LACHMAN CONSULTANT SERVICES, INC. CONSULTANTS TO THE PHARMACEUTICAL AND ALLIED INDUSTRIES OVERNIGHT COURIER 4/25/2011 CITIZEN PETITION

Transcription

1 LACHMAN CONSULTANT SERVICES, INC. CONSULTANTS TO THE PHARMACEUTICAL AND ALLIED INDUSTRIES 1600 STEWART AVENUE, WESTBURY, NY (516) FAX (516) APR 2b P 12 : 25 April 25, 2011 OVERNIGHT COURIER 4/25/2011 Division of Dockets Management Food and Drug Administration (HFA-305) Department of Health and Human Services 5630 Fishers Lane, Room 1061 Rockville, MD Dear Sir or Madam: CITIZEN PETITION The undersigned submits this petition, in quadruplicate, pursuant to Section 505(j)(2)(C) of the Federal Food, Drug, and Cosmetic Act, and in accordance with 21 CFR on behalf of a client requesting the Commissioner of the Food and Drug Administration to declare that the drug products, Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets, 2.5 mg/325 mg, 5 mg/325 mg, 7.5 mg/325 mg, and 10 mg/325 mg are suitable for consideration in an abbreviated new drug application (ANDA). A. Action Requested The petitioner requests that the Commissioner of the Food and Drug Administration declare that Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets, 2.5 mg1325 mg, 5 mg/325 mg, 7.5 mg/325 mg, and 10 mg/325 mg are suitable for submission as an ANDA. The reference-listed drug product (RLD), upon which this petition is based, is Norco@ (Hydrocodone Bitartrate and Acetaminophen Tablets), 7.5 mg1325 mg, and 10 mg/325 mg, ANDA held by Watson Pharma, Inc. as designated in the Orange Book (See copy of the page from the current Electronic Edition of the Approved Druq Products with Therapeutic Eauivalence Evaluations (Attachment 1)). Supportive reference is also made to ANDA for Norco@ (Hydrocodone Bitartrate and Acetaminophen Tablets), 5 mg/325 mg held by Watson Pharma, Inc., and ANDA , for Hydrocodone Bitartrate and Acetaminophen Tablets, 2.5 mg1325 mg held by Mikart, Inc., to demonstrate that the Agency found no questions of safety or efficacy with the strengths proposed in this petition. Thus, the petitioner is seeking a change in dosage form (from an oral tablet to an effervescent tablet) and a change in strength (from 7.5 mg/325 mg and 10 mg/325 to also include 2.5 mg/325 mg and 5 mg/325 mg) from that of the listed drug product. B. Statement of Grounds The Federal Food, Drug, and Cosmetic Act provides for the submission of an Abbreviated New Drug Application for a drug product that differs in dosage strength and dosage form from that of the listed drug, provided the FDA has approved a petition that proposed filing such an application. The RLD, Norco@ (Hydrocodone Bitartrate and Acetaminophen Tablets) by Watson Pharma, Inc. is an oral tablet product currently available as 7.5 mg/325 mg, and 10 mg1325 mg. The proposed drug product represents an effervescent tablet for administration and will be available in the following strengths: 2.5 mg/325 mg, 5 mg/325 mg, 7.5 mg/325 mg and 10 mg/325 mg. The proposed drug product is designed to be dissolved in water immediately prior to administration. The petition is thus seeking a change in dosage form (from an oral tablet to an effervescent tablet) and a change in dosage strength (from 7.5 mg/325 mg and 10 mg/325 to also include 2.5 mg/325 mg and 5 mg/325 mg) from that of the RLD. The /1-12:wwc manconsuttan.com LCSOlachmanconsultants.com

