination with Alpha-Blocker Therapy (CombAT) 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 PSA Monitoring 17.2 Increased Risk of High-Grade Prostate Cancer 17.3 Exposure of Women Risk to Male Fetus 17.4 Blood Donation *Sections or subsections omitted from the full prescribing information are not listed. HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use dutasteride capsules safely and effectively. See full prescribing information for dutasteride capsules. DUTASTERIDE capsules, for oral use Initial U.S. Approval: RECENT MAJOR CHANGES Warnings and Precautions, Evaluation for Other Urological 3/2012 Diseases (5.3) INDICATIONS AND USAGE Dutasteride capsules are a 5 alpha-reductase inhibitor indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: (1.1) improve symptoms, reduce the risk of acute urinary retention, and reduce the risk of the need for BPH-related surgery. Dutasteride capsules in combination with the alpha adrenergic antagonist, tamsulosin, are indicated for the treatment of symptomatic BPH in men with an enlarged prostate. (1.2) Limitations of Use: Dutasteride capsules are not approved for the prevention of prostate cancer. (1.3) DOSAGE AND ADMINISTRATION Monotherapy: 0.5 mg once daily. (2.1) Combination with tamsulosin: 0.5 mg once daily and tamsulosin 0.4 mg once daily. (2.2) Dosing considerations: Swallow whole. May take with or without food. (2) DOSAGE FORMS AND STRENGTHS mg capsules (3) CONTRAINDICATIONS Pregnancy and women of childbearing potential. (4, 5.4, 8.1) Pediatric patients. (4) Patients with previously demonstrated, clinically significant hypersensitivity (e.g., serious skin reactions, angioedema) to dutasteride or other 5 alpha-reductase inhibitors. (4) WARNINGS AND PRECAUTIONS Dutasteride reduces serum prostate-specific antigen (PSA) concentration by approximately 50%. However, any confirmed increase in PSA while on dutasteride may signal the presence of prostate cancer and should be evaluated, even if those values are still within the normal range for untreated men. (5.1) Dutasteride may increase the risk of high-grade prostate cancer. (5.2, 6.1) Prior to initiating treatment with dutasteride, consideration should be given to other urological conditions that may cause similar symptoms. (5.3) Women who are pregnant or could become pregnant should not handle dutasteride capsules due to potential risk to a male fetus. (5.4, 8.1) Patients should not donate blood until 6 months after their last dose of dutasteride. (5.5) ADVERSE REACTIONS The most common adverse reactions, reported in 1% of subjects treated with dutasteride and more commonly than in subjects treated with placebo, are impotence, decreased libido, ejaculation disorders and breast disorders. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at ( INFO-RX) or FDA at FDA-1088 or DRUG INTERACTIONS Use with caution in patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir). (7) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. NOVEMBER 2014 DUTA:R1p/PL:DUTA:R1p PATIENT INFORMATION LEAFLET DUTASTERIDE CAPSULES (doo tas' ter ide) 0.5 mg Dutasteride is for use by men only. Read this patient information before you start taking dutasteride capsules and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What are dutasteride capsules? Dutasteride capsules are a prescription medicine that contains dutasteride. Dutasteride capsules are used to treat the symptoms of benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: improve symptoms reduce the risk of acute urinary retention (a complete blockage of urine flow) reduce the risk of the need for BPH-related surgery Who should NOT take dutasteride capsules? Do not take dutasteride capsules if you are: pregnant or could become pregnant. Du - tasteride capsules may harm your unborn baby. Pregnant women should not touch dutasteride capsules. If a woman who is pregnant with a male baby gets enough dutasteride in her body by swallowing or touching dutasteride capsules, the male baby may be born with sex organs that are not normal. If a pregnant woman or woman of childbearing potential comes in contact with leaking dutasteride capsules, the contact area should be washed immediately with soap and water. a child or a teenager. allergic to dutasteride or any of the ingredients in dutasteride capsules. See the end of this leaflet for a complete list of ingredients in dutasteride capsules. allergic to other 5 alpha-reductase inhib itors, for example, PROSCAR (finasteride) Tablets. What should I tell my healthcare provider before taking dutasteride capsules? Before you take dutasteride capsules, tell your healthcare provider if you: have liver problems. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Dutasteride capsules and other medicines may affect each other, causing side effects. Dutasteride capsules may affect the way other medicines work, and other medicines may affect how dutasteride capsules work. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take dutasteride capsules? Take one dutasteride capsule once a day. Swallow dutasteride capsules whole. Do not crush, chew, or open dutasteride capsules because the contents of the capsule may irritate your lips, mouth or throat. You can take dutasteride capsules with or without food. If you miss a dose, you may take it later that day. Do not make up the missed dose by taking two doses the next day. What should I avoid while taking dutasteride capsules? You should not donate blood while taking dutasteride capsules or for 6 months after you have stopped dutasteride capsules. This is important to prevent pregnant women from receiving dutasteride capsules through blood transfusions. What are the possible side effects of dutasteride capsules? Dutasteride capsules may cause serious side effects, including: Rare and serious allergic reactions, including: swelling of your face, tongue, or throat serious skin reactions, such as skin peeling Get medical help right away if you have these serious allergic reactions. Higher chance of a more serious form of prostate cancer. The most common side effects of dutasteride capsules include: trouble getting or keeping an erection (impotence)* a decrease in sex drive (libido)* ejaculation problems* enlarged or painful breasts. If you notice breast lumps or nipple discharge, you should talk to your healthcare provider. *Some of these events may continue after you stop taking dutasteride capsules. Depressed mood has been reported in patients receiving dutasteride capsules. Dutasteride capsules have been shown to reduce sperm count, semen volume, and sperm movement. However, the effect of dutasteride capsules on male fertility is not known. Prostate-Specific Antigen (PSA) Test: Your healthcare provider may check you for other prostate PATIENT INFORMATION LEAFLET DUTASTERIDE CAPSULES (doo tas' ter ide) 0.5 mg Dutasteride is for use by men only. Read this patient information before you start taking dutasteride capsules and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What are dutasteride capsules? Dutasteride capsules are a prescription medicine that contains dutasteride. Dutasteride capsules are used to treat the symptoms of benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: improve symptoms reduce the risk of acute urinary retention (a complete blockage of urine flow) reduce the risk of the need for BPH-related surgery Who should NOT take dutasteride capsules? Do not take dutasteride capsules if you are: pregnant or could become pregnant. Du - tasteride capsules may harm your unborn baby. Pregnant women should not touch dutasteride capsules. If a woman who is pregnant with a male baby gets enough dutasteride in her body by swallowing or touching dutasteride capsules, the male baby may be born with sex organs that are not normal. If a pregnant woman or woman of childbearing potential comes in contact with leaking dutasteride capsules, the contact area should be washed immediately with soap and water. a child or a teenager. allergic to dutasteride or any of the ingredients in dutasteride capsules. See the end of this leaflet for a complete list of ingredients in dutasteride capsules. allergic to other 5 alpha-reductase inhib itors, for example, PROSCAR (finasteride) Tablets. What should I tell my healthcare provider before taking dutasteride capsules? Before you take dutasteride capsules, tell your healthcare provider if you: have liver problems. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Dutasteride capsules and other medicines may affect each other, causing side effects. Dutasteride capsules may affect the way other medicines work, and other medicines may affect how dutasteride capsules work. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take dutasteride capsules? Take one dutasteride capsule once a day. Swallow dutasteride capsules whole. Do not crush, chew, or open dutasteride capsules because the contents of the capsule may irritate your lips, mouth or throat. You can take dutasteride capsules with or without food. If you miss a dose, you may take it later that day. Do not make up the missed dose by taking two doses the next day. What should I avoid while taking dutasteride capsules? You should not donate blood while taking dutasteride capsules or for 6 months after you have stopped dutasteride capsules. This is important to prevent pregnant women from receiving dutasteride capsules through blood transfusions. What are the possible side effects of dutasteride capsules? Dutasteride capsules may cause serious side effects, including: Rare and serious allergic reactions, including: swelling of your face, tongue, or throat serious skin reactions, such as skin peeling Get medical help right away if you have these serious allergic reactions. Higher chance of a more serious form of prostate cancer. The most common side effects of dutasteride capsules include: trouble getting or keeping an erection (impotence)* a decrease in sex drive (libido)* ejaculation problems* enlarged or painful breasts. If you notice breast lumps or nipple discharge, you should talk to your healthcare provider. *Some of these events may continue after you stop taking dutasteride capsules. Depressed mood has been reported in patients