Ciloxan Ophthalmic Solution (Ciprofloxacin)

Ciprofloxacin generally is well tolerated, and adverse effects of the drug are similar to those reported with other quinolone anti-infectives (e.g., norfloxacin, ofloxacin). Adverse effects have been reported in 5-14% of patients receiving ciprofloxacin and have been severe enough to require discontinuance in 2-3.5% of patients. The most frequent adverse effects involve the gastrointestinal (GI) tract or central nervous system (CNS); those requiring discontinuance also principally involve these organ systems.

Limited data currently are available regarding adverse effects of ciprofloxacin in individuals receiving anthrax postexposure prophylaxis regimens. In response to a questionnaire given to 490 such individuals in Florida on approximately day 7 or 14 of anti-infective prophylaxis, 19% sought medical attention for any anti-infective-related adverse effect or reported one or more of the following: pruritus, breathing problems, or swelling of the face, neck, or throat.

Although the percentage of patients in this subgroup who received ciprofloxacin versus other anti-infectives was not reported, 86% of all patients (i.e., those who did or did not answer the questionnaire) received ciprofloxacin and 80% continued to receive prophylaxis beyond 14 days. In an epidemiologic evaluation in 8424 postal workers who were offered 60 days of prophylaxis for anthrax and given a questionnaire in New Jersey, New York City, and the District of Columbia on days 7-10 of anti-infective prophylaxis, 5819 completed or were administered the questionnaire, of whom 3863 had initiated prophylaxis (3428 with ciprofloxacin).

Of the ciprofloxacin-treated individuals, 19% reported severe nausea, vomiting, diarrhea, and/or abdominal pain; 14% reported fainting, light-headedness, and/or dizziness; 7% reported heartburn or acid reflux; 6% reported rash, urticaria, and/or pruritus; and 8% discontinued therapy with the drug (3% for adverse effects, 1% for fear of developing an adverse effect, and 1% because they were confused about the need). Only 2% of those on any anti-infective sought medical attention for possible manifestations of anaphylaxis, none of whom required hospitalization.

GI Effects

Nausea, diarrhea, vomiting, and abdominal pain/discomfort have been reported in 2-10% of patients receiving ciprofloxacin. These effects generally are mild and transient and occur most frequently in geriatric patients and/or when high dosage is used. Anorexia, dyspepsia, flatulence, GI erosion and bleeding, dysphagia, bad taste, intestinal perforation, painful oral mucosa, and oral candidiasis have been reported in less than 1% of patients receiving the drug.

Effects on Fecal Flora

Ciprofloxacin exerts a selective effect on normal bowel flora. Although fluoroquinolones, including ciprofloxacin, are relatively inactive against Clostridium difficile in vitro, C. difficile-associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis) has been reported in 1% or less of patients receiving these drugs. In addition, C. difficile-associated diarrhea and colitis produced by other anti-infectives (e.g., ceftriaxone) has resolved in several patients following discontinuance of these other anti-infectives and initiation of ciprofloxacin.

The reason for this relative lack of association between ciprofloxacin and colitis has not been elucidated but may be related to achievement of fecal concentrations of the drug that substantially exceed the minimum inhibitory concentration (MIC) of C. difficile and/or the selective effect of the drug on normal GI flora. It should be noted, however, that initiation of ciprofloxacin in these patients may not have been responsible for resolution of the colitis but may have only passively allowed such resolution to occur following discontinuance of the offending anti-infective.

The possibility that diarrhea developing in any ciprofloxacin-treated patient may be secondary to C. difficile-associated colitis should be considered. C. difficile-associated diarrhea and colitis can range in severity from mild to life-threatening. Mild cases of colitis may respond to discontinuance of ciprofloxacin alone, but diagnosis and management of moderate to severe cases should include appropriate bacteriologic studies and treatment with fluid, electrolyte, and protein supplementation as indicated. If colitis is moderate to severe or is not relieved by discontinuance of ciprofloxacin, appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) should be administered. Isolation of the patient may be advisable. Other causes of colitis also should be considered.