2 LACHMAN CONSULTANT SERVICES, INC Westbury, NY Division of Dockets Management Food and Drug Administration April 25, 2011 Page 2 of 3 proposed drug product is consistent with the currently approved RLD product's labeling with the exception of the dosage form and strength. The proposed product will provide an alternate dosage form that may prove to be more convenient for patients who have difficulty swallowing a tablet. The additional strengths of the proposed product are also contemplated in the labeling of the RLD. The current labeling of the RLD states that, "Dosage should be adjusted according to the severity of the pain and the response of the patient." Thus, the additional strengths of the proposed product, i.e., 2.5 mg1325 mg and 5 mg/325 mg, provide greater flexibility to the healthcare practitioner so that the dose can be titrated according to the patients' level of pain. Also, we note that there are currently other approved products available as oral tablets for administration available in these two strengths: ANDA for Norco (Hydrocodone Bitartrate and Acetaminophen Tablets), 5 mg/325 mg held by Watson Pharma, Inc., and ANDA , for Hydrocodone Bitartrate and Acetaminophen Tablets, 2.5 mg/325 mg held by Mikart, Inc. The proposed product will be labeled in accordance with the approved labeling of the RLD product upon which this petition is based. Any difference in the labeling will relate only to the difference in dosage form and those differences that may be necessary because the products are made by different manufacturers or because of patent or exclusivity protections. The uses, indications, warnings, and directions for use will remain the same as that of the RLD. Draft labeling for the proposed product is included in Attachment 2, and the RLD's approved labeling is provided in Attachment 3. Therefore, the petitioner's request for the Commissioner to find that a change in dosage form from an oral tablet to an effervescent tablet and a change in dosage strength from 7.5 mg1325 mg and 10 mg/325 mg to also include 2.5 mg/325 mg and 5 mg/325 mg dosage strengths should raise no questions of safety or effectiveness, and the Agency should approve the petition. Pediatric Waiver Request In September of 2007, Congress reauthorized the Pediatric Research Equity Act of 2003 (PREA) that amended the Federal Food, Drug, and Cosmetic Act to provide the Agency authority to require drug firms to study drugs in pediatric patients, if the Agency concludes that such study would provide beneficial health data for that patient population. The Act specifically requires that a request for a new dosage form is subject to a pediatric evaluation. The act also provides for a waiver from such requirement if the drug: (I) does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients; and (II)is not likely to be used in a substantial number of pediatric patients. The petitioner hereby requests that a full waiver from the conduct of pediatric studies be granted for the approval of this petition to permit subsequent ANDA filing. The reference listed drug product that is the subject of this petition is an oral tablet. Hydrocodone Bitartrate and Acetaminophen Tablets was not on the list of drug products for which additional pediatric information may produce health benefits in the pediatric population (May 2001), nor are hydrocodone bitartrate or acetaminophen (components of the proposed product) on the National Institutes of Health's Annual Priority list of drugs for which pediatric studies are needed for off-patent drugs. Furthermore, we note that there are other FDA approved products for the same active ingredients in oral solution dosage forms (see Attachment 1) that are currently approved. The availability of FDA approved oral liquid dosage forms for hydrocodone bitartrate and acetaminophen contain labeling providing for appropriate dosing for pediatric patients for whom these products are indicated. LCSOlachmanconsultants.com

3 LACHMAN CONSULTANT SERVICES, INC. Westbury, NY Division of Dockets Management Food and Drug Administration April 25, 2011 Page 3 of 3 Thus, based on the nature of the medication, it is not likely that the product will be used in a substantial number of pediatric patients, nor will it provide a meaningful therapeutic benefit in pediatric patients compared to the other available products and pediatric friendly dosage forms already available. C. Environmental impact The petitioner claims a categorical exclusion under 21 CFR D. Economic impact The petitioner does not believe that this is applicable in this case, but will agree to provide such an analysis, if requested by the Agency. E. Certification The undersigned certifies that to the best knowledge and belief of the undersigned, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioner, which are unfavorable to the petition. Respectfully submitted, Robert W. Pollock Executive Vice President-VC RWP/pk Attachments: 1. Approved Drug Products with Therapeutic Equivalence Evaluations, Electronic Orange Book listing, accessed 4/21/ Draft insert labeling for proposed product 3. Approved labeling for reference listed drug, Norco@ Tablets cc: Johnny Young (OGD) Norco@ is a registered trademark of Watson Pharma, Inc. C55 HCB A PAP Petition LCSOlachmanconsultants.com

