1.1 Skin and Skin Structure Infections

Ciprofloxacin tablets, USP 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, USP 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, USP 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, USP are indicated in adult patients for treatment of infectious diarrhea caused by Escherichia coli (enterotoxigenic isolates), Campylobacter jejuni, Shigella boydii1, Shigella dysenteriae, Shigella flexneri or Shigella sonnei 1 when antibacterial therapy is indicated.

1

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, USP 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, USP are indicated in adult patients for treatment of uncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae [see Warnings and Precautions (5.16)].

1.7 Inhalational Anthrax (Post-Exposure)

Ciprofloxacin tablets, USP 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, USP 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, USP 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, USP 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 is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.

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

Because fluoroquinolones, including ciprofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions (5.1–5.15)] and for some patients AECB is self-limiting, reserve ciprofloxacin for treatment of AECB in patients who have no alternative treatment options.

1.11 Urinary Tract Infections

1.12 Acute Sinusitis

Ciprofloxacin tablets, USP are indicated in adult patients for treatment of acute sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis.

Because fluoroquinolones, including ciprofloxacin, 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 ciprofloxacin 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 and other antibacterial drugs, ciprofloxacin 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 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.

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.

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. Ciprofloxacin tablets should be administered as described in Table 3.

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.

When only the serum creatinine concentration is known, the following formulas may be used to estimate creatinine clearance:

The serum creatinine should represent a steady state of renal function.

In patients with severe infections and severe renal impairment, a unit dose of 750 mg may be administered at the intervals noted above. Patients should be carefully monitored.

Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of cUTI and pyelonephritis. No information is available on dosing adjustments necessary for pediatric patients with moderate to severe renal insufficiency (that is, creatinine clearance of < 50 mL/min/1.73m2).

2.4 Important Administration Instructions

3.1 Tablets

• 250 mg, round, convex, white tablets debossed and engraved "T92" on one side and plain on the other side
• 500 mg, oblong, capsule shaped convex, white tablets debossed and engraved "T95" on one side and plain on the other side
• 750 mg, oblong, capsule shaped convex, white tablets debossed and engraved "T97" on one side and plain on the other side

4.1 Hypersensitivity

Ciprofloxacin tablets are 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)].

5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects

Fluoroquinolones, including ciprofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting ciprofloxacin. Patients of any age or without pre-existing risk factors have experienced these adverse reactions [see Warnings and Precautions (5.2, 5.3, 5.4)].

Discontinue ciprofloxacin immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including ciprofloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

5.2 Tendinitis and Tendon Rupture

Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of tendinitis and tendon rupture in all ages [see Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. This adverse reaction most frequently involves the Achilles tendon, and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis or tendon rupture can occur, within hours or days of starting ciprofloxacin, or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally.

The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Discontinue ciprofloxacin immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including ciprofloxacin, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture [see Adverse Reactions (6.2)].

5.3 Peripheral Neuropathy

Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including ciprofloxacin. Symptoms may occur soon after initiation of ciprofloxacin and may be irreversible in some patients [see Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2)].

Discontinue ciprofloxacin immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in sensations including light touch, pain, temperature, position sense and vibratory sensation, and/or motor strength in order to minimize the development of an irreversible condition. Avoid fluoroquinolones, including ciprofloxacin, in patients who have previously experienced peripheral neuropathy [see Adverse Reactions (6.1, 6.2)].

5.4 Central Nervous System Effects

Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of central nervous system (CNS) effects, including convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis. Ciprofloxacin may also cause central nervous system (CNS) events including: nervousness, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, depression, and psychotic reactions have progressed to suicidal ideations/thoughts and self-injurious behavior such as attempted or completed suicide. These reactions may occur following the first dose. Advise patients receiving ciprofloxacin to inform their healthcare provider immediately if these reactions occur, discontinue the drug, and institute appropriate care. Ciprofloxacin, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold. As with all fluoroquinolones, use ciprofloxacin with caution in epileptic patients and patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (for example, severe cerebral arteriosclerosis, previous history of convulsion, reduced cerebral blood flow, altered brain structure, or stroke), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (for example, certain drug therapy, renal dysfunction). Use ciprofloxacin when the benefits of treatment exceed the risks, since these patients are endangered because of possible undesirable CNS side effects. Cases of status epilepticus have been reported. If seizures occur, discontinue ciprofloxacin [see Adverse Reactions (6.1) and Drug Interactions (7)].

5.5 Exacerbation of Myasthenia Gravis

Fluoroquinolones, including ciprofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Avoid ciprofloxacin in patients with known history of myasthenia gravis [see Adverse Reactions (6.2)].