Total bacterial counts of normal anaerobic fecal flora generally are unaffected during or following ciprofloxacin therapy. However, total bacterial counts of normal aerobic fecal flora are decreased within 2-5 days following initiation of therapy with the drug and generally return to pretreatment levels within 1-4 weeks after the drug is discontinued. Ciprofloxacin therapy generally markedly reduces or completely eradicates normal fecal Enterobacteriaceae; the drug reduces fecal aerobic gram-positive bacteria to a lesser extent. Ciprofloxacin therapy does not appear to affect total bacterial counts of normal salivary flora, including streptococci, staphylococci, and anaerobic bacteria.

Nervous System Effects

Headache and restlessness have been reported in about 1-2% of patients receiving ciprofloxacin. Dizziness, light-headedness, insomnia, nightmares, hallucinations, manic reaction, toxic psychosis, irritability, tremor, ataxia, seizures, lethargy, drowsiness, vertigo, anxiety, nervousness, confusion, weakness, malaise, phobia, depersonalization, depression, suicidal thoughts or acts, paresthesia, and increased intracranial pressure have been reported in less than 1% of patients. Some of these reactions may occur following the first dose. If seizures or other severe CNS reactions occur during ciprofloxacin therapy, the drug should be discontinued and appropriate measures instituted. (See Precautions and Contraindications.)

Some adverse CNS effects may be related to the fact that ciprofloxacin, like other fluoroquinolones, is a gamma-aminobutyric acid (GABA) inhibitor. In addition, it has been suggested that some CNS stimulant effects reported in patients receiving the drug may have resulted from ciprofloxacin-induced alterations in caffeine pharmacokinetics. (See Drug Interactions: Xanthine Derivatives.)

Dermatologic and Sensitivity Reactions

Mild, transient rash has been reported in 1-4% of patients, and eosinophilia, pruritus, urticaria, cutaneous candidiasis, hyperpigmentation, erythema nodosum, angioedema, and edema of the face, neck, lips, conjunctivae, or hands have been reported in less than 1%. Flushing, fever, chills, and photosensitivity also have been reported in less than 1% of patients receiving the drug. Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic necrosis (including fatal cases) have been reported rarely in patients receiving ciprofloxacin and other drugs concomitantly.

Toxic epidermal necrolysis has been reported rarely in patients receiving ciprofloxacin. Therefore, the manufacturer recommends that ciprofloxacin be discontinued at the first sign of rash or any other sign of hypersensitivity. In addition, serious and occasionally fatal hypersensitivity (anaphylactic and anaphylactoid) reactions have occurred, some with the initial dose, in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, paresthesia, pharyngeal or facial edema, dyspnea, urticaria, and/or pruritus; a history of hypersensitivity was present in only a few cases.

Limited evidence suggests that the frequency of severe hypersensitivity reactions may be higher in patients with acquired immunodeficiency syndrome (AIDS) than in other patients; the exact mechanism(s) of this increased risk has not been determined. If a severe hypersensitivity reaction occurs during ciprofloxacin therapy, the drug should be discontinued and the patient given appropriate therapy (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen, maintenance of blood pressure) as indicated.

Genitourinary Effects

Increased serum creatinine and blood urea nitrogen (BUN) concentrations have occurred in about 1% of patients receiving ciprofloxacin. Interstitial nephritis, nephritis, renal failure, dysuria, polyuria, urinary retention, albuminuria, urethral bleeding, vaginitis, and acidosis have been reported in less than 1% of patients. In at least one patient, acute renal failure associated with interstitial nephritis occurred within about 2 weeks after initiating ciprofloxacin and appeared to be a hypersensitivity reaction; renal biopsy showed marked interstitial edema with extensive lymphocytic infiltrations and occasional eosinophils. Crystalluria, cylindruria, and hematuria have been reported rarely.

Crystalluria generally occurs in patients with alkaline urine who receive high dosage and has not been associated with changes in renal function. The risk of crystal formation and crystalluria in patients receiving usual recommended dosages (250-750 mg) is low if urine pH is within the usual range (i.e., less than 6.8). Patients receiving the drug, particularly at relatively high dosages, should maintain adequate fluid intake; in addition, alkaline urine should be avoided. (See Cautions: Precautions and Contraindications.)

