RiteMED Ciprofloxacin

Ciprofloxacin hydrochloride.

Each film-coated tablet contains: Ciprofloxacin (as hydrochloride monohydrate), USP 500 mg.

Pharmacology: Mechanism of Action: Ciprofloxacin's bactericidal action results from the inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair and recombination.
Absorption: Ciprofloxacin is rapidly and well absorbed from the gastrointestinal tract following oral administration. Its absolute bioavailability is approximately 70% with no substantial loss by first pass metabolism. Ciprofloxacin's maximum serum concentrations and area under the curve are shown as follows: See Table 1.

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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 μg/mL, respectively. 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 250 mg Ciprofloxacin oral dose given every 12 hours produces an AUC equivalent to that produced by an infusion of 200 mg Ciprofloxacin given every 12 hours. A 500 mg oral dose given every 12 hours produces an AUC equivalent to that produced by an IV infusion of 400 mg Ciprofloxacin given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours produces an AUC at steady-state equivalent to that produced by an IV infusion of 400 mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a C_max similar to that observed with a 400 mg I.V. dose.
Distribution: Ciprofloxacin binds to serum proteins at 20-40%. Following oral administration, Ciprofloxacin diffuses readily into most body tissues and fluids. 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 is also detected in lung, skin, fat, muscle, cartilage and bone. It 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.
Metabolism: Four metabolites have been identified in human urine which account for approximately 15% of an oral dose. These metabolites have antimicrobial activity, but are less active than unchanged Ciprofloxacin.
Excretion: Ciprofloxacin is eliminated primarily by renal excretion. However, it is also metabolized and partially cleared through the biliary system of the liver and through the intestine.
Ciprofloxacin's 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 Ciprofloxacin 250 mg oral dose, urine concentrations exceed 200 μg/mL during the first two hours and are approximately 30 μg/mL at 8 to 12 hours after dosing. Ciprofloxacin's urinary excretion is virtually complete within 24 hours after dosing. Renal clearance is approximately 300 mL/minute and exceeds the normal glomerular filtration rate of 120 mL/minute. Thus, active tubular secretion plays a significant role in its elimination. Co-administration 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.
Antimicrobial Spectrum of Activity: Ciprofloxacin is active in vitro activity against a wide range of Gram-positive and Gram-negative microorganisms.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections: See Table 2.

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The following in vitro data are available, but their clinical significance is unknown. (See Table 3.)

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Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum levels as a surrogate marker. 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.

Treatment of the following infections caused by Ciprofloxacin-susceptible strains: Urinary tract infections: caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus or Enterococcus faecalis.
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.
Otitis Media: caused by Gram-negative organisms including Pseudomonas or by Staphylococcus.
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 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, Shigella dysenteriae, Shigella flexneri or Shigella sonnei 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.
Perform appropriate culture and susceptibility tests before treatment in order to isolate and identify organisms causing infection and to determine susceptibility to ciprofloxacin. Therapy with Ciprofloxacin may be initiated before results of these tests are known. Institute appropriate therapy once results become available. As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly 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 be administered orally. (See Table 4.)

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Duration of Therapy: Usual duration of treatment is 7 to 14 days; however, for severe and complicated infections more prolonged therapy may be required. Generally, Ciprofloxacin is continued for at least 2 days after the signs and symptoms of infection have disappeared, except for inhalational anthrax (post-exposure).
Patient Information: Ciprofloxacin may or may not be taken with meals. However, if taken on an empty stomach, the drug is absorbed more rapidly.
Do not take Ciprofloxacin with dairy products (like milk or yogurt) or calcium-fortified juices alone since absorption of ciprofloxacin may be significantly reduced; however ciprofloxacin may be taken with a meal that contain these products.
Drink fluids liberally.
Administer Ciprofloxacin at least 2 hours before or 6 hours after magnesium/aluminum antacids or sucralfate, didanosine chewable/buffered tablets or pediatric powder for oral solution or other products containing calcium, iron or zinc.
Patients started on Ciprofloxacin I.V. may be switched to Oral Ciprofloxacin when clinically indicated at the discretion of the physician (see Table 5.)

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Impaired Renal Function: Dosage modification is recommended particularly for patients with renal dysfunction. The following table provides dosage guidelines for use in patients with renal impairment; however, monitoring of serum drug levels provides the most reliable basis for dosage adjustment: See Table 6.

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

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Serum creatinine should represent a steady state of renal function.
In patients with severe infections and severe renal impairment, a unit dose of 750 mg may be administered at the intervals noted previously; however carefully monitor patients and periodically measure Ciprofloxacin's serum concentration. Peak concentrations (1 to 2 hours after dosing) ranges from 2 to 4 μg/mL.
For patients with changing renal function or for patients with renal impairment and hepatic insufficiency, measurement of serum concentrations of ciprofloxacin will provide additional guidance for adjusting dosage.

History of hypersensitivity to Ciprofloxacin or any member of the quinolone antibiotics.

