Cipro

6 ADVERSE REACTIONS The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: • Disabling and Potentially Irreversible Serious Adverse Reactions [see Warnings and Precautions ( 5.1 )] • Tendinitis and Tendon Rupture [see Warnings and Precautions ( 5.2 )] • Peripheral Neuropathy [see Warnings and Precautions ( 5.3 )] • Central Nervous System Effects [see Warnings and Precautions ( 5.4 )] Exacerbation of Myasthenia Gravis [see Warnings and Precautions ( 5.5 )] • Other Serious and Sometimes Fatal Adverse Reactions [see Warnings and Precautions ( 5.6 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )] • Hepatotoxicity [see Warnings and Precautions ( 5.8 )] • Risk of Aortic Aneurysm and Dissection [see Warnings and Precautions ( 5.9 )] • Serious Adverse Reactions with Concomitant Theophylline [see Warnings and Precautions ( 5.10) ] • Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions ( 5.11 )] • Prolongation of the QT Interval [see Warnings and Precautions ( 5.12 )] • Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions ( 5.13 )] • Photosensitivity/Phototoxicity [see Warnings and Precautions ( 5.14 )] • Development of Drug Resistant Bacteria [see Warnings and Precautions ( 5.15 )] The most common adverse reactions ≥1% were nausea, diarrhea, liver function tests abnormal, vomiting, and rash. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Adult Patients During clinical investigations with oral and parenteral CIPRO, 49,038 patients received courses of the drug. The most frequently reported adverse reactions, from clinical trials of all formulations, all dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1%), and rash (1%). Table 8: Medically Important Adverse Reactions That Occurred In less than 1% of Ciprofloxacin Patients System Organ Class Adverse Reactions Body as a Whole Headache Abdominal Pain/Discomfort Pain Cardiovascular Syncope Angina Pectoris Myocardial Infarction Cardiopulmonary Arrest Tachycardia Hypotension Central Nervous System Restlessness Dizziness Insomnia Nightmares Hallucinations Paranoia Psychosis (toxic) Manic Reaction Irritability Tremor Ataxia Seizures (including Status Epilepticus) Malaise Anorexia Phobia Depersonalization Depression (potentially culminating in self-injurious behavior (such as suicidal ideations/thoughts and attempted or completed suicide) Paresthesia Abnormal Gait Migraine Gastrointestinal Intestinal Perforation Gastrointestinal Bleeding Cholestatic Jaundice Hepatitis Pancreatitis Hemic/Lymphatic Petechia Metabolic/Nutritional Hyperglycemia Hypoglycemia Musculoskeletal Arthralgia Joint Stiffness Muscle Weakness Renal/Urogenital Interstitial Nephritis Renal Failure Respiratory Dyspnea Laryngeal Edema Hemoptysis Bronchospasm Skin/Hypersensitivity Anaphylactic Reactions including life-threatening anaphylactic shock Erythema Multiforme/Stevens-Johnson Syndrome Exfoliative Dermatitis Toxic Epidermal Necrolysis Pruritus Urticaria Photosensitivity/Phototoxicity reaction Flushing Fever Angioedema Erythema Nodosum Sweating Special Senses Blurred Vision Disturbed Vision (chromatopsia and photopsia) Decreased Visual Acuity Diplopia Tinnitus Hearing Loss Bad Taste In randomized, double-blind controlled clinical trials comparing CIPRO tablets [500 mg two times daily (BID)] to cefuroxime axetil (250 mg–500 mg BID) and to clarithromycin (500 mg BID) in patients with respiratory tract infections, CIPRO demonstrated a CNS adverse reaction profile comparable to the control drugs. Pediatric Patients Short (6 weeks) and long term (1 year) musculoskeletal and neurological safety of oral/intravenous ciprofloxacin, was compared to a cephalosporin for treatment of cUTI or pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years) in an international multicenter trial. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). A total of 335 ciprofloxacin- and 349 comparator-treated patients were enrolled. An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse reactions including abnormal gait or abnormal joint exam (baseline or treatment-emergent). Within 6 weeks of treatment initiation, the rates of musculoskeletal adverse reactions were 9.3% (31/335) in the ciprofloxacin-treated group versus 6% (21/349) in comparator-treated patients. All musculoskeletal adverse reactions occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm resolution of the adverse reactions. Ciprofloxacin-treated patients were more likely to report more than one adverse reaction and on more than one occasion compared to control patients. The rate of musculoskeletal adverse reactions was consistently higher in the ciprofloxacin group compared to the control group across all age subgroups. At the end of 1 year, the rate of these adverse reactions reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5% (33/349) in the comparator-treated patients (Table 9). Table 9: Musculoskeletal Adverse Reactions Included: arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint (knee, elbow, ankle, hip, wrist, and shoulder) as Assessed by the IPSC CIPRO Comparator All Patients (within 6 weeks) 31/335 (9.3%) 21/349 (6%) 95% Confidence Interval The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence interval indicated that it could not be concluded that the ciprofloxacin group had findings comparable to the control group. (-0.8%, +7.2%) Age Group 12 months < 24 months 1/36 (2.8%) 0/41 2 years < 6 years 5/124 (4%) 3/118 (2.5%) 6 years < 12 years 18/143 (12.6%) 12/153 (7.8%) 12 years to 17 years 7/32 (21.9%) 6/37 (16.2 %) All Patients (within 1 year) 46/335 (13.7%) 33/349 (9.5%) 95% Confidence Interval (-0.6%, + 9.1%) The incidence rates of neurological adverse reactions within 6 weeks of treatment initiation were 3% (9/335) in the CIPRO group versus 2% (7/349) in the comparator group and included dizziness, nervousness, insomnia, and somnolence. In this trial, the overall incidence rates of adverse reactions within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31% (109/349) in the comparator group. The most frequent adverse reactions were gastrointestinal: 15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of comparator patients. Serious adverse reactions were seen in 7.5% (25/335) of ciprofloxacin-treated patients compared to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse reaction was observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator patients. Other adverse reactions that occurred in at least 1% of ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%. Short-term safety data for ciprofloxacin was also collected in a randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5–17 years). Sixty seven patients received CIPRO IV 10 mg/kg/dose every 8 hours for one week followed by CIPRO tablets 20 mg/kg/dose every 12 hours to complete 10–21 days treatment and 62 patients received the combination of ceftazidime intravenous 50 mg/kg/dose every 8 hours and tobramycin intravenous 3 mg/kg/dose every 8 hours for a total of 10–21 days. Periodic musculoskeletal assessments were conducted by treatment-blinded examiners. Patients were followed for an average of 23 days after completing treatment (range 0–93 days). Musculoskeletal adverse reactions were reported in 22% of the patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other adverse reactions were similar in nature and frequency between treatment arms. The efficacy of CIPRO for the treatment of acute pulmonary exacerbations in pediatric cystic fibrosis patients has not been established. In addition to the adverse reactions reported in pediatric patients in clinical trials, it should be expected that adverse reactions reported in adults during clinical trials or postmarketing experience may also occur in pediatric patients. 6.2 Postmarketing Experience The following adverse reactions have been reported from worldwide marketing experience with fluoroquinolones, including CIPRO. 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 (Table 10). Table 10: Postmarketing Reports of Adverse Drug Reactions System Organ Class Adverse Reactions Cardiovascular QT prolongation Torsade de Pointes Vasculitis and ventricular arrhythmia Central Nervous System Hypertonia Myasthenia Exacerbation of myasthenia gravis Peripheral neuropathy Polyneuropathy Twitching Eye Disorders Nystagmus Gastrointestinal Pseudomembranous colitis Hemic/Lymphatic Pancytopenia (life threatening or fatal outcome) Methemoglobinemia Hepatobiliary Hepatic failure (including fatal cases) Infections and Infestations Candidiasis (oral, gastrointestinal, vaginal) Investigations Prothrombin time prolongation or decrease Cholesterol elevation (serum) Potassium elevation (serum) Musculoskeletal Myalgia Myoclonus Tendinitis Tendon rupture Psychiatric Disorders Agitation Confusion Delirium Skin/Hypersensitivity Acute generalize exanthematous pustulosis (AGEP) Fixed eruption Serum sickness-like reaction Special Senses Anosmia Hyperesthesia Hypesthesia Taste loss 6.3 Adverse Laboratory Changes Changes in laboratory parameters while on CIPRO are listed below: Hepatic –Elevations of ALT (SGPT), AST (SGOT), alkaline phosphatase, LDH, serum bilirubin. Hematologic–Eosinophilia, leukopenia, decreased blood platelets, elevated blood platelets, pancytopenia. Renal–Elevations of serum creatinine, BUN, crystalluria, cylindruria, and hematuria have been reported. Other changes occurring were: elevation of serum gammaglutamyl transferase, elevation of serum amylase, reduction in blood glucose, elevated uric acid, decrease in hemoglobin, anemia, bleeding diathesis, increase in blood monocytes, and leukocytosis.

4 CONTRAINDICATIONS • Known hypersensitivity to CIPRO or other quinolones ( 4.1 , 5.6 , 5.7) • Concomitant administration with tizanidine ( 4.2 ) 4.1 Hypersensitivity CIPRO is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antibacterials, or any of the product components [see Warnings and Precautions ( 5.7 )]. 4.2 Tizanidine Concomitant administration with tizanidine is contraindicated [see Drug Interactions ( 7 )].

11 DESCRIPTION CIPRO (ciprofloxacin hydrochloride) Tablets and CIPRO (ciprofloxacin) Oral Suspension are synthetic antimicrobial agents for oral administration. Ciprofloxacin hydrochloride, USP, a fluoroquinolone, is the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light yellow crystalline substance with a molecular weight of 385.8. Its empirical formula is C 17 H 18 FN 3 O 3 •HCl•H 2 O and its chemical structure is as follows: Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C 17 H 18 FN 3 O 3 and its molecular weight is 331.4. It is a faintly yellowish to light yellow crystalline substance and its chemical structure is as follows: CIPRO film-coated tablets are available in 250 mg and 500 mg (ciprofloxacin equivalent) strengths. Each CIPRO film-coated tablet contains 250 mg (equivalent to 291 mg ciprofloxacin hydrochloride monohydrate) or 500 mg of ciprofloxacin (equivalent to 582 mg ciprofloxacin hydrochloride monohydrate) CIPRO tablets are white to slightly yellowish. The inactive ingredients are cornstarch, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide, and titanium dioxide. CIPRO Oral Suspension is available in 5% (5 g ciprofloxacin in 100 mL) and 10% (10 g ciprofloxacin in 100 mL) strengths. CIPRO Oral Suspension is a white to slightly yellowish suspension with strawberry flavor which may contain yellow-orange droplets. It is composed of ciprofloxacin microcapsules and diluent which are mixed prior to dispensing [see Dosage and Administration ( 2.5 )] . The components of the suspension have the following compositions: • Microcapsules–ciprofloxacin, hypromellose, magnesium stearate, methacrylic acid copolymer, Polysorbate 20 and povidone. • Diluent–medium-chain triglycerides, sucrose, soy-lecithin, water, and strawberry flavor. • Five (5) mL of 5% suspension contains approximately 1.4 g of sucrose and 5 mL of 10% suspension contains approximately 1.3 g of sucrose. chem struc 1 chem struc 2