Musculoskeletal Effects

Arthralgia, joint or back pain, joint inflammation, joint stiffness, achiness, vasculitis, neck or chest pain, and flare-up of gout have been reported in less than 1% of patients. Achilles and other tendon ruptures that required surgical repair or resulted in prolonged disability have been reported in patients receiving fluoroquinolones, including ciprofloxacin.

Ciprofloxacin should be discontinued in any patient who experiences pain, inflammation, or rupture of a tendon. Ciprofloxacin, like most other fluoroquinolones, causes arthropathy in immature animals of various species. (See Cautions: Pediatric Precautions.) Ciprofloxacin has caused damage to weight-bearing joints in juvenile dogs and rats. In young beagles, ciprofloxacin 100 mg/kg for 4 weeks caused degenerative articular changes of the knee joint; at 30 mg/kg daily, effects were minimal, although some damage to weight-bearing joints was observed even at the lower dosage. Removal of weight bearing from the joint reduced the lesions but did not totally prevent them.

Morphologic changes observed in animals with quinolone-induced arthropathies include erosions in joint cartilage accompanied by noninflammatory, cell-free effusion of the joint space; the cartilage is incapable of regeneration and may serve as a site for the development of arthropathy deformans. In addition, breakdown products of cartilage may irritate the synovia. The relationship of these effects in animals and the rheumatologic symptoms associated with use of ciprofloxacin in humans is unknown.

Hepatic Effects

Increased serum concentrations of aspartate aminotransferase (AST; formerly SGOT) and alanine aminotransferase (ALT; formerly SGPT) have been reported in about 2% of patients. Increased serum concentrations of alkaline phosphatase, lactate dehydrogenase (LDH), bilirubin, and gamma-glutamyltransferase (GGT; also called GGTP) have been reported in less than 1%. Fulminant and occasionally fatal hepatic failure has occurred rarely in patients receiving ciprofloxacin.

Hematologic Effects

Eosinophilia, leukopenia, neutropenia, increased or decreased platelet count, and pancytopenia have been reported in less than 1% of patients. Anemia, decreased hemoglobin, increased monocytes, leukocytosis, and bleeding diathesis have been reported in less than 1%. Transient acquired von Willebrand disease has been reported rarely; factor VIII concentration returned to normal values several months (i.e., 5-6 months) following discontinuance of the drug.

Cardiovascular Effects

Palpitation, atrial flutter, ventricular ectopy, syncope, hypertension, angina pectoris, chest pain, myocardial infarction, cardiopulmonary arrest, and cerebral thrombosis have been reported in less than 1% of patients.

Local Effects

Local adverse effects have been reported at the site of infusion following IV administration of ciprofloxacin. These reactions generally resolve rapidly after completion of the infusion and have been reported most frequently when IV infusions were given over 30 minutes or less. The manufacturer states that adverse local reactions do not contraindicate subsequent IV administration unless the reactions recur or worsen.

Other Adverse Effects

Epistaxis, laryngeal or pulmonary edema, hiccups, hemoptysis, dyspnea, bronchospasm, and pulmonary embolism have been reported in less than 1% of patients. Blurred vision, disturbed vision (e.g., change in color perception, overbrightness of lights), decreased visual acuity, diplopia, and eye pain have been reported in less than 1% of patients receiving ciprofloxacin. Tinnitus, anosmia, increased serum amylase, decreased blood glucose, and increased serum uric acid concentrations have been reported rarely (i.e., in less than 0.1% of patients).

Precautions and Contraindications

Crystalluria has been reported rarely. Although crystalluria is not expected to occur under usual conditions with usual recommended dosages, patients should be instructed to drink sufficient quantities of fluids to ensure proper hydration and adequate urinary output during ciprofloxacin therapy. Measures also should be taken to avoid alkaline urine, and the recommended dosage should not be exceeded.

