200 to 400 mg. 6 mg/kg to 10 mg/kg (maximum 400 mg per dose) 10 mg/kg (maximum 400 mg per dose) 10 mg/kg (maximum 400 mg per dose) Every 8 hours

Transcription

1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights d nt include all the infrmatin needed t use CIPRO IV safely and effectively. See full prescribing infrmatin fr CIPRO IV. CIPRO IV (ciprflxacin) injectin, fr intravenus use Initial U.S. Apprval: 1987 WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS See full prescribing infrmatin fr cmplete bxed warning. Flurquinlnes, including CIPRO IV, have been assciated with disabling and ptentially irreversible serius adverse reactins that have ccurred tgether (5.1), including: Tendinitis and tendn rupture (5.2) Peripheral neurpathy (5.3) Central nervus system effects (5.4) Discntinue CIPRO immediately and avid the use f flurquinlnes, including CIPRO, in patients wh experience any f these serius adverse reactins (5.1) Flurquinlnes, including CIPRO IV, may exacerbate muscle weakness in patients with myasthenia gravis. Avid CIPRO IV in patients with knwn histry f myasthenia gravis. (5.5) Because flurquinlnes, including CIPRO, have been assciated with serius adverse reactins ( ), reserve CIPRO fr use in patients wh have n alternative treatment ptins fr the fllwing indicatins: Acute exacerbatin f chrnic brnchitis (1.9) Acute sinusitis (1.11) RECENT MAJOR CHANGES Warnings and Precautins (5.15) 7/ INDICATIONS AND USAGE CIPRO IV is a flurquinlne antibacterial indicated in adults ( 18 years f age) with the fllwing infectins caused by designated, susceptible bacteria and in pediatric patients where indicated: Skin and Skin structure Infectins (1.1) Bne and Jint infectins (1.2) Cmplicated Intra-Abdminal infectins (1.3) Nscmial Pneumnia (1.4) Empirical Therapy fr Febrile Neutrpenic Patients (1.5) Inhalatinal Anthrax Pst-Expsure in Adult and Pediatric Patients (1.6) Plague in adult and pediatric patients (1.7) Chrnic Bacterial Prstatitis (1.8) Lwer respiratry tract infectins (1.9) Acute Exacerbatin f Chrnic Brnchitis Urinary Tract Infectins (1.10) Urinary Tract Infectins (UTI) Cmplicated UTI and Pyelnephritis in Pediatric Patients Acute Sinusitis (1.11) Usage T reduce the develpment f drug-resistant bacteria and maintain the effectiveness f CIPRO IV and ther antibacterial drugs, CIPRO IV shuld be used nly t treat r prevent infectins that are prven r strngly suspected t be caused by bacteria. (1.12) DOSAGE AND ADMINISTRATION Adult Dsage Guidelines Infectin Dse Frequency Duratin Skin and Skin Structure 400 mg every 8 t 12 hurs 7 14 days Bne and Jint 400 mg every 8 t 12 hurs 4 t 8 weeks Cmplicated Intra-Abdminal 400 mg every 12 hurs 7 14 days Nscmial Pneumnia 400 mg every 8 hurs days 400 mg Empirical Therapy In Febrile and every 8 hurs Neutrpenic Patients Piperacillin 50 mg/kg every 4 hurs 7 14 days Inhalatinal anthrax(pst- 400 mg every 12 hurs 60 days expsure) Plague 400 mg every 8 t 12 hurs 14 days Chrnic Bacterial prstatitis 400 mg every 12 hurs 28 days Lwer Respiratry Tract 400 mg every 8 t 12 hurs 7 14 days Urinary Tract 200 t 400 mg every 8 t 12 hurs 7 14 days Acute Sinusitis 400 mg every 12 hurs 10 days Adults with creatinine clearance 5 29 ml/min mg q 18 h (2.3) Pediatric Intravenus Dsing Guidelines Infectin Dse Frequency Duratin Cmplicated UTI and Pyelnephritis (patients frm 1 t 17 years f age) Inhalatinal Anthrax (Pst-Expsure) Plague 6 mg/kg t 10 mg/kg (maximum 400 mg per dse) 10 mg/kg (maximum 400 mg per dse) 10 mg/kg (maximum 400 mg per dse) Every 8 hurs Every 12 hurs Every 8 t 12 hurs days 1 60 days days DOSAGE FORMS AND STRENGTHS Injectin: 400 mg/200 ml CONTRAINDICATIONS Knwn hypersensitivity t CIPRO r ther quinlnes (4.1, 5.7) Cncmitant administratin with tizanidine (4.2) WARNINGS AND PRECAUTIONS Hypersensitivity and ther serius reactins: Serius and smetimes fatal reactins (fr example, anaphylactic reactins) may ccur after first r subsequent dses f CIPRO IV. Discntinue CIPRO IV at the first sign f skin rash, jaundice r any sign f hypersensitivity. (4.1, 5.6, 5.7) Hepattxicity: Discntinue immediately if signs and symptms f hepatitis ccur. (5.8) Clstridium difficile-assciated Diarrhea: Evaluate if clitis ccurs. (5.10) QT Prlngatin: Prlngatin f the QT interval and islated cases f trsade de pintes have been reprted. Avid use in patients with knwn prlngatin, thse with hypkalemia, and with ther drugs that prlng the QT interval. (5.11, 7, 8.5) ADVERSE REACTIONS The mst cmmn adverse reactins 1% were nausea, diarrhea, liver functin tests abnrmal, vmiting, central nervus system disturbance, lcal intravenus site reactins esinphilia, headache, restlessness, and rash. (6) TO REPORT SUSPECTED ADVERSE REACTIONS, CONTACT BAYER HealthCare Pharmaceuticals Inc. at r FDA at FDA-1088 r DRUG INTERACTIONS Interacting Drug Interactin Thephylline Serius and fatal reactins. Avid cncmitant use. Mnitr serum level (7) Warfarin Anticagulant effect enhanced. Mnitr prthrmbin time, INR, and bleeding (7) Antidiabetic agents Hypglycemia including fatal utcmes have been reprted. Mnitr bld glucse (7) Phenytin Mnitr phenytin level (7) Methtrexate Mnitr fr methtrexate txicity (7) Cyclsprine May increase serum creatinine. Mnitr serum creatinine (7) USE IN SPECIFIC POPULATIONS See full prescribing infrmatin fr pediatric patients (8.4) and use in geriatric (8.5) See 17 fr PATIENT COUNSELING INFORMATION and Medicatin Guide Revised: 7/2017 NDA CIPRO IV FDA Apprved 26 Jul 2017

