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 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, 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, Staphylococcus aureus (methicillin-susceptible), Staphylococcus epidermidis , or Streptococcus pyogenes .

Bone and joint infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa.

Complicated intraabdominal 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 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 .

Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis .

Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.

If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be administered. 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.

CONTRAINDICATIONS: Ciprofloxacin HCl is contraindicated in persons with a history of hypersensitivity to Ciprofloxacin or any member of the quinolone class of antimicrobial agents.

CLINICAL PHARMACOLOGY :

Absorption: Ciprofloxacin 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.

Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500mg are 0.1, 0.2, and 0.4 µg/mL, respectively. The serum elimination half-life in subjects with normal renal function is approximately 4 hours.

Distribution: the 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.

Metabolism: the metabolites have antimicrobial activity, but are less active than unchanged Ciprofloxacin.

Excretion:  the 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. The urinary excretion of Ciprofloxacin is virtually complete within 24 hours after dosing.

Microbiology: Ciprofloxacin 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. In vitro resistance to Ciprofloxacin develops slowly by multiple step mutations.

WARNINGS:

THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN PEDIATRIC PATIENTS AND ADOLESCENTS (LESS THAN 18 YEARS OF AGE), - EXCEPT FOR USE IN INHALATIONAL ANTHRAX (POST-EXPOSURE), PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED.

Convulsions, 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.

SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar serious adverse effects have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by Ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated.

Pseudomembranous 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."

Achilles and other tendon ruptures that required surgical repair or resulted in prolonged disability have been reported with Ciprofloxacin and other quinolones. Ciprofloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon.

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

PRECAUTIONS:

General: crystals of Ciprofloxacin have been observed rarely in the urine of human subjects, Alkalinity of the urine should be avoided in patients receiving Ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine. Quinolones, including Ciprofloxacin, may also cause central nervous system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. Alteration of the dosage regimen is necessary for patients with impairment of renal function. Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction, 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.

Pregnancy: Pregnancy Category C

Nursing Mothers: Ciprofloxacin is excreted in human milk. 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 Use: safety and effectiveness in pediatric patients and adolescents less than 18 years of age have not been established, except for use in inhalational anthrax (post-exposure). For the indication of inhalational anthrax (post-exposure), the risk-benefit assessment indicates that administration of Ciprofloxacin to pediatric patients is appropriate.

Drug Interactions: 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.

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, or products containing calcium, iron, or zinc may substantially decrease its absorption, resulting in serum and urine levels considerably lower than desired. Histamine H 2 -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 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.

SIDE EFFECTS:

The most frequently reported events; drug related or not, was nausea (5.2%), diarrhea (2.3%), vomiting (2.0%), abdominal pain/discomfort (1.7%), headache (1.2%), restlessness (1.1%), and rash (1.1%).

Additional events that occurred in less than 1% of Ciprofloxacin patients are listed below.

BODY AS A WHOLE: foot pain

CARDIOVASCULAR: palpitation, atrial flutter, ventricular ectopy, syncope, hypertension, angina pectoris, myocardial infarction, cardiopulmonary arrest, cerebral thrombosis

CENTRAL NERVOUS SYSTEM: dizziness, lightheadedness, insomnia, nightmares, hallucinations, manic reaction, irritability, tremor, ataxia, convulsive seizures, lethargy, drowsiness, weakness, malaise, anorexia, phobia, depersonalization, depression, paresthesia (See above.)

GASTROINTESTINAL: painful oral mucosa, oral candidiasis, dysphagia, intestinal perforation, gastrointestinal bleeding (See above.) Cholestatic jaundice has been reported.

HEMIC/LYMPHATIC: lymphadenopathy

MUSCULOSKELETAL: arthralgia or back pain, joint stiffness, achiness, neck or chest pain, flare up of gout

RENAL/UROGENITAL: interstitial nephritis, nephritis, renal failure, polyuria, urinary retention, urethral bleeding, vaginitis, acidosis, breast pain

RESPIRATORY: dyspnea, epistaxis, laryngeal or pulmonary edema, hiccough, hemoptysis, bronchospasm, pulmonary embolism

SKIN/HYPERSENSITIVITY: pruritus, urticaria, photosensitivity, flushing, fever, chills, angioedema, edema of the face, neck, lips, conjunctivae or hands, cutaneous candidiasis, hyperpigmentation, erythema nodosum (See above.)

Allergic reactions ranging from urticaria to anaphylactic reactions have been reported.

SPECIAL SENSES: blurred vision, disturbed vision (change in color perception, overbrightness of lights), decreased visual acuity, diplopia, eye pain, tinnitus, hearing loss, bad taste.