2 DOSAGE AND ADMINISTRATION CIPRO Tablets and Oral Suspension should be administered orally as described in the appropriate Dosage Guidelines tables. Adult Dosage Guidelines Infection Dose Frequency Duration Skin and Skin Structure 500 -750 mg every 12 hours 7 to 14 days Bone and Joint 500-750 mg every 12 hours 4 to 8 weeks Complicated Intra-Abdominal 500 mg every 12 hours 7 to 14 days Infectious Diarrhea 500 mg every 12 hours 5 to 7 days Typhoid Fever 500 mg every 12 hours 10 days Uncomplicated Gonorrhea 250 mg single dose single dose Inhalational anthrax (post-exposure) 500 mg every 12 hours 60 days Plague 500–750 mg every 12 hours 14 days Chronic Bacterial Prostatitis 500 mg every 12 hours 28 days Lower Respiratory Tract 500 -750 mg every 12 hours 7 to 14 days Urinary Tract 250-500 mg every 12 hours 7 to 14 days Acute Uncomplicated Cystitis 250 mg every 12 hours 3 days Acute Sinusitis 500 mg every 12 hours 10 days • Adults with creatinine clearance 30–50 mL/min 250–500 mg q 12 h (2.3 ) • Adults with creatinine clearance 5–29 mL/min 250–500 mg q 18 h ( 2.3 ) • Patients on hemodialysis or peritoneal dialysis 250–500 mg q 24 h (after dialysis) ( 2.3 ) Pediatric Oral Dosage Guidelines Infection Dose Frequency Duration Complicated UTI and Pyelonephritis (1 to 17 years of age) 10–20 mg/kg (maximum 750 mg per dose) Every 12 hours 10–21 days Inhalational Anthrax (Post-Exposure) 15 mg/kg (maximum 500 mg per dose) Every 12 hours 60 days Plague 15 mg/kg (maximum 500 mg per dose) Every 8 to 12 hours 14 days 2.1 Dosage in Adults The determination of dosage and duration for any particular patient must take into consideration the severity and nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s host-defense mechanisms, and the status of renal and hepatic function. CIPRO Tablets or CIPRO for Oral Suspension may be administered to adult patients when clinically indicated at the discretion of the physician. Administer CIPRO for Oral Suspension using the co-packaged graduated spoon [see Dosage and Administration ( 2.7 )]. Table 1: Adult Dosage Guidelines Infection Dose Frequency Usual Durations Generally ciprofloxacin should be continued for at least 2 days after the signs and symptoms of infection have disappeared, except for inhalational anthrax (post-exposure). Skin and Skin Structure 500–750 mg every 12 hours 7 to 14 days Bone and Joint 500–750 mg every 12 hours 4 to 8 weeks Complicated Intra–Abdominal Used in conjunction with metronidazole. 500 mg every 12 hours 7 to 14 days Infectious Diarrhea 500 mg every 12 hours 5 to 7 days Typhoid Fever 500 mg every 12 hours 10 days Uncomplicated Urethral and Cervical Gonococcal Infections 250 mg single dose single dose Inhalational anthrax (post-exposure) Begin drug administration as soon as possible after suspected or confirmed exposure. 500 mg every 12 hours 60 days Plague 500–750 mg every 12 hours 14 days Chronic Bacterial Prostatitis 500 mg every 12 hours 28 days Lower Respiratory Tract Infections 500–750 mg every 12 hours 7 to 14 days Urinary Tract Infections 250–500 mg every 12 hours 7 to 14 days Acute Uncomplicated Cystitis 250 mg every 12 hours 3 days Acute Sinusitis 500 mg every 12 hours 10 days Conversion of IV to Oral Dosing in Adults Patients whose therapy is started with CIPRO IV may be switched to CIPRO Tablets or Oral Suspension when clinically indicated at the discretion of the physician (Table 2) [see Clinical Pharmacology (12.3)]. Table 2: Equivalent AUC Dosing Regimens CIPRO Oral Dosage Equivalent CIPRO IV Dosage 250 mg Tablet every 12 hours 200 mg intravenous every 12 hours 500 mg Tablet every 12 hours 400 mg intravenous every 12 hours 750 mg Tablet every 12 hours 400 mg intravenous every 8 hours 2.2 Dosage in Pediatric Patients Dosing and initial route of therapy (that is, IV or oral) for cUTI or pyelonephritis should be determined by the severity of the infection. CIPRO should be administered as described in Table 3. Administer CIPRO for Oral Suspension using the co-packaged graduated spoon [see Dosage and Administration (2.7)]. Table 3: Pediatric Dosage Guidelines Infection Dose Frequency Total Duration Complicated Urinary Tract or Pyelonephritis (patients from 1 to 17 years of age) 10 mg/kg to 20 mg/kg (maximum 750 mg per dose; not to be exceeded even in patients weighing more than 51 kg) Every 12 hours 10–21 days Inhalational Anthrax (Post-Exposure) 2 15 mg/kg (maximum 500 mg per dose) Every 12 hours 60 days Plague 2,3 15 mg/kg (maximum 500 mg per dose) Every 8 to 12 hours 14 days 2.3 Dosage Modifications in Patients with Renal Impairment Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine. These alternative pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with severe renal dysfunction. Dosage guidelines for use in patients with renal impairment are shown in Table 4. Table 4: Recommended Starting and Maintenance Doses for Adult Patients with Impaired Renal Function Creatinine Clearance (mL/min) Dose > 50 See Usual Dosage. 30–50 250–500 mg every 12 hours 5–29 250–500 mg every 18 hours Patients on hemodialysis or Peritoneal dialysis 250–500 mg every 24 hours (after dialysis) When only the serum creatinine concentration is known, the following formulas may be used to estimate creatinine clearance: Men - Creatinine clearance (mL/min) = Weight (kg) x (140–age) 72 x serum creatinine (mg/dL) Women - 0.85 x the value calculated for men. The serum creatinine should represent a steady state of renal function. In patients with severe infections and severe renal impairment, a unit dose of 750 mg may be administered at the intervals noted above. Patients should be carefully monitored. Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of cUTI and pyelonephritis. No information is available on dosing adjustments necessary for pediatric patients with moderate to severe renal insufficiency (that is, creatinine clearance of < 50 mL/min/1.73m 2 ). 2.4 Important Administration Instructions With Multivalent Cations Administer CIPRO at least 2 hours before or 6 hours after magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate) or sucralfate; Videx ® (didanosine) chewable/buffered tablets or pediatric powder for oral solution; other highly buffered drugs; or other products containing calcium, iron or zinc. With Dairy Products Concomitant administration of CIPRO with dairy products (like milk or yogurt) or calcium-fortified juices alone should be avoided since decreased absorption is possible; however, CIPRO may be taken with a meal that contains these products. Hydration of Patients Receiving CIPRO Assure adequate hydration of patients receiving CIPRO to prevent the formation of highly concentrated urine. Crystalluria has been reported with quinolones. Instruct the patient of the appropriate CIPRO administration [see Patient Counseling Information (17)]. Missed Doses If a dose is missed, it should be taken anytime but not later than 6 hours prior to the next scheduled dose. If less than 6 hours remain before the next dose, the missed dose should not be taken and treatment should be continued as prescribed with the next scheduled dose. Double doses should not be taken to compensate for a missed dose. Splitting CIPRO Tablets CIPRO Tablets, 250 mg and 500 mg are functionally scored tablets which can be split into one-half at the scored line to provide a 125 mg and 250 mg strength, respectively. 2.5 Directions for Reconstitution of the CIPRO Microcapsules for Oral Suspension CIPRO Oral Suspension is supplied in 5% (5 g ciprofloxacin in 100 mL) and 10% (10 g ciprofloxacin in 100 mL) strengths. CIPRO oral suspension is composed of two components (microcapsules and diluent) that must be combined prior to dispensing. Table 5: Appropriate Dosing Volumes of the Reconstituted Oral Suspensions Dose 5% (250 mg/5 mL) 10% (500 mg/5 mL) 250 mg 5 mL 2.5 mL 500 mg 10 mL 5 mL 750 mg 15 mL 7.5 mL Preparation of the suspension: Step1 The small bottle contains the microcapsules, the large bottle contains the diluent. Step 2 Open both bottles. Child-proof cap: Press down according to instructions on the cap while turning to the left. Step 3 Pour the microcapsules completely into the larger bottle of diluent. Do not add water to the suspension. Step 4 Remove the top layer of the diluent bottle label (to reveal the CIPRO Oral Suspension label). Close the large bottle completely according to the directions on the cap and shake vigorously for about 15 seconds. The suspension is ready for use. Step 5: Write the expiration date of the re-constituted oral suspension on the bottle label. Reconstituted product may be stored below 30°C (86°F) for 14 days. Protect from freezing. No additions should be made to the mixed final ciprofloxacin suspension. CIPRO Oral Suspension should not be administered through feeding or NG (nasogastric) tubes due to its physical characteristics. Step 1 Step 2 Step 3 Step 4 2.6 Administration Instructions for CIPRO for Oral Suspension After Reconstitution • Shake CIPRO Oral Suspension vigorously each time before use for approximately 15 seconds. • Administer CIPRO Oral Suspension using the co-packaged graduated teaspoon provided for the patient (see Figure 1) Figure 1: Co-packaged 5 mL graduated teaspoon The Co-packaged graduated teaspoon (5mL) is provided, with markings for 1/2 (2.5 mL) and 1/1 (5 mL) • After use, clean the graduated teaspoon under running water with dish detergent and dry thoroughly. • Do Not chew the microcapsules in the CIPRO Oral Suspension, instead swallow them whole. • Water may be taken afterwards. • Reclose the bottle properly after each use according to instructions on the cap. After treatment has been completed, CIPRO Oral Suspension should not be reused. gradated spoon 2.7 Dosing of CIPRO for Oral Suspension using the Co-Packaged Spoon in Adults and Pediatric Patients Table : 5% Cipro for Oral Suspension: 250 mg ciprofloxacin per 5 mL after reconstitution Infection Body weight (kg) Dose by Measuring Spoonful(s) using Co-Packed Spoon* (teaspoonful (s) (volume (mL)) Dose Strength (mg) Complicated Urinary Tract or Pyelonephritis (patients from 1 to 17 years of age) 1 and Plague 2 9 kg to 12 kg ½ teaspoonful (2.5 mL) 125 mg 13 kg to 18 kg 1 teaspoonful (5 mL) 250 mg 19 kg to 24 kg 1 to 1 ½ teaspoonful(s) (5 mL to 7.5 mL) 250 mg to 375 mg 25 kg to 31 kg 1 ½ to 2 teaspoonfuls (7.5 mL to 10 mL) 375 mg to 500 mg 32 kg to 37 kg 1 ½ to 2 ½ teaspoonfuls (7.5 mL to 12.5 mL) 375 mg to 625 mg 38 kg or more 2 to 3 teaspoonfuls (10 mL to 15 mL) 500 mg to 750 mg Inhalational Anthrax (Post-Exposure) 3 9 kg to 12 kg ½ teaspoonful (2.5 mL) 125 mg 13 kg to 18 kg 1 teaspoonful (5 mL) 250 mg 19 kg to 24 kg 1 to 1 ½ teaspoonful(s) (5 mL to 7.5 mL) 250 mg to 375 mg 25 kg or more 2 teaspoonfuls (10 mL) 500 mg * A graduated teaspoon (5mL) with markings 1/2 (2.5) mL and 1/1 (5 mL) is provided for the patient. 1 Administer every 12 hours for 10-21 days [see Dosage and Administration (2.2)] 2 Administer every 8-12 hours for 10-21 days for Pediatric patients [see Dosage and Administration (2.2)] ; for adults administer every 12 hours for 14 days [see Dosage and Administration (2.1)] 3 Administer every 12 hours for 60 days [see Dosage and Administration (2.1 and 2.2)] Table 7: 10% Oral Suspension: 500 mg ciprofloxacin per 5 mL after reconstitution (not appropriate for children weighing less than 13 kg) Infection Body weight (kg) Dose by Measuring Spoonful(s) using Co-Packed Spoon* (teaspoonful (s) (volume (mL)) Dose Strength (mg) Complicated Urinary Tract or Pyelonephritis (patients from 1 to 17 years of age) 1 and Plague 2 13 kg to 24 kg ½ teaspoonful (2.5 mL) 250 mg 25 kg ½ to 1 teaspoonful (2.5 mL to 5 mL) 250 mg to 500 mg 26 kg to 37 kg 1 teaspoonful (5 mL) 500 mg 38 kg or more 1 to 1½ teaspoonful(s) (5 mL to 7.5 mL) 500 mg to maximum dose of 750 mg Inhalational Anthrax (Post-Exposure) 3 13 kg to 24 kg ½ teaspoonful (2.5 mL) 250 mg 25 kg or more 1 teaspoonful (5 mL) 500 mg * A graduated teaspoon (5mL) with markings 1/2 (2.5) mL and 1/1 (5 mL) is provided for the patient. 1 Administer every 12 hours for 10-21 days [see Dosage and Administration (2.2)] 2 Administer every 8-12 hours for 10-21 days for Pediatric patients [see Dosage and Administration (2.2)] ; for adults administer every 12 hours for 14 days [see Dosage and Administration (2.1)] 3 Administer every 12 hours for 60 days [see Dosage and Administration (2.1 and 2.2)]