Safety and effectiveness of ciprofloxacin in pediatric and adolescents (less than 18 years of age) except for use in inhalational anthrax (post-exposure), pregnant women ad lactating women have not been established.
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 produced erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species.
Achilles and other tendon ruptures that required surgical repair or resulted to prolonged disability have been reported with ciprofloxacin and other quinolones. Discontinue Ciprofloxacin if the patient experiences pain, inflammation or rupture of a tendon.
Convulsions, increased intracranial pressure and toxic psychosis have been reported in patients receiving quinolones, including Ciprofloxacin. Ciprofloxacin may also cause 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, discontinue the drug and institute appropriate measures. Use ciprofloxacin with caution in patients with known or suspected CNS disorders that may predispose to 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).
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, monitor serum levels of theophylline and adjust dosage appropriately.
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. In such cases, administer oxygen, intravenous steroids, and airway management, including intubation.
Rarely, severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice and hepatic necrosis with fatal outcome have also been reported in patients receiving Ciprofloxacin along with other drugs. Discontinue Ciprofloxacin at the first appearance of a skin rash or any other sign of hypersensitivity.
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." After pseudomembranous colitis has been established, initiate therapeutic measures. Mild causes of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consider management with fluids and electrolytes, protein supplementation and treatment with antibacterial drug clinically effective against Clostridium difficile colitis.
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. Advise all patients with gonorrhea to have a serologic test for syphilis at the time of diagnosis and to have a follow-up serologic test for syphilis after three months.

General: Ciprofloxacin crystals have been observed rarely in the urine of human subjects but more frequently in the urine of laboratory animals, which is usually alkaline. Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Avoid alkalinity of the urine in patients receiving ciprofloxacin. Hydrate patients well to prevent the formation of highly concentrated urine.
Quinolones, including ciprofloxacin, may also cause CNS events, including nervousness, agitation, insomnia, anxiety, nightmares or paranoia.
Alteration of the drug regimen is necessary for patients with renal function impairment.
Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has been observed in patients who are exposed to direct sunlight while receiving some quinolone antibiotics. Avoid excessive sunlight. Discontinue therapy 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.
Ciprofloxacin intake can interfere with one's ability to drive an automobile or operate machinery. Use Ciprofloxacin with caution in such instances and in activities where a person may be requiring mental alertness and coordination.

Frequently reported adverse events, drug related or not, were nausea (5.2%), diarrhea (2.3%), abdominal pain/discomfort (1.7%), headache (1.2%), restlessness (1.1%) and rash (1.1%).
Additional events which occurred in less than 1% of ciprofloxacin patients include the following: Central nervous system: dizziness, lightheadedness, insomnia, nightmares, hallucinations, manic reaction, irritability, tremor, ataxia, convulsive seizures, lethargy, drowsiness, weakness, malaise, anorexia, phobia, depersonalization, depression, paresthesia.
Cardiovascular: palpitation, atrial flutter, ventricular ectopy, syncope, hypertension, angina pectoris, myocardial infarction, cardiopulmonary arrest, cerebral thrombosis.
Respiratory: dyspnea, epistaxis, laryngeal or pulmonary edema, hiccough, hemoptysis, bronchospasm, pulmonary embolism.
Gastrointestinal: painful oral mucosa, oral candidiasis, dysphagia, intestinal perforation, gastrointestinal bleeding. Cholestatic jaundice has been reported.
Skin/hypersensitivity: pruritus, urticaria, photosensitivity, flushing, fever, chills, angioedema, edema of the face, neck, lips, conjunctivae or hands, cutaneous candidiasis, hyperpigmentation, erythema nodosum. Allergic reactions ranging from urticaria to anaphylactic reactions have also been reported.
Renal/urogenital: interstitial nephritis, nephritis, renal failure, polyuria, urinary retention, urethral bleeding, vaginitis, acidosis, breast pain.
Musculoskeletal: arthralgia, or back pain, joint stiffness, achiness, neck or chest pain, flare up of gout.
Hemic/lymphatic: lymphadenopathy.
Special senses: blurred vision, disturbed vision (change in color perception, overbrightness of lights), decreased visual acuity, diplopia, eye pain, tinnitus, hearing loss, bad taste.
Adverse Laboratory Changes: Changes in laboratory parameters listed as adverse events without regard to drug relationship are as follows: Hepatic: elevations of ALT (1.9%), AST (1.7%), alkaline phosphatase (0.8%), LDH (0.4%), serum bilirubin (0.3%).
Hematologic: eosinophilia (0.6%), leucopenia (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, cylinduria, and hematuria have been reported.
Other changes reported in less than 0.1% of patients were: elevation of serum gammaglutamyl transferase, elevation of serum amylase, reduction in blood glucose, elevated uric acid, decrease in hemoglobin, anemia, bleeding diathesis, increase in blood monocytes, and leukocytosis.

Concurrent administration 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 is necessary, monitor serum levels of theophylline and adjust dosage appropriately.
Ciprofloxacin interferes with caffeine's metabolism leading to reduced clearance and prolongation of its serum half-life.
Altered Phenytoin serum levels (increased or decreased) have been reported in patients given Ciprofloxacin.
Concomitant administration of Ciprofloxacin with Cyclosporine has resulted in transient elevations in serum creatinine.
Ciprofloxacin enhances the effects of oral anticoagulant warfarin or its derivatives. When these products are administered simultaneously, closely monitor prothrombin time or other suitable coagulation tests.
Probenecid interferes with renal tubular secretion of Ciprofloxacin and produces an increase in Ciprofloxacin level in the serum.

Store temperatures not exceeding 25°C.

Quinolones

J01MA02 - ciprofloxacin ; Belongs to the class of fluoroquinolones. Used in the systemic treatment of infections.

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