4 CI I LACHMAN CONSULTANT SERVICES, INC Westbury, NY ATTACHMENT 1

5 4/21/2011 Actiye Ingredient Search Page 1 of 9 Quick Links: Skip to main page content Skip to Search Skip to Topics Menu Skip to Section Content Menu Skip to Common Links Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations Active Ingredient Search Results from "OB_Rx" table for query on "hydrocodone." Appl TE RID Active No Code Ingredient Dosage Strength Form; Route A AA No ; CAPSULE; 500MG;5MG Proprietary Applicant Name MIKART AND A AA No ; CAPSULE; 500MG;5MG MIKART AND A AA No ; SOLUTION; 500MG/15ML;7.5MG/15ML AND KV PHARM A Yes ; SOLUTION; 500MG/15ML;10MG/15ML AND MALLINCKRODT A AA No ; SOLUTION; 500MG/15ML;7.5MG/15ML AND MALLINCKRODT A Yes ; SOLUTION; 300MG/15ML;10MG/15ML AND MIKART A Yes ; SOLUTION; 325MG/15ML;7.5MG/15ML AND MIKART A AA Yes ; SOLUTION; 500MG/15ML;7.5MG/15ML AND MIKART A Yes ; SOLUTION; 325MG/15ML;10MG/15ML AND PHARM ASSOC A AA No ; SOLUTION; 500MG/15ML;7.5MG/15ML AND PHARM ASSOC A AA No ; SOLUTION; 500MG/15ML;7.5MG/15ML AND

6 4/21/2011 Actiye Ingredient Search Page 2 of 9 A AA Yes ; TABLET; 500MG;5MG VICODIN ABBOTT A AA No ; TABLET; 660MG;10MG VICODIN HP ABBOTT A AA Yes ; TABLET; 750MG; 7. 5MG VICODIN ES ABBOTT A AA No ; TABLET; 325MG;10MG AND AMNEAL NY A AA No ; TABLET; 325MG;5MG AND AMNEAL NY A AA No ; TABLET; 500MG;10MG AND AMNEAL NY A AA No ; TABLET; 500MG;5MG AND AMNEAL NY A AA No ; TABLET; 500MG;7.5MG AND AMNEAL NY A AA No ; TABLET; 650MG;10MG AND AMNEAL NY A AA No ; TABLET; 650MG;7.5MG AND AMNEAL NY A AA No ; TABLET; 750MG; 7. 5MG AND AMNEAL NY A AA No ; TABLET; 300MG;10MG AND BOCA PHARMA A AA No ; TABLET; 300MG;5MG AND BOCA PHARMA A AA No ; TABLET; 300MG;7.5MG AND BOCA PHARMA

7 Actiye Ingredient Search Page 3 of 9 A Yes ; TABLET; 400MG;10MG ZYDONE ENDO A Yes ; TABLET; 400MG; 5MG ZYDONE ENDO A Yes ; TABLET; 400MG;7.5MG ZYDONE ENDO A AA No ; TABLET; 325MG;10MG AND MALLINCKRODT A AA No ; TABLET; 325MG;5MG ANEXSIA 5/325 MALUNCKRODT A AA No ; TABLET; 325MG;7.5MG ANEXSIA 7.5/325 MALUNCKRODT A AA No ; TABLET; 500MG;10MG MALUNCKRODT AND A AA No ; TABLET; 500MG;5MG ANEXSIA MALLINCKRODT A AA No ; TABLET; 500MG; 5MG MALLINCKRODT AND A AA No ; TABLET; 500MG;7.5MG MALLINCKRODT AND A AA No ; TABLET; 650MG;10MG MALUNCKRODT AND A AA No ; TABLET; 650MG;7.5MG ANEXSIA 7.5/650 MALLINCKRODT A AA Yes ; TABLET; 660MG;10MG MALLINCKRODT AND A AA No ; TABLET; 750MG;10MG ANEXSIA MALUNCKRODT 4/21/2011