1 INDICATIONS AND USAGE CIPRO is a fluoroquinolone antibacterial indicated in adults (18 years of age and older) with the following infections caused by designated, susceptible bacteria and in pediatric patients where indicated: • Skin and Skin Structure Infections ( 1.1 ) • Bone and Joint Infections ( 1.2 ) • Complicated Intra-Abdominal Infections ( 1.3 ) • Infectious Diarrhea ( 1.4 ) • Typhoid Fever (Enteric Fever) ( 1.5 ) • Uncomplicated Cervical and Urethral Gonorrhea ( 1.6 ) • Inhalational Anthrax post-exposure in adult and pediatric patients ( 1.7) • Plague in adult and pediatric patients ( 1.8 ) • Chronic Bacterial Prostatitis ( 1.9 ) • Lower Respiratory Tract Infections ( 1.10 ) • Acute Exacerbation of Chronic Bronchitis • Urinary Tract Infections ( 1.11 ) • Urinary Tract Infections (UTI) • Acute Uncomplicated Cystitis • Complicated UTI and Pyelonephritis in Pediatric Patients • Acute Sinusitis ( 1.12 ) Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO and other antibacterial drugs, CIPRO should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.13 ) 1.1 Skin and Skin Structure Infections CIPRO is indicated in adult patients for treatment of skin and skin structure infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus pyogenes. 1.2 Bone and Joint Infections CIPRO is indicated in adult patients for treatment of bone and joint infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa. 1.3 Complicated Intra-Abdominal Infections CIPRO is indicated in adult patients for treatment of complicated intra-abdominal infections (used in combination with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis. 1.4 Infectious Diarrhea CIPRO is indicated in adult patients for treatment of infectious diarrhea caused by Escherichia coli (enterotoxigenic isolates), Campylobacter jejuni, Shigella boydii † , Shigella dysenteriae, Shigella flexneri or Shigella sonnei † when antibacterial therapy is indicated. † Although treatment of infections due to this organism in this organ system demonstrated a clinically significant outcome, efficacy was studied in fewer than 10 patients. 1.5 Typhoid Fever (Enteric Fever) CIPRO is indicated in adult patients for treatment of typhoid fever (enteric fever ) caused by Salmonella typhi. The efficacy of ciprofloxacin in the eradication of the chronic typhoid carrier state has not been demonstrated. 1.6 Uncomplicated Cervical and Urethral Gonorrhea CIPRO is indicated in adult patients for treatment of uncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae [see Warnings and Precautions ( 5.17 )]. 1.7 Inhalational Anthrax (Post-Exposure) CIPRO is indicated in adults and pediatric patients from birth to 17 years of age for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably likely to predict clinical benefit and provided the initial basis for approval of this indication. 1 Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained during the anthrax bioterror attacks of October 2001 [see Clinical Studies ( 14.2 )]. 1.8 Plague CIPRO is indicated for treatment of plague, including pneumonic and septicemic plague, due to Yersinia pestis (Y. pestis) and prophylaxis for plague in adults and pediatric patients from birth to 17 years of age. Efficacy studies of ciprofloxacin could not be conducted in humans with plague for feasibility reasons. Therefore this indication is based on an efficacy study conducted in animals only [see Clinical Studies ( 14.3 )] . 1.9 Chronic Bacterial Prostatitis CIPRO is indicated in adult patients for treatment of chronic bacterial prostatitis caused by Escherichia coli or Proteus mirabilis. 1.10 Lower Respiratory Tract Infections CIPRO is indicated in adult patients for treatment of lower respiratory tract infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or Streptococcus pneumoniae. CIPRO is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae. CIPRO is indicated for the treatment of acute exacerbations of chronic bronchitis (AECB) caused by Moraxella catarrhalis. Because fluoroquinolones, including CIPRO, have been associated with serious adverse reactions [see Warnings and Precautions ( 5.1–5.16 )] and for some patients AECB is self-limiting, reserve CIPRO for treatment of AECB in patients who have no alternative treatment options . 1.11 Urinary Tract Infections Urinary Tract Infections in Adults CIPRO is indicated in adult patients for treatment of urinary tract infections caused by Escherichia coli , Klebsiella pneumoniae , Enterobacter cloacae , Serratia marcescens , Proteus mirabilis , Providencia rettgeri , Morganella morganii , Citrobacter koseri , Citrobacter freundii , Pseudomonas aeruginosa , methicillin-susceptible Staphylococcus epidermidis , Staphylococcus saprophyticus , or Enterococcus faecalis . Acute Uncomplicated Cystitis CIPRO is indicated in adult female patients for treatment of acute uncomplicated cystitis caused by Escherichia coli or Staphylococcus saprophyticus. Because fluoroquinolones, including CIPRO, have been associated with serious adverse reactions [see Warnings and Precautions ( 5 .1-5.16)] and for some patients acute uncomplicated cystitis is self-limiting, reserve CIPRO for treatment of acute uncomplicated cystitis in patients who have no alternative treatment options. Complicated Urinary Tract Infection and Pyelonephritis in Pediatric Patients CIPRO is indicated in pediatric patients aged one to 17 years of age for treatment of complicated urinary tract infections (cUTI) and pyelonephritis due to Escherichia coli [see Use in Specific Populations ( 8.4 )] . Although effective in clinical trials, CIPRO is not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to controls, including reactions related to joints and/or surrounding tissues . CIPRO, like other fluoroquinolones, is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals [see Warnings and Precautions ( 5.13 ), Adverse Reactions ( 6.1 ), Use in Specific Populations ( 8.4 ) and Nonclinical Toxicology ( 13.2 )]. 1.12 Acute Sinusitis CIPRO is indicated in adult patients for treatment of acute sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis. Because fluoroquinolones, including CIPRO, have been associated with serious adverse reactions [see Warnings and Precautions ( 5.1-5.16 )] and for some patients acute sinusitis is self-limiting, reserve CIPRO for treatment of acute sinusitis in patients who have no alternative treatment options . 1.13 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO and other antibacterial drugs, CIPRO 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. If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be administered. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with CIPRO may be initiated before results of these tests are known; once results become available appropriate therapy should be continued. As with other drugs, some isolates of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial resistance.

10 OVERDOSAGE In the event of acute overdosage, reversible renal toxicity has been reported in some cases. Empty the stomach by inducing vomiting or by gastric lavage. Observe the patient carefully and give supportive treatment, including monitoring of renal function, urinary pH and acidify, if required, to prevent crystalluria and administration of magnesium, aluminum, or calcium containing antacids which can reduce the absorption of ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (less than 10%) is removed from the body after hemodialysis or peritoneal dialysis.

