1.

Indications and Usage 1.1 Skin and Skin Structure Infections Ciprofloxacin tablets are 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 tablets are 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 tablets are 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 Ciprofloxacin tablets are 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) Ciprofloxacin tablets are 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 Ciprofloxacin tablets are 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) Ciprofloxacin tablets are 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 Ciprofloxacin tablets are 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 Ciprofloxacin tablets are indicated in adult patients for treatment of chronic bacterial prostatitis caused by Escherichia coli or Proteus mirabilis.

1.10 Lower Respiratory Tract Infections Ciprofloxacin tablets are 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 tablets are not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.

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

Because fluoroquinolones, including ciprofloxacin tablets, 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 tablets for treatment of AECB in patients who have no alternative treatment options.

1.11 Urinary Tract Infections Urinary Tract Infections in Adults Ciprofloxacin tablets are 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 Ciprofloxacin tablets are indicated in adult female patients for treatment of acute uncomplicated cystitis caused by Escherichia coli or Staphylococcus saprophyticus.

Because fluoroquinolones, including ciprofloxacin tablets, have been associated with serious adverse reactions [see WARNINGS AND PRECAUTIONS (5.1 to 5.16)] and for some patients acute uncomplicated cystitis is self-limiting, reserve ciprofloxacin tablets for treatment of acute uncomplicated cystitis in patients who have no alternative treatment options.

Complicated Urinary Tract Infection and Pyelonephritis in Pediatric Patients Ciprofloxacin tablets are 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, ciprofloxacin tablets are 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 tablets, 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 Ciprofloxacin tablets are indicated in adult patients for treatment of acute sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis.

Because fluoroquinolones, including ciprofloxacin tablets, 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 tablets 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 ciprofloxacin tablets and other antibacterial drugs, ciprofloxacin tablets 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 tablets 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)] 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%).

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 ciprofloxacin tablets [500 mg two times daily (BID)] to cefuroxime axetil (250 mg to 500 mg BID) and to clarithromycin (500 mg BID) in patients with respiratory tract infections, ciprofloxacin 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 Reactions1 as Assessed by the IPSC Ciprofloxacin Comparator All Patients (within 6 weeks) 31/335 (9.3%) 21/349 (6%) 95% Confidence Interval2 (-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 Interval1 (-0.6%, + 9.1%) 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.

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 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 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 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 ciprofloxacin 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.