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|Ciprofloxacin Ciprofloxacin Extended Release Tablets |
| Drugs search, click the first letter of a drug name: | A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | 1 | 2 | 3 | 4 | 5 | 6 | 8 | 9 Home CiprofloxacinDosage Form: TabletsTo reduce the development of drug-resistant bacteria and maintain the effectiveness of Ciprofloxacin tablets and other antibacterial drugs, Ciprofloxacin tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. Ciprofloxacin DescriptionCiprofloxacin tablets are synthetic broad spectrum antimicrobial agents for oral administration. Ciprofloxacin hydrochloride, USP, a fluoroquinolone, is the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light yellow crystalline substance. Its chemical structure is as follows:  C17H18FN3O3•HCl•H2O M.W. 385.8 Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light yellow crystalline substance and its chemical structure is as follows:  C17H18FN3O3 M.W. 331.4 Ciprofloxacin tablets are available as film-coated tablets in 250 mg, 500 mg and 750 mg (Ciprofloxacin equivalent) strengths. Ciprofloxacin tablets are white to off-white. The inactive ingredients are colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and povidone. The film coating contains hypromellose, polyethylene glycol, and titanium dioxide. Ciprofloxacin - Clinical PharmacologyAbsorptionCiprofloxacin given as an oral tablet is rapidly and well absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability is approximately 70% with no substantial loss by first pass metabolism. Ciprofloxacin maximum serum concentrations and area under the curve are shown in the chart for the 250 mg to 1000 mg dose range.
Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 mcg/mL, respectively. The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Serum concentrations increase proportionately with doses up to 1000 mg. A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg Ciprofloxacin given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has been shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion of 400 mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a Cmax similar to that observed with a 400 mg I.V. dose. A 250 mg oral dose given every 12 hours produces an AUC equivalent to that produced by an infusion of 200 mg Ciprofloxacin given every 12 hours.
DistributionThe binding of Ciprofloxacin to serum proteins is 20 to 40% which is not likely to be high enough to cause significant protein binding interactions with other drugs. After oral administration, Ciprofloxacin is widely distributed throughout the body. Tissue concentrations often exceed serum concentrations in both men and women, particularly in genital tissue including the prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions, mucosa of the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. Ciprofloxacin has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into the cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye. MetabolismFour metabolites have been identified in human urine which together account for approximately 15% of an oral dose. The metabolites have antimicrobial activity, but are less active than unchanged Ciprofloxacin. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Coadministration of Ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the coadministered drug. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS, Drug Interactions.) ExcretionThe serum elimination half-life in subjects with normal renal function is approximately 4 hours. Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged drug. After a 250 mg oral dose, urine concentrations of Ciprofloxacin usually exceed 200 mcg/mL during the first two hours and are approximately 30 mcg/mL at 8 to 12 hours after dosing. The urinary excretion of Ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of Ciprofloxacin, which is approximately 300 mL/minute, exceeds the normal glomerular filtration rate of 120 mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination. Coadministration of probenecid with Ciprofloxacin results in about a 50% reduction in the Ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation. Although bile concentrations of Ciprofloxacin are several fold higher than serum concentrations after oral dosing, only a small amount of the dose administered is recovered from the bile as unchanged drug. An additional 1 to 2% of the dose is recovered from the bile in the form of metabolites. Approximately 20 to 35% of an oral dose is recovered from the feces within 5 days after dosing. This may arise from either biliary clearance or transintestinal elimination. With oral administration, a 500 mg dose, given as 10 mL of the 5% Ciprofloxacin suspension (containing 250 mg Ciprofloxacin/5mL) is bioequivalent to the 500 mg tablet. A 10 mL volume of the 5% Ciprofloxacin suspension (containing 250 mg Ciprofloxacin/5mL) is bioequivalent to a 5 mL volume of the 10% Ciprofloxacin suspension (containing 500 mg Ciprofloxacin/5mL). Drug-Drug InteractionsWhen Ciprofloxacin tablet is given concomitantly with food, there is a delay in the absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing rather than 1 hour. The overall absorption of Ciprofloxacin tablet, however, is not substantially affected. Concurrent administration of antacids containing magnesium hydroxide or aluminum hydroxide may reduce the bioavailability of Ciprofloxacin by as much as 90%. (See PRECAUTIONS.) The serum concentrations of Ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly. Concomitant administration with tizanidine is contraindicated. (See CONTRAINDICATIONS.) Concomitant administration of Ciprofloxacin with theophylline decreases the clearance of theophylline resulting in elevated serum theophylline levels and increased risk of a patient developing CNS or other adverse reactions. Ciprofloxacin also decreases caffeine clearance and inhibits the formation of paraxanthine after caffeine administration. (See WARNINGS and PRECAUTIONS.) Special PopulationsPharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of Ciprofloxacin indicate that plasma concentrations of Ciprofloxacin are higher in elderly subjects (> 65 years) as compared to young adults. Although the Cmax is increased 16 to 