2 FULL PRESCRIBING INFORMATION: CONTENTS WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS 1 INDICATIONS AND USAGE 1.1 Skin and Skin Structure Infectins 1.2 Bne and Jint Infectins 1.3 Cmplicated Intra-Abdminal Infectins 1.4 Nscmial Pneumnia 1.5 Empirical Therapy fr Febrile Neutrpenia Patients 1.6 Inhalatinal Anthrax (Pst-Expsure) 1.7 Plague 1.8 Chrnic Bacterial Prstatitis 1.9 Lwer Respiratry Tract Infectins 1.10 Urinary Tract Infectins 1.11 Acute Sinusitis 1.12 Usage 2 DOSAGE AND ADMINISTRATION 2.1 Dsage in Adults 2.2 Dsage in Pediatric Patients 2.3 Dsage Mdificatins in Patients with Renal Impairment 2.4 Preparatin f CIPRO IV fr Administratin 2.5 Imprtant Administratin Instructins 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Hypersensitivity 4.2 Tizanidine 5 WARNINGS AND PRECAUTIONS 5.1 Disabling and Ptentially Irreversible Serius Adverse Reactins Including Tendinitis and Tendn Rupture, Peripheral Neurpathy, and Central Nervus System Effects 5.2 Tenditis and Tendn Rupture 5.3 Peripheral Neurpathy 5.4 Central Nervus System Effects 5.5 Exacerbatin f Myasthenia Gravis 5.6 Other Serius and Smetimes Fatal Reactins 5.7 Hypersensitivity Reactins 5.8 Hepattxicity 5.9 Serius Adverse Reactins with Cncmitant Thephylline 5.10 Clstridium difficile-assciated Diarrhea 5.11 Prlngatin f the QT Interval 5.12 Musculskeletal Disrders in Pediatric Patients and Arthrpathic Effects in Animals 5.13 Phtsensitivity/Phttxicity 5.14 Develpment f Drug Resistant Bacteria 5.15 Ptential Risks With Cncmitant Use f Drugs Metablized by Cytchrme P450 1A2 Enzymes 5.17 Crystalluria 5.16 Peridic Assessment f Organ System Functins 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Pstmarketing Experience 6.3 Adverse Labratry Changes 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mthers 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 f Actin 12.3 Pharmackinetics 12.4 Micrbilgy 13 NONCLINICAL TOXICOLOGY 13.1 Carcingenesis, Mutagenesis, Impairment f Fertility 13.2 Animal Txiclgy and/r Pharmaclgy 14 CLINICAL STUDIES 14.1 Empirical Therapy In Adult Febrile Neutrpenic Patients 14.2 Cmplicated Urinary Tract Infectin and Pyelnephritis Efficacy in Pediatric Patients 14.3 Inhalatinal Anthrax in Adults and Pediatrics 14.4 Plague 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sectins r subsectins mitted frm the full prescribing infrmatin are nt listed. NDA CIPRO IV FDA Apprved 26 Jul 2017

3 FULL PRESCRIBING INFORMATION WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS Flurquinlnes, including CIPRO IV, have been assciated with disabling and ptentially irreversible serius adverse reactins that have ccurred tgether [see Warnings and Precautins (5.1)] including: Tendinitis and tendn rupture [see Warnings and Precautins (5.2)] Peripheral neurpathy [see Warnings and Precautins (5.3)] Central nervus system effects [see Warnings and Precautins (5.4)] Discntinue CIPRO immediately and avid the use f flurquinlnes, including CIPRO, in patients wh experience any f these serius adverse reactins [see Warnings and Precautins (5.1)]. Flurquinlnes, including CIPRO IV, may exacerbate muscle weakness in patients with myasthenia gravis. Avid CIPRO IV in patients with knwn histry f myasthenia gravis [see Warnings and Precautins (5.5)]. Because flurquinlnes, including CIPRO, have been assciated with serius adverse reactins [see Warnings and Precautins ( )], reserve CIPRO fr use in patients wh have n alternative treatment ptins fr the fllwing indicatins: Acute exacerbatin f chrnic brnchitis [see Indicatins and Usage (1.9)] Acute Sinusitis [see Indicatins and Usage (1.11)] 1 INDICATIONS AND USAGE 1.1 Skin and Skin Structure Infectins CIPRO IV is indicated in adult patients fr treatment f skin and skin structure infectins caused by Escherichia cli, Klebsiella pneumniae, Enterbacter clacae, Prteus mirabilis, Prteus vulgaris, Prvidencia stuartii, Mrganella mrganii, Citrbacter freundii, Pseudmnas aeruginsa, methicillin-susceptible Staphylcccus aureus, methicillinsusceptible Staphylcccus epidermidis, r Streptcccus pygenes. 1.2 Bne and Jint Infectins CIPRO IV is indicated in adult patients fr treatment f bne and jint infectins caused by Enterbacter clacae, Serratia marcescens, r Pseudmnas aeruginsa. 1.3 Cmplicated Intra-Abdminal Infectins CIPRO IV is indicated in adult patients fr treatment f cmplicated intra-abdminal infectins (used in cmbinatin with metrnidazle) caused by Escherichia cli, Pseudmnas aeruginsa, Prteus mirabilis, Klebsiella pneumniae, r Bacterides fragilis. 1.4 Nscmial Pneumnia CIPRO IV is indicated in adult patients fr treatment f nscmial pneumnia caused by Haemphilus influenzae r Klebsiella pneumniae. NDA CIPRO IV FDA Apprved 26 Jul 2017