In several instances nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to be related to elevated serum levels of theophylline possibly as a result of drug interaction with Ciprofloxacin.

Post-Marketing Adverse Events: additional adverse events, regardless of relationship to drug, reported from worldwide marketing experience with quinolones, including Ciprofloxacin, are:

agitation, agranulocytosis, albuminuria, anaphylactic reactions, anosmia, candiduria, cholesterol elevation (serum), confusion, constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, flatulence, glucose (blood), hemolytic anemia, hepatic necrosis, hypotension (postural), jaundice, methemoglobinemia, myalgia, myasthenia gravis (possible exacerbation), myoclonus, nystagmus, pancreatitis, phenytoin alteration (serum), potassium elevation (serum), prothrombin time prolongation, pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur during or after antimicrobial treatment.), psychosis (toxic), renal calculi, Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, toxic epidermal necrolysis, triglyceride elevation (serum), vaginal candidiasis, and vasculitis.

Adverse Laboratory Changes: changes in laboratory parameters listed as adverse events without regard to drug relationship are listed below:

Hepatic- elevations of ALT (SGPT) (1.9%), AST (SGOT) (1.7%), alkaline phosphatase (0.8%), LDH (0.4%), serum bilirubin (0.3%).

Hematologic - eosinophilia (0.6%), leukopenia (0.4%), decreased blood platelets (0.1%),  elevated blood platelets (0.1%), pancytopenia (0.1%).

Renal- elevations of serum creatinine (1.1%), BUN (0.9%), CRYSTALLURIA, CYLINDRURIA, AND HEMATURIA HAVE BEEN REPORTED.

OVERDOSAGE:

In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully observed and given supportive treatment. Adequate hydration must be maintained. Only a small amount of Ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal dialysis.

DOSAGE AND ADMINISTRATION:

Urinary tract infection, Acute Uncomplicated, Mild/Moderate 250 mg q 12 h 7 to 14 Days, Severe/Complicated 500 mg q 12 h 7 to 14 Days

Chronic bacterial prostatitis; Mild/Moderate 500 mg q 12 h 28 Days

Lower respiratory tract; Mild/Moderate 500 mg q 12 h 7 to 14 Days

Severe/Complicated 750 mg q 12 h 7 to 14 Days

Acute sinusitis, Mild/Moderate, 500 mg q 12 h 10 Days

Skin and skin structure; Mild/Moderate 500 mg q 12 h 7 to 14 Days

Severe/Complicated 750 mg q 12 h 7 to 14 Days

Bone and joint ; Mild/Moderate 500 mg q 12 h >/= 4 to 6 weeks

Severe/Complicated 750 mg q 12 h >/= 4 to 6 weeks

Intra-abdominal complicated; 500 mg q 12 h  7 to 14 Days

Infectious diarrhea; Mild/Moderate/Severe 500 mg q 12 h 5 to 7 Days

Typhoid fever; Mild/Moderate 500 mg q 12 h 10 Days

Urethral and cervical gonococcal infections Uncomplicated 250 mg single dose

Inhalational anthrax (post-exposure); adult 500 mg q 12 h 60 Days, pediatric 15 mg/kg per dose, not to exceed 500 mg per dose q 12 h 60 Days

Generally Ciprofloxacin should be continued for at least 2 days after the signs and symptoms of infection have disappeared, except for inhalational anthrax (post-exposure).

Impaired renal function: Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine.

RECOMMENDED STARTING AND MAINTENANCE DOSES FOR PATIENTS WITH IMPAIRED RENAL FUNCTION

Creatinine Clearance (mL/min) > 50; See Usual Dosage.

Creatinine Clearance (mL/min) 30 – 50; 250 - 500 mg q 12 h

Creatinine Clearance (mL/min) 5 – 29; 250 - 500 mg q 18 h

Patients on hemodialysis or Peritoneal dialysis; 250 - 500 mg q 24 h (after dialysis)

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

Men: Creatinine clearance (mL/min) =    Weight (kg) × (140 - age) 72 × serum creatinine (mg/dL)

Women: 0.85 × the value calculated for men.

HOW SUPPLIED: Each pack of Ruz-Ciprofloxacin 250 mg or 500 mg film coated tablets contain 20 tablets in 2 blisters.

STORAGE: Store below 30°C. Protect from light and moisture.

Reference: PDR 2000, page 678-83

                  USPDI for Professional Health Care, 2004, Page 1380-90

                      Martindale 2005, Page 188-92