receiving dutasteride capsules. Dutasteride capsules have been shown to reduce sperm count, semen volume, and sperm movement. However, the effect of dutasteride capsules on male fertility is not known. Prostate-Specific Antigen (PSA) Test: Your healthcare provider may check you for other prostate PATIENT INFORMATION LEAFLET DUTASTERIDE CAPSULES (doo tas' ter ide) 0.5 mg Dutasteride is for use by men only. Read this patient information before you start taking dutasteride capsules and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What are dutasteride capsules? Dutasteride capsules are a prescription medicine that contains dutasteride. Dutasteride capsules are used to treat the symptoms of benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: improve symptoms reduce the risk of acute urinary retention (a complete blockage of urine flow) reduce the risk of the need for BPH-related surgery Who should NOT take dutasteride capsules? Do not take dutasteride capsules if you are: pregnant or could become pregnant. Du - tasteride capsules may harm your unborn baby. Pregnant women should not touch dutasteride capsules. If a woman who is pregnant with a male baby gets enough dutasteride in her body by swallowing or touching dutasteride capsules, the male baby may be born with sex organs that are not normal. If a pregnant woman or woman of childbearing potential comes in contact with leaking dutasteride capsules, the contact area should be washed immediately with soap and water. a child or a teenager. allergic to dutasteride or any of the ingredients in dutasteride capsules. See the end of this leaflet for a complete list of ingredients in dutasteride capsules. allergic to other 5 alpha-reductase inhib itors, for example, PROSCAR (finasteride) Tablets. What should I tell my healthcare provider before taking dutasteride capsules? Before you take dutasteride capsules, tell your healthcare provider if you: have liver problems. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Dutasteride capsules and other medicines may affect each other, causing side effects. Dutasteride capsules may affect the way other medicines work, and other medicines may affect how dutasteride capsules work. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take dutasteride capsules? Take one dutasteride capsule once a day. Swallow dutasteride capsules whole. Do not crush, chew, or open dutasteride capsules because the contents of the capsule may irritate your lips, mouth or throat. You can take dutasteride capsules with or without food. If you miss a dose, you may take it later that day. Do not make up the missed dose by taking two doses the next day. What should I avoid while taking dutasteride capsules? You should not donate blood while taking dutasteride capsules or for 6 months after you have stopped dutasteride capsules. This is important to prevent pregnant women from receiving dutasteride capsules through blood transfusions. What are the possible side effects of dutasteride capsules? Dutasteride capsules may cause serious side effects, including: Rare and serious allergic reactions, including: swelling of your face, tongue, or throat serious skin reactions, such as skin peeling Get medical help right away if you have these serious allergic reactions. Higher chance of a more serious form of prostate cancer. The most common side effects of dutasteride capsules include: trouble getting or keeping an erection (impotence)* a decrease in sex drive (libido)* ejaculation problems* enlarged or painful breasts. If you notice breast lumps or nipple discharge, you should talk to your healthcare provider. *Some of these events may continue after you stop taking dutasteride capsules. Depressed mood has been reported in patients receiving dutasteride capsules. Dutasteride capsules have been shown to reduce sperm count, semen volume, and sperm movement. However, the effect of dutasteride capsules on male fertility is not known. Prostate-Specific Antigen (PSA) Test: Your healthcare provider may check you for other prostate PHARMACIST - DETACH AT EACH PERFORATION AND GIVE LEAFLET TO PATIENT

42 Dutasteride does not inhibit the in vitro metabolism of model substrates for the major human cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) at a concentration of 1,000 ng/ml, 25 times greater than steady-state serum concentrations in humans. Alpha Adrenergic Antagonists: In a single-sequence, crossover trial in healthy volunteers, the administration of tamsulosin or terazosin in combination with dutasteride had no effect on the steady-state pharmacokinetics of either alpha adrenergic antagonist. Although the effect of administration of tamsulosin or terazosin on dutasteride pharmacokinetic parameters was not evaluated, the percent change in DHT concentrations was similar for dutasteride alone compared with the combination treatment. Calcium Channel Antagonists: In a population pharmacokinetics analysis, a decrease in clearance of dutasteride was noted when coadministered with the CYP3A4 inhibitors verapamil (-37%, n = 6) and diltiazem (-44%, n = 5). In contrast, no decrease in clearance was seen when amlodipine, another calcium channel antagonist that is not a CYP3A4 inhibitor, was coadministered with dutasteride (+7%, n = 4). The decrease in clearance and subsequent increase in exposure to dutasteride in the presence of verapamil and diltiazem is not considered to be clinically significant. No dose adjustment is recommended. Cholestyramine: Administration of a single 5 mg dose of dutasteride followed one hour later by 12 g cholestyramine did not affect the relative bioavailability of dutasteride in 12 normal volunteers. Digoxin: In a trial of 20 healthy volunteers, dutasteride did not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at a dose of 0.5 mg/day for 3 weeks. Warfarin: In a trial of 23 healthy volunteers, 3 weeks of treatment with dutasteride 0.5 mg/day did not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time when administered with warfarin. Other Concomitant Therapy: Although specific interaction trials were not performed with other compounds, approximately 90% of the subjects in the three randomized doubleblind, placebo-controlled safety and efficacy trials receiving dutasteride were taking other medications concomitantly. No clinically significant adverse interactions could be attributed to the combination of dutasteride and concurrent therapy when dutasteride was coadministered with anti-hyperlipidemics, angiotensin-converting enzyme (ACE) inhibitors, beta-adrenergic blocking agents, calcium channel blockers, corticosteroids, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), phosphodiesterase Type V inhibitors and quinolone antibiotics. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: A 2-year carcinogenicity study was conducted in B6C3F1 mice at doses of 3, 35, 250 and 500 mg/kg/day for males and 3, 35 and 250 mg/kg/day for females; an increased incidence of benign hepatocellular adenomas was noted at 250 mg/kg/day (290-fold the MRHD of a 0.5 mg daily dose) in female mice only. Two of the three major human metabolites have been detected in mice. The exposure to these metabolites in mice is either lower than in humans or is not known. In a 2-year carcinogenicity study in Han Wistar rats, at doses of 1.5, 7.5 and 53 mg/kg/day in males and 0.8, 6.3 and 15 mg/kg/day in females, there was an increase in Leydig cell adenomas in the testes at 135-fold the MRHD (53 mg/kg/day and greater). An increased incidence of Leydig cell hyperplasia was present at 52-fold the MRHD (male rat doses of 7.5 mg/kg/day and greater). A positive correlation between proliferative changes in the Leydig cells and an increase in circulating luteinizing hormone levels has been demonstrated with 5 alpha-reductase inhibitors and is consistent with an effect on the hypothalamicpituitary-testicular axis following 5 alpha-reductase inhibition. At tumorigenic doses, luteinizing hormone levels in rats were increased by 167%. In this study, the major human metabolites were tested for carcinogenicity at approximately 1 to 3 times the expected clinical exposure. Mutagenesis: Dutasteride was tested for genotoxicity in a bacterial mutagenesis assay (Ames test), a chromosomal aberration assay in CHO cells and a micronucleus assay in rats. The results did not indicate any genotoxic potential of the parent drug. Two major human metabolites were also negative in either the Ames test or an abbreviated Ames test. Impairment of Fertility: Treatment of sexually mature male rats with dutasteride at 0.1- to 110-fold the MRHD (animal doses of 0.05, 10, 50 and 500 mg/kg/day for up to 31 weeks) resulted in dose- and time-dependent decreases in fertility; reduced cauda epididymal (absolute) sperm counts but not sperm concentration (at 50 and 500 mg/kg/day); reduced weights of the epididymis, prostate and seminal vesicles; and microscopic changes in the male reproductive organs. The fertility effects were reversed by recovery week 6 at all doses and sperm counts were normal at the end of a 14 week recovery period. The 5 alpha-reductase-related changes consisted of cytoplasmic vacuolation of tubular epithelium in the epididymides and decreased cytoplasmic content of epithelium, consistent with decreased secretory activity in the prostate and seminal vesicles. The microscopic changes were no longer present at recovery week 14 in the low-dose group and were partly recovered in the remaining treatment groups. Low levels of dutasteride (0.6 to 17 ng/ml) were detected in the serum of untreated female rats mated to males dosed at 10, 50 or 500 mg/kg/day for 29 to 30 weeks. In a fertility study in female rats, oral administration of dutasteride at doses of 0.05, 2.5, 12.5 and 30 mg/kg/day resulted in reduced litter size, increased embryo resorption, and feminization of male fetuses (decreased anogenital distance) at 2- to 10-fold the MRHD (animal doses of 2.5 mg/kg/day or greater). Fetal body weights were also reduced at less than 0.02-fold the MRHD in rats (0.5 mg/kg/day) Animal Toxicology and/or Pharmacology Central Nervous System Toxicology Studies: In rats and dogs, repeated oral administration of dutasteride resulted in some animals showing signs of non-specific, reversible, centrally-mediated toxicity without associated histopathological changes at exposures 425- and 315-fold the expected clinical exposure (of parent drug), respectively. 