40%, the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant. (See PRECAUTIONS, Geriatric Use.) In patients with reduced renal function, the half-life of Ciprofloxacin is slightly prolonged. Dosage adjustments may be required. (See DOSAGE AND ADMINISTRATION.) In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in Ciprofloxacin pharmacokinetics have been observed. The kinetics of Ciprofloxacin in patients with acute hepatic insufficiency, however, have not been fully elucidated. Information related to pharmacokinetics in pediatric patients is approved for Bayer Pharmaceutical Corporation’s Ciprofloxacin drug products. However, due to Bayer’s marketing exclusivity rights, this drug product, produced by TEVA Pharmaceuticals USA, is not labeled for pediatric use, except for inhalational anthrax (post-exposure). MicrobiologyCiprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive microorganisms. The bactericidal action of Ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones, including Ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to Ciprofloxacin and other quinolones. There is no known cross-resistance between Ciprofloxacin and other classes of antimicrobials. In vitro resistance to Ciprofloxacin develops slowly by multiple step mutations. Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal inhibitory concentration (MIC) by more than a factor of 2. Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for Ciprofloxacin tablets.
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum levels as a surrogate marker. (See INDICATIONS AND USAGE and INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.) The following in vitro data are available, but their clinical significance is unknown. Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 mcg/mL or less against most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of Ciprofloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant to Ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile. Susceptibility TestsDilution TechniquesQuantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of Ciprofloxacin powder. The MIC values should be interpreted according to the following criteria: For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species, penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas aeruginosa: a4
For testing Haemophilus influenzae and Haemophilus parainfluenzae:b5
The current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing. For testing Neisseria gonorrhoeae:c6
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard Ciprofloxacin powder should provide the following MIC values:
Diffusion TechniquesQuantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg Ciprofloxacin to test the susceptibility of microorganisms to Ciprofloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg Ciprofloxacin disk should be interpreted according to the following criteria: For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species, penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas aeruginosa:a9
For testing Haemophilus influenzae and Haemophilus parainfluenzae:b10
The current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing. For testing Neisseria gonorrhoeae:c11
Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for Ciprofloxacin. As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5 mcg Ciprofloxacin disk should provide the following zone diameters in these laboratory test quality control strains:
Indications and Usage for CiprofloxacinCiprofloxacin tablets are indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions and patient populations listed below. Please see DOSAGE AND ADMINISTRATION for specific recommendations. Adult PatientsUrinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus saprophyticus, or Enterococcus faecalis. Acute Uncomplicated Cystitis in females caused by Escherichia coli or Staphylococcus saprophyticus. Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis. Lower Respiratory Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae. Also, Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis. NOTE: Although effective in clinical trials, Ciprofloxacin is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae. Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus pneumoniae, or Moraxella catarrhalis. 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. Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa. Complicated Intra-Abdominal Infections (used in combination with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis. Infectious Diarrhea caused by Escherichia coli (enterotoxigenic strains), Campylobacter jejuni, Shigella boydii*14, Shigella dysenteriae, Shigella flexneri or Shigella sonnei*14 when antibacterial therapy is indicated. Typhoid Fever (Enteric Fever) caused by Salmonella typhi. NOTE: The efficacy of Ciprofloxacin in the eradication of the chronic typhoid carrier state has not been demonstrated. Uncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae. Pediatric Patients (1 to 17 Years of Age)Information related to the treatment of pediatric patients for complicated urinary tract infections and pyelonephritis is approved for Bayer Pharmaceutical Corporation’s Ciprofloxacin drug products. Ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues. (See WARNINGS, PRECAUTIONS, Pediatric Use, and ADVERSE REACTIONS). Ciprofloxacin, like other fluoroquinolones, is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals. (See ANIMAL PHARMACOLOGY.) Due to Bayer"s marketing exclusivity rights, this drug product, produced by TEVA Pharmaceuticals USA, is not labeled for pediatric use, except for inhalational anthrax (post-exposure). Adult and Pediatric PatientsInhalational 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.4 Supportive clinical information for Ciprofloxacin for anthrax post-exposure prophylaxis was obtained during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION). If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be administered. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to Ciprofloxacin. Therapy with Ciprofloxacin tablets may be initiated before results of these tests are known; once results become available appropriate therapy should be continued. As with other drugs, some strains 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. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ciprofloxacin tablets and other antibacterial drugs, Ciprofloxacin tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