7 DRUG INTERACTIONS Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration of CIPRO with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the co-administered drug. Table 11: Drugs That are Affected by and Affecting CIPRO Drugs That are Affected by CIPRO Drug(s) Recommendation Comments Tizanidine Contraindicated Concomitant administration of tizanidine and CIPRO is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications ( 4.2 ) ] Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of CIPRO with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions ( 5.10 )]. Drugs Known to Prolong QT Interval Avoid Use CIPRO may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.12 ) and Use in Specific Populations ( 8.5 )]. Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when CIPRO and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when CIPRO is co-administered with oral antidiabetic drugs [see Adverse Reactions ( 6.1 )]. Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon CIPRO discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of CIPRO with phenytoin. Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when CIPRO is co-administered with cyclosporine. Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of CIPRO to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of CIPRO with an oral anti-coagulant (for example, warfarin). Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant CIPRO therapy is indicated. Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with CIPRO [see Warnings and Precautions ( 5.16 )]. Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with CIPRO are advised. NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. Sildenafil Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity [see Clinical Pharmacology ( 12.3 ) ] . Duloxetine Avoid Use Five-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life CIPRO inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. Zolpidem Avoid Use Co-administration with ciprofloxacin may increase blood levels of zolpidem, concurrent use is not recommended Drug(s) Affecting Pharmacokinetics of CIPRO Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) CIPRO should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration ( 2.4 )]. Decrease CIPRO absorption, resulting in lower serum and urine levels Probenecid Use with caution (interferes with renal tubular secretion of CIPRO and increases CIPRO serum levels) Potentiation of CIPRO toxicity may occur. Interacting Drug Interaction Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7 ) Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7 ) Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7 ) Phenytoin Monitor phenytoin level ( 7 ) Methotrexate Monitor for methotrexate toxicity ( 7 ) Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7 ) Multivalent cation-containing products including antacids, metal cations or didanosine Decreased CIPRO absorption. Take CIPRO 2 hours before or 6 hours after administration of multivalent cation containing drugs ( 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ciprofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology ( 12.4 )]. 12.3 Pharmacokinetics Absorption The absolute bioavailability of ciprofloxacin when given as an oral tablet is approximately 70% with no substantial loss by first pass metabolism. Ciprofloxacin maximum serum concentrations (C max ) and area under the curve (AUC) are shown in the chart for the 250 mg to 1000 mg dose range (Table 12). Table 12: Ciprofloxacin C max and AUC Following Adminstration of Single Doses of CIPRO Tablets to Healthy Subjects Dose (mg) C max AUC (mcg•hr/mL) 250 1.2 4.8 500 2.4 11.6 750 4.3 20.2 1000 5.4 30.8 Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 mcg/mL, respectively. The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Serum concentrations increase proportionately with doses up to 1000 mg. A 500 mg oral dose given every 12 hours has been shown to produce AUC equivalent to that produced by an intravenous infusion of 400 mg CIPRO given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has been shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion of 400 mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a C max similar to that observed with a 400 mg intravenous dose (Table 13). A 250 mg oral dose given every 12 hours produces an AUC equivalent to that produced by an infusion of 200 mg CIPRO given every 12 hours. Table 13: Steady-state Pharmacokinetic Parameters Following Multiple Oral and Intravenous Doses (Adults) Parameters 500 mg 400 mg 750 mg 400 mg every 12 hours, orally every 12 hours, intravenously every 12 hours, orally every 8 hours, intravenously AUC 0-24h,ss (µg•h/mL) 27.4 AUC 0-12h x 2 25.4 * 31.6 * 32.9** C max , ss (µg/mL) 2.97 4.56 3.59 4.07 Food When CIPRO Tablet is given concomitantly with food, there is a delay in the absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing rather than 1 hour whereas there is no delay observed when CIPRO Suspension is given with food. The overall absorption of CIPRO Tablet or CIPRO Suspension, however, is not substantially affected. The pharmacokinetics of ciprofloxacin given as the suspension are also not affected by food. Avoid concomitant administration of CIPRO with dairy products (like milk or yogurt) or calcium-fortified juices alone since decreased absorption is possible; however, CIPRO may be taken with a meal that contains these products With oral administration, a 500 mg dose, given as 10 mL of the 5% CIPRO Suspension (containing 250 mg ciprofloxacin/5mL) is bioequivalent to the 500 mg tablet. A 10 mL volume of the 5% CIPRO Suspension (containing 250 mg ciprofloxacin/5mL) is bioequivalent to a 5 mL volume of the 10% CIPRO Suspension (containing 500 mg ciprofloxacin/5mL). Distribution The binding of ciprofloxacin to serum proteins is 20% to 40% which is not likely to be high enough to cause significant protein binding interactions with other drugs. After oral administration, ciprofloxacin is widely distributed throughout the body. Tissue concentrations often exceed serum concentrations in both men and women, particularly in genital tissue including the prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions, mucosa of the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. Ciprofloxacin has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into the cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye. Metabolism Four metabolites have been identified in human urine which together account for approximately 15% of an oral dose. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the co-administered drug [see Contraindications ( 4.2 ), Warnings and Precautions ( 5.10 , 5.16 ), and Drug Interactions ( 7 )]. Excretion The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged drug. After a 250 mg oral dose, urine concentrations of ciprofloxacin usually exceed 200 mcg/mL during the first two hours and are approximately 30 mcg/mL at 8 to 12 hours after dosing. The urinary excretion of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of ciprofloxacin, which is approximately 300 mL/minute, exceeds the normal glomerular filtration rate of 120 mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination. Co-administration of probenecid with ciprofloxacin results in about a 50% reduction in the ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation. Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after oral dosing, only a small amount of the dose administered is recovered from the bile as unchanged drug. An additional 1% to 2% of the dose is recovered from the bile in the form of metabolites. Approximately 20% to 35% of an oral dose is recovered from the feces within 5 days after dosing. This may arise from either biliary clearance or transintestinal elimination. Specific Populations Elderly Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (older than 65 years) as compared to young adults. Although the C max is increased 16% to 40%, the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant [see Use in Specific Populations ( 8.5 )]. Renal Impairment In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage adjustments may be required [see Use in Specific Populations ( 8.6 ) and Dosage and Administration ( 2.3 )]. Hepatic Impairment In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, have not been fully studied. Pediatrics Table 14: Estimated AUC 0–24,ss and C max,ss for Intravenous Treatment (1-h infusion) in Pediatric Patients Following a Multiple Dosing Regimen of 10 mg/kg, Three Times Daily Age AUC0–24,ss (mg h/L) Cmax,ss (mg/L) Less than1 year 30.9 2.8 1 to less than 2 years 27.8 3.6 2 to less than 6 years 28.9 2.7 6 to less than 12 years 20.4 2.0 These values are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric patients with various infections, the predicted mean half-life in children is approximately 4 hours –5 hours, and the bioavailability of the oral suspension is approximately 60%. Drug-Drug Interactions Antacids Concurrent administration of antacids containing magnesium hydroxide or aluminum hydroxide may reduce the bioavailability of ciprofloxacin by as much as 90% [see Dosage and Administration ( 2.4 ) and Drug Interactions ( 7 )]. Histamine H2-receptor antagonists Histamine H 2 -receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin. Metronidazole The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly. Tizanidine In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (C max 7-fold, AUC 10-fold) when the drug was given concomitantly with CIPRO (500 mg twice a day for 3 days). Concomitant administration of tizanidine and CIPRO is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications ( 4.2 )]. Ropinirole In a study conducted in 12 patients with Parkinson’s disease who were administered 6 mg ropinirole once daily with 500 mg CIPRO twice-daily, the mean C max and mean AUC of ropinirole were increased by 60% and 84%, respectively. Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with CIPRO [see Warnings and Precautions ( 5.10 )]. Clozapine Following concomitant administration of 250 mg CIPRO with 304 mg clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with CIPRO are advised. Sildenafil Following concomitant administration of a single oral dose of 50 mg sildenafil with 500 mg CIPRO to healthy subjects, the mean C max and mean AUC of sildenafil were both increased approximately two-fold. Use sildenafil with caution when co-administered with CIPRO due to the expected two-fold increase in the exposure of sildenafil upon co-administration of CIPRO. Duloxetine In clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in a 5-fold increase in mean AUC and a 2.5-fold increase in mean C max of duloxetine. Lidocaine In a study conducted in 9 healthy volunteers, concomitant use of 1.5 mg/kg IV lidocaine with CIPRO 500 mg twice daily resulted in an increase of lidocaine C max and AUC by 12% and 26%, respectively. Although lidocaine treatment was well tolerated at this elevated exposure, a possible interaction with CIPRO and an increase in adverse reactions related to lidocaine may occur upon concomitant administration. Metoclopramide Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in a shorter time to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of ciprofloxacin. Omeprazole When CIPRO was administered as a single 1000 mg dose concomitantly with omeprazole (40 mg once daily for three days) to 18 healthy volunteers, the mean AUC and C max of ciprofloxacin were reduced by 20% and 23%, respectively. The clinical significance of this interaction has not been determined. 12.4 Microbiology Mechanism of Action The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination. Mechanism of Resistance The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to ciprofloxacin. Resistance to fluoroquinolones occurs primarily by either mutations in the DNA gyrases, decreased outer membrane permeability, or drug efflux. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10 -9 to 1x10 -6 . Cross Resistance There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials. Ciprofloxacin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage ( 1 )]. Gram-positive bacteria Bacillus anthracis Enterococcus faecalis Staphylococcus aureus (methicillin-susceptible isolates only) Staphylococcus epidermidis (methicillin-susceptible isolates only) Staphylococcus saprophyticus Streptococcus pneumoniae Streptococcus pyogenes Gram-negative bacteria Campylobacter jejuni Citrobacter koseri Citrobacter freundii Enterobacter cloacae Escherichia coli Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumoniae Moraxella catarrhalis Morganella morganii Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Providencia rettgeri Providencia stuartii Pseudomonas aeruginosa Salmonella typhi Serratia marcescens Shigella boydii Shigella dysenteriae Shigella flexneri Shigella sonnei Yersinia pestis 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 ciprofloxacin against isolates of similar genus or organism group. However, the efficacy of ciprofloxacin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials. Gram-positive bacteria Staphylococcus haemolyticus (methicillin-susceptible isolates only) Staphylococcus hominis (methicillin-susceptible isolates only) Gram-negative bacteria Acinetobacter lwoffi Aeromonas hydrophila Edwardsiella tarda Enterobacter aerogenes Klebsiella oxytoca Legionella pneumophila Pasteurella multocida Salmonella enteritidis Vibrio cholerae Vibrio parahaemolyticus Vibrio vulnificus Yersinia enterocolitica Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC .

12.1 Mechanism of Action Ciprofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology ( 12.4 )].

12.3 Pharmacokinetics Absorption The absolute bioavailability of ciprofloxacin when given as an oral tablet is approximately 70% with no substantial loss by first pass metabolism. Ciprofloxacin maximum serum concentrations (C max ) and area under the curve (AUC) are shown in the chart for the 250 mg to 1000 mg dose range (Table 12). Table 12: Ciprofloxacin C max and AUC Following Adminstration of Single Doses of CIPRO Tablets to Healthy Subjects Dose (mg) C max AUC (mcg•hr/mL) 250 1.2 4.8 500 2.4 11.6 750 4.3 20.2 1000 5.4 30.8 Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 mcg/mL, respectively. The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Serum concentrations increase proportionately with doses up to 1000 mg. A 500 mg oral dose given every 12 hours has been shown to produce AUC equivalent to that produced by an intravenous infusion of 400 mg CIPRO given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has been shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion of 400 mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a C max similar to that observed with a 400 mg intravenous dose (Table 13). A 250 mg oral dose given every 12 hours produces an AUC equivalent to that produced by an infusion of 200 mg CIPRO given every 12 hours. Table 13: Steady-state Pharmacokinetic Parameters Following Multiple Oral and Intravenous Doses (Adults) Parameters 500 mg 400 mg 750 mg 400 mg every 12 hours, orally every 12 hours, intravenously every 12 hours, orally every 8 hours, intravenously AUC 0-24h,ss (µg•h/mL) 27.4 AUC 0-12h x 2 25.4 * 31.6 * 32.9** C max , ss (µg/mL) 2.97 4.56 3.59 4.07 Food When CIPRO Tablet is given concomitantly with food, there is a delay in the absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing rather than 1 hour whereas there is no delay observed when CIPRO Suspension is given with food. The overall absorption of CIPRO Tablet or CIPRO Suspension, however, is not substantially affected. The pharmacokinetics of ciprofloxacin given as the suspension are also not affected by food. Avoid concomitant administration of CIPRO with dairy products (like milk or yogurt) or calcium-fortified juices alone since decreased absorption is possible; however, CIPRO may be taken with a meal that contains these products With oral administration, a 500 mg dose, given as 10 mL of the 5% CIPRO Suspension (containing 250 mg ciprofloxacin/5mL) is bioequivalent to the 500 mg tablet. A 10 mL volume of the 5% CIPRO Suspension (containing 250 mg ciprofloxacin/5mL) is bioequivalent to a 5 mL volume of the 10% CIPRO Suspension (containing 500 mg ciprofloxacin/5mL). Distribution The binding of ciprofloxacin to serum proteins is 20% to 40% which is not likely to be high enough to cause significant protein binding interactions with other drugs. After oral administration, ciprofloxacin is widely distributed throughout the body. Tissue concentrations often exceed serum concentrations in both men and women, particularly in genital tissue including the prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions, mucosa of the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. Ciprofloxacin has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into the cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye. Metabolism Four metabolites have been identified in human urine which together account for approximately 15% of an oral dose. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the co-administered drug [see Contraindications ( 4.2 ), Warnings and Precautions ( 5.10 , 5.16 ), and Drug Interactions ( 7 )]. Excretion The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged drug. After a 250 mg oral dose, urine concentrations of ciprofloxacin usually exceed 200 mcg/mL during the first two hours and are approximately 30 mcg/mL at 8 to 12 hours after dosing. The urinary excretion of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of ciprofloxacin, which is approximately 300 mL/minute, exceeds the normal glomerular filtration rate of 120 mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination. Co-administration of probenecid with ciprofloxacin results in about a 50% reduction in the ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation. Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after oral dosing, only a small amount of the dose administered is recovered from the bile as unchanged drug. An additional 1% to 2% of the dose is recovered from the bile in the form of metabolites. Approximately 20% to 35% of an oral dose is recovered from the feces within 5 days after dosing. This may arise from either biliary clearance or transintestinal elimination. Specific Populations Elderly Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (older than 65 years) as compared to young adults. Although the C max is increased 16% to 40%, the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant [see Use in Specific Populations ( 8.5 )]. Renal Impairment In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage adjustments may be required [see Use in Specific Populations ( 8.6 ) and Dosage and Administration ( 2.3 )]. Hepatic Impairment In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, have not been fully studied. Pediatrics Table 14: Estimated AUC 0–24,ss and C max,ss for Intravenous Treatment (1-h infusion) in Pediatric Patients Following a Multiple Dosing Regimen of 10 mg/kg, Three Times Daily Age AUC0–24,ss (mg h/L) Cmax,ss (mg/L) Less than1 year 30.9 2.8 1 to less than 2 years 27.8 3.6 2 to less than 6 years 28.9 2.7 6 to less than 12 years 20.4 2.0 These values are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric patients with various infections, the predicted mean half-life in children is approximately 4 hours –5 hours, and the bioavailability of the oral suspension is approximately 60%. Drug-Drug Interactions Antacids Concurrent administration of antacids containing magnesium hydroxide or aluminum hydroxide may reduce the bioavailability of ciprofloxacin by as much as 90% [see Dosage and Administration ( 2.4 ) and Drug Interactions ( 7 )]. Histamine H2-receptor antagonists Histamine H 2 -receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin. Metronidazole The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly. Tizanidine In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (C max 7-fold, AUC 10-fold) when the drug was given concomitantly with CIPRO (500 mg twice a day for 3 days). Concomitant administration of tizanidine and CIPRO is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications ( 4.2 )]. Ropinirole In a study conducted in 12 patients with Parkinson’s disease who were administered 6 mg ropinirole once daily with 500 mg CIPRO twice-daily, the mean C max and mean AUC of ropinirole were increased by 60% and 84%, respectively. Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with CIPRO [see Warnings and Precautions ( 5.10 )]. Clozapine Following concomitant administration of 250 mg CIPRO with 304 mg clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with CIPRO are advised. Sildenafil Following concomitant administration of a single oral dose of 50 mg sildenafil with 500 mg CIPRO to healthy subjects, the mean C max and mean AUC of sildenafil were both increased approximately two-fold. Use sildenafil with caution when co-administered with CIPRO due to the expected two-fold increase in the exposure of sildenafil upon co-administration of CIPRO. Duloxetine In clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in a 5-fold increase in mean AUC and a 2.5-fold increase in mean C max of duloxetine. Lidocaine In a study conducted in 9 healthy volunteers, concomitant use of 1.5 mg/kg IV lidocaine with CIPRO 500 mg twice daily resulted in an increase of lidocaine C max and AUC by 12% and 26%, respectively. Although lidocaine treatment was well tolerated at this elevated exposure, a possible interaction with CIPRO and an increase in adverse reactions related to lidocaine may occur upon concomitant administration. Metoclopramide Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in a shorter time to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of ciprofloxacin. Omeprazole When CIPRO was administered as a single 1000 mg dose concomitantly with omeprazole (40 mg once daily for three days) to 18 healthy volunteers, the mean AUC and C max of ciprofloxacin were reduced by 20% and 23%, respectively. The clinical significance of this interaction has not been determined.