4 1.5 Empirical Therapy fr Febrile Neutrpenic Patients CIPRO IV is indicated in adult patients fr the treatment f febrile neutrpenia in cmbinatin with piperacillin sdium [see Clinical Studies (14.1)]. 1.6 Inhalatinal Anthrax (Pst-Expsure) CIPRO IV is indicated in adults and pediatric patients frm birth t 17 years f age fr treatment f inhalatinal anthrax (pst-expsure) t reduce the incidence r prgressin f disease fllwing expsure t aerslized Bacillus anthracis. Ciprflxacin serum cncentratins achieved in humans served as a surrgate endpint reasnably likely t predict clinical benefit and prvided the initial basis fr apprval f this indicatin. 1 Supprtive clinical infrmatin fr ciprflxacin fr anthrax pst-expsure prphylaxis was btained during the anthrax biterrr attacks f Octber 2001 [see Clinical Studies (14.3)]. 1.7 Plague CIPRO IV is indicated fr treatment f plague, including pneumnic and septicemic plague, due t Yersinia pestis (Y. pestis) and prphylaxis fr plague in adults and pediatric patients frm birth t 17 years f age. Efficacy studies f ciprflxacin culd nt be cnducted in humans with plague fr feasibility reasns. Therefre this indicatin is based n an efficacy study cnducted in animals nly [see Clinical Studies (14.4)]. 1.8 Chrnic Bacterial Prstatitis CIPRO IV is indicated in adult patients fr treatment f chrnic bacterial prstatitis caused by Escherichia cli r Prteus mirabilis. 1.9 Lwer Respiratry Tract Infectins CIPRO IV is indicated in adult patients fr treatment f lwer respiratry tract infectins caused by Escherichia cli, Klebsiella pneumniae, Enterbacter clacae, Prteus mirabilis, Pseudmnas aeruginsa, Haemphilus influenzae, Haemphilus parainfluenzae, r Streptcccus pneumniaecipro IV is nt a drug f first chice in the treatment f presumed r cnfirmed pneumnia secndary t Streptcccus pneumnia. CIPRO IV is indicated fr the treatment f acute exacerbatins f chrnic brnchitis (AECB) caused by Mraxella catarrhalis. Because flurquinlnes, including CIPRO IV, have been assciated with serius adverse reactins [see Warnings and Precautins ( )] and fr sme patients AECB is self-limiting, reserve CIPRO IV fr treatment f AECB in patients wh have n alternative treatment ptins Urinary Tract Infectins Urinary Tract Infectin in Adults CIPRO IV is indicated in adult patients fr treatment f urinary tract infectins caused by Escherichia cli, Klebsiella pneumniae, Enterbacter clacae, Serratia marcescens, Prteus mirabilis, Prvidencia rettgeri, Mrganella mrganii, Citrbacter kseri, Citrbacter freundii, Pseudmnas aeruginsa, methicillin-susceptible Staphylcccus epidermidis, Staphylcccus saprphyticus, r Entercccus faecalis. Cmplicated Urinary Tract Infectins and Pyelnephritis in Pediatric Patients CIPRO IV is indicated in pediatric patients ne t 17 years f age fr treatment f cmplicated urinary tract infectins (cuti) and pyelnephritis due t Escherichia cli [see Use in Specific Ppulatins (8.4)]. Althugh effective in clinical trials, CIPRO IV is nt a drug f first chice in the pediatric ppulatin due t an increased incidence f adverse reactins cmpared t cntrls, including reactins related t jints and/r surrunding tissues. CIPRO IV, like ther flurquinlnes, is assciated with arthrpathy and histpathlgical changes in weight-bearing jints f juvenile animals [see Warnings and Precautins (5.12), Adverse Reactins (6.1), Use in Specific Ppulatins (8.4), and Nnclinical Txiclgy (13.2)]. NDA CIPRO IV FDA Apprved 26 Jul 2017

5 1.11 Acute Sinusitis CIPRO IV is indicated in adult patients fr treatment f acute sinusitis caused by Haemphilus influenzae, Streptcccus pneumniae, r Mraxella catarrhalis. Because flurquinlnes, including CIPRO IV, have been assciated with serius adverse reactins [see Warnings and Precautins ( )] and fr sme patients acute sinusitis is self-limiting, reserve CIPRO fr treatment f acute sinusitis in patients wh have n alternative treatment ptins Usage T reduce the develpment f drug-resistant bacteria and maintain the effectiveness f CIPRO IV and ther antibacterial drugs, CIPRO IV shuld be used nly t treat r prevent infectins that are prven r strngly suspected t be caused by susceptible bacteria. When culture and susceptibility infrmatin are available, they shuld be cnsidered in selecting r mdifying antibacterial therapy. In the absence f such data, lcal epidemilgy and susceptibility patterns may cntribute t the empiric selectin f therapy. If anaerbic rganisms are suspected f cntributing t the infectin, apprpriate therapy shuld be administered. Apprpriate culture and susceptibility tests shuld be perfrmed befre treatment in rder t islate and identify rganisms causing infectin and t determine their susceptibility t ciprflxacin. Therapy with CIPRO IV may be initiated befre results f these tests are knwn; nce results becme available apprpriate therapy shuld be cntinued. As with ther drugs, sme islates f Pseudmnas aeruginsa may develp resistance fairly rapidly during treatment with ciprflxacin. Culture and susceptibility testing perfrmed peridically during therapy will prvide infrmatin nt nly n the therapeutic effect f the antimicrbial agent but als n the pssible emergence f bacterial resistance. 2 DOSAGE AND ADMINISTRATION CIPRO IV shuld be administered intravenusly at dsages described in the apprpriate Dsage Guidelines tables. 2.1 Dsage in Adults The determinatin f dsage and duratin fr any particular patient must take int cnsideratin the severity and nature f the infectin, the susceptibility f the causative micrrganism, the integrity f the patient s hst-defense mechanisms, and the status f renal and hepatic functin. Table 1: Adult Dsage Guidelines Infectin 1 Dse Frequency Usual Duratin Skin and Skin Structure 400 mg every 8 t 12 hurs 7 14 days Bne and Jint 400 mg every 8 t 12 hurs 4 t 8 weeks Cmplicated Intra- Abdminal mg every 12 hurs 7 14 days Nscmial Pneumnia 400 mg every 8 hurs days Empirical Therapy In Febrile Neutrpenic CIPRO IV 400 mg and every 8 hurs 7 14 days Patients Piperacillin 50 mg/kg every 4 hurs Inhalatinal Anthrax(Pst-Expsure) mg every 12 hurs 60 days Plague mg every 8 t 12 hurs 14 days Chrnic Bacterial Prstatitis 400 mg every 12 hurs 28 days Lwer Respiratry Tract Infectins 400 mg every 8 t 12 hurs 7 14 days Urinary Tract Infectins 200 mg t 400 mg every 8 t 12 hurs 7 14 days NDA CIPRO IV FDA Apprved 26 Jul 2017