8 Actiye Ingredient Search Page 4 of 9 A AA No ; TABLET; 750MG;7.5MG MALUNCKRODT AND A AA Yes ; TABLET; 300MG;10MG MIKART AND A AA Yes ; TABLET; 300MG;5MG MIKART AND A AA Yes ; TABLET; 300MG;7.5MG HYDROCO DON E MIKART AND A No ; TABLET; 325MG;2.5MG MIKART AND A AA No ; TABLET; 325MG;7.5MG AND MIKART A AA Yes ; TABLET; 500MG;2.5MG AND MIKART A AA Yes ; TABLET; 500MG;7.5MG MIKART AND A AA Yes ; TABLET; 650MG;10MG AND MIKART A No ; TABLET; 650MG;5MG MIKART AND A AA Yes ; TABLET; 650MG;7.5MG MIKART AND A AA No ; TABLET; 325MG;10MG AND RANBAXY A AA No ; TABLET; 500MG;10MG RANBAXY AND A AA No ; TABLET; 500MG;5MG AND ACETAMINOPH EN RANBAXY 4/21/2011

9 Actiye Ingredient Search Page 5 of 9 A AA No ; TABLET; 750MG;7.5MG AND RANBAXY A AA No ; TABLET; 325MG;10MG HYDROCO DON E AND SUN PHARM INDS INC A AA No ; TABLET; 325MG;5MG AND SUN PHARM INDS INC A AA No ; TABLET; 325MG;7.5MG AND SUN PHARM INDS INC A AA No ; TABLET; 500MG;10MG AND SUN PHARM INDS INC A AA No ; TABLET; 500MG;5MG AND SUN PHARM INDS INC A AA No ; TABLET; 500MG;7.5MG AND SUN PHARM INDS INC A AA No ; TABLET; 650MG;10MG AND SUN PHARM INDS INC A AA No ; TABLET; 650MG;7.5MG AND SUN PHARM INDS INC A AA No ; TABLET; 660MG;10MG AND SUN PHARM INDS INC A AA No ; TABLET; 750MG;7.5MG AND SUN PHARM INDS INC A AA Yes ; TABLET; 500MG;10MG LORTAB UCB INC A AA No ; TABLET; 500MG;5MG LORTAB UCB INC A AA No ; TABLET; 500MG;5MG CO-GESIC UCB INC 4/21/2011

10 111 Active Ingredient Search Page 6 of 9 A AA No ; TABLET; 325MG;10MG AND A AA No ; TABLET; 325MG; 5MG AND A AA No ; TABLET; 325MG;7.5MG AND A AA No ; TABLET; 500MG;10MG AND A AA No ; TABLET; 500MG; 2. 5MG AND A AA No ; TABLET; 500MG; 5MG AND ACETAMINOPH EN A AA No ; TABLET; 500MG; 7.5MG AND A AA No ; TABLET; 650MG; 10MG AND A AA No ; TABLET; 650MG; 7. 5MG AND ACETAMINOPH EN A AA No ; TABLET; 660MG;10MG AND A AA No ; TABLET; 750MG; 7.5MG AND A AA Yes ; TABLET; 325MG; 10MG NORCO WATSON LABS A AA No ; TABLET; 325MG; 10MG AND WATSON LABS A AA Yes ; TABLET; 325MG; 5MG NORCO WATSON LABS 4/21/2011

11 Actiye Ingredient Search Page 7 of 9 A AA Yes ; TABLET; 325MG;7.5MG NORCO WATSON LABS A AA No ; TABLET; 500MG; 10MG WATSON LABS AND A AA No ; TABLET; 500MG; 2. 5M G WATSON LABS AND A AA No ; TABLET; 500MG; 2.5MG WATSON LABS AND A AA No ; TABLET; 500M G ; 5MG WATSON LABS AND A AA No ; TABLET; 500MG; 7.5MG WATSON LABS AND A AA No ; TABLET; 500MG; 7. 5MG WATSON LABS AND A AA No ; TABLET; 650MG;10MG WATSON LABS AND A AA No ; TABLET; 650MG;10MG WATSON LABS AND A AA No ; TABLET; 650MG;7.5MG WATSON LABS AND A AA No ; TABLET; 650MG;7.5MG WATSON LABS AND A AA No ; TABLET; 660MG;10MG WATSON LABS AND A AA Yes ; TABLET; 750MG;10MG WATSON LABS AND A AA No ; TABLET; 750MG;7.5MG WATSON LABS AND 4/21/2011