Because ciprofloxacin may cause CNS stimulation that potentially could result in tremor, restlessness, light-headedness, mental confusion, toxic psychosis, and/or seizures, the drug should be used with caution in patients with known or suspected CNS disorders (e.g., severe cerebral arteriosclerosis, seizure disorders) that predispose to seizures or lower the seizure threshold, and in the presence of other factors (e.g., certain drug therapies, renal dysfunction) that predispose to seizures or lower the seizure threshold. Patients should be advised that ciprofloxacin may cause dizziness or light-headedness, and their individual susceptibility should be determined before operating a motor vehicle or machinery or engaging in activities requiring mental alertness and coordination.

Patients receiving a theophylline derivative or caffeine concomitantly also may be at increased risk of these CNS effects. Serious and fatal reactions, including cardiac arrest, seizures, status epilepticus, and respiratory failure, have been reported during concurrent theophylline and ciprofloxacin therapy. (See Drug Interactions: Xanthine Derivatives.) Patients should be advised to discontinue the drug and inform their physician if they experience pain, inflammation, or rupture of a tendon and to rest and refrain from exercise.

As with other anti-infectives, ciprofloxacin may result in overgrowth of nonsusceptible organisms, especially enterococci or Candida. Resistant strains of some organisms (e.g., Pseudomonas aeruginosa, staphylococci) have developed during ciprofloxacin therapy. Careful monitoring of the patient and periodic in vitro susceptibility tests are essential. If superinfection occurs, appropriate therapy should be instituted. Doses and/or frequency of IV ciprofloxacin, conventional tablets, or oral suspension should be decreased in patients with severe renal impairment since serum concentrations are higher and prolonged compared with patients with normal renal function.

The manufacturer recommends that organ system function, including renal, hepatic, and hematopoietic, be monitored periodically during prolonged ciprofloxacin therapy. Patients should be advised to avoid excessive exposure to sunlight or artificial ultraviolet light and to discontinue therapy if phototoxicity occurs. Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has been reported during exposure to direct sunlight in patients receiving some fluoroquinolones (e.g., lomefloxacin, ofloxacin, sparfloxacin).

Ciprofloxacin can cause serious, potentially fatal hypersensitivity reactions, occasionally following the initial dose. Patients should be advised of this possibility and instructed to discontinue the drug and contact their physician at the first sign of rash or any other sign of hypersensitivity. Ciprofloxacin is contraindicated in patients with a history of hypersensitivity to the drug or to other quinolones.

Pediatric Precautions

Anthrax

Ciprofloxacin may be used in children for inhalational anthrax (postexposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis spores, and the Centers for Disease Control and Prevention (CDC) and other experts (US Working Group on Civilian Biodefense) recommend that initial treatment of inhalational or systemic (including GI and oropharyngeal) anthrax consist of either IV ciprofloxacin or doxycycline plus 1 or 2 additional anti-infectives. Because of potential adverse effects from prolonged use of ciprofloxacin in infants and children, amoxicillin is an option for completion of the remaining 60 days of therapy when susceptibility to penicillin is known; amoxicillin is not recommended for initial treatment. Amoxicillin also can be considered as an alternative to ciprofloxacin for postexposure prophylaxis when there are concerns about prolonged quinolone therapy in children.

Other Infections

Because ciprofloxacin causes arthropathy in immature animals, the manufacturer states that safety and efficacy for other indications in children and adolescents younger than 18 years of age have not been established. Some clinicians suggest quinolones may be used cautiously in adolescents if skeletal growth is complete and that potential benefits may outweigh possible risks in certain children 9-18 years of age with serious infections (e.g., cystic fibrosis, typhoid fever) when the causative organism is resistant to other available anti-infectives.

The American Academy of Pediatrics (AAP) states that use of fluoroquinolones (e.g., ciprofloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, sparfloxacin) in children younger than 18 years of age may be justified in special circumstances; however, the drugs should be used only after careful assessment of risks and benefits for the individual patient and after these have been explained to parents or caregivers.