20230131

28

3 DOSAGE FORMS AND STRENGTHS • Tablets: 250 mg, functionally scored and 500 mg ( 3 ) • Oral Suspension: 5% (250 mg/5 mL), 10% (500 mg/5 mL) (3 ) 3.1 Tablets • 250 mg slightly yellowish, film-coated, round, functionally scored, imprinted with “BAYER” on one side and “CIP 250” on the other • 500 mg, slightly yellowish, film-coated, capsule shaped, functionally scored, imprinted with “BAYER” on one side and “CIP 500” on the other 3.2 Oral Suspension • 5% Oral Suspension: 250 mg ciprofloxacin per 5 mL after reconstitution • 10% Oral Suspension: 500 mg ciprofloxacin per 5 mL after reconstitution

Cipro ciprofloxacin hydrochloride CIPROFLOXACIN HYDROCHLORIDE CIPROFLOXACIN STARCH, CORN MICROCRYSTALLINE CELLULOSE SILICON DIOXIDE CROSPOVIDONE (120 .MU.M) MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE POLYETHYLENE GLYCOL, UNSPECIFIED ROUND BAYER;CIP;250 Cipro ciprofloxacin hydrochloride CIPROFLOXACIN HYDROCHLORIDE CIPROFLOXACIN STARCH, CORN MICROCRYSTALLINE CELLULOSE SILICON DIOXIDE CROSPOVIDONE (120 .MU.M) MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE POLYETHYLENE GLYCOL, UNSPECIFIED OVAL CIPRO;500 Cipro ciprofloxacin Cipro ciprofloxacin hydrochloride CIPROFLOXACIN HYDROCHLORIDE CIPROFLOXACIN POVIDONE, UNSPECIFIED METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1) HYPROMELLOSE, UNSPECIFIED MAGNESIUM STEARATE POLYSORBATE 20 diluent diluent SUCROSE WATER Cipro ciprofloxacin Cipro ciprofloxacin hydrochloride CIPROFLOXACIN HYDROCHLORIDE CIPROFLOXACIN POVIDONE, UNSPECIFIED METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1) HYPROMELLOSE, UNSPECIFIED MAGNESIUM STEARATE POLYSORBATE 20 diluent diluent SUCROSE WATER

13.2 Animal Toxicology and/or Pharmacology Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see Warnings and Precautions ( 5.13 )] . Damage of weight bearing joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately 1.3-times and 3.5-times the pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks caused articular changes which were still observed by histopathology after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric dose based upon comparative plasma AUCs), no effects on joints were observed. This dose was also not associated with arthrotoxicity after an additional treatment-free period of 5 months. In another study, removal of weight bearing from the joint reduced the lesions but did not totally prevent them. Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5 mg/kg. (approximately 0.07-times the highest recommended therapeutic dose based upon body surface area). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration (approximately 0.2-times the highest recommended therapeutic dose based upon body surface area). In dogs, ciprofloxacin at 3 mg/kg and 10 mg/kg by rapid intravenous injection (15 sec.) produces pronounced hypotensive effects. These effects are considered to be related to histamine release, since they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous injection also produces hypotension but the effect in this species is inconsistent and less pronounced. In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of quinolones. Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eight in vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are listed below: • Salmonella/Microsome Test (Negative) • E. coli DNA Repair Assay (Negative) • Mouse Lymphoma Cell Forward Mutation Assay (Positive) • Chinese Hamster V 79 Cell HGPRT Test (Negative) • Syrian Hamster Embryo Cell Transformation Assay (Negative) • Saccharomyces cerevisiae Point Mutation Assay (Negative) • Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative) • Rat Hepatocyte DNA Repair Assay (Positive) • Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative results: • Rat Hepatocyte DNA Repair Assay • Micronucleus Test (Mice) • Dominant Lethal Test (Mice) Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to ciprofloxacin at daily oral dose levels up to 250 mg/kg and 750 mg/kg to rats and mice, respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon body surface area, respectively). Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum recommended human dose based upon body surface area), as opposed to 34 weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from 16 weeks to 32 weeks in mice treated concomitantly with UVA and other quinolones. 9 In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of these findings to humans is unknown. Fertility studies performed in male and female rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 0.6-times the highest recommended therapeutic dose based upon body surface area) revealed no evidence of impairment. Male rats received oral ciprofloxacin for 10 weeks prior to mating and females were dosed for 3 weeks prior to mating through Gestation Day 7.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Eight in vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are listed below: • Salmonella/Microsome Test (Negative) • E. coli DNA Repair Assay (Negative) • Mouse Lymphoma Cell Forward Mutation Assay (Positive) • Chinese Hamster V 79 Cell HGPRT Test (Negative) • Syrian Hamster Embryo Cell Transformation Assay (Negative) • Saccharomyces cerevisiae Point Mutation Assay (Negative) • Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative) • Rat Hepatocyte DNA Repair Assay (Positive) • Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative results: • Rat Hepatocyte DNA Repair Assay • Micronucleus Test (Mice) • Dominant Lethal Test (Mice) Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to ciprofloxacin at daily oral dose levels up to 250 mg/kg and 750 mg/kg to rats and mice, respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon body surface area, respectively). Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum recommended human dose based upon body surface area), as opposed to 34 weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from 16 weeks to 32 weeks in mice treated concomitantly with UVA and other quinolones. 9 In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of these findings to humans is unknown. Fertility studies performed in male and female rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 0.6-times the highest recommended therapeutic dose based upon body surface area) revealed no evidence of impairment. Male rats received oral ciprofloxacin for 10 weeks prior to mating and females were dosed for 3 weeks prior to mating through Gestation Day 7. 13.2 Animal Toxicology and/or Pharmacology Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see Warnings and Precautions ( 5.13 )] . Damage of weight bearing joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately 1.3-times and 3.5-times the pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks caused articular changes which were still observed by histopathology after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric dose based upon comparative plasma AUCs), no effects on joints were observed. This dose was also not associated with arthrotoxicity after an additional treatment-free period of 5 months. In another study, removal of weight bearing from the joint reduced the lesions but did not totally prevent them. Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5 mg/kg. (approximately 0.07-times the highest recommended therapeutic dose based upon body surface area). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration (approximately 0.2-times the highest recommended therapeutic dose based upon body surface area). In dogs, ciprofloxacin at 3 mg/kg and 10 mg/kg by rapid intravenous injection (15 sec.) produces pronounced hypotensive effects. These effects are considered to be related to histamine release, since they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous injection also produces hypotension but the effect in this species is inconsistent and less pronounced. In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of quinolones. Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals

NDA019537

Cipro

ciprofloxacin hydrochloride

50419-754

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Cipro 250 mg 100 Tablets NDC 50419-758-01 Cipro® (ciprofloxacin hydrochloride) Equivalent to 250 mg ciprofloxacin 100 Tablets Rx Only Attention Pharmacist: Dispense the enclosed Medication Guide to each patient. Manufactured by: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981 Manufactured in Germany 250 mg Label

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA- approved patient labeling (Medication Guide) Serious Adverse Reactions Advise patients to stop taking CIPRO if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug. Inform patients of the following serious adverse reactions that have been associated with CIPRO or other fluoroquinolone use: • Disabling and potentially irreversible serious adverse reactions that may occur together: Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated with use of CIPRO and may occur together in the same patient. Inform patients to stop taking CIPRO immediately if they experience an adverse reaction and to call their healthcare provider. • Tendinitis and tendon rupture: Instruct patients to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue CIPRO treatment. Symptoms may be irreversible. The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. • Peripheral Neuropathies: Inform patients that peripheral neuropathies have been associated with ciprofloxacin use, symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, immediately discontinue CIPRO and tell them to contact their physician. • Central nervous system effects (for example, convulsions, dizziness, lightheadedness, increased intracranial pressure) : Inform patients that convulsions have been reported in patients receiving fluoroquinolones, including Ciprofloxacin. Instruct patients to notify their physician before taking this drug if they have a history of convulsions. Inform patients that they should know how they react to CIPRO before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Instruct patients to notify their physician if persistent headache with or without blurred vision occurs. • Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any history of myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties. • Hypersensitivity Reactions: Inform patients that ciprofloxacin can cause hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction. • Hepatotoxicity: Inform patients that severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients taking CIPRO. Instruct patients to inform their physician if they experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light colored bowel movements or dark colored urine. • Aortic aneurysm and dissection: Inform patients to seek emergency medical care if they experience sudden chest, stomach, or back pain. • Diarrhea: 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 two or more months after having taken the last dose of the antibiotic. If this occurs, instruct patients to contact their physician as soon as possible. • Prolongation of the QT Interval: Instruct patients to inform their physician of any personal or family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia; if they are taking any Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Instruct patients to notify their physician if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness. • Musculoskeletal Disorders in Pediatric Patients: Instruct parents to inform their child’s physician if the child has a history of joint-related problems before taking this drug. Inform parents of pediatric patients to notify their child’s physician of any joint-related problems that occur during or following ciprofloxacin therapy [see Warnings and Precautions ( 5.13 ) and Use in Specific Populations ( 8.4 )]. • Tizanidine: Instruct patients not to use ciprofloxacin if they are already taking tizanidine. CIPRO increases the effects of tizanidine (Zanaflex ® ). • Theophylline: Inform patients that ciprofloxacin CIPRO may increase the effects of theophylline. Life-threatening CNS effects and arrhythmias can occur. Advise the patients to immediately seek medical help if they experience seizures, palpitations, or difficulty breathing. • Caffeine: Inform patients that CIPRO may increase the effects of caffeine. There is a possibility of caffeine accumulation when products containing caffeine are consumed while taking quinolones. • Photosensitivity/Phototoxicity: Inform patients that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolones. Inform patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, instruct them to wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, instruct patients to contact their physician. • Blood Glucose Disturbances: Inform the patients that if they are diabetic and are being treated with insulin or an oral hypoglycemic agent and a hypoglycemic reaction occurs, they should discontinue CIPRO and consult a physician. • Lactation: For indications other than inhalational anthrax (post exposure), advise a woman that breastfeeding is not recommended during treatment with Cipro and for an additional 2 days after the last dose. Alternatively, a woman may pump and discard during treatment and for additional 2 days after the last dose [see Use in Specific Populations ( 8.2 )]. Antibacterial Resistance Inform patients that antibacterial drugs including CIPRO Tablets and CIPRO Oral Suspension should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When CIPRO Tablets and CIPRO Oral Suspension 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 CIPRO Tablets and CIPRO Oral Suspension or other antibacterial drugs in the future. Administration Instructions Instruct the Patient • To shake CIPRO Oral Suspension vigorously each time before use for approximately 15 seconds. • To always use the co-packaged graduated measuring spoon with markings for 1/2 (2.5 mL) and 1/1 (5 mL), to obtain the exact dose. • After use, the graduated measuring spoon should be cleaned under running water with dish detergent and dried thoroughly. • Not to chew the microcapsules, but to swallow them whole. • That water may be taken afterwards. • Reclose the bottle properly after each use according to instructions on the cap. • After treatment has been completed, CIPRO Oral Suspension should not be reused. Inform patients that CIPRO may be taken with or without food. Inform patients to drink fluids liberally while taking CIPRO to avoid formation of highly concentrated urine and crystal formation in the urine. Inform patients that antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine should be taken at least two hours before or six hours after CIPRO administration. CIPRO should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone since absorption of ciprofloxacin may be significantly reduced; however, CIPRO may be taken with a meal that contains these products. Advise patients that if a dose is missed, it should be taken anytime but not later than 6 hours prior to the next scheduled dose. If less than 6 hours remain before the next dose, the missed dose should not be taken and treatment should be continued as prescribed with the next scheduled dose. Double doses should not be taken to compensate for a missed dose. Advise patients that CIPRO Tablets (250 mg and 500 mg) are scored and can be split into one-half at the scored line to provide a 125 mg or 250 mg strength, respectively. Drug Interactions Oral Antidiabetic Agents Inform patients that hypoglycemia has been reported when ciprofloxacin and oral antidiabetic agents were co-administered; if low blood sugar occurs with CIPRO, instruct them to consult their physician and that their antibacterial medicine may need to be changed. Anthrax and Plague Studies Inform patients given CIPRO for these conditions that efficacy studies could not be conducted in humans for feasibility reasons. Therefore, approval for these conditions was based on efficacy studies conducted in animals.