ContraindicationsCiprofloxacin tablets are contraindicated in persons with a history of hypersensitivity to Ciprofloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components. Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS, Drug Interactions.) WarningsPregnant WomenTHE SAFETY AND EFFECTIVENESS OF Ciprofloxacin IN PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS, Pregnancy and Nursing Mothers subsections.) PediatricsCiprofloxacin should be used in pediatric patients (less than 18 years of age) only for inhalational anthrax (post-exposure). Information related to an additional use of Ciprofloxacin in the pediatric population is approved for Bayer Pharmaceutical Corporation’s Ciprofloxacin drug products. An increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues, has been observed. (See ADVERSE REACTIONS.) Due to Bayer’s marketing exclusivity rights, this drug product, produced by TEVA Pharmaceuticals USA, is not labeled for pediatric use, except for inhalational anthrax (post-exposure). 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.) Cytochrome P450 (CYP45)Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Coadministration of Ciprofloxacin and other drugs primarily metabolized by the CYP1A2 (e.g., theophylline, methylxanthines, tizanidine) results in increased plasma concentrations of the coadministered drug and could lead to clinically significant pharmacodynamic side effects of the coadministered drug. Central Nervous System DisordersConvulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones, including Ciprofloxacin. Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving Ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all quinolones, Ciprofloxacin should be used with caution in patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction). (See PRECAUTIONS, General, Information for Patients, Drug Interactions and ADVERSE REACTIONS.) TheophyllineSERIOUS 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. Hypersensitivity ReactionsSerious 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. Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic necrosis with fatal outcome have also been rarely reported in patients receiving Ciprofloxacin along with other drugs. The possibility that these reactions were related to Ciprofloxacin cannot be excluded. Ciprofloxacin should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Pseudomembranous ColitisPseudomembranous colitis has been reported with nearly all antibacterial agents, including Ciprofloxacin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic-associated colitis.” After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis. Drugs that inhibit peristalsis should be avoided. Peripheral NeuropathyRare 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. Tendon EffectsRuptures of the shoulder, hand, Achilles tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including Ciprofloxacin. Postmarketing surveillance reports indicate that the risk may be increased in patients receiving concomitant corticosteroids, especially in the elderly. Ciprofloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been excluded. Tendon rupture can occur during or after therapy with quinolones, including Ciprofloxacin. SyphilisCiprofloxacin 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. PrecautionsGeneralCrystals 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 ANIMAL PHARMACOLOGY.) Crystalluria related to Ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving Ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine. Central Nervous SystemQuinolones, including Ciprofloxacin, may also cause central nervous system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See WARNINGS, Information for Patients and Drug Interactions.) Renal ImpairmentAlteration of the dosage regimen is necessary for patients with impairment of renal function. (See DOSAGE AND ADMINISTRATION.) PhototoxicityModerate to severe phototoxicity manifested as an exaggerated sunburn reaction has been observed in patients who are exposed to direct sunlight while receiving some members of the quinolone class of drugs. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs. As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is advisable during prolonged therapy. 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. Information for PatientsPatients should be advised:
Drug InteractionsIn a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (Cmax 7 fold, AUC 10 fold) when the drug was given concomitantly with Ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also potentiated. Concomitant administration of tizanidine and Ciprofloxacin is contraindicated. As with some other quinolones, concurrent administration of Ciprofloxacin with theophylline may lead to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate. Some quinolones, including Ciprofloxacin, have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of its serum half-life. Concurrent administration of a quinolone, including Ciprofloxacin, with multivalent cation-containing products such as magnesium/aluminum antacids, sucralfate, didanosine chewable/buffered tablets or pediatric powder, other highly buffered drugs, or products containing calcium, iron, or zinc may substantially decrease its absorption, resulting in serum and urine levels considerably lower than desired. (See DOSAGE AND ADMINISTRATION for concurrent administration of these agents with Ciprofloxacin.) Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of Ciprofloxacin. Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant Ciprofloxacin. The concomitant administration of Ciprofloxacin with the sulfonylurea glyburide has, on rare occasions, resulted in severe hypoglycemia. Some quinolones, including Ciprofloxacin, have been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly. Quinolones, including Ciprofloxacin, have been reported to enhance the effects of the oral anticoagulant warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored. Probenecid interferes with renal tubular secretion of Ciprofloxacin and produces an increase in the level of Ciprofloxacin in the serum. This should be considered if patients are receiving both drugs concomitantly. Renal tubular transport of methotrexate may be inhibited by concomitant administration of Ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should be carefully monitored when concomitant Ciprofloxacin therapy is indicated. Metoclopramide significantly accelerates the absorption of oral Ciprofloxacin resulting in shorter time to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of Ciprofloxacin. Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies. Carcinogenesis, Mutagenesis, Impairment of FertilityEight 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 and 750 mg/kg to rats and mice, respectively (approximately 1.7 and 2.5 times the highest recommended therapeutic dose based upon mg/m2). 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 mg/m2), as opposed to 34 weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from 16 to 32 weeks in mice treated concomitantly with UVA and other quinolones.3 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 mg/m2) revealed no evidence of impairment. PregnancyTeratogenic EffectsPregnancy category CThere are no adequate and well-controlled studies in pregnant women. An expert review of published data on experiences with Ciprofloxacin use during pregnancy by TERIS – the Teratogen Information System – concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data = fair), but the data are insufficient to state that there is no risk.7 A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to Ciprofloxacin and 68% first trimester exposures) during gestation.8 In utero exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major malformations. The reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group (background incidence of major malformations is 1 to 5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the Ciprofloxacin exposed children. Another prospective follow-up study reported on 549 pregnancies with flouroquinolone exposure (93% first trimester exposures).9 There were 70 Ciprofloxacin exposures, all within the first trimester. The malformation rates among live-born babies exposed to Ciprofloxacin and to fluoroquinolones overall were both within background incidence ranges. No specific patterns of congenital abnormalities were found. The study did not reveal any clear adverse reactions due to in utero exposure to Ciprofloxacin. No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to Ciprofloxacin during pregnancy.7,8 However, these small postmarketing epidemiology studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the safety of Ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother. (See WARNINGS.) Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and 0.3 times the maximum daily human dose based upon body surface area, respectively) and have revealed no evidence of harm to the fetus due to Ciprofloxacin. In rabbits, oral Ciprofloxacin dose levels of 30 and 100 mg/kg (approximately 0.4 and 1.3 times the highest recommended therapeutic dose based upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous administration of doses up to 20 mg/kg (approximately 0.3 times the highest recommended therapeutic dose based upon mg/m2) no maternal toxicity was produced and no embryotoxicity or teratogenicity was observed. (See WARNINGS.) Nursing MothersCiprofloxacin is excreted in human milk. The amount of Ciprofloxacin absorbed by the nursing infant is unknown. Because of the potential for serious adverse reactions 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. Pediatric UseCiprofloxacin, like other quinolones, causes arthropathy and histological changes in weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL PHARMACOLOGY.) Inhalation Anthrax (Post-Exposure)Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of Ciprofloxacin to pediatric patients is appropriate. For information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE AND ADMINISTRATION and INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION. Complicated Urinary Tract Infection and PyelonephritisInformation related to the safety and efficacy of Ciprofloxacin in pediatric patients for the treatment of complicated urinary tract infections and pyelonephritis is approved for Bayer Pharmaceutical Corporation’s Ciprofloxacin drug products. Ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues. The rates of these events in pediatric patients with complicated urinary tract infection and pyelonephritis within six weeks of follow-up were 9.3% (31/335) versus 6.0% (21/349) for control agents. The rates of these events occurring at any time up to the one year follow-up were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all adverse events regardless of drug relationship at six weeks was 41% (138/335) in the Ciprofloxacin arm compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS.) Due to Bayer’s marketing exclusivity rights, this drug product, produced by TEVA Pharmaceuticals USA, is not labeled for pediatric use, except for inhalational anthrax (post-exposure). Cystic FibrosisShort-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5 to 17 years), 67 patients received Ciprofloxacin I.V. 10 mg/kg/dose q8h for one week followed by Ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10 to 21 days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10 to 21 days. Patients less than 5 years of age were not studied. Safety monitoring in the study included periodic range of motion examinations and gait assessments by treatment-blinded examiners. Patients were followed for an average of 23 days after completing treatment (range 0 to 93 days). This study was not designed to determine long term effects and the safety of repeated exposure to Ciprofloxacin. Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in the Ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in 12% of the subjects in the Ciprofloxacin group and 16% in the comparison group. Arthralgia was reported in 10% of the patients in the Ciprofloxacin group and 11% in the comparison group. Other adverse events were similar in nature and frequency between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days after a ten day course of treatment with Ciprofloxacin. Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalitie
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