Ciprofloxacin has been used in children with cystic fibrosis, but transient arthropathy has occurred occasionally. In at least one 16-year-old, arthropathy was associated with relatively high dosages (750 mg twice daily) for several weeks. Ciprofloxacin also has been used in a limited number of children with typhoid fever resistant to other anti-infectives (e.g., ampicillin, amoxicillin, chloramphenicol, co-trimoxazole). Short-term safety data are available from a randomized, double-blind study in children and adolescents 5-17 years of age with cystic fibrosis who received IV ciprofloxacin for acute pulmonary exacerbations.

Patients received IV ciprofloxacin (10 mg/kg every 8 hours) for 1 week followed by oral ciprofloxacin (20 mg/kg every 12 hours) to complete 10-21 days of therapy, or IV ceftazidime (50 mg/kg every 8 hours) plus IV tobramycin (3 mg/kg every 8 hours) for 10-21 days. Safety was monitored by periodic range-of-motion examinations and gait assessments; patients were followed for an average of 23 days after completion of therapy (range: 0-93 days). Local reactions at the injection site were reported more frequently with ciprofloxacin (24%) than with ceftazidime/tobramycin (8%), but other adverse effects were similar. In the ciprofloxacin group, musculoskeletal adverse effects, decreased range of motion, and arthralgia were reported in 22%, 12%, and 10%, respectively; in the combination group, these effects were 21%, 16%, and 11%.

One pediatric patient developed arthritis of the knee 9 days after a 10-day regimen of ciprofloxacin; clinical symptoms resolved, but magnetic resonance imaging (MRI) showed knee effusion without other abnormalities 8 months after treatment. A causative relationship could not be established, particularly since cystic fibrosis patients may develop arthralgias and/or arthritis as part of the underlying disease process.

Geriatric Precautions

Retrospective analysis of 23 multiple-dose controlled clinical studies evaluating ciprofloxacin in over 3500 patients revealed that 25% were 65 years of age or older and 10% were 75 years of age or older. Although no overall differences in safety or efficacy were observed between geriatric individuals and younger adults, the possibility that some older patients may exhibit increased sensitivity cannot be ruled out. Ciprofloxacin is substantially eliminated by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Although dosage does not need to be modified in individuals older than 65 years of age with normal renal function, the greater frequency of decreased renal function in the elderly should be considered and dosage carefully selected; monitoring renal function may be useful.

Mutagenicity and Carcinogenicity

Ciprofloxacin was not mutagenic in the rat hepatocyte DNA repair assay or dominant lethal or micronucleus tests in mice. Ciprofloxacin was positive for mutagenicity in the mouse lymphoma cell forward mutation assay and rat hepatocyte DNA repair assay; however, the drug was not mutagenic in other in vitro studies, including the Ames microbial (Salmonella) mutagen test with metabolic activation, Escherichia coli DNA repair assay, Chinese hamster V-79 cell HGPRT test, Syrian hamster embryo cell transformation assay, Saccharomyces cerevisiae point mutation assay, and mitotic crossover and gene conversion assays. No evidence of carcinogenic or tumorigenic potential was seen in mice or rats receiving oral ciprofloxacin 700 mg/kg daily or 250 mg/kg daily, respectively, for up to 2 years.

Pregnancy, Fertility and Lactation

There are no adequate and controlled studies to date using ciprofloxacin in pregnant women. Since the drug, like most other fluoroquinolones, causes arthropathy in immature animals, ciprofloxacin should not be used in pregnant women except for the treatment or prevention of inhalational anthrax. (See Inhalational Anthrax: Postexposure Prophylaxis, in Uses.)

Reproduction studies in rats and mice using ciprofloxacin dosages up to 6 times the usual human dosage have not revealed evidence of impaired fertility or harm to the fetus. In rabbits, ciprofloxacin 30 and 100 mg/kg caused adverse GI effects resulting in maternal weight loss and an increased incidence of abortion, but there was no evidence of teratogenicity. IV ciprofloxacin in rabbits up to 20 mg/kg did not result in maternal toxicity, embryotoxicity, or teratogenicity.

