Data from FDA - Curated by EPG Health - Last updated 01 September 2017

Indication(s)

1 INDICATIONS AND USAGE CIPRO IV is a fluoroquinolone antibacterial indicated in adults (≥18 years of age) 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) •Nosocomial Pneumonia (1.4) •Empirical Therapy for Febrile Neutropenic Patients (1.5) •Inhalational Anthrax Post-Exposure in Adult and Pediatric Patients (1.6) •Plague in adult and pediatric patients (1.7) •Chronic Bacterial Prostatitis (1.8) •Lower respiratory tract infections (1.9) oAcute Exacerbation of Chronic Bronchitis •Urinary Tract Infections (1.10) oUrinary Tract Infections (UTI) oComplicated UTI and Pyelonephritis in Pediatric Patients •Acute Sinusitis (1.11) Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO IV and other antibacterial drugs, CIPRO IV should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1.12) 1.1 Skin and Skin Structure Infections CIPRO IV is indicated in adult patients for treatment of skin and skin structure infectionscaused 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 IV is indicated in adult patients for treatment of bone and joint infectionscaused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa. 1.3 Complicated Intra-Abdominal Infections CIPRO IV 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 Nosocomial Pneumonia CIPRO IV is indicated in adult patients for treatment of nosocomial pneumoniacaused by Haemophilus influenzae or Klebsiella pneumoniae. 1.5 Empirical Therapy for Febrile Neutropenic Patients CIPRO IV is indicated in adult patients for the treatment of febrile neutropenia in combination with piperacillin sodium [see Clinical Studies (14.1)]. 1.6 Inhalational Anthrax (Post-Exposure) CIPRO IV is indicated in adults and pediatric patients from birth to 17 years of age for treatment of 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 (14.3)]. 1.7 Plague CIPRO IV 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 (14.4)]. 1.8 Chronic Bacterial Prostatitis CIPRO IV is indicated in adult patients for treatment of chronic bacterial prostatitis caused by Escherichia coli or Proteus mirabilis. 1.9 Lower Respiratory Tract Infections CIPRO IV is indicated in adult patients for treatment of lower respiratory tract infectionscaused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or Streptococcus pneumoniaeCIPRO IV is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumonia. CIPRO IV is indicated for the treatment of acute exacerbations of chronic bronchitis (AECB) caused by Moraxella catarrhalis. Because fluoroquinolones, including CIPRO IV, have been associated with serious adverse reactions [see Warnings and Precautions (5.1-5.15)] and for some patients AECB is self-limiting, reserve CIPRO IV for treatment of AECB in patients who have no alternative treatment options. 1.10 Urinary Tract Infections Urinary Tract Infection in Adults CIPRO IV is indicated in adult patients for treatment of urinary tract infectionscaused 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. Complicated Urinary Tract Infections and Pyelonephritis in Pediatric Patients CIPRO IV is indicated in pediatric patients 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 IV 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 IV, like other fluoroquinolones, is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals [see Warnings and Precautions (5.12), Adverse Reactions (6.1), Use in Specific Populations (8.4), and Nonclinical Toxicology (13.2)]. 1.11 Acute Sinusitis CIPRO IV is indicated in adult patients for treatment of acute sinusitiscaused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis. Because fluoroquinolones, including CIPRO IV, have been associated with serious adverse reactions [see Warnings and Precautions (5.1–5.15)] and for some patients acute sinusitis is self-limiting, reserve CIPRO for treatment of acute sinusitis in patients who have no alternative treatment options. 1.12 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO IV and other antibacterial drugs, CIPRO IV 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 IV 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.