Medication Guide Medication Guide CIPRO ® (Sip-row) (ciprofloxacin hydrochloride) tablets, for oral use CIPRO ® (Sip-row) (ciprofloxacin) for oral suspension Read this Medication Guide before you start taking CIPRO and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about CIPRO? CIPRO, a fluoroquinolone antibacterial medicine, can cause serious side effects. Some of these serious side effects can happen at the same time and could result in death. If you get any of the following serious side effects while you take CIPRO, you should stop taking CIPRO immediately and get medical help right away. 1. Tendon rupture or swelling of the tendon (tendinitis). • Tendon problems can happen in people of all ages who take CIPRO. Tendons are tough cords of tissue that connect muscles to bones. Symptoms of tendon problems may include: o pain o swelling o tears and swelling of the tendons including the back of the ankle (Achilles), shoulder, hand, thumb, or other tendon sites. • The risk of getting tendon problems while you take CIPRO is higher if you: o are over 60 years of age o are taking steroids (corticosteroids) o have had a kidney, heart or lung transplant. • Tendon problems can happen in people who do not have the above risk factors when they take CIPRO. • Other reasons that can increase your risk of tendon problems can include: o physical activity or exercise o kidney failure o tendon problems in the past, such as in people with rheumatoid arthritis (RA). • Stop taking CIPRO immediately and get medical help right away at the first sign of tendon pain, swelling or inflammation. The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This can also happen with other tendons. • Tendon rupture can happen while you are taking or after you have finished taking CIPRO. Tendon ruptures can happen within hours or days of taking CIPRO and have happened up to several months after people have finished taking their fluoroquinolone. • Stop taking CIPRO immediately and get medical help right away if you get any of the following signs or symptoms of a tendon rupture: o hear or feel a snap or pop in a tendon area o bruising right after an injury in a tendon area o unable to move the affected area or bear weight The tendon problems may be permanent. 2. Changes in sensation and possible nerve damage (Peripheral Neuropathy). Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones, including CIPRO. Stop taking CIPRO immediately and talk to your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet: CIPRO may need to be stopped to prevent permanent nerve damage. 3. Central Nervous System (CNS) effects. Mental health problems and seizures have been reported in people who take fluoroquinolone antibacterial medicines, including CIPRO. Tell your healthcare provider if you have a history of seizures before you start taking CIPRO. CNS side effects may happen as soon as after taking the first dose of CIPRO. Stop taking CIPRO immediately and talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior: These changes may be permanent. 4. Worsening of myasthenia gravis (a problem that causes muscle weakness). Fluoroquinolones like CIPRO may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Tell your healthcare provider if you have a history of myasthenia gravis before you start taking CIPRO. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems. What is CIPRO? CIPRO is a fluoroquinolone antibacterial medicine used in adults age 18 years and older to treat certain infections caused by certain germs called bacteria. These bacterial infections include: o urinary tract infection o bone and joint infection o cervical and urethral gonorrhea, uncomplicated o chronic prostate infection o nosocomial pneumonia o people with a low white blood cell count and a fever o lower respiratory tract infection o intra-abdominal infection, complicated o inhalational anthrax o sinus infection o infectious diarrhea o plague o skin infection o typhoid (enteric) fever • Studies of CIPRO for use in the treatment of plague and anthrax were done in animals only, because plague and anthrax could not be studied in people. • CIPRO should not be used in people with acute exacerbation of chronic bronchitis, acute uncomplicated cystitis, and sinus infections, if there are other treatment options available. • CIPRO should not be used as the first choice of antibacterial medicine to treat lower respiratory tract infections caused by a certain type of bacterial called Streptococcus pneumoniae . • CIPRO is also used in children younger than 18 years of age to treat complicated urinary tract and kidney infections or who may have breathed in anthrax germs, have plague or have been exposed to plague germs. • Children younger than 18 years of age have a higher chance of getting bone, joint, or tendon (musculoskeletal) problems such as pain or swelling while taking CIPRO. CIPRO should not be used as the first choice of antibacterial medicine in children under 18 years of age. • Who should not take CIPRO? Do not take CIPRO if you: • have ever had a severe allergic reaction to an antibacterial medicine known as a fluoroquinolone, or are allergic to ciprofloxacin hydrochloride or any of the ingredients in CIPRO. See the end of this Medication Guide for a complete list of ingredients in CIPRO. • also take a medicine called tizanidine (Zanaflex ® ). Ask your healthcare provider if you are not sure. What should I tell my healthcare provider before taking CIPRO? Before you take CIPRO, tell your healthcare provider about all your medical conditions, including if you: • have tendon problems. CIPRO should not be used in people who have a history of tendon problems. • have a disease that causes muscle weakness (myasthenia gravis). CIPRO should not be used in people who have a known history of myasthenia gravis. • have liver problems. • have central nervous system problems (such as epilepsy). • have nerve problems. CIPRO should not be used in people who have a history of a nerve problem called peripheral neuropathy have or anyone in your family has an irregular heartbeat, or heart attack, especially a condition called “QT prolongation”. • have low blood potassium (hypokalemia) or low magnesium (hypomagnesemia). • have or have had seizures. • have kidney problems. You may need a lower dose of CIPRO if your kidneys do not work well. • have diabetes or problems with low blood sugar (hypoglycemia). • have joint problems including rheumatoid arthritis (RA). • have trouble swallowing pills. • are pregnant or plan to become pregnant. It is not known if CIPRO will harm your unborn baby. • are breastfeeding or plan to breastfeed. CIPRO passes into your breast milk. o You should not breastfeed during treatment with CIPRO and for 2 days after taking your last dose of CIPRO. You may pump your breast milk and throw it away during treatment with CIPRO and for 2 days after taking your last dose of CIPRO. o If you are taking CIPRO for inhalation anthrax, you and your healthcare provider should decide whether you can continue breastfeeding while taking CIPRO. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. • CIPRO and other medicines can affect each other causing side effects. • Especially tell your healthcare provider if you take : o a steroid medicine. o an anti-psychotic medicine. o a tricyclic antidepressant. o a water pill (diuretic). o theophylline (such as Theo-24 ® , Elixophyllin ® , Theochron ® , Uniphyl ® , Theolair ® ). o a medicine to control your heart rate or rhythm (antiarrhythmics). o an oral anti-diabetes medicine. o phenytoin (Fosphenytoin Sodium ® , Cerebyx ® , Dilantin-125 ® , Dilantin ® , Extended Phenytoin Sodium ® , Prompt Phenytoin Sodium ® , Phenytek ® ). o cyclosporine (Gengraf ® , Neoral ® , Sandimmune ® , Sangcya ® ). o a blood thinner (such as warfarin, Coumadin ® , Jantoven ® ). o methotrexate (Trexall ® ). o ropinirole (Requip ® ). o clozapine (Clozaril ® , Fazaclo ® ODT ® ). o a Non-Steroidal Anti-Inflammatory Drug (NSAID). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take CIPRO or other fluoroquinolones may increase your risk of central nervous system effects and seizures. o sildenafil (Viagra ® , Revatio ® ). o duloxetine. o products that contain caffeine. o probenecid (Probalan ® , Col-probenecid ® ). • Certain medicines may keep CIPRO Tablets and CIPRO Oral Suspension from working correctly. Take CIPRO Tablets and Oral Suspension either 2 hours before or 6 hours after taking these medicines, vitamins, or supplements: o an antacid, multivitamin, or other medicine or supplements that has magnesium, calcium, aluminum, iron, or zinc. o sucralfate (Carafate ® ). o didanosine (Videx ® , Videx EC ® ). Ask your healthcare provider for a list of these medicines if you are not sure. 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 CIPRO? • Take CIPRO exactly as your healthcare provider tells you to take it. • Your healthcare provider will tell you how much CIPRO to take and when to take it. • CIPRO can be taken with or without food. • CIPRO should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone but may be taken with a meal that contains these products. • Drink plenty of fluids while taking CIPRO. • Do not skip any doses of CIPRO, or stop taking it, even if you begin to feel better, until you finish your prescribed treatment unless: o you have tendon problems. See “What is the most important information I should know about CIPRO?” o you have nerve problems. See “What is the most important information I should know about CIPRO?” o you have central nervous system problems. See “What is the most important information I should know about CIPRO?” o you have a serious allergic reaction. See “ What are the possible side effects of CIPRO?” o your healthcare provider tells you to stop taking CIPRO. Taking all of your CIPRO doses will help make sure that all of the bacteria are killed. Taking all of your CIPRO doses will help lower the chance that the bacteria will become resistant to CIPRO. If you become resistant to CIPRO, CIPRO and other antibacterial medicines may not work for you in the future. • If you take too much CIPRO, call your healthcare provider or get medical help right away. • CIPRO is supplied as a scored tablet (CIPRO Tablets), oral suspension (CIPRO Oral Suspension), extended-release tablet (CIPRO XR) and injection for intravenous infusion (CIPRO IV). Read and follow the instructions below for the type of CIPRO your healthcare provider has prescribed for you . CIPRO Tablets : • CIPRO Tablets comes as 250 mg and 500 mg scored tablets that can be taken whole or may be broken in half at the scored line. Your healthcare provider will tell you how much CIPRO Tablets to take and if you will need to break CIPRO Tablets in half to get your prescribed dose. • Take CIPRO Tablets in the morning and evening at about the same time each day. Do not crush or chew the tablet. Tell your healthcare provider if you cannot swallow the tablet. • If you miss a dose of CIPRO Tablets and it is: o 6 hours or more until your next scheduled dose, take your missed dose right away. Then take the next dose at your regular time. o less than 6 hours until your next scheduled dose, do not take the missed dose. Take the next dose at your regular time. • Do not take 2 doses of CIPRO Tablets at 1 time to make up for a missed dose. If you are not sure about when to take CIPRO Tablets after a missed dose, ask your healthcare provider or pharmacist. CIPRO Oral Suspension : • Take CIPRO Oral Suspension in the morning and evening at about the same time each day. Shake the CIPRO Oral Suspension bottle well each time before use for about 15 seconds to make sure the suspension is mixed well. Close the bottle completely after use. • If you miss a dose of CIPRO Oral Suspension and it is: o 6 hours or more until your next scheduled dose, take your missed dose right away. Then take the next dose at your regular time. o less than 6 hours until your next scheduled dose, do not take the missed dose. Take the next dose at your regular time. • Do not take 2 doses of CIPRO Oral Suspension at 1 time to make up for a missed dose. If you are not sure about when to take CIPRO Oral Suspension after a missed dose, ask your healthcare provider or pharmacist. • What should I avoid while taking CIPRO? • CIPRO can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how CIPRO affects you. • Avoid sunlamps, tanning beds, and try to limit your time in the sun. CIPRO can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get a severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while you take CIPRO, call your healthcare provider right away. You should use a sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight. What are the possible side effects of CIPRO? CIPRO may cause serious side effects, including: • See “What is the most important information I should know about CIPRO?” • Serious allergic reactions. Serious allergic reactions, including death, can happen in people taking fluoroquinolones, including CIPRO, even after only 1 dose. Stop taking CIPRO and get emergency medical help right away if you get any of the following symptoms of a severe allergic reaction: Skin rash may happen in people taking CIPRO even after only 1 dose. Stop taking CIPRO at the first sign of a skin rash and call your healthcare provider. Skin rash may be a sign of a more serious reaction to CIPRO. • Liver damage (hepatotoxicity). Hepatotoxicity can happen in people who take CIPRO. Call your healthcare provider right away if you have unexplained symptoms such as: • Aortic aneurysm and dissection. Tell your healthcare provider if you have ever been told that you have an aortic aneurysm, a swelling of the large artery that carries blood from the heart to the body. Get emergency medical help right away if you have sudden chest, stomach, or back pain. • Intestine infection ( Clostridioides difficile – associated diarrhea). Clostridioides difficile -associated diarrhea (CDAD) can happen with many antibacterial medicines, including CIPRO. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever. CDAD can happen 2 or more months after you have finished your antibacterial medicine. • Serious heart rhythm changes (QT prolongation and torsade de pointes). Tell your healthcare provider right away if you have a change in your heartbeat (a fast or irregular heartbeat), or if you faint. CIPRO may cause a rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this event are higher in people: o who are elderly. o with a family history of prolonged QT interval. o with low blood potassium (hypokalemia) or low magnesium (hypomagnesemia). o who take certain medicines to control heart rhythm (antiarrhythmics). • Joint Problems. Increased chance of problems with joints and tissues around joints in children under 18 years old can happen. Tell your child’s healthcare provider if your child has any joint problems during or after treatment with CIPRO. • Sensitivity to sunlight (photosensitivity). See “What should I avoid while taking CIPRO? ” • Changes in blood sugar. People who take CIPRO and other fluoroquinolone medicines with oral anti-diabetes medicines or with insulin can get low blood sugar (hypoglycemia) and high blood sugar (hyperglycemia). Follow your healthcare provider's instructions for how often to check your blood sugar. If you have diabetes and you get low blood sugar while taking CIPRO, stop taking CIPRO and call your healthcare provider right away. Your antibiotic medicine may need to be changed. The most common side effects of CIPRO include: • nausea • diarrhea • changes in liver function tests • vomiting • rash Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of CIPRO. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store CIPRO? CIPRO Tablets • Store at room temperature between 68°F to 77°F (20°C to 25°C). CIPRO Oral Suspension • Store microcapsules and diluent at room temperature up to 77°F (25°C). • Do not freeze. • After your CIPRO treatment is finished, safely throw away any unused oral suspension. Keep CIPRO and all medicines out of the reach of children. General Information about the safe and effective use of CIPRO. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use CIPRO for a condition for which it is not prescribed. Do not give CIPRO to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about CIPRO. If you would like more information about CIPRO, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about CIPRO that is written for health professionals. What are the ingredients in CIPRO? CIPRO Tablets: • Active ingredient: ciprofloxacin hydrochloride • Inactive ingredients: cornstarch, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide, and titanium dioxide. CIPRO Oral Suspension: • Active ingredient: ciprofloxacin • Inactive ingredients: o Microcapsules contains: hypromellose, magnesium stearate, methacrylic acid copolymer, and Polysorbate 20 and povidone. o Diluent contains: medium-chain triglycerides, sucrose, soy-lecithin, water, and strawberry flavor. Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981 CIPRO is a registered trademark of Bayer Aktiengesellschaft. Rx Only ©1987 Bayer HealthCare Pharmaceuticals Inc. For more information, call 1-1-888-842-2937. This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 11/2021