6 Acute Sinusitis 400 mg every 12 hurs 10 days 1. Due t the designated pathgens (see Indicatins and Usage.) 2. Used in cnjunctin with metrnidazle. 3. Begin administratin as sn as pssible after suspected r cnfirmed expsure. Cnversin f Intravenus t Oral Dsing in Adults Patients whse therapy is started with CIPRO IV may be switched t CIPRO Tablets r Oral Suspensin when clinically indicated at the discretin f the physician (Table 2) [see Clinical Pharmaclgy (12.3)]. Table 2: Equivalent AUC Dsing Regimens CIPRO Oral Dsage Equivalent CIPRO IV Dsage 250 mg Tablet every 12 hurs 200 mg intravenus every 12 hurs 500 mg Tablet every 12 hurs 400 mg intravenus every 12 hurs 750 mg Tablet every 12 hurs 400 mg intravenus every 8 hurs 2.2 Dsage in Pediatric Patients Dsing and initial rute f therapy (that is, IV r ral) fr cuti r pyelnephritis shuld be determined by the severity f the infectin. Table 3: Pediatric Dsage Guidelines Infectin Cmplicated Urinary Tract r Pyelnephritis (patients frm 1 t 17 years f age) 1 Inhalatinal Anthrax (Pst-Expsure) 2 Plague 2,3 NDA CIPRO IV FDA Apprved 26 Jul 2017 Dse (mg/kg) Frequency Ttal Duratin 6 mg/kg t 10 mg/kg (maximum 400 mg per dse; nt t be exceeded even in patients Every 8 hurs days 1 weighing mre than 51 kg) 10 mg/kg Every 12 (maximum 400 mg per dse) hurs 60 days 10 mg/kg Every 8 t 12 (maximum 400 mg per dse) hurs days 1. The ttal duratin f therapy fr cuti and pyelnephritis in the clinical trial was determined by the physician. The mean duratin f treatment was 11 days (range 10 t 21 days). 2. Begin drug administratin as sn as pssible after suspected r cnfirmed expsure. 3. Begin drug administratin as sn as pssible after suspected r cnfirmed expsure t Y. pestis. 2.3 Dsage Mdificatins in Patients with Renal Impairment Ciprflxacin is eliminated primarily by renal excretin; hwever, the drug is als metablized and partially cleared thrugh the biliary system f the liver and thrugh the intestine. These alternative pathways f drug eliminatin appear t cmpensate fr the reduced renal excretin in patients with renal impairment. Nnetheless, sme mdificatin f dsage is recmmended, particularly fr patients with severe renal dysfunctin. Dsage guidelines fr use in patients with renal impairment are shwn in Table 4. Table 4: Recmmended Starting and Maintenance Dses fr Adult Patients with Impaired Renal Functin Creatinine Clearance (ml/min) Dse >30 See Usual Dsage mg every hurs When nly the serum creatinine cncentratin is knwn, the fllwing frmulas may be used t estimate creatinine clearance: Men - Creatinine clearance (ml/min) = Weight (kg) x (140 age) 72 x serum creatinine (mg/dl)

7 Wmen x the value calculated fr men. The serum creatinine shuld represent a steady state f renal functin. In patients with severe infectins and severe renal impairment and hepatic insufficiency, careful mnitring is suggested. Pediatric patients with mderate t severe renal insufficiency were excluded frm the clinical trial f cuti and pyelnephritis. N infrmatin is available n dsing adjustments necessary fr pediatric patients with mderate t severe renal insufficiency (that is, creatinine clearance f < 50 ml/min/1.73m 2 ). 2.4 Preparatin f CIPRO IV fr Administratin Flexible Cntainers CIPRO IV is available as a 0.2% premixed slutin in 5% dextrse in flexible cntainers f 200 ml. The slutins in flexible cntainers d nt need t be diluted and may be infused as described abve. 2.5 Imprtant Administratin Instructins Intravenus Infusin CIPRO IV shuld be administered by intravenus infusin ver a perid f 60 minutes. Slw infusin f a dilute slutin int a larger vein will minimize patient discmfrt and reduce the risk f venus irritatin. Hydratin f Patients Receiving CIPRO IV Adequate hydratin f patients receiving CIPRO IV shuld be maintained t prevent the frmatin f highly cncentrated urine. Crystalluria has been reprted with quinlnes [see Warnings and Precautins (5.16), Adverse Reactins (6.1), Nnclinical Txiclgy (13.2) and Patient Cunseling Infrmatin (17)]. 3 DOSAGE FORMS AND STRENGTHS Injectin: (200 ml in 5% Dextrse, 400 mg, 0.2%) Premix in Flexible Cntainers, fr intravenus infusin. 4 CONTRAINDICATIONS 4.1 Hypersensitivity Ciprflxacin is cntraindicated in persns with a histry f hypersensitivity t ciprflxacin, any member f the quinlne class f antibacterials, r any f the prduct cmpnents [see Warnings and Precautins (5.7)]. 4.2 Tizanidine Cncmitant administratin with tizanidine is cntraindicated [see Drug Interactins (7)]. 5 WARNINGS AND PRECAUTIONS 5.1 Disabling and Ptentially Irreversible Serius Adverse Reactins Including Tendinitis and Tendn Rupture, Peripheral Neurpathy, and Central Nervus System Effects Flurquinlnes, including CIPRO IV, have been assciated with disabling and ptentially irreversible serius adverse reactins frm different bdy systems that can ccur tgether in the same patient. Cmmnly seen adverse reactins include tendinitis, tendn rupture, arthralgia, myalgia, peripheral neurpathy, and central nervus system effects (hallucinatins, anxiety, depressin, insmnia, severe headaches, and cnfusin). These reactins can ccur within hurs t weeks after starting CIPRO IV. Patients f any age r withut pre-existing risk factrs have experienced these adverse reactins [see Warnings and Precautins (5.2, 5.3, 5.4)]. Discntinue CIPRO IV immediately at the first signs r symptms f any serius adverse reactin. In additin, avid the use f flurquinlnes, including CIPRO IV, in patients wh have experienced any f these serius adverse reactins assciated with flurquinlnes. NDA CIPRO IV FDA Apprved 26 Jul 2017