12 Actiye Ingredient Search Page 8 of 9 A AA No ; TABLET; 500MG;5MG WATSON LABS AND FLORIDA ACETAMINOPH EN A AA No ; TABLET; 660MG; 10MG WATSON LABS AND FLORIDA ACETAMINOPH EN A AA No ; TABLET; 750MG;7.5MG WATSON LABS AND FLORIDA A No CHLORPHENIRAMINE CAPSULE, EQ 4MG MALEATE;EQ TUSSICAPS TYCO POUSTIREX; EXTENDED 5MG HLTHCARE RELEASE; POUSTIREX A Yes CHLORPHENIRAMINE CAPSULE, EQ 8MG MALEATE;EQ POUSTIREX; EXTENDED 10MG RELEASE; POUSTIREX TUSSICAPS TYCO HLTHCARE A AB No CHLORPHENIRAMINE SUSPENSION, EQ 8MG MALEATE/5ML;EQ TRIS PHARMA POUSTIREX; EXTENDED 10MG /5ML POUSTIREX AND INC RELEASE; CHLORPHENIRAMINE POUSTIREX POUSTIREX N AB Yes CHLORPHENIRAMINE SUSPENSION, EQ 8MG MALEATE/5ML;EQ TUSSIONEX POUSTIREX; EXTENDED 10MG /5ML PENNKINETIC RELEASE; POUSTIREX UCB INC A AA No HOMATROPINE METHYLBROMIDE; SYRUP; 1.5MG/5ML;5MG/5ML AND HOMATROPINE METHYLBROMIDE ACTAVIS MID ATLANTIC A AA Yes HOMATROPINE METHYLBROMIDE; SYRUP; 1.5MG/5ML;5MG/5ML AND HOMATROPINE METHYLBROMIDE HI TECH PHARMA A AA No HOMATROPINE METHYLBROMIDE; SYRUP; 1.5MG/5ML;5MG/5ML AND HOMATROPINE METHYLBROMIDE WOCKHARDT A Yes HOMATROPINE TABLET; 1.5MG;5MG TUSSIGON KING METHYLBROMIDE; NO20716 AB Yes TABLET; 7.5MG;200MG VICOPROFEN ABBOTT ; 4/21/2011

13 . Active Ingredient Search Page 9 of 9 A No ; TABLET; 10MG;200MG REPREXAIN AMNEAL NY A No ; TABLET; 2.5MG;200MG REPREXAIN AMNEAL NY A AB No ; TABLET; 5MG;200MG AMNEAL AND NY A AB No ; TABLET; 7.5MG;200MG HYDROCODON E AM N EAL AND NY A AB No ; TABLET; 7.5MG;200MG TEVA AND A AB No ; TABLET; 10MG;200MG AND A AB No ; TABLET; 5MG;200MG AND A AB No ; TABLET; 7.5MG;200MG AND A AB No ; TABLET; 5MG;200MG WATSON LABS AND FLORIDA A AB No ; TABLET; 7.5MG;200MG WATSON LABS AND FLORIDA Return to Electronic Orange Book Home Pam FDNCenter for Drug Evaluation and Research Office of Generic Drugs Division of Labeling and Program Support Update Frequency: Orange Book Data - Monthly Generic Drug Product Information & Patent Information - Daily Orange Book Data Updated Through March, 2011 Patent and Generic Drug Product Data Last Updated: April 19, /21/2011