14 CLINICAL STUDIES 14.1 Complicated Urinary Tract Infection and Pyelonephritis–Efficacy in Pediatric Patients CIPRO administered intravenously and/or orally was compared to a cephalosporin for treatment of cUTI and pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety. Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no protocol violation, and no premature discontinuation or loss to follow-up (among other criteria). The clinical success and bacteriologic eradication rates in the Per Protocol population were similar between CIPRO and the comparator group as shown below. Table 15: Clinical Success and Bacteriologic Eradication at Test of Cure (5 to 9 Days Post-Therapy) CIPRO Comparator Randomized Patients 337 352 Per Protocol Patients 211 231 Clinical Response at 5 to 9 Days Post-Treatment 95.7% (202/211) 92.6% (214/231) 95% CI [-1.3%, 7.3%] Bacteriologic Eradication by Patient at 5 to 9 Days Post-Treatment Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with superinfections or new infections. 84.4% (178/211) 78.3% (181/231) 95% CI [-1.3%, 13.1%] Bacteriologic Eradication of the Baseline Pathogen at 5 to 9 Days Post-Treatment Escherichia coli 156/178 (88%) 161/179 (90%) 14.2 Inhalational Anthrax in Adults and Pediatrics The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving oral and intravenous regimens. Ciprofloxacin pharmacokinetics have been evaluated in various human populations. The mean peak serum concentration achieved at steady-state in human adults receiving 500 mg orally every 12 hours is 2.97 mcg/mL, and 4.56 mcg/mL following 400 mg intravenously every 12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 mcg/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration achieved is 8.3 mcg/mL and trough concentrations range from 0.09 mcg/mL to 0.26 mcg/mL, following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3.6 mcg/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the administration of CIPRO to pediatric patients are limited. Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication. 1 A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD 50 (~5.5 x 10 5 spores (range 5–30 LD 50 ) of B. anthracis was conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 mcg/mL. In the animals studied, mean serum concentrations of ciprofloxacin achieved at expected T max (1 hour post-dose) following oral dosing to steady-state ranged from 0.98 mcg/mL to 1.69 mcg/mL. Mean steady-state trough concentrations at 12 hours post-dose ranged from 0.12 mcg/mL to 0.19 mcg/mL. 6 Mortality due to anthrax for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was significantly lower (1/9), compared to the placebo group (9/10) [p= 0.001]. The one CIPRO-treated animal that died of anthrax did so following the 30-day drug administration period. 7 More than 9300 persons were recommended to complete a minimum of 60 days of antibacterial prophylaxis against possible inhalational exposure to B. anthracis during 2001. CIPRO was recommended to most of those individuals for all or part of the prophylaxis regimen. Some persons were also given anthrax vaccine or were switched to alternative antibacterial drugs. No one who received CIPRO or other therapies as prophylactic treatment subsequently developed inhalational anthrax. The number of persons who received CIPRO as all or part of their post-exposure prophylaxis regimen is unknown. 14.3 Plague A placebo-controlled animal study in African green monkeys exposed to an inhaled mean dose of 110 LD 50 (range 92 to 127 LD 50 ) of Yersinia pestis (CO92 strain) was conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin for the Y. pestis strain used in this study was 0.015 mcg/mL. Mean peak serum concentrations of ciprofloxacin achieved at the end of a single 60 minute infusion were 3.49 ± mcg/mL 0.55 mcg/mL, 3.91 mcg/mL ± 0.58 mcg/mL and 4.03 mcg/mL ± 1.22 mcg/mL on Day 2, Day 6 and Day 10 of treatment in African green monkeys, respectively All trough concentrations (Day 2, Day 6 and Day 10) were <0.5 mcg /mL. Animals were randomized to receive either a 10-day regimen of intravenous ciprofloxacin 15 mg/kg, or placebo beginning when animals were found to be febrile (a body temperature greater than 1.5 o C over baseline for two hours), or at 76 hours post-challenge, whichever occurred sooner. Mortality in the ciprofloxacin group was significantly lower (1/10) compared to the placebo group (2/2) [difference: -90.0%, 95% exact confidence interval: -99.8% to -5.8%]. The one ciprofloxacin-treated animal that died did not receive the proposed dose of ciprofloxacin due to a failure of the administration catheter. Circulating ciprofloxacin concentration was below 0.5 mcg/mL at all timepoints tested in this animal. It became culture negative on Day 2 of treatment, but had a resurgence of low grade bacteremia on Day 6 after treatment initiation. Terminal blood culture in this animal was negative. 12

15 REFERENCES 1. 21 CFR 314.510 (Subpart H–Accelerated Approval of New Drugs for Life-Threatening Illnesses). 2. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. 3. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother. 1998;42(6):1336-1339. 4. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European network of teratology information services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69:83-89. 5. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug Product’s Advisory Committee meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA. 6. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166:1184-7. 7. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect Dis 1993; 167:1239-42. 8. Anti-infective Drugs Advisory Committee Meeting, April 3, 2012 - The efficacy of Ciprofloxacin for treatment of Pneumonic Plague.

8.5 Geriatric Use Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as CIPRO. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing CIPRO to elderly patients especially those on corticosteroids. Patients should be informed of this potential adverse reaction and advised to discontinue CIPRO and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur . [see Boxed Warning , Warnings and Precautions ( 5.2 ), and Adverse Reactions ( 6.2 )]. Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients [see Warnings and Precautions ( 5.9 )]. In a retrospective analysis of 23 multiple-dose controlled clinical trials of CIPRO encompassing over 3500 ciprofloxacin-treated patients, 25% of patients were greater than or equal to 65 years of age and 10% were greater than or equal to 75 years of age. 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 on any drug therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age with normal renal function. However, since some older individuals experience reduced renal function by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal function monitoring may be useful in these patients [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )]. In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using CIPRO with concomitant drugs that can result in prolongation of the QT interval (for example, class IA or class III antiarrhythmics) or in patients with risk factors for torsade de pointes (for example, known QT prolongation, uncorrected hypokalemia) [see Warnings and Precautions ( 5.12 )].

8.4 Pediatric Use Although effective in clinical trials, CIPRO is not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to controls. Quinolones, including CIPRO, cause arthropathy (arthralgia, arthritis), in juvenile animals [see Warnings and Precautions ( 5.13 ) and Nonclinical Toxicology ( 13.2 )] . Complicated Urinary Tract Infection and Pyelonephritis CIPRO is indicated for the treatment of cUTI and pyelonephritis due to Escherichia coli in pediatric patients 1 to 17 years of age . Although effective in clinical trials, CIPRO is not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to the controls, including events related to joints and/or surrounding tissues [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.1 )]. Inhalational Anthrax (Post-Exposure) CIPRO is indicated in pediatric patients from birth to 17 years of age, for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate [see Dosage and Administration ( 2.2 ) and Clinical Studies ( 14.2 )]. Plague CIPRO is indicated in pediatric patients from birth to 17 years of age, for treatment of plague, including pneumonic and septicemic plague due to Yersinia pestis (Y. pestis) and prophylaxis for plague. Efficacy studies of CIPRO could not be conducted in humans with pneumonic plague for feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals. The risk-benefit assessment indicates that administration of CIPRO to pediatric patients is appropriate [see Indications and Usage ( 1.8 ), Dosage and Administration ( 2.2 ) and Clinical Studies ( 14.3 )].

8.1 Pregnancy Risk Summary Prolonged experience with ciprofloxacin in pregnant women over several decades, based on available published information from case reports, case control studies and observational studies on ciprofloxacin administered during pregnancy, have not identified any drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes (see Data) . Oral administration of ciprofloxacin during organogenesis at doses up to 100 mg/kg to pregnant mice and rats, and up to 30 mg/kg to pregnant rabbits did not cause fetal malformations (see Data). These doses were up to 0.3, 0.6, and 0.4 times the maximum recommended clinical oral dose in mice, rats, and rabbits, respectively, based on body surface area. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data While available studies cannot definitively establish the absence of risk, published data from prospective observational studies over several decades have not established an association with ciprofloxacin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. Available studies have methodological limitations including small sample size and some of them are not specific for ciprofloxacin. A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation. In utero exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major malformations. The reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group (background incidence of major malformations is 1–5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children. Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester exposures). There were 70 ciprofloxacin exposures, all within the first trimester. The malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were both within background incidence ranges. No specific patterns of congenital abnormalities were found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin. No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to ciprofloxacin during pregnancy. However, these small postmarketing epidemiology studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in pregnant women and their developing fetuses. Animal Data Developmental toxicology studies have been performed with ciprofloxacin in rats, mice, and rabbits. In rats and mice, oral doses up to 100 mg/kg administered during organogenesis (Gestation Days, GD, 6-17) were not associated with adverse developmental outcomes, including embryofetal toxicity or malformations. In rats and mice, a 100 mg/kg dose is approximately 0.6 and 0.3 times the maximum daily human oral dose (1500 mg/day) based upon body surface area, respectively. In a series of rabbit developmental toxicology studies, does received oral or intravenous ciprofloxacin for one of the following 5 day periods: GD 6 to 10, GD 10 to 14, or GD 14 to 18, intended to cover the period of organogenesis. This was an attempt to mitigate the gastrointestinal intolerance observed in rabbits that receive antibacterials manifested by reduced maternal food consumption and weight loss, that can lead to embryofetal resorption or spontaneous abortion. An oral ciprofloxacin dose of 100 mg/kg (approximately 1.3 times the highest recommended clinical oral dose based on body surface area) caused excessive maternal toxicity confounding evaluation of the fetuses. A 30 mg/kg oral dose (approximately 0.4 times the highest recommended clinical oral dose) was associated with suppression of maternal and fetal body weight gain, but fetal malformations were not observed. Intravenous administration of doses up to 20 mg/kg (approximately 0.3 times the highest recommended clinical oral dose based upon body surface area) to pregnant rabbits was not maternally toxic and neither embryofetal toxicity nor fetal malformations were observed. In peri- and post-natal studies, rats received ciprofloxacin doses up to 200 mg/kg/day (oral) or up to 30 mg/kg/day (subcutaneous) from GD 16 to 22 days postpartum. The 200 mg/kg dose is approximately 1.3-times the maximum recommended clinical oral dose based on body surface area. Neither maternal toxicity nor adverse effects on growth and development of the pups were observed, including no sign of arthropathy on the rear leg joints of the pups. Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested when administered directly [see Warnings and Precautions ( 5.13 ) and Nonclinical Toxicology 13.2 ] .