8 5.2 Tendinitis and Tendn Rupture Flurquinlnes, including CIPRO IV, have been assciated with an increased risk f tendinitis and tendn rupture in all ages [see Warnings and Precautins (5.1) and Adverse Reactins (6.2)]. This adverse reactin mst frequently invlves the Achilles tendn, and has als been reprted with the rtatr cuff (the shulder), the hand, the biceps, the thumb, and ther tendns. Tendinitis r tendn rupture can ccur, within hurs r days f starting CIPRO IV, r as lng as several mnths after cmpletin f flurquinlne therapy. Tendinitis and tendn rupture can ccur bilaterally. The risk f develping flurquinlne-assciated tendinitis and tendn rupture is increased in patients ver 60 years f age, in patients taking crticsterid drugs, and in patients with kidney, heart r lung transplants. Other factrs, that may independently increase the risk f tendn rupture include strenuus physical activity, renal failure, and previus tendn disrders such as rheumatid arthritis. Tendinitis and tendn rupture have als ccurred in patients taking flurquinlnes wh d nt have the abve risk factrs. Discntinue CIPRO IV immediately if the patient experiences pain, swelling, inflammatin r rupture f a tendn. Avid flurquinlnes, including CIPRO IV, in patients wh have a histry f tendn disrders r have experienced tendinitis r tendn rupture [see Adverse Reactins (6.2)]. 5.3 Peripheral Neurpathy Flurquinlnes, including CIPRO IV, have been assciated with an increased risk f peripheral neurpathy. Cases f sensry r sensrimtr axnal plyneurpathy affecting small and/r large axns resulting in paresthesias, hypesthesias, dysesthesias and weakness have been reprted in patients receiving flurquinlnes, including CIPRO IV. Symptms may ccur sn after initiatin f CIPRO IV and may be irreversible in sme patients [see Warnings and Precautins (5.1) and Adverse Reactins (6.1, 6.2)]. Discntinue CIPRO IV immediately if the patient experiences symptms f peripheral neurpathy including pain, burning, tingling, numbness, and/r weakness, r ther alteratins in sensatins including light tuch, pain, temperature, psitin sense and vibratry sensatin, and/r mtr strength in rder t minimize the develpment f an irreversible cnditin. Avid flurquinlnes, including CIPRO IV, in patients wh have previusly experienced peripheral neurpathy [see Adverse Reactins (6.1, 6.2).] 5.4 Central Nervus System Effects Flurquinlnes, including CIPRO IV, have been assciated with an increased risk f central nervus system (CNS) effects, including cnvulsins, increased intracranial pressure (including pseudtumr cerebri), and txic psychsis CIPRO IV may als cause central nervus system (CNS) events including: nervusness, agitatin, insmnia, anxiety, nightmares, parania, dizziness, cnfusin, tremrs, hallucinatins, depressin, and, psychtic reactins have prgressed t suicidal ideatins/thughts and self-injurius behavir such as attempted r cmpleted suicide. These reactins may ccur fllwing the first dse. Advise patients receiving CIPRO IV t infrm their healthcare prvider immediately if these reactins ccur, discntinue the drug, and institute apprpriate care. CIPRO IV, like ther flurquinlnes, is knwn t trigger seizures r lwer the seizure threshld. As with all flurquinlnes, use CIPRO IV with cautin in epileptic patients and patients with knwn r suspected CNS disrders that may predispse t seizures r lwer the seizure threshld (fr example, severe cerebral arterisclersis, previus histry f cnvulsin, reduced cerebral bld flw, altered brain structure, r strke), r in the presence f ther risk factrs that may predispse t seizures r lwer the seizure threshld (fr example, certain drug therapy, renal dysfunctin). Use CIPRO IV when the benefits f treatment exceed the risks, since these patients are endangered because f pssible undesirable CNS side effects. Cases f status epilepticus have been reprted. If seizures ccur, discntinue CIPRO IV [see Adverse Reactins (6.1) and Drug Interactins (7)]. 5.5 Exacerbatin f Myasthenia Gravis Flurquinlnes, including CIPRO IV, have neurmuscular blcking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Pstmarketing serius adverse reactins, including deaths and requirement fr ventilatry supprt, have been assciated with flurquinlne use in patients with myasthenia gravis. Avid CIPRO IV in patients with knwn histry f myasthenia gravis [see Adverse Reactins (6.2)]. NDA CIPRO IV FDA Apprved 26 Jul 2017

9 5.6 Other Serius and Smetimes Fatal Adverse Reactins Other serius and smetimes fatal adverse reactins, sme due t hypersensitivity, and sme due t uncertain etilgy, have been reprted in patients receiving therapy with quinlnes, including CIPRO IV. These events may be severe and generally ccur fllwing the administratin f multiple dses. Clinical manifestatins may include ne r mre f the fllwing: Fever, rash, r severe dermatlgic reactins (fr example, txic epidermal necrlysis, Stevens-Jhnsn syndrme); Vasculitis; arthralgia; myalgia; serum sickness; Allergic pneumnitis; Interstitial nephritis; acute renal insufficiency r failure; Hepatitis; jaundice; acute hepatic necrsis r failure; Anemia, including hemlytic and aplastic; thrmbcytpenia, including thrmbtic thrmbcytpenic purpura; leukpenia; agranulcytsis; pancytpenia; and/r ther hematlgic abnrmalities. Discntinue CIPRO IV immediately at the first appearance f a skin rash, jaundice, r any ther sign f hypersensitivity and supprtive measures instituted [see Adverse Reactins (6.1, 6.2)]. 5.7 Hypersensitivity Reactins Serius and ccasinally fatal hypersensitivity (anaphylactic) reactins, sme fllwing the first dse, have been reprted in patients receiving flurquinlne therapy, including CIPRO IV. Sme reactins were accmpanied by cardivascular cllapse, lss f cnsciusness, tingling, pharyngeal r facial edema, dyspnea, urticaria, and itching. Only a few patients had a histry f hypersensitivity reactins. Serius anaphylactic reactins require immediate emergency treatment with epinephrine and ther resuscitatin measures, including xygen, intravenus fluids, intravenus antihistamines, crticsterids, pressr amines, and airway management, including intubatin, as indicated [see Adverse Reactins (6.1)]. 5.8 Hepattxicity Cases f severe hepattxicity, including hepatic necrsis, life-threatening hepatic failure, and fatal events, have been reprted with CIPRO IV. Acute liver injury is rapid in nset (range 1 39 days), and is ften assciated with hypersensitivity. The pattern f injury can be hepatcellular, chlestatic r mixed. Mst patients with fatal utcmes were lder than 55 years ld. In the event f any signs and symptms f hepatitis (such as anrexia, jaundice, dark urine, pruritus, r tender abdmen), discntinue treatment immediately. There can be a temprary increase in transaminases, alkaline phsphatase, r chlestatic jaundice, especially in patients with previus liver damage, wh are treated with CIPRO IV [see Adverse Reactins (6.2, 6.3)]. 5.9 Serius Adverse Reactins with Cncmitant Thephylline Serius and fatal reactins have been reprted in patients receiving cncurrent administratin f Intravenus CIPRO and thephylline. These reactins have included cardiac arrest, seizure, status epilepticus, and respiratry failure. Instances f nausea, vmiting, tremr, irritability, r palpitatin have als ccurred. Althugh similar serius adverse reactins have been reprted in patients receiving thephylline alne, the pssibility that these reactins may be ptentiated by CIPRO cannt be eliminated. If cncmitant use cannt be avided, mnitr serum levels f thephylline and adjust dsage as apprpriate [see Drug Interactins (7)] Clstridium difficile-assciated Diarrhea Clstridium difficile (C. difficile)-assciated diarrhea (CDAD) has been reprted with use f nearly all antibacterial agents, including CIPRO IV, and may range in severity frm mild diarrhea t fatal clitis. Treatment with antibacterial agents alters the nrmal flra f the cln leading t vergrwth f C. difficile. C. difficile prduces txins A and B which cntribute t the develpment f CDAD. Hypertxin prducing islates f C. difficile cause increased mrbidity and mrtality, as these infectins can be refractry t antimicrbial therapy and may require clectmy. CDAD must be cnsidered in all patients wh present with diarrhea fllwing antibacterial use. NDA CIPRO IV FDA Apprved 26 Jul 2017