14 CLINICAL STUDIES 14.1 Monotherapy Dutasteride 0.5 mg/day (n = 2,167) or placebo (n = 2,158) was evaluated in male subjects with BPH in three 2-year multicenter, placebo-controlled, double-blind trials, each with 2-year open-label extensions (n = 2,340). More than 90% of the trial population was Caucasian. Subjects were at least 50 years of age with a serum PSA 1.5 ng/ml and < 10 ng/ml and BPH diagnosed by medical history and physical examination, including enlarged prostate ( 30 cc) and BPH symptoms that were moderate to severe according to the American Urological Association Symptom Index (AUA-SI). Most of the 4,325 subjects randomly assigned to receive either dutasteride or placebo completed 2 years of double-blind treatment (70% and 67%, respectively). Most of the 2,340 subjects in the trial extensions completed 2 additional years of open-label treatment (71%). Effect on Symptom Scores: Symptoms were quantified using the AUA-SI, a questionnaire that evaluates urinary symptoms (incomplete emptying, frequency, intermittency, urgency, weak stream, straining and nocturia) by rating on a 0 to 5 scale for a total possible score of 35, with higher numerical total symptom scores representing greater severity of symptoms. The baseline AUA-SI score across the three trials was approximately 17 units in both treatment groups. Subjects receiving dutasteride achieved statistically significant improvement in symptoms versus placebo by Month 3 in 1 trial and by Month 12 in the other two pivotal trials. At Month 12, the mean decrease from baseline in AUA-SI total symptom scores across the three trials pooled was -3.3 units for dutasteride and -2 units for placebo with a mean difference between the two treatment groups of -1.3 (range: -1.1 to -1.5 units in each of the three trials, P < 0.001) and was consistent across the three trials. At Month 24, the mean decrease from baseline was -3.8 units for dutasteride and -1.7 units for placebo with a mean difference of -2.1 (range: -1.9 to -2.2 units in each of the three trials, P < 0.001). See Figure 1. The improvement in BPH symptoms seen during the first 2 years of double-blind treatment was maintained throughout an additional 2 years of open-label extension trials. These trials were prospectively designed to evaluate effects on symptoms based on prostate size at baseline. In men with prostate volumes 40 cc, the mean decrease was -3.8 units for dutasteride and -1.6 units for placebo, with a mean difference between the two treatment groups of -2.2 at Month 24. In men with prostate volumes < 40 cc, the mean decrease was -3.7 units for dutasteride and -2.2 units for placebo, with a mean difference between the two treatment groups of -1.5 at Month 24. Figure 1. AUA-SI Scorea Change from Baseline (Randomized, Double-Blind, Placebo- Controlled Trials Pooled) a AUA-SI score ranges from 0 to 35. Effect on Acute Urinary Retention and the Need for BPH-Related Surgery: Efficacy was also assessed after two years of treatment by the incidence of AUR requiring catheterization and BPH-related urological surgical intervention. Compared with placebo, dutasteride was associated with a statistically significantly lower incidence of AUR (1.8% for dutasteride versus 4.2% for placebo, P < 0.001; 57% reduction in risk, [95% CI: 38% to 71%]) and with a statistically significantly lower incidence of surgery (2.2% for dutasteride versus 4.1% for placebo, P < 0.001; 48% reduction in risk, [95% CI: 26% to 63%]). See Figures 2 and 3. Figure 2. Percent of Subjects Developing Acute Urinary Retention Over a 24-Month Period (Randomized, Double-Blind, Placebo-Controlled Trials Pooled) Figure 3. Percent of Subjects Having Surgery for Benign Prostatic Hyperplasia Over a 24-Month Period (Randomized, Double-Blind, Placebo-Controlled Trials Pooled) Effect on Prostate Volume: A prostate volume of at least 30 cc measured by transrectal ultrasound was required for trial entry. The mean prostate volume at trial entry was approximately 54 cc. Statistically significant differences (dutasteride versus placebo) were noted at the earliest post-treatment prostate volume measurement in each trial (Month 1, Month 3 or Month 6) and continued through Month 24. At Month 12, the mean percent change in prostate volume across the three trials pooled was -24.7% for dutasteride and -3.4% for placebo; the mean difference (dutasteride minus placebo) was -21.3% (range: -21% to -21.6% in each of the three trials, P < 0.001). At Month 24, the mean percent change in prostate volume across the three trials pooled was -26.7% for dutasteride and -2.2% for placebo with a mean difference of -24.5% (range: -24% to -25.1% in each of the three trials, P < 0.001). See Figure 4. The reduction in prostate volume seen during the first 2 years of double-blind treatment was maintained throughout an additional 2 years of open-label extension trials. Figure 4. Prostate Volume Percent Change from Baseline (Randomized, Double-Blind, Placebo-Controlled Trials Pooled) Effect on Maximum Urine Flow Rate: A mean peak urine flow rate (Q max ) of 15 ml/sec was required for trial entry. Q max was approximately 10 ml/sec at baseline across the three pivotal trials. Differences between the two groups were statistically significant from baseline at Month 3 in all three trials and were maintained through Month 12. At Month 12, the mean increase in Q max across the three trials pooled was 1.6 ml/sec for dutasteride and 0.7 ml/sec for placebo; the mean difference (dutasteride minus placebo) was 0.8 ml/sec (range: 0.7 to 1 ml/sec in each of the three trials, P < 0.001). At Month 24, the mean increase in Q max was 1.8 ml/sec for dutasteride and 0.7 ml/sec for placebo, with a mean difference of 1.1 ml/sec (range: 1 to 1.2 ml/sec in each of the three trials, P < 0.001). See Figure 5. The increase in maximum urine flow rate seen during the first 2 years of double-blind treatment was maintained throughout an additional 2 years of open-label extension trials. Figure 5. Q max Change from Baseline (Randomized, Double-Blind, Placebo-Controlled Trials Pooled) Summary of Clinical Trials: Data from three large, well controlled efficacy trials demonstrate that treatment with dutasteride (0.5 mg once daily) reduces the risk of both AUR and BPH-related surgical intervention relative to placebo, improves BPH-related symptoms, decreases prostate volume and increases maximum urinary flow rates. These data suggest that dutasteride arrests the disease process of BPH in men with an enlarged prostate Combination with Alpha-Blocker Therapy (CombAT) The efficacy of combination therapy (dutasteride 0.5 mg/day plus tamsulosin 0.4 mg/day, n = 1,610) was compared with dutasteride alone (n = 1,623) or tamsulosin alone (n = 1,611) in a 4-year multicenter, randomized, double-blind trial. Trial entry criteria were similar to the double-blind, placebo-controlled monotherapy efficacy trials described above in section Eighty-eight percent (88%) of the enrolled trial population was Caucasian. Approximately 52% of subjects had previous exposure to 5 alpha-reductase inhibitor or alpha adrenergic antagonist treatment. Of the 4,844 subjects randomly assigned to receive treatment, 69% of subjects in the combination group, 67% in the group receiving dutasteride, and 61% in the tamsulosin group completed 4 years of double-blind treatment. Effect on Symptom Score: Symptoms were quantified using the first seven questions of the International Prostate Symptom Score (IPSS) (identical to the AUA-SI). The baseline score was approximately 16.4 units for each treatment group. Combination therapy was statistically superior to each of the monotherapy treatments in decreasing symptom score at Month 24, the primary time point for this endpoint. At Month 24 the mean changes from baseline (± SD) in IPSS total symptom scores were -6.2 (± 7.14) for combination, -4.9 (± 6.81) for dutasteride, and -4.3 (± 7.01) for tamsulosin, with a mean difference between combination and dutasteride of -1.3 units (P < 0.001; [95% CI: -1.69, -0.86]), and between combination and tamsulosin of -1.8 units (P < 0.001; [95% CI: -2.23, -1.40]). A significant difference was seen by Month 9 and continued through Month 48. At Month 48 the mean changes from baseline (± SD) in IPSS total symptom scores were -6.3 (± 7.4) for combination, -5.3 (± 7.14) for dutasteride, and -3.8 (± 7.74) for tamsulosin, with a mean difference between combination and dutasteride of units (P < 0.001; [95% CI: -1.4, -0.52]), and between combination and tamsulosin of -2.5 units (P < 0.001; [95% CI: -2.96, -2.07]). See Figure 6. Figure 6. International Prostate Symptom Score Change from Baseline Over a 48-Month Period (Randomized, Double-Blind, Parallel Group Trial [CombAT Trial]) Effect on Acute Urinary Retention or the Need for BPH-Related Surgery: After 4 years of treatment, combination therapy with dutasteride and tamsulosin did not provide benefit over monotherapy with dutasteride in reducing the incidence of AUR or BPH-related surgery. Effect on Maximum Urine Flow Rate: The baseline Q max was approximately 10.7 ml/sec for each treatment group. Combination therapy was statistically superior to each of the monotherapy treatments in increasing Q max at Month 24, the primary time point for this endpoint. At Month 24, the mean increases from baseline (± SD) in Q max were 2.4 (± 5.26) ml/sec for combination, 1.9 (± 5.1) ml/sec for dutasteride, and 0.9 (± 4.57 ml/sec for tamsulosin, with a mean difference between combination and dutasteride of 0.5 ml/sec (P = 0.003; [95% CI: 0.17, 0.84]) and between combination and tamsulosin of 1.5 ml/sec (P < 0.001; [95% CI: 1.19, 1.86]). This difference was seen by Month 6 and continued through Month 24. See Figure 7. The additional improvement in Q max of combination therapy over monotherapy with dutasteride was no longer statistically significant at Month 48. Figure 7. Q max Change from Baseline Over a 24-Month Period (Randomized, Double- Blind, Parallel Group Trial [CombAT Trial]) Effect on Prostate Volume: The mean prostate volume at trial entry was approximately 55 cc. At Month 24, the primary time point for this endpoint, the mean percent changes from baseline (± SD) in prostate volume were -26.9% (± 22.57) for combination therapy, -28% (± 24.88) for dutasteride, and 0% (± 31.14) for tamsulosin, with a mean difference between combination and dutasteride of 1.1% (P = NS; [95% CI: -0.6, 2.8]) and between combination and tamsulosin of -26.9% (P < 0.001; [95% CI: -28.9, -24.9]). Similar changes were seen at Month 48: -27.3% (± 24.91) for combination therapy, -28% (± 25.74) for dutasteride, and +4.6% (± 35.45) for tamsulosin. 