ciprofloxacin

Warnings and Precautions Hypersensitivity Reactions ( 5.7 ) 09/2024

1 INDICATIONS AND USAGE Ciprofloxacin Injection 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 ) Acute Exacerbation of Chronic Bronchitis Urinary Tract Infections ( 1.10 ) Urinary Tract Infections (UTI) Complicated UTI and Pyelonephritis in Pediatric Patients Acute Sinusitis ( 1.11 ) Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ciprofloxacin Injection and other antibacterial drugs, Ciprofloxacin Injection 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 Ciprofloxacin Injection (in 5% Dextrose Injection) 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 Ciprofloxacin Injection 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 Ciprofloxacin Injection 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 Ciprofloxacin Injection is indicated in adult patients for treatment of nosocomial pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae. 1.5 Empirical Therapy for Febrile Neutropenic Patients Ciprofloxacin Injection 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) Ciprofloxacin Injection 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 Ciprofloxacin Injection 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 Ciprofloxacin Injection is indicated in adult patients for treatment of chronic bacterial prostatitis caused by Escherichia coli or Proteus mirabilis . 1.9 Lower Respiratory Tract Infections Ciprofloxacin Injection is indicated in adult patients for treatmen …

2 DOSAGE AND ADMINISTRATION Ciprofloxacin injection 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 to 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 to 14 days Nosocomial Pneumonia 400 mg every 8 hours 10 to 14 days Empirical Therapy In Febrile Neutropenic Patients 400 mg and Piperacillin 50 mg/kg every 8 hours every 4 hours 7 to 14 days 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 to 14 days Urinary Tract 200 to 400 mg every 8 to 12 hours 7 to 14 days Acute Sinusitis 400 mg every 12 hours 10 days Adults with creatinine clearance 5 to 29 mL/min 250 to 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 to 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 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. Table 1: Adult Dosage Guidelines 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. Infection 1 Dose Frequency Usual Duration Skin and Skin Structure 400 mg every 8 to 12 hours 7 to 14 days Bone and Joint 400 mg every 8 to 12 hours 4 to 8 weeks Complicated Intra-Abdominal 2 400 mg every 12 hours 7 to 14 days Nosocomial Pneumonia 400 mg every 8 hours 10 to 14 days Empirical Therapy In Febrile Neutropenic Patients Ciprofloxacin 400 mg and Piperacillin 50 mg/kg every 8 hours every 4 hours 7 to 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 to 14 days Urinary Tract Infections 200 mg to 400 mg every 8 to 12 hours 7 to 14 days Acute Sinusitis 400 mg every 12 hours 10 days Conversion of Intravenous to Oral Dosing in Adults Patients whose therapy is started with ciprofloxacin injection may be switched to ciprofloxacin 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 Ciprofloxacin Oral Dosage Equivalent Ciprofloxacin Injection 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 1. The total duration of therapy for cUTI and pyelonephritis in the clinical trial was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days). 2. Begin drug administration as soon as possible after suspected or confirmed exposure. 3. Begin drug administration as soon as possible after suspected or confirmed exposure to Y. pestis . Infection Dose (mg/kg) Frequency Total Duration Complicated Urinary Tract or Pyelonephritis (patients from 1 to 17 years of age) 1 6 …

3 DOSAGE FORMS AND STRENGTHS Ciprofloxacin Injection, USP (in 5% Dextrose) is a sterile, ready-for-use solution for intravenous infusion, available as: 200 mg per 100 mL (in 5% Dextrose) in Flexible Containers 400 mg per 200 mL (in 5% Dextrose) in Flexible Containers Ciprofloxacin Injection (in 5% Dextrose): 200 mg per 100 mL and 400 mg per 200 mL ( 3 )

4 CONTRAINDICATIONS Known hypersensitivity to ciprofloxacin injection 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 )] .

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, central nervous system disturbance, local intravenous site reactions eosinophilia, headache, restlessness, and rash. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals at 1-866-625-1618 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 ciprofloxacin, 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 ciprofloxacin: 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 Hypoglycem …

7 DRUG INTERACTIONS 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. Table 8: Drugs That are Affected by and Affecting Ciprofloxacin Drugs That are Affected by Ciprofloxacin Drug(s) Recommendation Comments Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin 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 ciprofloxacin 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 Ciprofloxacin 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 ciprofloxacin 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 ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin 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 ciprofloxacin 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 ciprofloxacin 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 ciprofloxacin 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 ciprofloxacin [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 ciprofloxacin 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 wi …

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. See full prescribing information for pediatric patients ( 8.4 ) and use in geriatric ( 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 to 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 to 17) were not associated with adverse developmental outcomes, including embryofetal toxicity o …

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

11 DESCRIPTION Ciprofloxacin Injection, USP (in 5% Dextrose Injection) is a synthetic antimicrobial agent for intravenous (IV) administration. Ciprofloxacin, a fluoroquinolone, 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 chemical structure is: Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. Ciprofloxacin Injection, USP solution is a sterile 0.2% ready-for-use infusion solution in 5% Dextrose Injection. The formula contains lactic acid 0.644 mg per mL as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for the 0.2% ready-for-use infusion solutions is 3.5 to 4.6. The plastic container is not made with natural rubber latex and is fabricated from a specially formulated polyvinyl chloride. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, for example, Cyclohexanone and Chlorobenzene, up to 115 and 0.09 parts per million, respectively. The suitability of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. The glucose content for the 100 mL bag is 5 g and 10 g for the 200 mL flexible container. Chemical Structure

10 OVERDOSAGE In the event of acute overdosage, reversible renal toxicity has been reported in some cases. Observe the patient carefully and give supportive treatment, including monitoring of renal function, urinary pH and acidify, if required, to prevent crystalluria. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (less than 10%) is removed from the body after hemodialysis or peritoneal dialysis. In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at intravenous doses of ciprofloxacin between 125 mg/kg and 300 mg/kg.

16 HOW SUPPLIED/STORAGE AND HANDLING Ciprofloxacin Injection, USP (in 5% Dextrose Injection) is available in 200 mg and 400 mg strengths supplied in flexible containers as follows: Ciprofloxacin Injection, USP in NDC 5% Dextrose (2 mg per mL) Package Factor 25021-192-82 200 mg per 100 mL single-dose 24 bags per carton flexible container bag 25021-192-87 400 mg per 200 mL single-dose 24 bags per carton flexible container bag Ciprofloxacin Injection, USP (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution. Storage Conditions Store between 5° and 25°C (41° and 77°F). Protect from light. Avoid excessive heat. Protect from freezing. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free, PVC-free, DEHP-free. The container and container closure are not made with natural rubber latex.