5.6 Other Serious and Sometimes Fatal Adverse Reactions

Other serious and sometimes fatal adverse reactions, some due to hypersensitivity, and some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including ciprofloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:

• Fever, rash, or severe dermatologic reactions (for example, toxic epidermal necrolysis, Stevens-Johnson syndrome);
• Vasculitis; arthralgia; myalgia; serum sickness;
• Allergic pneumonitis;
• Interstitial nephritis; acute renal insufficiency or failure;
• Hepatitis; jaundice; acute hepatic necrosis or failure;
• Anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.

Discontinue ciprofloxacin immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted [see Adverse Reactions (6.1, 6.2)].

5.7 Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving fluoroquinolone therapy, including ciprofloxacin. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, including intubation, as indicated [see Adverse Reactions (6.1)].

5.8 Hepatotoxicity

Cases of severe hepatotoxicity, including hepatic necrosis, life-threatening hepatic failure, and fatal events, have been reported with ciprofloxacin. Acute liver injury is rapid in onset (range 1 to 39 days), and is often associated with hypersensitivity. The pattern of injury can be hepatocellular, cholestatic, or mixed. Most patients with fatal outcomes were older than 55 years old. In the event of any signs and symptoms of hepatitis (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), discontinue treatment immediately.

There can be a temporary increase in transaminases, alkaline phosphatase, or cholestatic jaundice, especially in patients with previous liver damage, who are treated with ciprofloxacin [see Adverse Reactions (6.2, 6.3)].

5.9 Serious Adverse Reactions with Concomitant Theophylline

Serious and fatal reactions have been reported in patients receiving concurrent administration of ciprofloxacin and theophylline. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Instances of nausea, vomiting, tremor, irritability, or palpitation have also occurred.

Although similar serious adverse reactions have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Drug Interactions (7)].

5.10 Clostridium difficile-Associated Diarrhea

Clostridium difficile (C. difficile)-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ciprofloxacin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated [see Adverse Reactions (6.1)].

5.11 Prolongation of the QT Interval

Some fluoroquinolones, including ciprofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and cases of arrhythmia. Cases of torsade de pointes have been reported during postmarketing surveillance in patients receiving fluoroquinolones, including ciprofloxacin.

Avoid ciprofloxacin in patients with known prolongation of the QT interval, risk factors for QT prolongation or torsade de pointes (for example, congenital long QT syndrome, uncorrected electrolyte imbalance, such as hypokalemia or hypomagnesemia and cardiac disease, such as heart failure, myocardial infarction, or bradycardia), and patients receiving Class IA antiarrhythmic agents (quinidine, procainamide), or Class III antiarrhythmic agents (amiodarone, sotalol), tricyclic antidepressants, macrolides, and antipsychotics. Elderly patients may also be more susceptible to drug-associated effects on the QT interval [see Adverse Reactions (6.2), Use in Specific Populations (8.5)].

5.12 Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals

Ciprofloxacin is indicated in pediatric patients (less than 18 years of age) only for cUTI, prevention of inhalational anthrax (post exposure), and plague [see Indications and Usage (1.7, 1.8, 1.11)]. An increased incidence of adverse reactions compared to controls, including reactions related to joints and/or surrounding tissues, has been observed [see Adverse Reactions (6.1)].

In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs. Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species [see Use in Specific Populations (8.4) and Nonclinical Toxicology (13.2)].

5.13 Photosensitivity/Phototoxicity

Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (for example, burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones including ciprofloxacin after sun or UV light exposure. Therefore, avoid excessive exposure to these sources of light. Discontinue ciprofloxacin if phototoxicity occurs [see Adverse Reactions (6.1)].

5.14 Development of Drug Resistant Bacteria

Prescribing ciprofloxacin tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

5.15 Potential Risks with Concomitant Use of Drugs Metabolized by Cytochrome P450 1A2 Enzymes

Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Co-administration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (for example, theophylline, methylxanthines, caffeine, tizanidine, ropinirole, clozapine, olanzapine) results in increased plasma concentrations of the co-administered drug and could lead to clinically significant pharmacodynamic adverse reactions of the co-administered drug [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

5.16 Interference with Timely Diagnosis of Syphilis

Ciprofloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high dose for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. Perform a serologic test for syphilis in all patients with gonorrhea at the time of diagnosis. Perform follow-up serologic test for syphilis three months after ciprofloxacin treatment.

5.17 Crystalluria

Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently in the urine of laboratory animals, which is usually alkaline [see Nonclinical Toxicology (13.2)]. Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Avoid alkalinity of the urine in patients receiving ciprofloxacin. Hydrate patients well to prevent the formation of highly concentrated urine [see Dosage and Administration (2.4)].

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.

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 8).

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.

8.1 Pregnancy

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 ciprofloxacin, 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, ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to controls. Quinolones, including ciprofloxacin, cause arthropathy in juvenile animals [see Warnings and Precautions (5.12) and Nonclinical Toxicology (13.2)].