16 HOW SUPPLIED/STORAGE AND HANDLING Dutasteride Capsules contain 0.5 mg of dutasteride. The Dutasteride 0.5 mg hard-shell gelatin capsules have a buff opaque cap and buff opaque body and are filled with clear liquid. The capsule has a blue gelatin band and is radially printed with MYLAN on the cap and DU 0.5 on the body in black ink. They are available as follows: bottles of 30 capsules bottles of 90 capsules Store at 20 to 25 C (68 to 77 F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Dispense a Patient Information Leaflet with each prescription. Dutasteride is absorbed through the skin. Dutasteride capsules should not be handled by women who are pregnant or who could become pregnant because of the potential for absorption of dutasteride and the subsequent potential risk to a developing male fetus [see Warnings and Precautions (5.4)]. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) PSA Monitoring Physicians should inform patients that dutasteride capsules reduce serum PSA levels by approximately 50% within 3 to 6 months of therapy, although it may vary for each individual. For patients undergoing PSA screening, increases in PSA levels while on treatment with dutasteride capsules may signal the presence of prostate cancer and should be evaluated by a healthcare provider [see Warnings and Precautions (5.1)] Increased Risk of High-Grade Prostate Cancer Physicians should inform patients that there was an increase in high-grade prostate cancer in men treated with 5 alpha-reductase inhibitors (which are indicated for BPH treatment), including dutasteride capsules, compared with those treated with placebo in trials looking at the use of these drugs to reduce the risk of prostate cancer [see Indications and Usage (1.3), Warnings and Precautions (5.2), Adverse Reactions (6.1)] Exposure of Women Risk to Male Fetus Physicians should inform patients that dutasteride capsules should not be handled by a woman who is pregnant or who could become pregnant because of the potential for absorption of dutasteride and the subsequent potential risk to a developing male fetus. Dutasteride is absorbed through the skin and could result in unintended fetal exposure. If a pregnant woman or woman of childbearing potential comes in contact with leaking dutasteride capsules, the contact area should be washed immediately with soap and water [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)] Blood Donation Physicians should inform men treated with dutasteride that they should not donate blood until at least 6 months following their last dose to prevent pregnant women from receiving dutasteride through blood transfusion [see Warnings and Precautions (5.5)]. Serum levels of dutasteride are detectable for 4 to 6 months after treatment ends [see Clinical Pharma - cology (12.3)]. PATIENT INFORMATION LEAFLET DUTASTERIDE CAPSULES (doo tas' ter ide) 0.5 mg Dutasteride is for use by men only. Read this patient information before you start taking dutasteride capsules and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What are dutasteride capsules? Dutasteride capsules are a prescription medicine that contains dutasteride. Dutasteride capsules are used to treat the symptoms of benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: improve symptoms reduce the risk of acute urinary retention (a complete blockage of urine flow) reduce the risk of the need for BPH-related surgery Who should NOT take dutasteride capsules? Do not take dutasteride capsules if you are: pregnant or could become pregnant. Dutasteride capsules may harm your unborn baby. Pregnant women should not touch dutasteride capsules. If a woman who is pregnant with a male baby gets enough dutasteride in her body by swallowing or touching dutasteride capsules, the male baby may be born with sex organs that are not normal. If a pregnant woman or woman of childbearing potential comes in contact with leaking dutasteride capsules, the contact area should be washed immediately with soap and water. a child or a teenager. allergic to dutasteride or any of the ingredients in dutasteride capsules. See the end of this leaflet for a complete list of ingredients in dutasteride capsules. allergic to other 5 alpha-reductase inhibitors, for example, PROSCAR (finasteride) Tablets. What should I tell my healthcare provider before taking dutasteride capsules? Before you take dutasteride capsules, tell your healthcare provider if you: have liver problems. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Dutasteride capsules and other medicines may affect each other, causing side effects. Dutasteride capsules may affect the way other medicines work, and other medicines may affect how dutasteride capsules work. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take dutasteride capsules? Take one dutasteride capsule once a day. Swallow dutasteride capsules whole. Do not crush, chew, or open dutasteride capsules because the contents of the capsule may irritate your lips, mouth or throat. You can take dutasteride capsules with or without food. If you miss a dose, you may take it later that day. Do not make up the missed dose by taking two doses the next day. What should I avoid while taking dutasteride capsules? You should not donate blood while taking dutasteride capsules or for 6 months after you have stopped dutasteride capsules. This is important to prevent pregnant women from receiving dutasteride capsules through blood transfusions. What are the possible side effects of dutasteride capsules? Dutasteride capsules may cause serious side effects, including: Rare and serious allergic reactions, including: swelling of your face, tongue, or throat serious skin reactions, such as skin peeling Get medical help right away if you have these serious allergic reactions. Higher chance of a more serious form of prostate cancer. The most common side effects of dutasteride capsules include: trouble getting or keeping an erection (impotence)* a decrease in sex drive (libido)* ejaculation problems* enlarged or painful breasts. If you notice breast lumps or nipple discharge, you should talk to your healthcare provider. *Some of these events may continue after you stop taking dutasteride capsules. Depressed mood has been reported in patients receiving dutasteride capsules. Dutasteride capsules have been shown to reduce sperm count, semen volume, and sperm movement. However, the effect of dutasteride capsules on male fertility is not known. Prostate-Specific Antigen (PSA) Test: Your healthcare provider may check you for other prostate problems, including prostate cancer before you start and while you take dutasteride capsules. A blood test called PSA (prostatespecific antigen) is sometimes used to see if you might have prostate cancer. Dutasteride capsules will reduce the amount of PSA measured in your blood. Your healthcare provider is aware of this effect and can still use PSA to see if you might have prostate cancer. Increases in your PSA levels while on treatment with dutasteride capsules (even if the PSA levels are in the normal range) should be evaluated by your healthcare provider. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects with dutasteride capsules. For more information, ask you healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at FDA How should I store dutasteride capsules? Store dutasteride capsules at 20 to 25 C (68 to 77 F). Dutasteride capsules may become deformed and/or discolored if kept at high temperatures. Do not use dutasteride capsules if your capsules are deformed, discolored, or leaking. Safely throw away medicine that is no longer needed. Keep dutasteride capsules and all medicines out of the reach of children. Medicines are sometimes prescribed for purposes other than those listed in a patient leaflet. Do not use dutasteride capsules for a condition for which it was not prescribed. Do not give dutasteride capsules to other people, even if they have the same symptoms that you have. It may harm them. This patient information leaflet summarizes the most important information about dutasteride capsules. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about dutasteride capsules that is written for health professionals. For more information, call Mylan Pharmaceuticals at ( INFO-RX). What are the ingredients in dutasteride capsules? Active ingredient: dutasteride. Inactive ingredients: FD&C Blue No. 1, gelatin, polysorbate 80, red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. The gelatin capsules are printed with edible black ink that contains the following inactive ingredients: black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution. How do dutasteride capsules work? Prostate growth is caused by a hormone in the blood called dihydrotestosterone (DHT). Dutasteride lowers DHT production in the body, leading to shrinkage of the enlarged prostate in most men. While some men have fewer problems and symptoms after 3 months of treatment with dutasteride, a treatment period of at least 6 months is usually necessary to see if dutasteride will work for you. Mylan Pharmaceuticals Inc. Morgantown, WV U.S.A. NOVEMBER 2014 DUTA:R1p problems, including prostate cancer before you start and while you take dutasteride capsules. A blood test called PSA (prostate-specific antigen) is sometimes used to see if you might have prostate cancer. Dutasteride capsules will reduce the amount of PSA measured in your blood. Your healthcare provider is aware of this effect and can still use PSA to see if you might have prostate cancer. Increases in your PSA levels while on treatment with dutasteride capsules (even if the PSA levels are in the normal range) should be evaluated by your healthcare provider. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects with dutasteride capsules. For more information, ask you healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at FDA How should I store dutasteride capsules? Store dutasteride capsules at 20 to 25 C (68 to 77 F). Dutasteride capsules may become deformed and/or discolored if kept at high temperatures. Do not use dutasteride capsules if your capsules are deformed, discolored, or leaking. Safely throw away medicine that is no longer needed. Keep dutasteride capsules and all medicines out of the reach of children. Medicines are sometimes prescribed for purposes other than those listed in a patient leaflet. Do not use dutasteride capsules for a condition for which it was not prescribed. Do not give dutasteride capsules to other people, even if they have the same symptoms that you have. It may harm them. This patient information leaflet summarizes the most important information about dutasteride capsules. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about dutasteride capsules that is written for health professionals. For more information, call Mylan Pharmaceuticals at ( INFO-RX). What are the ingredients in dutasteride capsules? Active ingredient: dutasteride. Inactive ingredients: FD&C Blue No. 1, gelatin, polysorbate 80, red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. The gelatin capsules are printed with edible black ink that contains the following inactive ingredients: black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution. How do dutasteride capsules work? Prostate growth is caused by a hormone in the blood called dihydrotestosterone (DHT). Dutasteride lowers DHT production in the body, leading to shrinkage of the enlarged prostate in most men. While some men have fewer problems and symptoms after 3 months of treatment with dutasteride, a treatment period of at least 6 months is usually necessary to see if dutasteride will work for you. Mylan Pharmaceuticals Inc. Morgantown, WV U.S.A. NOVEMBER 2014 PL:DUTA:R1p problems, including prostate cancer before you start and while you take dutasteride capsules. A blood test called PSA (prostate-specific antigen) is sometimes used to see if you might have prostate cancer. Dutasteride capsules will reduce the amount of PSA measured in your blood. Your healthcare provider is aware of this effect and can still use PSA to see if you might have prostate cancer. Increases in your PSA levels while on treatment with dutasteride capsules (even if the PSA levels are in the normal range) should be evaluated by your healthcare provider. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects with dutasteride capsules. For more information, ask you healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at FDA How should I store dutasteride capsules? Store dutasteride capsules at 20 to 25 C (68 to 77 F). Dutasteride capsules may become deformed and/or discolored if kept at high temperatures. Do not use dutasteride capsules if your capsules are deformed, discolored, or leaking. Safely throw away medicine that is no longer needed. Keep dutasteride capsules and all medicines out of the reach of children. Medicines are sometimes prescribed for purposes other than those listed in a patient leaflet. Do not use dutasteride capsules for a condition for which it was not prescribed. Do not give dutasteride capsules to other people, even if they have the same symptoms that you have. It may harm them. This patient information leaflet summarizes the most important information about dutasteride capsules. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about dutasteride capsules that is written for health professionals. For more information, call Mylan Pharmaceuticals at ( INFO-RX). What are the ingredients in dutasteride capsules? Active ingredient: dutasteride. Inactive ingredients: FD&C Blue No. 1, gelatin, polysorbate 80, red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. The gelatin capsules are printed with edible black ink that contains the following inactive ingredients: black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution. How do dutasteride capsules work? Prostate growth is caused by a hormone in the blood called dihydrotestosterone (DHT). Dutasteride lowers DHT production in the body, leading to shrinkage of the enlarged prostate in most men. While some men have fewer problems and symptoms after 3 months of treatment with dutasteride, a treatment period of at least 6 months is usually necessary to see if dutasteride will work for you. Mylan Pharmaceuticals Inc. Morgantown, WV U.S.A. NOVEMBER 2014 PL:DUTA:R1p problems, including prostate cancer before you start and while you take dutasteride capsules. A blood test called PSA (prostate-specific antigen) is sometimes used to see if you might have prostate cancer. Dutasteride capsules will reduce the amount of PSA measured in your blood. Your healthcare provider is aware of this effect and can still use PSA to see if you might have prostate cancer. Increases in your PSA levels while on treatment with dutasteride capsules (even if the PSA levels are in the normal range) should be evaluated by your healthcare provider. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects with dutasteride capsules. For more information, ask you healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at FDA How should I store dutasteride capsules? Store dutasteride capsules at 20 to 25 C (68 to 77 F). Dutasteride capsules may become deformed and/or discolored if kept at high temperatures. Do not use dutasteride capsules if your capsules are deformed, discolored, or leaking. Safely throw away medicine that is no longer needed. Keep dutasteride capsules and all medicines out of the reach of children. Medicines are sometimes prescribed for purposes other than those listed in a patient leaflet. Do not use dutasteride capsules for a condition for which it was not prescribed. Do not give dutasteride capsules to other people, even if they have the same symptoms that you have. It may harm them. This patient information leaflet summarizes the most important information about dutasteride capsules. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about dutasteride capsules that is written for health professionals. For more information, call Mylan Pharmaceuticals at ( INFO-RX). What are the ingredients in dutasteride capsules? Active ingredient: dutasteride. Inactive ingredients: FD&C Blue No. 1, gelatin, polysorbate 80, red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. The gelatin capsules are printed with edible black ink that contains the following inactive ingredients: black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution. How do dutasteride capsules work? Prostate growth is caused by a hormone in the blood called dihydrotestosterone (DHT). Dutasteride lowers DHT production in the body, leading to shrinkage of the enlarged prostate in most men. While some men have fewer problems and symptoms after 3 months of treatment with dutasteride, a treatment period of at least 6 months is usually necessary to see if dutasteride will work for you. Mylan Pharmaceuticals Inc. Morgantown, WV U.S.A. NOVEMBER 2014 PL:DUTA:R1p

43 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FENOFIBRATE TABLETS safely and effectively. See full prescribing information for FENOFIBRATE TABLETS. FENOFIBRATE Tablets USP, for oral use Initial U.S. Approval: INDICATIONS AND USAGE Fenofibrate tablets, USP are a peroxisome proliferator receptor alpha (PPARα) activator indicated as an adjunct to diet: to reduce elevated LDL-C, Total-C, TG, and Apo B, and to increase HDL-C in adult patients with primary hypercholesterolemia or mixed dyslipidemia. (1.1) to treat adult patients with severe hypertriglyceridemia. (1.2) Important Limitation of Use: Fenofibrate tablets were not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus. (5.1) DOSAGE AND ADMINISTRATION Primary hypercholesterolemia or mixed dyslipidemia: 120 mg per day (2.2) Severe hypertriglyceridemia: 40 to 120 mg per day; the dose should be adjusted according to patient response (2.3) Renally impaired patients: Initial dose of 40 mg per day; the dose should be increased according to the effect on renal function and lipid levels (2.4) Geriatric patients: Select dose on the basis of renal function (2.5) To increase absorption of fenofibrate, take with food DOSAGE FORMS AND STRENGTHS Oral tablets: 40 mg and 120 mg CONTRAINDICATIONS Severe renal dysfunction, including patients receiving dialysis (4, 8.6, 12.3) Active liver disease (4, 5.3) Gallbladder disease (4, 5.5) Nursing mothers (4, 8.3) Known hypersensitivity to fenofibrate (4) WARNINGS AND PRECAUTIONS Myopathy and rhabdomyolysis have been reported in patients taking fenofibrate. The risk for serious muscle toxicity is increased when fibrates are co-administered with a statin (with a significantly higher rate observed for gemfibrozil), particularly in elderly patients and in patients with diabetes, renal failure, or hypothyroidism. (5.2) Fenofibrate can increase serum transaminases. Monitor liver tests, including ALT, periodically during therapy (5.3). Fenofibrate can reversibly increase serum creatinine levels. (5.4) Monitor renal function periodically in patients with renal impairment. (8.6) Fenofibrate increases cholesterol excretion into the bile, leading to risk of cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. (5.5) Exercise caution in concomitant treatment with coumarin anticoagulants. Adjust the dosage of coumarin to maintain the prothrombin time/inr at the desired level to prevent bleeding complications. (5.6) ADVERSE REACTIONS The most common adverse reactions (> 2% and at least 1% greater than placebo) are abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis. (6) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at ( INFO-RX) or FDA at FDA-1088 or DRUG INTERACTIONS Coumarin Anticoagulants: (7.1) Immunosupressants: (7.2) Bile-Acid Binding Resins: (7.2) USE IN SPECIFIC POPULATIONS Geriatric Use: Determine dose selection on the basis of renal function. (8.5) Renal impairment: Avoid use in patients with severe renal impairment. Dose reduction is required in patients with mild to moderate renal impairment. (8.6) See 17 for PATIENT COUNSELING INFORMATION JUNE 2015 MX:FNFB:R1 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Primary Hypercholesterolemia and Mixed Dyslipidemia 1.2 Severe Hypertriglyceridemia 1.3 Important Limitations of Use 2 DOSAGE AND ADMINISTRATION 2.1 General Considerations 2.2 Primary Hypercholesterolemia or Mixed Dyslipidemia 2.3 Severe Hypertriglyceridemia 2.4 Impaired Renal Function 2.5 Geriatric Patients 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Mortality and Coronary Heart Disease Morbidity 5.2 Skeletal Muscle 5.3 Liver Function 5.4 Serum Creatinine 5.5 Cholelithiasis 5.6 Coumarin Anticoagulants 5.7 Pancreatitis 5.8 Hematologic Changes 5.9 Hypersensitivity Reactions 5.10 Venothromboembolic Disease 5.11 Paradoxical Decreases in HDL Cholesterol Levels 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Coumarin Anticoagulants 7.2 Immunosuppressants 7.3 Bile-Acid Binding Resins 7.4 Colchicine 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Primary Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia 14.2 Severe Hypertriglyceridemia 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. 1

