Ciloxan Ophthalmic Solution (Ciprofloxacin)

Ciprofloxacin is generally well tolerated, and its side effects are similar to those reported with other quinolone anti-infectives (for example, norfloxacin and ofloxacin). In UK clinical practice, prescribers would typically advise patients to watch for gastrointestinal (GI) or central nervous system (CNS) symptoms during treatment. Side effects have been reported in 5-14% of patients receiving ciprofloxacin and have been severe enough to require stopping treatment in 2-3.5% of patients. The most common side effects affect the gastrointestinal (GI) tract or central nervous system (CNS); those leading to discontinuation also mainly involve these organ systems.

There is currently limited information on the side effects of ciprofloxacin in people receiving anthrax post-exposure prophylaxis. In response to a questionnaire given to 490 such individuals in Florida on about day 7 or 14 of anti-infective prophylaxis, 19% sought medical attention for an anti-infective-related side effect or reported one or more of the following: itching, breathing problems, or swelling of the face, neck, or throat.

Although the percentage of patients in this subgroup who received ciprofloxacin rather than other anti-infectives was not reported, 86% of all patients (that is, those who did or did not answer the questionnaire) received ciprofloxacin and 80% continued prophylaxis beyond 14 days. In an epidemiological evaluation of 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 given the questionnaire, of whom 3863 had started prophylaxis (3428 with ciprofloxacin).

Of the individuals treated with ciprofloxacin, 19% reported severe nausea, vomiting, diarrhoea, and/or abdominal pain; 14% reported fainting, light-headedness, and/or dizziness; 7% reported heartburn or acid reflux; 6% reported rash, urticaria, and/or itching; and 8% stopped treatment with the drug (3% because of side effects, 1% for fear of developing a side effect, and 1% because they were confused about whether it was needed). Only 2% of those taking any anti-infective sought medical attention for possible signs of anaphylaxis, and none required hospitalisation.

GI Effects

Nausea, diarrhoea, vomiting, and abdominal pain or discomfort have been reported in 2-10% of patients receiving ciprofloxacin. These effects are generally mild and temporary and occur most often in older patients and/or when high doses are used. Loss of appetite, 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 has a selective effect on normal bowel flora. Although fluoroquinolones, including ciprofloxacin, are relatively inactive against Clostridium difficile in vitro, C. difficile-associated diarrhoea and colitis (also known as antibiotic-associated pseudomembranous colitis) have been reported in 1% or fewer patients receiving these drugs. In addition, C. difficile-associated diarrhoea and colitis caused by other anti-infectives (for example, ceftriaxone) have resolved in several patients after these other anti-infectives were stopped and ciprofloxacin was started.

The reason for this relatively weak association between ciprofloxacin and colitis is not clear, but it may be related to faecal concentrations of the drug substantially exceeding the minimum inhibitory concentration (MIC) of C. difficile and/or the drug's selective effect on normal GI flora. It should be noted, however, that starting ciprofloxacin in these patients may not have been responsible for resolution of the colitis, but may simply have allowed it to settle after the offending anti-infective was stopped.

The possibility that diarrhoea developing in any patient treated with ciprofloxacin may be secondary to C. difficile-associated colitis should be considered. C. difficile-associated diarrhoea and colitis can range in severity from mild to life-threatening. Mild cases of colitis may respond to stopping ciprofloxacin alone, but diagnosing and managing moderate to severe cases should include appropriate bacteriological studies and treatment with fluid, electrolyte, and protein replacement as needed. If colitis is moderate to severe or is not relieved by stopping ciprofloxacin, appropriate anti-infective treatment (for example, oral metronidazole or vancomycin) should be given. Isolating the patient may be advisable. Other causes of colitis should also be considered.

Total bacterial counts of normal anaerobic faecal flora are generally unaffected during or after ciprofloxacin therapy. However, total bacterial counts of normal aerobic faecal flora decrease within 2-5 days after treatment with the drug is started and generally return to pre-treatment levels within 1-4 weeks after the drug is stopped. Ciprofloxacin therapy generally markedly reduces or completely eradicates normal faecal Enterobacteriaceae; the drug reduces faecal 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, depersonalisation, depression, suicidal thoughts or acts, paraesthesia, and increased intracranial pressure have been reported in less than 1% of patients. Some of these reactions may occur after the first dose. If seizures or other severe CNS reactions occur during ciprofloxacin therapy, the drug should be discontinued and appropriate measures taken.

