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 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 .

Ciprofloxacin Injection is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumonia .

Ciprofloxacin Injection is indicated for the treatment of acute exacerbations of chronic bronchitis (AECB) caused by Moraxella catarrhalis.

Because fluoroquinolones, including Ciprofloxacin Injection, have been associated with serious adverse reactions [see Warnings and Precautions ( 5.1 to 5.16 )] and for some patients AECB is self-limiting, reserve Ciprofloxacin Injection for treatment of AECB in patients who have no alternative treatment options.

1.10 Urinary Tract Infections Urinary Tract Infection in Adults Ciprofloxacin Injection 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 .

Complicated Urinary Tract Infections and Pyelonephritis in Pediatric Patients Ciprofloxacin Injection 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, Ciprofloxacin Injection 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.

Ciprofloxacin Injection, 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 )].

1.11 Acute Sinusitis Ciprofloxacin Injection is indicated in adult patients for treatment of acute sinusitis caused by Haemophilus influenzae , Streptococcus pneumoniae , or Moraxella catarrhalis .

Because fluoroquinolones, including Ciprofloxacin Injection, have been associated with serious adverse reactions [see Warnings and Precautions ( 5.1 to 5.16 )] and for some patients acute sinusitis is self-limiting, reserve Ciprofloxacin 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 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 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 Ciprofloxacin Injection 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.

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 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 ciprofloxacin (Intravenous and Intravenous/Oral sequential) with intravenous beta-lactam control antibiotics, the CNS adverse reaction profile of ciprofloxacin 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 Reactions 1 as Assessed by the IPSC 1.

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) 2.

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.

Ciprofloxacin Comparator All Patients (within 6 weeks) 31/335 (9.3%) 21/349 (6%) 95% Confidence Interval 2 (-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 2 (-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 to 17 years).

Sixty-seven patients received ciprofloxacin IV 10 mg/kg/dose every 8 hours for one week followed by ciprofloxacin tablets 20 mg/kg/dose every 12 hours to complete 10 to 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 to 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 to 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 ciprofloxacin 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 ciprofloxacin.

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 Acute myocardial ischemia with or without myocardial infarction occurring as part of an allergic reaction 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 generalized 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 ciprofloxacin 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.