14 LACHMAN CONSULTANT SERVICES, INC. Westbury, NY ATTACHMENT 2

15 CHI Rx Only Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets 2.5 mg/325 mg, 5 mg1325 mg, 7.5 mg/325 mg, and 10 mg/325 mg DESCRIPTION Hydrocodone bitartrate and acetaminophen is supplied as an effervescent tablet for oral administration after the tablet is dissolved in water. Hydrocodone bitartrate is an opioid analgesic and antitussive and occurs as fine, white crystals or as a crystalline powder. It is affected by light. The chemical name is: 4,5a-epoxy-3-methoxy-17- methylmorphinan-6-one tartrate (1:1) hydrate (2:5). It has the following structural formula: f00- (?HOH)2.21/2H20 COOH Cl8H21NO3.C4H /2H20 M.W Acetaminophen, 4'-hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula: OH C8H9NO2 M.W Each Effervescent Tablet contains: 2.5 mg/325 mg: Acetaminophen 325 mg and Hydrocodone Bitartrate 2.5 mg 5 mg/325 mg: Acetaminophen 325 mg and Hydrocodone Bitartrate 5 mg 7.5 mg/325 mg: Acetaminophen 325 mg and Hydrocodone Bitartrate 7.5 mg 10 mg1325 mg: Acetaminophen 325 mg and Hydrocodone Bitartrate 10 mg In addition each tablet contains the following inactive ingredients: To be determined (information will be provided when the application is filed) Meets USP Dissolution CLINICAL PHARMACOLOGY

16 CIII Rx Only Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets 2.5 mg/325 mg, 5 mg/325 mg, 7.5 mg/325 mg, and 10 mg/325 mg Hydrocodone is a semisynthetic narcotic analgesic and antitussive with multiple actions qualitatively similar to those of codeine. Most of these involve the central nervous system and smooth muscle. The precise mechanism of action of hydrocodone and other opiates is not known, although it is believed to relate to the existence of opiate receptors in the central nervous system. In addition to analgesia, narcotics may produce drowsiness, changes in mood and mental clouding. The analgesic action of acetaminophen involves peripheral influences, but the specific mechanism is as yet undetermined. Antipyretic activity is mediated through hypothalamic heat regulating centers. Acetaminophen inhibits prostaglandin synthetase. Therapeutic doses of acetaminophen have negligible effects on the cardiovascular or respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing. Ph armacokinetics The behavior of the individual components is described below. Hydrocodone Following a 10 mg oral dose of hydrocodone administered to five adult male subjects, the mean peak concentration was 23.6 ± 5.2 ng/ml. Maximum serum levels were achieved at 1.3 ± 0.3 hours and thehalf-life was determined to be 3.8 ± 0.3 hours. Hydrocodone exhibits a complex pattern of metabolism including 0-demethylation, N-demethylation and 6-keto reduction to the corresponding 6-a- and 6-13-hydroxy-metabolites. See OVERDOSAGE for toxicity information. Acetaminophen Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug. See OVERDOSAGE for toxicity information. INDICATIONS AND USAGE Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets are indicated for the relief of moderate to moderately severe pain.

17 CIII Rx Only Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets 2.5 mg/325 mg, 5 mg/325 mg, 7.5 mg/325 mg, and 10 mg/325 mg CONTRAINDICATIONS This product should not be administered to patients who have previously exhibited hypersensitivity to hydrocodone or acetaminophen. Patients known to be hypersensitive to other opioids may exhibit cross-sensitivity to hydrocodone. WARNINGS Respiratory Depression At high doses or in sensitive patients, hydrocodone may produce dose-related respiratory depression by acting directly on the brain stem respiratory center. Hydrocodone also affects the center that controls respiratory rhythm, and may produce irregular and periodic breathing. Head Injury and Increased Intracranial Pressure The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a preexisting increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries. Acute Abdominal Conditions The administration of narcotics may obscure the diagnosis or clinical course of patients with acute abdominal conditions. PRECAUTIONS General Special Risk Patients As with any narcotic analgesic agent, Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets should be used with caution in elderly or debilitated patients and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy or urethral stricture. The usual precautions should be observed and the possibility of respiratory depression should be kept in mind. Cough Reflex Hydrocodone suppresses the cough reflex; as with all narcotics, caution should be exercised when Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets are used postoperatively and in patients with pulmonary disease.