10 Careful medical histry is necessary since CDAD has been reprted t ccur ver tw mnths after the administratin f antibacterial agents. If CDAD is suspected r cnfirmed, nging antibacterial use nt directed against C. difficile may need t be discntinued. Apprpriate fluid and electrlyte management, prtein supplementatin, antibacterial treatment f C. difficile, and institute surgical evaluatin as clinically indicated [see Adverse Reactins (6.1)] Prlngatin f the QT Interval Sme flurquinlnes, including CIPRO IV, have been assciated with prlngatin f the QT interval n the electrcardigram and cases f arrhythmia. Cases f trsade de pintes have been reprted during pstmarketing surveillance in patients receiving flurquinlnes, including CIPRO IV. Avid CIPRO IV in patients with knwn prlngatin f the QT interval, risk factrs fr QT prlngatin r trsade de pintes (fr example, cngenital lng QT syndrme, uncrrected electrlyte imbalance, such as hypkalemia r hypmagnesemia and cardiac disease, such as heart failure, mycardial infarctin, r bradycardia), and patients receiving Class IA antiarrhythmic agents (quinidine, prcainamide), r Class III antiarrhythmic agents (amidarne, stall), tricyclic antidepressants, macrlides, and antipsychtics. Elderly patients may als be mre susceptible t drug-assciated effects n the QT interval [see Adverse Reactins (6.2) and Use in Specific Ppulatins (8.5)] Musculskeletal Disrders in Pediatric Patients and Arthrpathic Effects in Animals CIPRO IV is indicated in pediatric patients (less than 18 years f age) nly fr cuti, preventin f inhalatinal anthrax (pst expsure), and plague [see Indicatins and Usage (1.10, 1.6, 1.7)]. An increased incidence f adverse reactins cmpared t cntrls, including reactins related t jints and/r surrunding tissues, has been bserved [see Adverse Reactins (6.1)]. In pre-clinical studies, ral administratin f CIPRO IV caused lameness in immature dgs. Histpathlgical examinatin f the weight-bearing jints f these dgs revealed permanent lesins f the cartilage. Related quinlneclass drugs als prduce ersins f cartilage f weight-bearing jints and ther signs f arthrpathy in immature animals f varius species[see Use in Specific Ppulatins (8.4) and Nnclinical Txiclgy (13.2)] Phtsensitivity/Phttxicity Mderate t severe phtsensitivity/phttxicity reactins, the latter f which may manifest as exaggerated sunburn reactins (fr example, burning, erythema, exudatin, vesicles, blistering, edema) invlving areas expsed t light (typically the face, V area f the neck, extensr surfaces f the frearms, drsa f the hands), can be assciated with the use f quinlnes, including CIPRO IV, after sun r UV light expsure. Therefre, avid excessive expsure t these surces f light. Discntinue CIPRO IV if phttxicity ccurs[see Adverse Reactins (6.1).] 5.14 Develpment f Drug Resistant Bacteria Prescribing CIPRO IV in the absence f a prven r strngly suspected bacterial infectin r a prphylactic indicatin is unlikely t prvide benefit t the patient and increases the risk f the develpment f drug-resistant bacteria Ptential Risks with Cncmitant Use f Drugs Metablized by Cytchrme P450 1A2 Enzymes Ciprflxacin is an inhibitr f the hepatic CYP1A2 enzyme pathway. C-administratin f CIPRO IV and ther drugs primarily metablized by CYP1A2 (fr example, thephylline, methylxanthines, caffeine, tizanidine, rpinirle, clzapine, lanzapine, and zlpidem) results in increased plasma cncentratins f the c-administered drug and culd lead t clinically significant pharmacdynamic adverse reactins f the c-administered drug [see Drug Interactins (7) and Clinical Pharmaclgy (12.3)] Crystalluria Crystals f ciprflxacin have been bserved rarely in the urine f human subjects but mre frequently in the urine f labratry animals, which is usually alkaline [see Nnclinical Txiclgy (13.2)]. Crystalluria related t ciprflxacin has been reprted nly rarely in humans because human urine is usually acidic. Avid alkalinity f the urine in patients NDA CIPRO IV FDA Apprved 26 Jul 2017

11 receiving CIPRO IV. Hydrate patients well t prevent the frmatin f highly cncentrated urine [see Dsage and Administratin (2.4)] Peridic Assessment f Organ System Functins As with any ptent drug, peridic assessment f rgan system functins, including renal, hepatic, and hematpietic functin, is advisable during prlnged therapy. 6 ADVERSE REACTIONS The fllwing serius and therwise imprtant adverse drug reactins are discussed in greater detail in ther sectins f labeling: Disabling and Ptentially Irreversible Serius Adverse Reactins [see Warnings and Precautins (5.1)] Tendinitis and Tendn Rupture [see Warnings and Precautins (5.2)] Peripheral Neurpathy [see Warnings and Precautins (5.3)] Central Nervus System Effects [see Warnings and Precautins (5.4)] Exacerbatin f Myasthenia Gravis [see Warnings and Precautins (5.5)] Other Serius and Smetimes Fatal Adverse Reactins [see Warnings and Precautins (5.6)] Hypersensitivity Reactins [see Warnings and Precautins (5.7)] Hepattxicity [see Warnings and Precautins (5.8)] Serius Adverse Reactins with Cncmitant Thephylline [see Warnings and Precautins (5.9)] Clstridium difficile-assciated Diarrhea [see Warnings and Precautins (5.10)] Prlngatin f the QT Interval [see Warnings and Precautins (5.11)] Musculskeletal Disrders in Pediatric Patients [see Warnings and Precautins (5.12)] Phtsensitivity/Phttxicity [see Warnings and Precautins (5.13)] Develpment f Drug Resistant Bacteria [see Warnings and Precautins (5.14)] 6.1 Clinical Trials Experience Because clinical trials are cnducted under widely varying cnditins, adverse reactin rates bserved in the clinical trials f a drug cannt be directly cmpared t rates in the clinical trials f anther drug and may nt reflect the rates bserved in practice. Adult Patients During clinical investigatins with ral and parenteral CIPRO IV, 49,038 patients received curses f the drug. The mst frequently reprted adverse reactins, frm clinical trials f all frmulatins, all dsages, all drug-therapy duratins, and fr all indicatins f ciprflxacin therapy were nausea (2.5%), diarrhea (1.6%), liver functin tests abnrmal (1.3%), vmiting (1%), and rash (1%). In clinical trials the fllwing adverse reactins were reprted in greater than 1% f patients treated with intravenus CIPRO IV: nausea, diarrhea, central nervus system disturbance, lcal intravenus site reactins, liver functin tests abnrmal, esinphilia, headache, restlessness, and rash. Lcal intravenus site reactins are mre frequent if the infusin time is 30 minutes r less. These may appear as lcal skin reactins that reslve rapidly upn cmpletin f the infusin. Subsequent intravenus administratin is nt cntraindicated unless the reactins recur r wrsen. Table 5: Medically Imprtant Adverse Reactins That Occurred in less than 1% Ciprflxacin Patients System Organ Class Bdy as a Whle Cardivascular NDA CIPRO IV FDA Apprved 26 Jul 2017 Adverse Reactins Abdminal Pain/Discmfrt Pain Cardipulmnary Arrest Mycardial Infarctin