Ciprofloxacin distributes into milk. Because of the potential for serious adverse effects in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the woman. However, the AAP considers ciprofloxacin to be usually compatible with breast-feeding since the amount potentially absorbed by nursing infants would be small and no observable change in infants has been reported to date. Because the long-term safety of prolonged exposure (e.g., a 60-day regimen for anthrax) is not known, the CDC recommends that lactating women who are concerned about ciprofloxacin during anthrax prophylaxis consider expressing and discarding breast milk so that breast-feeding can be resumed once prophylaxis is complete.

Ciprofloxacin Hydrochloride: Drug Interactions

Antacids

Antacids containing magnesium, aluminum, or calcium decrease absorption of oral ciprofloxacin, resulting in decreased serum and urine concentrations. Serum ciprofloxacin concentrations generally are decreased by 14-50%, but may be decreased up to 90% in patients receiving an antacid concomitantly; treatment failure may occur as a result of reduced absorption.

The mechanism has not been fully elucidated, but magnesium, aluminum, and other divalent ions may bind to and form insoluble complexes with quinolones in the GI tract. The manufacturer states that ciprofloxacin extended-release tablets, conventional tablets, or oral suspension should be administered at least 2 hours before or 6 hours after antacids containing magnesium or aluminum.

Some clinicians suggest instructing patients not to ingest antacids containing magnesium, aluminum, or calcium concomitantly with, or within 2-4 hours of, a ciprofloxacin dose; however, others state that these antacids should not be used in patients receiving ciprofloxacin and that ciprofloxacin probably should not be used in patients with renal failure who require aluminum hydroxide or aluminum carbonate for intestinal binding of phosphate.

Aminoglycosides

The antibacterial activities of ciprofloxacin and aminoglycosides have been additive or synergistic in vitro against some strains of Enterobacteriaceae and Pseudomonas aeruginosa. However, synergism is unpredictable, and indifference generally occurs when ciprofloxacin is used with amikacin, gentamicin, or tobramycin against P. aeruginosa or Enterobacteriaceae. Indifference also generally occurs when ciprofloxacin is used with tobramycin against Acinetobacter.

Beta-Lactam Antibiotics

An additive or synergistic effect has occurred occasionally in vitro against some strains of P. aeruginosa and Stenotrophomonas maltophilia (formerly Pseudomonas maltophilia) when ciprofloxacin was used with an extended-spectrum penicillin (e.g., mezlocillin, piperacillin). Indifference generally occurs when ciprofloxacin is used with an extended-spectrum penicillin against Enterobacteriaceae. Ciprofloxacin used with imipenem, cefoxitin, or a cephalosporin (e.g., cefotaxime, ceftazidime, ceftizoxime) has been reported to be additive or synergistic against some strains of P. aeruginosa or Enterobacteriaceae; however, these combinations generally are indifferent rather than additive or synergistic. Ciprofloxacin with cefotaxime has shown synergistic activity in vitro against many strains of Bacteroides fragilis; antagonism did not occur.

Didanosine

Concomitant use of oral ciprofloxacin and didanosine administered as chewable/dispersible buffered tablets or pediatric powder for oral solution (admixed with antacid) may decrease absorption of ciprofloxacin, resulting in decreased serum and urine concentrations. The manufacturer states that ciprofloxacin extended-release tablets, conventional tablets, or oral suspension should be administered at least 2 hours before or 6 hours after these didanosine preparations.

Other Anti-infectives

The combination of ciprofloxacin and clindamycin has been synergistic in vitro against many strains of Peptostreptococcus, Lactobacillus, and B. fragilis. Synergism does not occur in vitro when ciprofloxacin is used with vancomycin against Staphylococcus epidermidis, S. aureus (including oxacillin-resistant strains), Corynebacterium, or Listeria monocytogenes. In vitro, the combination of ciprofloxacin and rifampin generally is indifferent against S. aureus; antagonism has been reported rarely.