18 CHI Rx Only Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets 2.5 mg1325 mg, 5 mg/325 mg, 7.5 mg/325 mg, and 10 mg/325 mg Information for Patients Hydrocodone, like all narcotics, may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery; patients should be cautioned accordingly. Alcohol and other CNS depressants may produce an additive CNS depression, when taken with this combination product, and should be avoided. Hydrocodone may be habit forming. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed. Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets should not be chewed, swallowed whole, or dissolved on the tongue. Laboratory Tests In patients with severe hepatic or renal disease, effects of therapy should be monitored with serial liver and/or renal function tests. Drug Interactions Patients receiving other narcotic analgesics, antihistamines, antipsychotics, antianxiety agents, or other CNS depressants (including alcohol) concomitantly with Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets may exhibit an additive CNS depression. When combined therapy is contemplated, the dose of one or both agents should be reduced. The use of MAO inhibitors or tricyclic antidepressants with hydrocodone preparations may increase the effect of either the antidepressant or hydrocodone. Drug/Laboratory Test Interactions Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid. Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether hydrocodone or acetaminophen have a potential for carcinogenesis, mutagenesis, or impairment of fertility. Pregnancy Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

19 CIII Rx Only Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets 2.5 mg/325 mg, 5 mg/325 mg, 7.5 mg1325 mg, and 10 mg/325 mg Nonteratogenic Effects: Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal. Labor and Delivery As with all narcotics, administration of Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used. Nursing Mothers Acetaminophen is excreted in breast milk in small amounts, but the significance of its effects on nursing infants is not known. It is not known whether hydrocodone is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from hydrocodone and acetaminophen, 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. Pediatric Use Safety and effectiveness in the pediatric population have not been established. Geriatric Use Clinical studies of hydrocodone bitartrate 5 mg and acetaminophen 500 mg 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. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Hydrocodone and the major metabolites of acetaminophen are known to be substantially excreted by the kidney. Thus the risk of toxic reactions may be greater in patients with impaired renal function due to accumulation of the parent compound and/or metabolites in the plasma. 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. Hydrocodone may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of hydrocodone bitartrate and acetaminophen tablets and observed closely. ADVERSE REACTIONS

20 CIII Rx Only Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets 2.5 mg/325 mg, 5 mg/325 mg, 7.5 mg/325 mg, and 10 mg/325 mg The most frequently reported adverse reactions include: lightheadedness, dizziness, sedation, nausea and vomiting. These effects seem to be more prominent in ambulatory than in nonambulatory patients and some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include: Central Nervous System Drowsiness, mental clouding, lethargy, impairment of mental and physical performance, anxiety, fear, dysphoria, psychic dependence, mood changes. Gastrointestinal System Prolonged administration of Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets may produce constipation. Genitourinary System Ureteral spasm, spasm of vesical sphincters and urinary retention have been reported with opiates. Respiratory Depression Hydrocodone bitartrate may produce dose-related respiratory depression by acting directly on the brain stem respiratory center. (see OVERDOSAGE). Special Senses Cases of hearing impairment or permanent loss have been reported predominantly in patients with chronic overdose. Dermatological Skin rash, pruritus. The following adverse drug events may be borne in mind as potential effects of acetaminophen: allergic reactions, rash, thrombocytopenia, agranulocytosis. Potential effects of high dosage are listed in the OVERDOSAGE section. DRUG ABUSE AND DEPENDENCE Controlled Substance: Hydrocodone Bitartrate and Acetaminophen Effervescent Tabelts are classified as a Schedule III controlled substance.

21 CHI Rx Only Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets 2.5 mg/325 mg, 5 mg/325 mg, 7.5 mg/325 mg, and 10 mg/325 mg Abuse and Dependence: Psychic dependence, physical dependence, and tolerance may develop upon repeated administration of narcotics; therefore, this product should be prescribed and administered with caution. However, psychic dependence is unlikely to develop when NORCO is used for a short time for the treatment of pain. Physical dependence, the condition in which continued administration of the drug is required to prevent the appearance of a withdrawal syndrome, assumes clinically significant proportions only after several weeks of continued narcotic use, although some mild degree of physical dependence may develop after a few days of narcotic therapy. Tolerance, in which increasingly large doses are required in order to produce the same degree of analgesia, is manifested initially by a shortened duration of analgesic effect, and subsequently by decreases in the intensity of analgesia. The rate of development of tolerance varies among patients. OVERDOSAGE Following an acute overdosage, toxicity may result from hydrocodone or acetaminophen. Signs and Symptoms Hydrocodone Serious overdose with hydrocodone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. Acetaminophen In acetaminophen overdosage: dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and thrombocytopenia may also occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. In adults, hepatic toxicity has rarely been reported with acute overdoses of less than 10 grams and fatalities with less than 15 grams. Treatment A single or multiple overdose with hydrocodone and acetaminophen is a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended. Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption. Vomiting should be induced mechanically, or with syrup of ipecac, if the patient is