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Advisory information

contraindications
4 CONTRAINDICATIONS •Known hypersensitivity to CIPRO or other quinolones (4.1, 5.7) •Concomitant administration with tizanidine (4.2) 4.1 Hypersensitivity Ciprofloxacin 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)].
Adverse reactions
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)] •Serious Adverse Reactions with Concomitant Theophylline [see Warnings and Precautions (5.9)] •Clostridium difficile-Associated Diarrhea [see Warnings and Precautions ( 5.10)] •Prolongation of the QT Interval [see Warnings and Precautions ( 5.11)] •Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions ( 5.12)] •Photosensitivity/Phototoxicity [see Warnings and Precautions ( 5.13)] •Development of Drug Resistant Bacteria [see Warnings and Precautions ( 5.14)] The most common adverse reactions ≥1% were nausea, diarrhea, liver function tests abnormal, vomiting, central nervous system disturbance, local intravenous site reactions eosinophilia, headache, restlessness, 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 IV, 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%). In clinical trials the following adverse reactions were reported in greater than 1% of patients treated with intravenous CIPRO IV: nausea, diarrhea, central nervous system disturbance, local intravenous site reactions, liver function tests abnormal, eosinophilia, headache, restlessness, and rash. Local intravenous site reactions are more frequent if the infusion time is 30 minutes or less. These may appear as local skin reactions that resolve rapidly upon completion of the infusion. Subsequent intravenous administration is not contraindicated unless the reactions recur or worsen. Table 5: Medically Important Adverse Reactions That Occurred in less than 1% Ciprofloxacin Patients System Organ Class Adverse Reactions Body as a Whole Abdominal Pain/Discomfort Pain Cardiovascular Cardiopulmonary Arrest Myocardial Infarction Tachycardia Syncope Hypertension Angina Pectoris Vasodilation Central Nervous System Restlessness Seizures (including Status Epilepticus) Paranoia Psychosis (toxic) Depression (potentially culminating in self-injurious behavior, such as suicidal ideations/thoughts and attempted or completed suicide) Phobia Depersonalization Manic Reaction Unresponsiveness Ataxia Hallucinations Dizziness Paresthesia Tremor Insomnia Nightmares Irritability Malaise Abnormal Gait Migraine Gastrointestinal Ileus Gastrointestinal Bleeding Pancreatitis Hepatic Necrosis Intestinal Perforation Dyspepsia Constipation Oral Ulceration Mouth Dryness Anorexia Flatulence Hepatitis Hemic/Lymphatic Agranulocytosis Prolongation of Prothrombin Time Petechia Metabolic/Nutritional Hyperglycemia Hypoglycemia Musculoskeletal Arthralgia Joint Stiffness Muscle Weakness Renal/Urogenital Renal Failure Interstitial Nephritis Hemorrhagic Cystitis Renal Calculi Frequent Urination Gynecomastia Crystalluria Cylindruria Hematuria Albuminuria Respiratory Respiratory Arrest Dyspnea Laryngeal Edema Hemoptysis Bronchospasm Skin/Hypersensitivity Allergic Reactions Anaphylactic Reactions including life-threatening anaphylactic shock Erythema Multiforme/Stevens-Johnson Syndrome Exfoliative Dermatitis Toxic Epidermal Necrolysis Vasculitis Angioedema Extremities Purpura Fever Pruritus Urticaria Increased Perspiration Erythema Nodosum Thrombophlebitis Burning Photosensitivity/Phototoxicity Reaction Special Senses Decreased Visual Acuity Blurred Vision Disturbed Vision (diplopia, chromatopsia, and photopsia) Anosmia Hearing Loss Tinnitus Nystagmus Bad Taste In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to be related to elevated serum levels of theophylline possibly as a result of drug interaction with ciprofloxacin. In randomized, double-blind controlled clinical trials comparing CIPRO (Intravenous and Intravenous/Oral. sequential) with intravenous beta-lactam control antibiotics, the CNS adverse reaction profile of CIPRO was comparable to that of 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 6). Table 6: Musculoskeletal Adverse Reactions1 as Assessed by the IPSC CIPRO Comparator All Patients (within 6 weeks) 31/335 (9.3%) 21/349 (6%) 95% Confidence Interval (-0.8%, +7.2%) Age Group 12 months to 24 months 1/36 (2.8%) 0/41 2 years to <6 years 5/124 (4%) 3/118 (2.5%) 6 years to <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 ciprofloxacin 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 events 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 IV. 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 7). Table 7: 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 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 Nystagmus Taste loss 6.3 Adverse Laboratory Changes Changes in laboratory parameters while on CIPRO IV therapy are listed below: •Hepatic-Elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and serum bilirubin •Hematologic-Elevated eosinophil and platelet counts, decreased platelet counts, hemoglobin and/or hematocrit •Renal-Elevations of serum creatinine, BUN, and uric acid •Other elevations of serum creatine phosphokinase, serum theophylline (in patients receiving theophylline concomitantly), blood glucose, and triglycerides Other changes occurring were: decreased leukocyte count, elevated atypical lymphocyte count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase (gGT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin, decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes occurring during administration of ciprofloxacin were: elevation of serum amylase, decrease of blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin, decreased prothrombin time, hemolytic anemia, and bleeding diathesis.