WARNINGS

Fluoroquinolones, including ciprofloxacin, are associated with an increased risk of tendinitis and tendon rupture in all ages.

This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair.

Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported.

The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.

Factors, in addition to age and corticosteroid use, 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.

Inflammation and tendon rupture can occur, sometimes bilaterally, even within the first 48 hours, during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported.

Ciprofloxacin should be used with caution in patients with a history of tendon disorders.

Ciprofloxacin should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon.

Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug.

Fluoroquinolones, including ciprofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis.

Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis.

Avoid ciprofloxacin in patients with known history of myasthenia gravis.

(See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS: Post-Marketing Adverse Event Reports.

) THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED.

(See PRECAUTIONS: Pregnancy , and Nursing Mothers subsections.) Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy.

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.

Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated.

Other Serious and Sometimes Fatal Reactions Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely 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.

The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS ).

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 1-39 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), treatment should be discontinued immediately (see ADVERSE REACTIONS ).

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 ).

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.

Although similar serious adverse effects 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, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.

Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis have been reported in patients receiving fluoroquinolones, including ciprofloxacin.

Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, 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.

If these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued, patients should be advised to inform their healthcare provider immediately and appropriate measures instituted.

Ciprofloxacin, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold.

As with all fluoroquinolones, ciprofloxacin should be used 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).

Ciprofloxacin should only be used where 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, ciprofloxacin should be discontinued.

(See PRECAUTIONS: General , Information for Patients , Drug Interactions and ADVERSE REACTIONS .

) Clostridium 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 antibiotic 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 antibiotic use not directed against C.

difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C.

difficile , and surgical evaluation should be instituted as clinically indicated.

Rare 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 quinolones, including ciprofloxacin.

Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition.

Patients treated with ciprofloxacin should be advised to inform their healthcare provider prior to continuing treatment if symptoms of neuropathy develop.

Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for infections listed in the INDICATIONS AND USAGE section.

An increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues, has been observed.

(See ADVERSE REACTIONS .

) 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 ANIMAL PHARMACOLOGY .

) Some fluoroquinolones, including ciprofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia.

Rare cases of torsade de pointes have been spontaneously reported during postmarketing surveillance in patients receiving fluoroquinolones, including ciprofloxacin.

Ciprofloxacin should be avoided 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 PRECAUTIONS , Drug Interactions and Geriatric Use ).

Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway.

Coadministration of ciprofloxacin and other drugs primarily metabolized by the CYP1A2 (for example, theophylline, methylxanthines, caffeine, tizanidine, ropinirole, clozapine, olanzapine) results in increased plasma concentrations of the coadministered drug and could lead to clinically significant pharmacodynamic side effects of the coadministered drug (See PRECAUTIONS , Drug Interactions ) .

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.

All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis.

Patients treated with ciprofloxacin should have a follow-up serologic test for syphilis after three months.