Some CNS side 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 changes in caffeine pharmacokinetics.

Dermatologic and Sensitivity Reactions

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

Toxic epidermal necrolysis has been reported rarely in patients receiving ciprofloxacin. Therefore, the manufacturer recommends that ciprofloxacin should be stopped 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, sometimes with the initial dose, in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, paraesthesia, pharyngeal or facial oedema, dyspnoea, urticaria, and/or itching; 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 or mechanisms behind this increased risk have not been determined. If a severe hypersensitivity reaction occurs during ciprofloxacin therapy, the drug should be discontinued and the patient given appropriate treatment (for example, epinephrine, corticosteroids, maintenance of an adequate airway, oxygen, and maintenance of blood pressure) as needed.

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 of starting ciprofloxacin and appeared to be a hypersensitivity reaction; renal biopsy showed marked interstitial oedema with extensive lymphocytic infiltrations and occasional eosinophils. Crystalluria, cylindruria, and haematuria have been reported rarely.

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

Musculoskeletal Effects

Arthralgia, joint or back pain, joint inflammation, joint stiffness, aches, 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. 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 seen even at the lower dose. Removing weight-bearing from the joint reduced the lesions but did not prevent them completely.

Morphological changes seen in animals with quinolone-induced arthropathies include erosions in joint cartilage accompanied by non-inflammatory, 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 between these effects in animals and the rheumatological symptoms associated with the 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. Anaemia, decreased haemoglobin, 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 (that is, 5-6 months) after the drug was discontinued.

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 side effects have been reported at the infusion site following IV administration of ciprofloxacin. These reactions generally resolve quickly after the infusion is completed and have been reported most often when IV infusions were given over 30 minutes or less. The manufacturer states that local reactions do not rule out subsequent IV administration unless the reactions recur or worsen.

Other Adverse Effects

Epistaxis, laryngeal or pulmonary oedema, hiccups, haemoptysis, dyspnoea, bronchospasm, and pulmonary embolism have been reported in less than 1% of patients. Blurred vision, disturbed vision (for example, change in colour perception, over-brightness 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 (that is, 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 the usual recommended doses, patients should be advised to drink enough fluids to ensure proper hydration and adequate urine output during ciprofloxacin therapy. Measures should also be taken to avoid alkaline urine, and the recommended dose should not be exceeded.

Because ciprofloxacin may cause CNS stimulation that 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 (for example, severe cerebral arteriosclerosis, seizure disorders) that predispose to seizures or lower the seizure threshold, and in the presence of other factors (for example, 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 they should see how it affects them before driving, operating machinery, or doing activities that require mental alertness and coordination.

Patients receiving a theophylline derivative or caffeine at the same time may also 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. Patients should be advised to stop the drug and tell their doctor if they experience pain, inflammation, or rupture of a tendon, and to rest and avoid exercise.

As with other anti-infectives, ciprofloxacin may result in overgrowth of non-susceptible organisms, especially enterococci or Candida. Resistant strains of some organisms (for example, 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 treatment should be started. Doses and/or frequency of IV ciprofloxacin, conventional tablets, or oral suspension should be reduced 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 haematopoietic function, should 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, seen as an exaggerated sunburn reaction, has been reported during exposure to direct sunlight in patients receiving some fluoroquinolones (for example, lomefloxacin, ofloxacin, sparfloxacin).

Ciprofloxacin can cause serious, potentially fatal hypersensitivity reactions, sometimes after the initial dose. Patients should be advised of this possibility and instructed to stop the drug and contact their doctor 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 (post-exposure) to reduce the risk or progression of disease after exposure to aerosolised Bacillus anthracis spores, and UK public health guidance and other expert recommendations advise that initial treatment of inhalational or systemic anthrax (including GI and oropharyngeal disease) should consist of either IV ciprofloxacin or doxycycline plus 1 or 2 additional anti-infectives. Because of the potential side effects of prolonged ciprofloxacin use in infants and children, amoxicillin may be used to complete the remainder of a 60-day course when penicillin susceptibility is known; amoxicillin is not recommended for initial treatment. Amoxicillin may also be considered as an alternative to ciprofloxacin for post-exposure 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 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 aged 9-18 years with serious infections (for example, cystic fibrosis, typhoid fever) when the causative organism is resistant to other available anti-infectives.

In UK clinical practice, the use of fluoroquinolones (for example, ciprofloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, sparfloxacin) in children younger than 18 years may be justified in special circumstances; however, these drugs should be used only after careful assessment of the risks and benefits for the individual patient and after these have been explained to parents or carers.