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION CIPRO IV should be administered intravenously at dosages described in the appropriate Dosage Guidelines tables. Adult Dosage Guidelines Infection Dose Frequency Duration Skin and Skin Structure 400 mg every 8 to 12 hours 7–14 days Bone and Joint 400 mg every 8 to 12 hours 4 to 8 weeks Complicated Intra-Abdominal 400 mg every 12 hours 7–14 days Nosocomial Pneumonia 400 mg every 8 hours 10–14 days Empirical Therapy In Febrile Neutropenic Patients 400 mg and every 8 hours 7–14 days Piperacillin 50 mg/kg every 4 hours Inhalational anthrax(post-exposure) 400 mg every 12 hours 60 days Plague 400 mg every 8 to 12 hours 14 days Chronic Bacterial prostatitis 400 mg every 12 hours 28 days Lower Respiratory Tract 400 mg every 8 to 12 hours 7–14 days Urinary Tract 200 to 400 mg every 8 to 12 hours 7–14 days Acute Sinusitis 400 mg every 12 hours 10 days •Adults with creatinine clearance 5–29 mL/min 250–500 mg q 18 h (2.3) Pediatric Intravenous Dosing Guidelines Infection Dose Frequency Duration Complicated UTI and Pyelonephritis (patients from 1 to 17 years of age) 6 mg/kg to 10 mg/kg (maximum 400 mg per dose) Every 8 hours 10–21 days 1 Inhalational Anthrax (Post-Exposure) 10 mg/kg (maximum 400 mg per dose) Every 12 hours 60 days Plague 10 mg/kg (maximum 400 mg per dose) Every 8 to 12 hours 10–21 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. Table 1: Adult Dosage Guidelines Infection 1 Dose Frequency Usual Duration Skin and Skin Structure 400 mg every 8 to 12 hours 7–14 days Bone and Joint 400 mg every 8 to 12 hours 4 to 8 weeks Complicated Intra-Abdominal2 400 mg every 12 hours 7–14 days Nosocomial Pneumonia 400 mg every 8 hours 10–14 days Empirical Therapy In Febrile Neutropenic Patients CIPRO IV 400 mg and Piperacillin 50 mg/kg every 8 hours every 4 hours 7–14 days Inhalational Anthrax(Post-Exposure)3 400 mg every 12 hours 60 days Plague 3 400 mg every 8 to 12 hours 14 days Chronic Bacterial Prostatitis 400 mg every 12 hours 28 days Lower Respiratory Tract Infections 400 mg every 8 to 12 hours 7–14 days Urinary Tract Infections 200 mg to 400 mg every 8 to 12 hours 7–14 days Acute Sinusitis 400 mg every 12 hours 10 days 1.Due to the designated pathogens (see Indications and Usage.) 2. Used in conjunction with metronidazole. 3.Begin administration as soon as possible after suspected or confirmed exposure. Conversion of Intravenous 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. Table 3: Pediatric Dosage Guidelines Infection Dose (mg/kg) Frequency Total Duration Complicated Urinary Tract or Pyelonephritis (patients from 1 to 17 years of age)1 6 mg/kg to 10 mg/kg (maximum 400 mg per dose; not to be exceeded even in patients weighing more than 51 kg) Every 8 hours 10–21 days Inhalational Anthrax (Post-Exposure) 10 mg/kg (maximum 400 mg per dose) Every 12 hours 60 days Plague 2,3 10 mg/kg (maximum 400 mg per dose) Every 8 to 12 hours 10–21 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 >30 See Usual Dosage. 5–29 200–400 mg every 18–24 hours 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 and hepatic insufficiency, careful monitoring is suggested. 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/1.73m2). 2.4 Preparation of CIPRO IV for Administration Flexible Containers CIPRO IV is available as a 0.2% premixed solution in 5% dextrose in flexible containers of 200 mL. The solutions in flexible containers do not need to be diluted and may be infused as described above. 2.5 Important Administration Instructions Intravenous Infusion CIPRO IV should be administered by intravenous infusion over a period of 60 minutes. Slow infusion of a dilute solution into a larger vein will minimize patient discomfort and reduce the risk of venous irritation. Hydration of Patients Receiving CIPRO IV Adequate hydration of patients receiving CIPRO IV should be maintained to prevent the formation of highly concentrated urine. Crystalluria has been reported with quinolones [see Warnings and Precautions ( 5.16 ), Adverse Reactions (6.1), Nonclinical Toxicology (13.2) and Patient Counseling Information (17)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS See full prescribing information for pediatric patients (8.4) and use in geriatric (8.5) 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. CIPRO IV should not be used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother. An expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS–the Teratogen Information System–concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that there is no risk.2 A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation.3 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).4 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.2, 3 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. Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and 0.3 times the maximum daily human dose based upon body surface area, respectively) and have revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose based upon body surface area) produced gastrointestinal toxicity resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic dose based upon body surface area), no maternal toxicity was produced and no embryotoxicity or teratogenicity was observed. 8.3 Nursing Mothers Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by the nursing infant is unknown. Because of the potential risk of serious adverse reactions (including articular damage) in infants nursing from mothers taking CIPRO IV, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Although effective in clinical trials, CIPRO IV 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 IV, cause arthropathy (arthralgia, arthritis) in juvenile animals [see Warnings and Precautions (5.12) and Nonclinical Toxicology (13.2)]. Complicated Urinary Tract Infection and Pyelonephritis CIPRO IV is indicated for the treatment of cUTI and pyelonephritisdue to Escherichia coli in pediatric patients 1 to 17 years of age. Although effective in clinical trials, CIPRO IV 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 (14.2)]. Inhalational Anthrax (Post-Exposure) CIPRO IV 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 (14.3)]. Plague CIPRO IV 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 IV 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 (1.7), Dosage and Administration (2.2), and Clinical Studies (14.4)]. 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 IV. 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 IV 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)]. 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 IV 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 (5.11)]. 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.