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 ciprofloxacin. 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 ciprofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential adverse reaction and advised to discontinue ciprofloxacin 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 ciprofloxacin 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 ciprofloxacin 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.

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Eight in vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are listed below:

• Salmonella/Microsome Test (Negative)
• E. coli DNA Repair Assay (Negative)
• Mouse Lymphoma Cell Forward Mutation Assay (Positive)
• Chinese Hamster V79 Cell HGPRT Test (Negative)
• Syrian Hamster Embryo Cell Transformation Assay (Negative)
• Saccharomyces cerevisiae Point Mutation Assay (Negative)
• Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
• Rat Hepatocyte DNA Repair Assay (Positive)
• Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative results:
• Rat Hepatocyte DNA Repair Assay
• Micronucleus Test (Mice)
• Dominant Lethal Test (Mice)

Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to ciprofloxacin at daily oral dose levels up to 250 mg/kg and 750 mg/kg to rats and mice, respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon body surface area, respectively).

Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum recommended human dose based upon body surface area), as opposed to 34 weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from 16 weeks to 32 weeks in mice treated concomitantly with UVA and other quinolones.9

In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of these findings to humans is unknown.

Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 0.7-times the highest recommended therapeutic dose based upon body surface area) revealed no evidence of impairment.

13.2 Animal Toxicology and/or Pharmacology

Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see Warnings and Precautions (5.12)]. Damage of weight bearing joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately 1.3-times and 3.5-times the pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks caused articular changes which were still observed by histopathology after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric dose based upon comparative plasma AUCs), no effects on joints were observed. This dose was also not associated with arthrotoxicity after an additional treatment-free period of 5 months. In another study, removal of weight bearing from the joint reduced the lesions but did not totally prevent them.

Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5 mg/kg. (approximately 0.07-times the highest recommended therapeutic dose based upon body surface area). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration (approximately 0.2-times the highest recommended therapeutic dose based upon body surface area).

In dogs, ciprofloxacin at 3 mg/kg and 10 mg/kg by rapid intravenous injection (15 sec.) produces pronounced hypotensive effects. These effects are considered to be related to histamine release, since they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous injection also produces hypotension but the effect in this species is inconsistent and less pronounced.

In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of quinolones.

Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals

14.1 Complicated Urinary Tract Infection and Pyelonephritis–Efficacy in Pediatric Patients

Ciprofloxacin administered intravenously and/or orally was compared to a cephalosporin for treatment of cUTI and pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety.

Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).

The clinical success and bacteriologic eradication rates in the Per Protocol population were similar between ciprofloxacin and the comparator group as shown below.

14.2 Inhalational Anthrax in Adults and Pediatrics

The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving oral and intravenous regimens. Ciprofloxacin pharmacokinetics have been evaluated in various human populations. The mean peak serum concentration achieved at steady-state in human adults receiving 500 mg orally every 12 hours is 2.97 mcg/mL, and 4.56 mcg/mL following 400 mg intravenously every 12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 mcg/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration achieved is 8.3 mcg/mL and trough concentrations range from 0.09 mcg/mL to 0.26 mcg/mL, following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3.6 mcg/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the administration of ciprofloxacin to pediatric patients are limited. Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.1

A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50 (~5.5 × 105 spores (range 5 to 30 LD50) of B. anthracis was conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 mcg/mL. In the animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour post-dose) following oral dosing to steady-state ranged from 0.98 mcg/mL to 1.69 mcg/mL. Mean steady-state trough concentrations at 12 hours post-dose ranged from 0.12 mcg/mL to 0.19 mcg/mL.10 Mortality due to anthrax for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was significantly lower (1/9), compared to the placebo group (9/10) [p= 0.001]. The one ciprofloxacin -treated animal that died of anthrax did so following the 30-day drug administration period.11

More than 9300 persons were recommended to complete a minimum of 60 days of antibacterial prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin was recommended to most of those individuals for all or part of the prophylaxis regimen. Some persons were also given anthrax vaccine or were switched to alternative antibacterial drugs. No one who received ciprofloxacin or other therapies as prophylactic treatment subsequently developed inhalational anthrax. The number of persons who received ciprofloxacin as all or part of their post-exposure prophylaxis regimen is unknown.