22 CIII Rx Only Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets 2.5 mg/325 mg, 5 mg/325 mg, 7.5 mg/325 mg, and 10 mg/325 mg alert (adequate pharyngeal and laryngeal reflexes). Oral activated charcoal (1 g/kg) should follow gastric emptying. The first dose should be accompanied by an appropriate cathartic. If repeated doses are used, the cathartic might be included with alternate doses as required. Hypotension is usually hypovolemic and should respond to fluids. Vasopressors and other supportive measures should be employed as indicated. A cuffed endo-tracheal tube should be inserted before gastric lavage of the unconscious patient and, when necessary, to provide assisted respiration. Meticulous attention should be given to maintaining adequate pulmonary ventilation. In severe cases of intoxication, peritoneal dialysis, or preferably hemodialysis may be considered. If hypoprothrombinemia occurs due to acetaminophen overdose, vitamin K should be administered intravenously. Naloxone, a narcotic antagonist, can reverse respiratory depression and coma associated with opioid overdose. Naloxone hydrochloride 0.4 mg to 2 mg is given parenterally. Since the duration of action of hydrocodone may exceed that of the naloxone, the patient should be kept under continuous surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. A narcotic antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. If the dose of acetaminophen may have exceeded 140 mg/kg, acetylcysteine should be administered as early as possible. Serum acetaminophen levels should be obtained, since levels four or more hours following ingestion help predict acetaminophen toxicity. Do not await acetaminophen assay results before initiating treatment. Hepatic enzymes should be obtained initially, and repeated at 24-hour intervals. Methemoglobinemia over 30% should be treated with methylene blue by slow intravenous administration. The toxic dose for adults for acetaminophen is 10 g. DOSAGE AND ADMINISTRATION Dosage should be adjusted according to the severity of the pain and the response of the patient. However, it should be kept in mind that tolerance to hydrocodone can develop with continued use and that the incidence of untoward effects is dose related. The usual adult dosage is one effervescent tablet every four to six hours as needed for pain. The total daily dose should not exceed 6 tablets Preparation of Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets: Tablets should not be chewed, swallowed whole, or dissolved on the tongue. Dissolve each dose in approximately 6 to 8 oz of water immediately before drinking.

23 CHI Rx Only Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets 2.5 mg/325 mg, 5 mg/325 mg, 7.5 mg1325 mg, and 10 mg/325 mg HOW SUPPLIED Hydrocodone Bitartrate and Acetaminophen Effervescent Tablets are available in the following dosage strengths: 2.5 mg/325 mg 5 mg1325 mg 7.5 mg/325 mg 10 mg/325 mg. Imprinting and packaging information will be provided at time of application Storage Store at controlled room temperature C (59-86 F). Dispense in a tight, light-resistant container with a child-resistant closure as defined in the USP. Manufactured by: Name/Address Revision Date: CIII Rx Only

24 Page 1 of 1 From: (516) Origin ID: RMEA Westbury Office LACHMAN CONSULTANT SERVICES 1600 STEWART AVE SUITE 604 WESTBURY, NY Fedaz. Enna Ship Date: 25APR11 ActWgt 1.0 LB CAD: WINET3130 Delivery Address Bar Code J SHIP TO: (301) BILL SENDER Division of Dockets Management FDA, DHHS-HFA Fishers Lane, Room Ref # LCS Dominants Invoice # PO # Dept # Rockville, MD TR" I 0201 ZD OBTA TUE - 26 APR A2 STANDARD OVERNIGHT DSR MD-US IAD retnrnonanoryrrn