44 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Primary Hypercholesterolemia and Mixed Dyslipidemia Fenofibrate tablets, USP are indicated as adjunctive therapy to diet to reduce elevated lowdensity lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), Triglycerides (TG), and apolipoprotein B (Apo B), and to increase high-density lipoprotein (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia. 1.2 Severe Hypertriglyceridemia Fenofibrate tablets are also indicated as adjunctive therapy to diet for treatment of adult patients with severe hypertriglyceridemia. Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually reduce fasting triglycerides and eliminate chylomicronemia thereby obviating the need for pharmacologic intervention. Markedly elevated levels of serum triglycerides (e.g. > 2,000 mg/dl) may increase the risk of developing pancreatitis. The effect of fenofibrate tablet therapy on reducing this risk has not been adequately studied. 1.3 Important Limitations of Use Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus [see Warnings and Precautions (5.1)]. 2 DOSAGE AND ADMINISTRATION 2.1 General Considerations Fenofibrate tablets should be given with food to optimize the absorption of the medicine. Patients should be advised to swallow fenofibrate tablets whole. Do not crush, dissolve or chew tablets. The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, thiazide diuretics and beta-blockers, are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia. Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of fenofibrate tablets if lipid levels fall significantly below the targeted range. Therapy should be withdrawn in patients who do not have an adequate response after 2 months of treatment with the maximum recommended dose of 120 mg once daily. 2.2 Primary Hypercholesterolemia or Mixed Dyslipidemia The initial dose of fenofibrate tablets is 120 mg per day. 2.3 Severe Hypertriglyceridemia The initial dose is 40 mg to 120 mg per day. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals. The maximum dose is 120 mg per day. 2.4 Impaired Renal Function Treatment with fenofibrate tablets should be initiated at a dose of 40 mg per day in patients with mild to moderately impaired renal function, and increased only after evaluation of the effects on renal function and lipid levels at this dose. The use of fenofibrate tablets should be avoided in patients with severe renal impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 2.5 Geriatric Patients Dose selection for the elderly should be made on the basis of renal function [see Use in Specific Populations (8.5)]. 3 DOSAGE FORMS AND STRENGTHS 40 mg: White, capsule shaped, unscored tablets debossed with M on one side of the tablet and FT1 on the other side. 120 mg: White, capsule shaped, unscored tablets debossed with M on one side of the tablet and FT2 on the other side. 4 CONTRAINDICATIONS Fenofibrate is contraindicated in: patients with severe renal dysfunction, including those receiving dialysis [see Clinical Pharmacology (12.3)]. patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see Warnings and Precautions (5.3)]. in patients with pre-existing gallbladder disease [see Warnings and Precautions (5.5)]. nursing mothers [see Use in Specific Populations (8.3)]. patients with a known hypersensitivity to fenofibrate [see Warnings and Precautions (5.9)]. 5 WARNINGS AND PRECAUTIONS 5.1 Mortality and Coronary Heart Disease Morbidity The effect of fenofibrate on coronary heart disease morbidity and mortality and noncardiovascular mortality has not been established. The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) trial was a randomized placebo-controlled study of 5,518 patients with type 2 diabetes mellitus on background statin therapy treated with fenofibrate. The mean duration of follow-up was 4.7 years. Fenofibrate plus statin combination therapy showed a non-significant 8% relative risk reduction in the primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular disease death (hazard ratio [HR] 0.92, 95% 2 CI 0.79 to 1.08) (p = 0.32) as compared to statin monotherapy. In a gender subgroup analysis, the hazard ratio for MACE in men receiving combination therapy versus statin monotherapy was 0.82 (95% CI 0.69 to 0.99), and the hazard ratio for MACE in women receiving combination therapy versus statin monotherapy was 1.38 (95% CI 0.98 to 1.94) (interaction p = 0.01). The clinical significance of this subgroup finding is unclear. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomized, placebo-controlled study of 9,795 patients with type 2 diabetes mellitus treated with fenofibrate. Fenofibrate demonstrated a non-significant 11% relative reduction in the primary outcome of coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75 to 1.05, p = 0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80 to 0.99], p = 0.04). There was a non-significant 11% (HR 1.11 [0.95, 1.29], p = 0.18) and 19% (HR 1.19 [0.90, 1.57], p = 0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared to placebo. Because of chemical, pharmacological, and clinical similarities between fenofibrate, clofibrate, and gemfibrozil, the adverse findings in four large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to fenofibrate. In the Coronary Drug Project, a large study of post myocardial infarction of patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group. There was however, a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3.0% vs. 1.8%). In a study conducted by the World Health Organization (WHO), 5000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one year. There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, p = < 0.01). Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, postcholecystectomy complications, and pancreatitis. This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project. The Helsinki Heart Study was a large (n = 4,081) study of middle-aged men without a history of coronary artery disease. Subjects received either placebo or gemfibrozil for 5 years, with a 3.5 year open extension afterward. Total mortality was numerically higher in the gemfibrozil randomization group but did not achieve statistical significance (p = 0.19, 95% confidence interval f or relative risk G:P = 0.91 to 1.64). Although cancer deaths trended higher in the gemfibrozil group (p = 0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from the WHO study (RR = 1.29). A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease. Subjects received gemfibrozil or placebo for 5 years. Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94 to 5.05). 5.2 Skeletal Muscle Fibrates increase the risk for myopathy and have been associated with rhabdomyolysis. The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes, renal insufficiency, or hypothyroidism. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase (CPK) levels. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms, and fenofibrate therapy should be discontinued if markedly elevated CPK levels occur or myopathy/myositis is suspected or diagnosed. Data from observational studies indicate that the risk for rhabdomyolysis is increased when fibrates, in particular gemfibrozil, are co-administered with an HMG-CoA reductase inhibitor (statin). The combination should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination [see Clinical Pharmacology (12.3)]. Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates coadministered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine [see Drug Interactions (7.4)]. 5.3 Liver Function Fenofibrate at doses equivalent to 87 mg to 130 mg fenofibrate per day [at the highest dose, comparable to fenofibrate, 120 mg] has been associated with increases in serum transaminases [AST (SGOT) or ALT (SGPT)]. In a pooled analysis of 10 placebo-controlled trials, increases to > 3 times the upper limit of normal occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo. When transaminase determinations were followed either after discontinuation of treatment or during continued treatment, a return to normal limits was usually observed. The incidence of increases in transaminases related to fenofibrate therapy appears to be dose related. In an 8-week dose-ranging study, the incidence of ALT or AST elevations to at least three times the upper limit of normal was 13% in patients receiving dosages equivalent to 87 mg to 130 mg fenofibrate per day and was 0% in those receiving dosages equivalent to 43 mg or less fenofibrate per day, or placebo. Hepatocellular, chronic active and cholestatic hepatitis have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis. Baseline and regular periodic monitoring of liver tests, including serum ALT (SGPT) should be performed for the duration of therapy with fenofibrate, and therapy discontinued if enzyme levels persist above three times the normal limit.