Interactions

7 DRUG INTERACTIONS Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration of CIPRO IV 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 8: Drugs That are Affected by and Affecting CIPRO IV Drugs That are Affected by CIPRO IV Drug(s) Recommendation Comments Tizanidine Contraindicated Concomitant administration of tizanidine and CIPRO IV 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 IV 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 [eee Warnings and Precautions (5.9)]. Drugs Known to Prolong QT Interval Avoid Use CIPRO IV 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 (5.11) 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 IV 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 ciprofloxacin 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 IV discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of CIPRO IV with phenytoin. Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin 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 IV 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 IV 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 IV 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 IV [see Warnings and Precautions (5.15)]. 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 IV 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 IV 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 Probenecid Use with caution (interferes with renal tubular secretion of CIPRO and increases CIPRO serum levels) Potentiation of CIPRO IV 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)

More information

Category Value
Authorisation number NDA019857
Agency product number 5E8K9I0O4U
Orphan designation No
Product NDC 50419-759
Date Last Revised 26-07-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1665214
Marketing authorisation holder Bayer HealthCare Pharmaceuticals Inc.
Warnings WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS • Fluoroquinolones, including CIPRO IV®, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together [see Warnings and Precautions (5.1)] including: oTendinitis and tendon rupture [see Warnings and Precautions (5.2)] oPeripheral neuropathy [see Warnings and Precautions (5.3)] oCentral 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 IV, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid CIPRO IV 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 (5.1–5.15)], reserve CIPRO for use in patients who have no alternative treatment options for the following indications: oAcute exacerbation of chronic bronchitis [see Indications and Usage (1.9)] oAcute Sinusitis [see Indications and Usage (1.11)] 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 IV®, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together (5.1), including: o Tendinitis and tendon rupture (5.2) o Peripheral neuropathy (5.3) o 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 IV, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid CIPRO IV in patients with known history of myasthenia gravis. (5.5) • Because fluoroquinolones, including CIPRO, have been associated with serious adverse reactions (5.1-5.15), reserve CIPRO for use in patients who have no alternative treatment options for the following indications: o Acute exacerbation of chronic bronchitis (1.9) o Acute sinusitis (1.11)