14.3 Plague

A placebo-controlled animal study in African green monkeys exposed to an inhaled mean dose of 110 LD50 (range 92 to 127 LD50) of Yersinia pestis (CO92 strain) was conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin for the Y. pestis strain used in this study was 0.015 mcg/mL. Mean peak serum concentrations of ciprofloxacin achieved at the end of a single 60 minute infusion were 3.49 mcg/mL ± 0.55 mcg/mL, 3.91 mcg/mL ± 0.58 mcg/mL and 4.03 mcg/mL ± 1.22 mcg/mL on Day 2, Day 6 and Day 10 of treatment in African green monkeys, respectively All trough concentrations (Day 2, Day 6 and Day 10) were <0.5 mcg /mL. Animals were randomized to receive either a 10-day regimen of intravenous ciprofloxacin 15 mg/kg, or placebo beginning when animals were found to be febrile (a body temperature greater than 1.5ºC over baseline for two hours), or at 76 hours post-challenge, whichever occurred sooner. Mortality in the ciprofloxacin group was significantly lower (1/10) compared to the placebo group (2/2) [difference: -90.0%, 95% exact confidence interval: -99.8% to -5.8%]. The one ciprofloxacin-treated animal that died did not receive the proposed dose of ciprofloxacin due to a failure of the administration catheter. Circulating ciprofloxacin concentration was below 0.5 mcg/mL at all timepoints tested in this animal. It became culture negative on Day 2 of treatment, but had a resurgence of low grade bacteremia on Day 6 after treatment initiation. Terminal blood culture in this animal was negative.12

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Serious Adverse Reactions

Advise patients to stop taking ciprofloxacin tablets if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug.

Inform patients of the following serious adverse reactions that have been associated with ciprofloxacin tablets or other fluoroquinolone use:

• Disabling and potentially irreversible serious adverse reactions that may occur together: Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated with use of ciprofloxacin and may occur together in the same patient. Inform patients to stop taking ciprofloxacin immediately if they experience an adverse reaction and to call their healthcare provider.
• Tendinitis and tendon rupture: Instruct patients to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue ciprofloxacin treatment. Symptoms may be irreversible. The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
• Peripheral Neuropathies: Inform patients that peripheral neuropathies have been associated with ciprofloxacin use, symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, immediately discontinue ciprofloxacin and tell them to contact their physician.
• Central nervous system effects (for example, convulsions, dizziness, lightheadedness, increased intracranial pressure): Inform patients that convulsions have been reported in patients receiving fluoroquinolones, including ciprofloxacin. Instruct patients to notify their physician before taking this drug if they have a history of convulsions. Inform patients that they should know how they react to ciprofloxacin before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Instruct patients to notify their physician if persistent headache with or without blurred vision occurs.
• Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any history of myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties.
• Hypersensitivity Reactions: Inform patients that ciprofloxacin can cause hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.
• Hepatotoxicity: Inform patients that severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients taking ciprofloxacin. Instruct patients to inform their physician if they experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light colored bowel movements or dark colored urine.
• Diarrhea: Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, instruct patients to contact their physician as soon as possible.
• Prolongation of the QT Interval: Instruct patients to inform their physician of any personal or family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia; if they are taking any Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Instruct patients to notify their physician if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness.
• Musculoskeletal Disorders in Pediatric Patients: Instruct parents to inform their child's physician if the child has a history of joint-related problems before taking this drug. Inform parents of pediatric patients to notify their child's physician of any joint-related problems that occur during or following ciprofloxacin therapy [see Warnings and Precautions (5.12) and Use in Specific Populations (8.4)].
• Tizanidine: Instruct patients not to use ciprofloxacin if they are already taking tizanidine. Ciprofloxacin increases the effects of tizanidine (Zanaflex®).
• Theophylline: Inform patients that ciprofloxacin may increase the effects of theophylline. Life-threatening CNS effects and arrhythmias can occur. Advise the patients to immediately seek medical help if they experience seizures, palpitations, or difficulty breathing.
• Caffeine: Inform patients that ciprofloxacin may increase the effects of caffeine. There is a possibility of caffeine accumulation when products containing caffeine are consumed while taking quinolones.
• Photosensitivity/Phototoxicity: Inform patients that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolones. Inform patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, instruct them to wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, instruct patients to contact their physician.

Antibacterial Resistance

Inform patients that antibacterial drugs including ciprofloxacin tablets should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When ciprofloxacin tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ciprofloxacin tablets or other antibacterial drugs in the future.

Administration with Food, Fluids, and Concomitant Medications

Inform patients that ciprofloxacin may be taken with or without food.

Inform patients to drink fluids liberally while taking ciprofloxacin to avoid formation of highly concentrated urine and crystal formation in the urine.

Inform patients that antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine should be taken at least two hours before or six hours after ciprofloxacin administration. Ciprofloxacin should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone since absorption of ciprofloxacin may be significantly reduced; however, ciprofloxacin may be taken with a meal that contains these products.

Drug Interactions Oral Antidiabetic Agents

Inform patients that hypoglycemia has been reported when ciprofloxacin and oral antidiabetic agents were co-administered; if low blood sugar occurs with ciprofloxacin, instruct them to consult their physician and that their antibacterial medicine may need to be changed.

Anthrax and Plague Studies

Inform patients given ciprofloxacin for these conditions that efficacy studies could not be conducted in humans for feasibility reasons. Therefore, approval for these conditions was based on efficacy studies conducted in animals.