Probenecid

Probenecid interferes with renal tubular secretion of ciprofloxacin, resulting in a 50% decrease in renal clearance, a 50% increase in systemic ciprofloxacin concentrations, and a prolonged serum half-life. This effect should be considered in patients receiving the drugs concomitantly.

Cimetidine, Ranitidine, and Sucralfate

Sucralfate (presumably because of its aluminum content) decreases GI absorption of ciprofloxacin and may result in a substantial (e.g., 50%) decrease in serum concentrations. Patients should be instructed to take ciprofloxacin extended-release tablets, conventional tablets, or oral suspension at least 2 hours before or 6 hours after sucralfate. Concomitant cimetidine or ranitidine does not appear to alter GI absorption of ciprofloxacin.

Coumarin Anticoagulants

Initiation of oral ciprofloxacin therapy in at least one patient stabilized on warfarin has resulted in prolongation of prothrombin time and hematemesis. Concomitant use of other fluoroquinolones (e.g., norfloxacin) in patients receiving coumarin anticoagulants also has resulted in increased prothrombin times. The mechanism has not been determined, but ciprofloxacin may displace anticoagulants from serum albumin binding sites. Ciprofloxacin should be administered with caution in patients receiving a coumarin anticoagulant.

Iron, Multivitamins, and Mineral Supplements

Oral multivitamin and mineral supplements containing divalent or trivalent cations such as calcium, iron, or zinc may interfere with oral absorption of ciprofloxacin, resulting in decreased serum and urine concentrations. These supplements should not be ingested concomitantly with ciprofloxacin. The manufacturer states that ciprofloxacin extended-release tablets, conventional tablets, or oral suspension should be administered at least 2 hours before or 6 hours after preparations containing calcium, iron, or zinc.

Xanthine Derivatives

Concomitant administration of ciprofloxacin in patients receiving a theophylline derivative may result in higher and prolonged serum theophylline concentrations and may increase the risk of theophylline-related adverse effects. Serum theophylline concentrations reportedly have increased by 17-254% and theophylline clearance decreased by 18-112% following initiation of ciprofloxacin; on average, clearance reductions have been about 20-35%.

Serious and fatal reactions have occurred during concomitant theophylline and ciprofloxacin therapy. If concomitant use is unavoidable, plasma theophylline concentrations should be monitored, the patient observed for toxicity, and dosage adjusted as needed. The need for dosage adjustment also should be considered when ciprofloxacin is discontinued.

Although the clinical importance has not been determined, ciprofloxacin prolongs caffeine elimination half-life and decreases its volume of distribution and total body clearance. Patients should be advised that high intake of coffee, tea, caffeine-containing soft drinks, or drugs during therapy may result in exaggerated or prolonged effects of caffeine; if excessive cardiac or CNS stimulation occurs, caffeine intake should be restricted.

Other Drugs

Although concomitant administration of ciprofloxacin extended-release tablets (a single 1-g dose) and omeprazole (40 mg once daily for 3 days) reduced peak plasma concentrations and area under the curve (AUC) by about 20%, the interaction was not considered clinically important. Concomitant use of ciprofloxacin and phenytoin has resulted in altered serum concentrations of phenytoin; caution is advised. Severe hypoglycemia has occurred rarely in patients receiving ciprofloxacin and glyburide.

Metoclopramide reportedly enhances the rate of GI absorption of ciprofloxacin, while antimuscarinics (e.g., scopolamine, pirenzepine) may delay GI absorption. Ciprofloxacin should be used cautiously in patients receiving drugs that depend on oxidative metabolism in the liver for elimination, particularly those with a narrow therapeutic range, since experience with xanthine derivatives indicates such interactions may be possible.

Acute renal failure occurred within 4 days after initiation of ciprofloxacin in a patient receiving cyclosporine maintenance therapy. The mechanism has not been elucidated but could involve synergistic nephrotoxic effects and/or interference with cyclosporine metabolism. It has been suggested that concomitant use of ciprofloxacin and a nonsteroidal anti-inflammatory drug (NSAID) could increase the risk of CNS stimulation (e.g., seizures), but additional study and experience are necessary.