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended during treatment, but a lactating woman may pump and discard breastmilk during treatment and an additional 2 days after the last dose. In patients treated for inhalational anthrax (post exposure), consider the risks and benefits of continuing breastfeeding. ( 8.2 ) See full prescribing information for use in pediatric and geriatric patients ( 8.4 , 8.5 ) 8.1 Pregnancy Risk Summary Prolonged experience with ciprofloxacin in pregnant women over several decades, based on available published information from case reports, case control studies and observational studies on ciprofloxacin administered during pregnancy, have not identified any drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes (see Data) . Oral administration of ciprofloxacin during organogenesis at doses up to 100 mg/kg to pregnant mice and rats, and up to 30 mg/kg to pregnant rabbits did not cause fetal malformations (see Data). These doses were up to 0.3, 0.6, and 0.4 times the maximum recommended clinical oral dose in mice, rats, and rabbits, respectively, based on body surface area. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data While available studies cannot definitively establish the absence of risk, published data from prospective observational studies over several decades have not established an association with ciprofloxacin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. Available studies have methodological limitations including small sample size and some of them are not specific for ciprofloxacin. A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation. In utero exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major malformations. The reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group (background incidence of major malformations is 1–5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children. Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester exposures). There were 70 ciprofloxacin exposures, all within the first trimester. The malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were both within background incidence ranges. No specific patterns of congenital abnormalities were found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin. No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to ciprofloxacin during pregnancy. However, these small postmarketing epidemiology studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in pregnant women and their developing fetuses. Animal Data Developmental toxicology studies have been performed with ciprofloxacin in rats, mice, and rabbits. In rats and mice, oral doses up to 100 mg/kg administered during organogenesis (Gestation Days, GD, 6-17) were not associated with adverse developmental outcomes, including embryofetal toxicity or malformations. In rats and mice, a 100 mg/kg dose is approximately 0.6 and 0.3 times the maximum daily human oral dose (1500 mg/day) based upon body surface area, respectively. In a series of rabbit developmental toxicology studies, does received oral or intravenous ciprofloxacin for one of the following 5 day periods: GD 6 to 10, GD 10 to 14, or GD 14 to 18, intended to cover the period of organogenesis. This was an attempt to mitigate the gastrointestinal intolerance observed in rabbits that receive antibacterials manifested by reduced maternal food consumption and weight loss, that can lead to embryofetal resorption or spontaneous abortion. An oral ciprofloxacin dose of 100 mg/kg (approximately 1.3 times the highest recommended clinical oral dose based on body surface area) caused excessive maternal toxicity confounding evaluation of the fetuses. A 30 mg/kg oral dose (approximately 0.4 times the highest recommended clinical oral dose) was associated with suppression of maternal and fetal body weight gain, but fetal malformations were not observed. Intravenous administration of doses up to 20 mg/kg (approximately 0.3 times the highest recommended clinical oral dose based upon body surface area) to pregnant rabbits was not maternally toxic and neither embryofetal toxicity nor fetal malformations were observed. In peri- and post-natal studies, rats received ciprofloxacin doses up to 200 mg/kg/day (oral) or up to 30 mg/kg/day (subcutaneous) from GD 16 to 22 days postpartum. The 200 mg/kg dose is approximately 1.3-times the maximum recommended clinical oral dose based on body surface area. Neither maternal toxicity nor adverse effects on growth and development of the pups were observed, including no sign of arthropathy on the rear leg joints of the pups. Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested when administered directly [see Warnings and Precautions ( 5.13 ) and Nonclinical Toxicology 13.2 ] . 8.2 Lactation Risk Summary Published literature reports that ciprofloxacin is present in human milk following intravenous and oral administration . There is no information regarding effects of CIPRO on milk production or the breastfed infant. Because of the potential risk of serious adverse reactions in breastfed infants, including arthropathy shown in juvenile animal studies [see Use in Specific Populations (8.4), (Clinical Considerations)], for most indications a lactating woman may consider pumping and discarding breast milk during treatment with CIPRO and an additional two days (five half-lives) after the last dose. Alternatively, advise a woman that breastfeeding is not recommended during treatment with CIPRO and for an additional two days (five half-lives) after the last dose. However, for inhalation anthrax (post exposure), during an incident resulting in exposure to anthrax, the risk-benefit assessment of continuing breastfeeding while the mother (and potentially the infant) is (are) on CIPRO may be acceptable [see Dosage and Administration ( 2.2 ), Pediatric Use ( 8.4 ), and Clinical Studies ( 14.2 )]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CIPRO and any potential adverse effects on the breastfed child from CIPRO or from the underlying maternal condition. Clinical Considerations Ciprofloxacin may cause intestinal flora alteration of the breastfeeding infant. Advise a woman to monitor the breastfed infant for loose or bloody stools and candidiasis (thrush, diaper rash). 8.4 Pediatric Use Although effective in clinical trials, CIPRO is not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to controls. Quinolones, including CIPRO, cause arthropathy (arthralgia, arthritis), in juvenile animals [see Warnings and Precautions ( 5.13 ) and Nonclinical Toxicology ( 13.2 )] . Complicated Urinary Tract Infection and Pyelonephritis CIPRO is indicated for the treatment of cUTI and pyelonephritis due to Escherichia coli in pediatric patients 1 to 17 years of age . Although effective in clinical trials, CIPRO is not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to the controls, including events related to joints and/or surrounding tissues [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.1 )]. Inhalational Anthrax (Post-Exposure) CIPRO is indicated in pediatric patients from birth to 17 years of age, for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate [see Dosage and Administration ( 2.2 ) and Clinical Studies ( 14.2 )]. Plague CIPRO is indicated in pediatric patients from birth to 17 years of age, for treatment of plague, including pneumonic and septicemic plague due to Yersinia pestis (Y. pestis) and prophylaxis for plague. Efficacy studies of CIPRO could not be conducted in humans with pneumonic plague for feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals. The risk-benefit assessment indicates that administration of CIPRO to pediatric patients is appropriate [see Indications and Usage ( 1.8 ), Dosage and Administration ( 2.2 ) and Clinical Studies ( 14.3 )]. 8.5 Geriatric Use Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as CIPRO. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing CIPRO to elderly patients especially those on corticosteroids. Patients should be informed of this potential adverse reaction and advised to discontinue CIPRO and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur . [see Boxed Warning , Warnings and Precautions ( 5.2 ), and Adverse Reactions ( 6.2 )]. Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients [see Warnings and Precautions ( 5.9 )]. In a retrospective analysis of 23 multiple-dose controlled clinical trials of CIPRO encompassing over 3500 ciprofloxacin-treated patients, 25% of patients were greater than or equal to 65 years of age and 10% were greater than or equal to 75 years of age. 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 on any drug therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age with normal renal function. However, since some older individuals experience reduced renal function by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal function monitoring may be useful in these patients [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )]. In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using CIPRO with concomitant drugs that can result in prolongation of the QT interval (for example, class IA or class III antiarrhythmics) or in patients with risk factors for torsade de pointes (for example, known QT prolongation, uncorrected hypokalemia) [see Warnings and Precautions ( 5.12 )]. 8.6 Renal Impairment Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine. These alternative pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with severe renal dysfunction [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )]. 8.7 Hepatic Impairment In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The pharmacokinetics of ciprofloxacin in patients with acute hepatic insufficiency, have not been studied.

16 HOW SUPPLIED/STORAGE AND HANDLING CIPRO (ciprofloxacin hydrochloride) Tablets are available as round, slightly yellowish film-coated tablets containing 250 mg ciprofloxacin. The 250 mg tablet is coded with the word “BAYER” on one side and functionally scored and engraved with “CIP 250” on the reverse side. CIPRO is also available as capsule shaped, slightly yellowish film-coated tablets containing 500 mg ciprofloxacin. The 500 mg tablet is coded with the word “BAYER” on one side and functionally scored and engraved with “CIP 500” on the reverse side. CIPRO 250 mg and 500 mg are available in bottles of 100. Strength NDC Code Tablet Identification Bottles of 100: 250 mg NDC 50419-758-01 CIPRO 250 500 mg NDC 50419-754-01 CIPRO 500 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. CIPRO Oral Suspension is supplied in 5% and 10% strengths. The drug product is composed of two components (microcapsules containing the active ingredient and diluent) which must be mixed by the pharmacist [see Dosage and Administration ( 2.5 )]. Strengths Total volume after reconstitution Ciprofloxacin Concentration Ciprofloxacin contents per bottle NDC Code 5% 100 mL 250 mg/5 mL 5,000 mg 50419-777-01 10% 100 mL 500 mg/5 mL 10,000 mg 50419-773-01 Store microcapsules and diluent below 25°C (77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from freezing. The reconstituted product may be stored at 25°C (77°F) for 14 days; excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from freezing. A graduated teaspoon (5mL) with markings 1/2 (2.5 mL) and 1/1 (5 mL) is provided for the patient.

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS • Fluoroquinolones, including CIPRO ® , have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together [see Warnings and Precautions ( 5.1 )], including: • Tendinitis and tendon rupture [see Warnings and Precautions ( 5.2 )]. • Peripheral neuropathy [see Warnings and Precautions ( 5.3 )]. • Central nervous system effects [see Warnings and Precautions ( 5.4 )]. Discontinue CIPRO immediately and avoid the use of fluoroquinolones, including CIPRO, in patients who experience any of these serious adverse reactions [see Warnings and Precautions ( 5.1 )] . • Fluoroquinolones, including CIPRO, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid CIPRO in patients with known history of myasthenia gravis . [see Warnings and Precautions ( 5.5 )]. • Because fluoroquinolones, including CIPRO, have been associated with serious adverse reactions [see Warnings and Precautions ( 5.1-5.16 )] , reserve CIPRO for use in patients who have no alternative treatment options for the following indications: • Acute exacerbation of chronic bronchitis [see Indications and Usage ( 1.10 )]. • Acute uncomplicated cystitis [see Indications and Usage ( 1.11 )]. • Acute sinusitis [see Indications and Usage ( 1.12 )]. WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS See full prescribing information for complete boxed warning. • Fluoroquinolones, including CIPRO ® , have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together ( 5.1 ), including: • Tendinitis and tendon rupture ( 5.2 ) • Peripheral neuropathy ( 5.3 ) • Central nervous system effects ( 5.4 ) Discontinue CIPRO immediately and avoid the use of fluoroquinolones, including CIPRO, in patients who experience any of these serious adverse reactions ( 5.1 ) • Fluoroquinolones, including CIPRO, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid CIPRO in patients with known history of myasthenia gravis. ( 5.5 ) • Because fluoroquinolones, including CIPRO, have been associated with serious adverse reactions ( 5.1-5.16 ), reserve CIPRO for use in patients who have no alternative treatment options for the following indications: • Acute exacerbation of chronic bronchitis ( 1.10 ) • Acute uncomplicated cystitis ( 1.11 ) Acute sinusitis ( 1.12 )