12 System Organ Class Central Nervus System Gastrintestinal Hemic/Lymphatic Metablic/Nutritinal Musculskeletal Renal/Urgenital Adverse Reactins Tachycardia Syncpe Hypertensin Angina Pectris Vasdilatin Restlessness Seizures (including Status Epilepticus) Parania Psychsis (txic) Depressin (ptentially culminating in self-injurius behavir, such as suicidal ideatins/thughts and attempted r cmpleted suicide) Phbia Depersnalizatin Manic Reactin Unrespnsiveness Ataxia Hallucinatins Dizziness Paresthesia Tremr Insmnia Nightmares Irritability Malaise Abnrmal Gait Migraine Ileus Gastrintestinal Bleeding Pancreatitis Hepatic Necrsis Intestinal Perfratin Dyspepsia Cnstipatin Oral Ulceratin Muth Dryness Anrexia Flatulence Hepatitis Agranulcytsis Prlngatin f Prthrmbin Time Petechia Hyperglycemia Hypglycemia Arthralgia Jint Stiffness Muscle Weakness Renal Failure Interstitial Nephritis Hemrrhagic Cystitis Renal Calculi Frequent Urinatin Gynecmastia NDA CIPRO IV FDA Apprved 26 Jul 2017

13 System Organ Class Respiratry Skin/Hypersensitivity Special Senses Adverse Reactins Crystalluria Cylindruria Hematuria Albuminuria Respiratry Arrest Dyspnea Laryngeal Edema Hemptysis Brnchspasm Allergic Reactins Anaphylactic Reactins including life-threatening anaphylactic shck Erythema Multifrme/Stevens-Jhnsn Syndrme Exfliative Dermatitis Txic Epidermal Necrlysis Vasculitis Angiedema Extremities Purpura Fever Pruritus Urticaria Increased Perspiratin Erythema Ndsum Thrmbphlebitis Burning Phtsensitivity/Phttxicity Reactin Decreased Visual Acuity Blurred Visin Disturbed Visin (diplpia, chrmatpsia, and phtpsia) Ansmia Hearing Lss Tinnitus Nystagmus Bad Taste In several instances, nausea, vmiting, tremr, irritability, r palpitatin were judged by investigatrs t be related t elevated serum levels f thephylline pssibly as a result f drug interactin with ciprflxacin. In randmized, duble-blind cntrlled clinical trials cmparing CIPRO (Intravenus and Intravenus/Oral sequential) with intravenus beta-lactam cntrl antibitics, the CNS adverse reactin prfile f CIPRO was cmparable t that f the cntrl drugs. Pediatric Patients Shrt (6 weeks) and lng term (1 year) musculskeletal and neurlgical safety f ral/intravenus ciprflxacin was cmpared t a cephalsprin fr treatment f cuti r pyelnephritis in pediatric patients 1 t 17 years f age (mean age f 6 ± 4 years) in an internatinal multicenter trial. The duratin f therapy was 10 t 21 days (mean duratin f treatment was 11 days with a range f 1 t 88 days). A ttal f 335 ciprflxacin- and 349 cmparatr-treated patients were enrlled. An Independent Pediatric Safety Cmmittee (IPSC) reviewed all cases f musculskeletal adverse reactins including abnrmal gait r abnrmal jint exam (baseline r treatment-emergent). Within 6 weeks f treatment initiatin, the rates f musculskeletal adverse reactins were 9.3% (31/335) in the ciprflxacin-treated grup versus 6% (21/349) in NDA CIPRO IV FDA Apprved 26 Jul 2017

14 cmparatr-treated patients. All musculskeletal adverse reactins ccurring by 6 weeks reslved (clinical reslutin f signs and symptms), usually within 30 days f end f treatment. Radilgical evaluatins were nt rutinely used t cnfirm reslutin f the adverse reactins. Ciprflxacin-treated patients were mre likely t reprt mre than ne adverse reactin and n mre than ne ccasin cmpared t cntrl patients. The rate f musculskeletal adverse reactins was cnsistently higher in the ciprflxacin grup cmpared t the cntrl grup acrss all age subgrups. At the end f 1 year, the rate f these adverse reactins reprted at any time during that perid was 13.7% (46/335) in the ciprflxacin-treated grup versus 9.5% (33/349) in the cmparatr-treated patients (Table 6). Table 6: Musculskeletal Adverse Reactins 1 as Assessed by the IPSC CIPRO Cmparatr All Patients (within 6 weeks) 31/335 (9.3%) 21/349 (6%) 95% Cnfidence Interval 2 (-0.8%, +7.2%) Age Grup 12 mnths t 24 mnths 1/36 (2.8%) 0/41 2 years t <6 years 5/124 (4%) 3/118 (2.5%) 6 years t <12 years 18/143 (12.6%) 12/153 (7.8%) 12 years t 17 years 7/32 (21.9%) 6/37 (16.2 %) All Patients (within 1 year) 46/335 (13.7%) 33/349 (9.5%) 95% Cnfidence Interval 2 (-0.6%, + 9.1%) 1. Included: arthralgia, abnrmal gait, abnrmal jint exam, jint sprains, leg pain, back pain, arthrsis, bne pain, pain, myalgia, arm pain, and decreased range f mtin in a jint (knee, elbw, ankle, hip, wrist, and shulder) 2. The study was designed t demnstrate that the arthrpathy rate fr the CIPRO grup did nt exceed that f the cntrl grup by mre than + 6%. At bth the 6 week and 1 year evaluatins, the 95% cnfidence interval indicated that it culd nt be cncluded that the ciprflxacin grup had findings cmparable t the cntrl grup. The incidence rates f neurlgical adverse reactins within 6 weeks f treatment initiatin were 3% (9/335) in the ciprflxacin grup versus 2% (7/349) in the cmparatr grup and included dizziness, nervusness, insmnia, and smnlence. In this trial, the verall incidence rates f adverse reactins within 6 weeks f treatment initiatin were 41% (138/335) in the ciprflxacin grup versus 31% (109/349) in the cmparatr grup. The mst frequent adverse reactins were gastrintestinal: 15% (50/335) f ciprflxacin patients cmpared t 9% (31/349) f cmparatr patients. Serius adverse reactins were seen in 7.5% (25/335) f ciprflxacin-treated patients cmpared t 5.7% (20/349) f cntrl patients. Discntinuatin f drug due t an adverse reactin was bserved in 3% (10/335) f ciprflxacin-treated patients versus 1.4% (5/349) f cmparatr patients. Other adverse events that ccurred in at least 1% f ciprflxacin patients were diarrhea 4.8%, vmiting 4.8%, abdminal pain 3.3%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%. Shrt-term safety data fr ciprflxacin was als cllected in a randmized, duble-blind clinical trial fr the treatment f acute pulmnary exacerbatins in cystic fibrsis patients (ages 5 17 years). Sixty seven patients received CIPRO IV 10 mg/kg/dse every 8 hurs fr ne week fllwed by CIPRO tablets 20 mg/kg/dse every 12 hurs t cmplete days treatment and 62 patients received the cmbinatin f ceftazidime intravenus 50 mg/kg/dse every 8 hurs and tbramycin intravenus 3 mg/kg/dse every 8 hurs fr a ttal f days. Peridic musculskeletal assessments were cnducted by treatment-blinded examiners. Patients were fllwed fr an average f 23 days after cmpleting treatment (range 0 93 days). Musculskeletal adverse reactins were reprted in 22% f the patients in the ciprflxacin grup and 21% in the cmparisn grup. Decreased range f mtin was reprted in 12% f the subjects in the ciprflxacin grup and 16% in the cmparisn grup. Arthralgia was reprted in 10% f the patients in the ciprflxacin grup and 11% in NDA CIPRO IV FDA Apprved 26 Jul 2017