Ciprofloxacin has been used in children with cystic fibrosis, but transient arthropathy has occasionally occurred. In at least one 16-year-old, arthropathy was associated with relatively high doses (750 mg twice daily) for several weeks. Ciprofloxacin has also been used in a limited number of children with typhoid fever resistant to other anti-infectives (for example, ampicillin, amoxicillin, chloramphenicol, co-trimoxazole). Short-term safety data are available from a randomised, double-blind study in children and adolescents aged 5-17 years 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 side effects were similar. In the ciprofloxacin group, musculoskeletal side 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 paediatric 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 causal relationship could not be established, particularly since patients with cystic fibrosis 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 found 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 older people and younger adults, the possibility that some older patients may have increased sensitivity cannot be ruled out. Ciprofloxacin is substantially eliminated by the kidneys, and the risk of side effects may be greater in patients with impaired renal function. Although the dose does not need to be modified in people older than 65 years with normal renal function, the greater frequency of reduced renal function in older people should be considered and the dose selected carefully; monitoring renal function may be useful.

Mutagenicity and Carcinogenicity

Ciprofloxacin was not mutagenic in the rat hepatocyte DNA repair assay or in 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 tumour-forming 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, well-controlled studies to date of ciprofloxacin use in pregnant women. Because the drug, like most other fluoroquinolones, causes arthropathy in immature animals, ciprofloxacin should not be used during pregnancy except for the treatment or prevention of inhalational anthrax.

Reproduction studies in rats and mice using ciprofloxacin doses up to 6 times the usual human dose have not shown 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 passes into breast milk. Because of the potential for serious side effects in breastfed infants, a decision should be made whether to stop breast-feeding or stop the drug, taking into account how important the treatment is to the woman. However, UK clinical guidance generally considers ciprofloxacin likely to be compatible with breast-feeding because the amount potentially absorbed by the infant is small and no observable effects in infants have been reported to date. Because the long-term safety of prolonged exposure (for example, a 60-day course for anthrax) is not known, UK public health advice is that lactating women who are concerned about ciprofloxacin during anthrax prophylaxis may wish to express and discard breast milk so that breast-feeding can resume once prophylaxis is complete.

Ciprofloxacin Hydrochloride: Drug Interactions

Antacids

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

The mechanism has not been fully clarified, but magnesium, aluminium 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 taken at least 2 hours before or 6 hours after antacids containing magnesium or aluminium.

Some clinicians suggest advising patients not to take antacids containing magnesium, aluminium or calcium at the same time as, 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 aluminium hydroxide or aluminium carbonate for intestinal binding of phosphate.

Aminoglycosides

The antibacterial activity of ciprofloxacin and aminoglycosides has 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 occasionally occurred 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 given as chewable/dispersible buffered tablets or paediatric powder for oral solution (mixed with antacid) may decrease absorption of ciprofloxacin, resulting in lower serum and urine concentrations. The manufacturer states that ciprofloxacin extended-release tablets, conventional tablets or oral suspension should be taken 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 at the same time.

Cimetidine, Ranitidine, and Sucralfate

Sucralfate (presumably because of its aluminium content) decreases GI absorption of ciprofloxacin and may result in a substantial (e.g., 50%) decrease in serum concentrations. Patients should be advised 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

Starting oral ciprofloxacin therapy in at least one patient stabilised on warfarin resulted in prolongation of prothrombin time and haematemesis. Concomitant use of other fluoroquinolones (e.g., norfloxacin) in patients receiving coumarin anticoagulants has also resulted in increased prothrombin times. The mechanism has not been determined, but ciprofloxacin may displace anticoagulants from serum albumin binding sites. Ciprofloxacin should be used 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 lower serum and urine concentrations. These supplements should not be taken at the same time as ciprofloxacin. The manufacturer states that ciprofloxacin extended-release tablets, conventional tablets or oral suspension should be taken 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 side 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 the dose adjusted as needed. The need for dose adjustment should also 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 a high intake of coffee, tea, caffeine-containing soft drinks or medicines 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 hypoglycaemia 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 ciclosporin maintenance therapy. The mechanism has not been clarified but could involve synergistic nephrotoxic effects and/or interference with ciclosporin metabolism. It has been suggested that concomitant use of ciprofloxacin and a non-steroidal anti-inflammatory drug (NSAID) could increase the risk of CNS stimulation (e.g., seizures), but additional study and experience are necessary.