45 5.4 Serum Creatinine Elevations in serum creatinine have been reported in patients on fenofibrate. These elevations tend to return to baseline following discontinuation of fenofibrate. The clinical significance of these observations is unknown. Monitor renal function in patients with renal impairment taking fenofibrate. Renal monitoring should also be considered for patients taking fenofibrate at risk for renal insufficiency such as the elderly and patients with diabetes. 5.5 Cholelithiasis Fenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibrate therapy should be discontinued if gallstones are found. 5.6 Coumarin Anticoagulants Caution should be exercised when anticoagulants are given in conjunction with fenofibrate because of the potentiation of coumarin-type anticoagulants in prolonging the prothrombin time/international Normalized Ratio (PT/INR). To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the anticoagulant are recommended until PT/INR has stabilized [see Drug Interactions (7.1)]. 5.7 Pancreatitis Pancreatitis has been reported in patients taking fenofibrate, gemfibrozil, and clofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct. 5.8 Hematologic Changes Mild to moderate hemoglobin, hemato crit, and white blood cell decreases have been observed in patients following initiation of fenofibrate therapy. However, these levels stabilize during long-term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with fenofibrate. Periodic monitoring of red and white blood cell counts are recommended during the first 12 months of fenofibrate administration. 5.9 Hypersensitivity Reactions Acute hypersensitivity reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis requiring patient hospitalization and treatment with steroids have been reported in individuals treated with fenofibrates Venothromboembolic Disease In the FIELD trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate than the placebo-treated group. Of 9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the fenofibrate group (p = 0.022). In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p < 0.01) Paradoxical Decreases in HDL Cholesterol Levels There have been postmarketing and clinical trial reports of severe decreases in HDL cholesterol levels (as low as 2 mg/dl) occurring in diabetic and non-diabetic patients initiated on fibrate therapy. The decrease in HDL-C is mirrored by a decrease in apolipoprotein A1. This decrease has been reported to occur within 2 weeks to years after initiation of fibrate therapy. The HDL-C levels remain depressed until fibrate therapy has been withdrawn; the response to withdrawal of fibrate therapy is rapid and sustained. The clinical significance of this decrease in HDL-C is unknown. It is recommended that HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDL-C level monitored until it has returned to baseline, and fibrate therapy should not be re-initiated. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect rates observed in clinical practice. Adverse reactions reported by 2% or more of patients treated with fenofibrate and greater than placebo during double-blind, placebo-controlled trials are listed in Table 1 below. Adverse reactions led to discontinuation of treatment in 5% of patients treated with fenofibrate and in 3% treated with placebo. Increases in liver function tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials. Table 1. Adverse Reactions Reported by 2% or More of Patients Treated with Fenofibrate and Greater than Placebo During the Double-Blind, Placebo-Controlled Trials BODY SYSTEM Adverse Reaction Fenofibrate* (N = 439) Placebo (N = 365) BODY AS A WHOLE Abdominal Pain 4.6% 4.4% Back Pain 3.4% 2.5% Headache 3.2% 2.7% DIGESTIVE Nausea 2.3% 1.9% Constipation 2.1% 1.4% Continued Table 1. Adverse Reactions Reported by 2% or More of Patients Treated with Fenofibrate and Greater than Placebo During the Double-Blind, Placebo-Controlled Trials BODY SYSTEM Adverse Reaction Fenofibrate* (N = 439) Placebo (N = 365) METABOLIC AND NUTRITIONAL DISORDERS Abnormal Liver Tests 7.5% 1.4% Increased AST 3.4% 0.5% Increased ALT 3% 1.6% Increased Creatine Phosphokinase 3% 1.4% RESPIRATORY Respiratory Disorder 6.2% 5.5% Rhinitis 2.3% 1.1% * Dosage equivalent to 130 mg fenofibrate 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of fenofibrate: myalgia, rhabdomyolysis, pancreatitis, acute renal failure, muscle spasms, hepatitis, cirrhosis, anemia, arthralgia, decreases in hematocrit, white blood cell decreases, asthenia, and severely depressed HDL cholesterol levels. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 7 DRUG INTERACTIONS 7.1 Coumarin Anticoagulants Caution should be exercised when coumarin anticoagulants are given in conjunction with fenofibrate. The dosage of the anticoagulants should be reduced to maintain the PT/INR at the desired level to prevent bleeding complications. Frequent PT/INR determinations are advisable until it has been definitely determined that the prothrombin time/inr has stabilized [see Warnings and Precautions (5.6)]. 7.2 Immunosupressants Immunosuppressants such as cyclosporine and tacrolimus can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the primary elimination route of fibrate drugs including fenofibrate, there is a risk that an interaction will lead to deterioration of renal function. The benefits and risks of using fenofibrate with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed and renal function monitored. 7.3 Bile-Acid Binding Resins Since bile acid resins may bind other drugs given concurrently, patients should take fenofibrate at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption. 7.4 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates coadministered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C: Safety in pregnant women has not been established. There are no adequate and well controlled studies of fenofibrate in pregnant women. Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In female rats given oral dietary doses of 15, 75, and 300 mg/kg/day of fenofibrate from 15 days prior to mating through weaning, maternal toxicity was observed at 0.3 times the maximum recommended human dose (MRHD), based on body surface area comparisons; mg/m2. In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6 to 15 during the period of organogenesis, adverse developmental findings were not observed at 14 mg/kg/day (less than 1 times the MRHD, based on body surface area comparisons; mg/m2). At higher multiples of human doses evidence of maternal toxicity was observed. In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6 to 18 during the period of organogenesis and allowed to deliver, aborted litters were observed at 150 mg/kg/day (10 times the MRHD, based on body surface area comparisons; mg/m2). No developmental findings were observed at 15 mg/kg/day (at less than 1 times the MRHD, based on body surface area comparisons; mg/m2). In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), maternal toxicity was observed at less than 1 times the MRHD, based on body surface area comparisons; mg/m Nursing Mothers Fenofibrate should not be used in nursing mothers. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and efficacy have not been established in pediatric patients. 8.5 Geriatric Use Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Fenofibric acid exposure is not influenced by age. Since elderly patients have a higher incidence of renal 3

46 impairment, dose selection for the elderly should be made on the basis of renal function [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking fenofibrate. 8.6 Renal Impairment The use of fenofibrate should be avoided in patients with severe renal impairment [see Contraindications (4)]. Dose reduction is required in patients with mild to moderate renal impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. Monitoring renal function in patients with renal impairment is recommended. 8.7 Hepatic Impairment The use of fenofibrate has not been evaluated in subjects with hepatic impairment [see Contraindications (4) and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no specific treatment for overdose with fenofibrate. General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Because fenofibrate is highly bound to plasma proteins, hemodialysis should not be considered. 11 DESCRIPTION Fenofibrate, USP is a lipid regulating agent available as tablets for oral administration. Each tablet contains 40 mg or 120 mg fenofibrate, USP. The chemical name for fenofibrate is 2-[4-4-chlorobenzoylphenoxy]-2-methylpropanoic acid 1-methylethyl ester with the following structural formula: The molecular formula is C 20 H 21 ClO 4 and the molecular weight is 360.8; fenofibrate is practically insoluble in water and slightly soluble in alcohol (methanol and ethanol) but freely soluble in Methylene chloride. The melting point is 79 to 82 C. Fenofibrate is a white or almost white crystalline powder which is stable under ordinary conditions. Inactive Ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, polyethylene glycol, polyoxyl 40 hydrogenated castor oil, povidone, pregelatinized starch (corn), silicified microcrystalline cellulose and vitamin E polyethylene glycol succinate. USP Dissolution Test Pending. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The active moiety of fenofibrate is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate. The lipid-lowering effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor a (PPARa). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting decrease in TG produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARa also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol. Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid Pharmacodynamics A variety of clinical studies have demonstrated that elevated levels of total-c, LDL-C, and apo B, an LDL membrane complex, are risk factors for human atherosclerosis. Similarly, decreased levels of HDL-C and its transport complex, apolipoprotein A (apo AI and apo AII) are risk factors for the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-c, LDL-C, and TG, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering TG on the risk of cardiovascular morbidity and mortality has not been determined. Fenofibric acid, the active metabolite of fenofibrate, produces reductions in TC, LDL-C, apo B, total triglycerides, and triglyceride-rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in HDL and apoproteins apo AI and apo AII Pharmacokinetics Fenofibrate is a pro-drug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation. Plasma concentrations of fenofibric acid after single-dose administration of fenofibrate tablets, 120 mg are equivalent to those of fenofibrate 130 mg capsules under high-fat conditions. A high-fat meal did not affect the fenofibric acid AUC after fenofibrate administration but did increase the mean C max by 44% compared to fasting conditions. Absorption: The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, 4 fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid from fenofibrate occur, on average, within 2 to 3 hours after administration. Doses of three fenofibrate tablets, 40 mg are considered to be equivalent to single doses of fenofibrate tablets, 120 mg. Distribution: In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within a week of dosing and did not demonstrate accumulation across time following multiple dose administration. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects. Metabolism: Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma. Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine. In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent. Elimination: After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces. Fenofibric acid from fenofibrate is eliminated with a half-life of 23 hours, allowing once daily dosing. Geriatrics: In elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that a similar dosage regimen can be used in the elderly, without increasing accumulation of the drug or metabolites [see Dosage and Administration (2.5) and Use in Specific Populations (8.5)]. Pediatrics: The pharmacokinetics of fenofibrate has not been studied in pediatric populations. Gender: No pharmacokinetic difference between males and females has been observed for fenofibrate. Race: The influence of race on the pharmacokinetics of fenofibrate has not been studied; however, fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability. Renal Impairment: The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (creatinine clearance [CrCl] 30 ml/min or estimated glomerular filtration rate [egfr] < 30 ml/min/1.73 m2) showed 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. Patients with mild to moderate renal impairment (CrCl 30 to 80 ml/min or egfr 30 to 59 ml/min/1.73 m2) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of fenofibrate should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment [see Dosage and Administration (2.4)]. Hepatic Impairment: No pharmacokinetic studies have been conducted in patients with hepatic impairment. Drug-Drug Interactions: In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations. Table 2 describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table 3 describes the effects of co-administered fenofibrate or fenofibric acid on other drugs systemic exposure. Table 2: Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibrate Administration Co-Administered Drug Lipid-lowering agents Atorvastatin Pravastatin Fluvastatin Anti-diabetic agents Glimepiride Dosage Regimen of Co-Administered Drug 20 mg once daily for 10 days 40 mg as a single dose 40 mg as a single dose 1 mg as a single dose Dosage Regimen of Fenofibrate Fenofibrate 160 mg1 once daily for 10 days Fenofibrate 3 x 67 mg2 as a single dose Fenofibrate 160 mg1 as a single dose Fenofibrate 145 mg1 once daily for 10 days Changes in Fenofibric Acid Exposure AUC C max 2% 4% 1% 2% 2% 10% 1% 1% Continued

47 Table 2: Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibrate Administration Co-Administered Drug Metformin Rosiglitazone Dosage Regimen of Co-Administered Drug 850 mg three times daily for 10 days 8 mg once daily for 5 days 1 TriCor (fenofibrate) oral tablet 2 TriCor (fenofibrate) oral micronized capsule Dosage Regimen of Fenofibrate Fenofibrate 54 mg1 three times daily for 10 days Fenofibrate 145 mg1 once daily for 14 days Changes in Fenofibric Acid Exposure AUC C max 9% 6% 10% 3% Table 3: Effects of Fenofibrate Co-Administration on Systemic Exposure of Other Drugs Dosage Regimen of Fenofibrate Lipid-lowering agents Fenofibrate 160 mg1 once daily for 10 days Fenofibrate 3 x 67 mg2 as a single dose Fenofibrate 160 mg1 as a single dose Anti-diabetic agents Fenofibrate 145 mg1 once daily for 10 days Fenofibrate 54 mg1 three times daily for 10 days Fenofibrate 145 mg1 once daily for 14 days Dosage Regimen of Co-Administered Drug Atorvastatin, 20 mg once daily for 10 days Pravastatin, 40 mg as a single dose Fluvastatin, 40 mg as a single dose Glimepiride, 1 mg as a single dose Metformin, 850 mg three times daily for 10 days Rosiglitazone, 8 mg once daily for 5 days 1 TriCor (fenofibrate) oral tablet 2 TriCor (fenofibrate) oral micronized capsule Change in Exposure Analyte Co-Administered Drug AUC C max Atorvastatin 17% 0% Pravastatin 3a-Hydroxyliso-pravastatin (+)-3R, 5S-Fluvastatin 13% 26% 13% 29% 15% 16% Glimepiride 35% 18% Metformin 3% 6% Rosiglitazone 6% 1% 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24-month study, Wistar rats were dosed with fenofibrate at 10, 45, and 200 mg/kg/day, approximately 0.3, 1, and 6 times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m2). At a dose of 200 mg/kg/day (at 6 times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at 6 times the MRHD in males. In a second 24-month rat carcinogenicity study in a different strain of rats (Sprague-Dawley), doses of 10 and 60 mg/kg/day (0.3 and 2 times the MRHD) produced significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in testicular interstitial cell tumors in males at 2 times the MRHD. A 117-week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 and 60 mg/kg/day (0.3 and 2 times the MRHD), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m2 surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females. Gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males. In a 21-month study in CF-1 mice, fenofibrate 10, 45, and 200 mg/kg/day (approximately 0.2, 1, and 3 times the MRHD on the basis of mg/m2 surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18-month study at 10, 60, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male mice and liver adenomas in female mice at 3 times the MRHD. Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual. Mutagenesis: Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis in primary rat hepatocytes. Impairment of Fertility: In fertility studies, rats were given oral dietary doses of fenofibrate, males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (~10 times the MRHD, based on mg/m2 surface area comparisons). 14 CLINICAL STUDIES 14.1 Primary Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia The effects of fenofibrate at a dose equivalent to 120 mg fenofibrate per day were assessed from four randomized, placebo-controlled, double-blind, parallel-group studies including patients with the following mean baseline lipid values: total-c mg/dl; LDL-C mg/dl; HDL-C 52.3 mg/dl; and triglycerides 191 mg/dl. Fenofibrate therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Fenofibrate therapy also lowered triglycerides and raised HDL-C (see Table 4). Table 4. Mean Percent Change in Lipid Parameters at End of Treatment* Treatment Group Total-C LDL-C HDL-C TG Pooled Cohort Mean baseline lipid values mg/dl mg/dl 52.3 mg/dl 191 mg/dl (n = 646) All FEN (n = 361) -18.7% -20.6% +11% -28.9% Placebo (n = 285) -0.4% -2.2% +0.7% +7.7% Baseline LDL-C > 160 mg/dl and TG < 150 mg/dl (Type IIa) Mean baseline lipid values mg/dl mg/dl 58.1 mg/dl mg/dl (n = 334) All FEN (n = 193) -22.4% -31.4% +9.8% -23.5% Placebo (n = 141) +0.2% -2.2% +2.6% +11.7% Baseline LDL-C > 160 mg/dl and TG 150 mg/dl (Type IIb) Mean baseline lipid values (n = 242) mg/dl mg/dl 46.7 mg/dl mg/dl All FEN (n = 126) -16.8% -20.1% +14.6% -35.9% Placebo (n = 116) -3% -6.6% +2.3% +0.9% * Duration of study treatment was 3 to 6 months. p = < 0.05 vs. placebo In a subset of the subjects, measurements of apo B were conducted. Fenofibrate treatment significantly reduced apo B from baseline to endpoint as compared with placebo (-25.1% vs. 2.4%, p < , n = 213 and 143 respectively) Severe Hypertriglyceridemia The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials of 147 hypertriglyceridemic patients. Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline TG levels of 500 to 1500 mg/dl, and the other TG levels of 350 to 500 mg/dl. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate at dosages equivalent to 120 mg fenofibrate tablets per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of patients with elevated triglycerides often results in an increase of LDL-C (see Table 5). Table 5. Effects of Fenofibrate in Patients With Severe Hypertriglyceridemia Study 1 Placebo Fenofibrate Baseline TG levels % 350 to 499 mg/dl Baseline Endpoint Change Baseline Endpoint N (Mean) (Mean) (Mean) N (Mean) (Mean) % Change (Mean) Triglycerides * VLDL Triglycerides * Total Cholesterol * HDL Cholesterol * LDL Cholesterol VLDL Cholesterol * Study 2 Placebo Fenofibrate Baseline TG levels 500 to 1500 mg/dl % Change (Mean) % Change (Mean) N Baseline (Mean) Endpoint (Mean) N Baseline (Mean) Endpoint (Mean) Triglycerides * VLDL Triglycerides * Total Cholesterol * HDL Cholesterol * LDL Cholesterol * VLDL Cholesterol * * = p < 0.05 vs. placebo 16 HOW SUPPLIED/STORAGE AND HANDLING Fenofibrate Tablets, USP are available containing 40 mg or 120 mg of fenofibrate, USP. 5

48 The 40 mg tablets are white, capsule shaped, unscored tablets debossed with M on one side of the tablet and FT1 on the other side. They are available as follows: NDC bottles of 90 tablets NDC bottles of 500 tablets The 120 mg tablets are white, capsule shaped, unscored tablets debossed with M on one side of the tablet and FT2 on the other side. They are available as follows: NDC bottles of 90 tablets NDC bottles of 500 tablets Store at 20 to 25 C (68 to 77 F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. 17 PATIENT COUNSELING INFORMATION Patients should be advised: of the potential benefits and risks of fenofibrate. not to use fenofibrate tablets if there is a known hypersensitivity to fenofibrate or fenofibric acid. that if they are taking coumarin anticoagulants, fenofibrate may increase their anticoagulant effect, and increased monitoring may be necessary. of medications that should not be taken in combination with fenofibrate. to continue to follow an appropriate lipid-modifying diet while taking fenofibrate. to take fenofibrate once daily, without regard to food, at the prescribed dose, swallowing each tablet whole. to inform their physician of all medications, supplements, and herbal preparations they are taking and any change to their medical condition. Patients should also be advised to inform their physicians prescribing a new medication that they are taking fenofibrate. to inform their physician of any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV U.S.A. Manufactured in India by: Mylan Laboratories Limited Hyderabad , India Code No.: MH/DRUGS/25/NKD/89 JUNE MX:FNFB:R1 6

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