15 the cmparisn grup. Other adverse reactins were similar in nature and frequency between treatment arms. The efficacy f CIPRO fr the treatment f acute pulmnary exacerbatins in pediatric cystic fibrsis patients has nt been established. In additin t the adverse reactins reprted in pediatric patients in clinical trials, it shuld be expected that adverse reactins reprted in adults during clinical trials r pstmarketing experience may als ccur in pediatric patients. 6.2 Pstmarketing Experience The fllwing adverse reactins have been reprted frm wrldwide marketing experience with flurquinlnes, including CIPRO IV. Because these reactins are reprted vluntarily frm a ppulatin f uncertain size, it is nt always pssible t reliably estimate their frequency r establish a causal relatinship t drug expsure (Table 7). Table 7: Pstmarketing Reprts f Adverse Drug Reactins System Organ Class Cardivascular Central Nervus System Gastrintestinal Hemic/Lymphatic Hepatbiliary Infectins and Infestatins Investigatins Musculskeletal Psychiatric Disrders Skin/Hypersensitivity Special Senses 6.3 Adverse Labratry Changes Adverse Reactins QT prlngatin Trsade de Pintes Vasculitis and ventricular arrhythmia Hypertnia Myasthenia Exacerbatin f myasthenia gravis Peripheral neurpathy Plyneurpathy Twitching Pseudmembranus clitis Pancytpenia (life threatening r fatal utcme) Methemglbinemia Hepatic failure (including fatal cases) Candidiasis (ral, gastrintestinal, vaginal) Prthrmbin time prlngatin r decrease Chlesterl elevatin (serum) Ptassium elevatin (serum) Myalgia Myclnus Tendinitis Tendn rupture Agitatin Cnfusin Delirium Acute generalize exanthematus pustulsis (AGEP) Fixed eruptin Serum sickness-like reactin Ansmia Hyperesthesia Hypesthesia Nystagmus Taste lss Changes in labratry parameters while n CIPRO IV therapy are listed belw: Hepatic-Elevatins f AST (SGOT), ALT (SGPT), alkaline phsphatase, LDH, and serum bilirubin Hematlgic-Elevated esinphil and platelet cunts, decreased platelet cunts, hemglbin and/r hematcrit Renal-Elevatins f serum creatinine, BUN, and uric acid NDA CIPRO IV FDA Apprved 26 Jul 2017

16 Other elevatins f serum creatine phsphkinase, serum thephylline (in patients receiving thephylline cncmitantly), bld glucse, and triglycerides Other changes ccurring were: decreased leukcyte cunt, elevated atypical lymphcyte cunt, immature WBCs, elevated serum calcium, elevatin f serum gamma-glutamyl transpeptidase (ggt), decreased BUN, decreased uric acid, decreased ttal serum prtein, decreased serum albumin, decreased serum ptassium, elevated serum ptassium, elevated serum chlesterl. Other changes ccurring during administratin f ciprflxacin were: elevatin f serum amylase, decrease f bld glucse, pancytpenia, leukcytsis, elevated sedimentatin rate, change in serum phenytin, decreased prthrmbin time, hemlytic anemia, and bleeding diathesis. 7 DRUG INTERACTIONS Ciprflxacin is an inhibitr f human cytchrme P450 1A2 (CYP1A2) mediated metablism. C-administratin f CIPRO IV with ther drugs primarily metablized by CYP1A2 results in increased plasma cncentratins f these drugs and culd lead t clinically significant adverse events f the c-administered drug. Table 8: Drugs That are Affected by and Affecting CIPRO IV Drugs That are Affected by CIPRO IV Drug(s) Recmmendatin Cmments Tizanidine Cntraindicated Cncmitant administratin f tizanidine and CIPRO IV is cntraindicated due t the ptentiatin f hyptensive and sedative effects f tizanidine [see Cntraindicatins (4.2)] Thephylline Drugs Knwn t Prlng QT Interval Oral antidiabetic drugs Phenytin Cyclsprine Avid Use (Plasma Expsure Likely t be Increased and Prlnged) Avid Use Use with cautin Glucse-lwering effect ptentiated Use with cautin Altered serum levels f phenytin (increased and decreased) Use with cautin (transient elevatins in serum creatinine) NDA CIPRO IV FDA Apprved 26 Jul 2017 Cncurrent administratin f CIPRO IV with thephylline may result in increased risk f a patient develping central nervus system (CNS) r ther adverse reactins. If cncmitant use cannt be avided, mnitr serum levels f thephylline and adjust dsage as apprpriate [see Warnings and Precautins (5.9)]. CIPRO IV may further prlng the QT interval in patients receiving drugs knwn t prlng the QT interval (fr example, class IA r III antiarrhythmics, tricyclic antidepressants, macrlides, antipsychtics) [see Warnings and Precautins (5.11) and Use in Specific Ppulatins (8.5)]. Hypglycemia smetimes severe has been reprted when CIPRO IV and ral antidiabetic agents, mainly sulfnylureas (fr example, glyburide, glimepiride), were c-administered, presumably by intensifying the actin f the ral antidiabetic agent. Fatalities have been reprted. Mnitr bld glucse when ciprflxacin is c-administered with ral antidiabetic drugs [see Adverse Reactins (6.1)]. T avid the lss f seizure cntrl assciated with decreased phenytin levels and t prevent phenytin verdse-related adverse reactins upn CIPRO IV discntinuatin in patients receiving bth agents, mnitr phenytin therapy, including phenytin serum cncentratin during and shrtly after c-administratin f CIPRO IV with phenytin. Mnitr renal functin (in particular serum creatinine) when ciprflxacin is c-administered with cyclsprine.