Noroxin (Norfloxacin)

NOROXIN®

MSD

Norfloxacin

Antibacterial Agent

Action And Clinical Pharmacology: Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal.

At the molecular level 3 specific actions have been attributed to norfloxacin in the inhibition of E. coli cells: inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase, inhibition of the relaxation of supercoiled DNA, promotion of double-stranded DNA breakage.

Pharmacokinetics: Mean peak serum concentrations were 0.8 and 1.5 mg/L occurring within 1 to 1.5 hours of oral administration of 200 and 400 mg doses respectively to 15 healthy fasting male volunteers.

The mean elimination half-life was approximately 3 hours. Therefore, as was noted in another group of 26 healthy male and 3 female volunteers aged 19 to 50 years, norfloxacin regimens of 400 mg given every 12 hours produced slight accumulation.

Theoretically it could be expected that steady-state concentrations will be attained after 2 days of recommended dosage.

Following oral administration to 15 healthy fasting male volunteers, aged 22 to 52 years, 25 to 30% of a dose was recovered unchanged in urine within 48 hours.

During the same period of time, an additional 8 to 10% of the dose was recovered as 6 metabolites with modifications on the piperazine ring. The 2 major metabolites are the 3-oxo-piperazinyl derivative and the 7-ethylenediamine derivative. The 3-oxo-piperazinyl predominates and no glucuronide conjugates were detected. Norfloxacin and these metabolites were detected in bile. The concentration of norfloxacin in bile was 5 µg/mL collected 1 to 2 hours after oral administration of a 200 mg dose to 1 patient with choledocholithiasis. A similar distribution ratio of the same 6 metabolites was in both bile and urine. These data suggest that 30 to 40% of an oral dose is absorbed. After a single 400 mg dose, mean antimicrobial activities equivalent to 164, 338, 632, and 126 µg of norfloxacin/g of feces were recovered over 0 to 12, 12 to 24, and 24 to 36, and 36 to 48 hours, respectively.

Renal excretion of norfloxacin occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance 275 mL/min, (4.58 mL/s). Two to three hours after a single 400 mg dose, mean urinary concentrations of 200 mg/L or more were obtained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 mg/L for at least 12 hours following a 400 mg dose.

Factors influencing the pharmacokinetics: Food: Food slightly reduces the absorption of norfloxacin as evidenced by a reduction of approximately 30% in peak serum concentration and of approximately 35% in peak urine concentration.

Geriatrics: In 4 females and 2 males, 67- to 74-year-old patients with normal renal function for their age i.e., creatinine clearance 91 mL/min/1.73 m norfloxacin was eliminated more slowly because of their slightly decreased renal function causing a small increase in plasma concentrations of drug.

Approximately 22% of the dose was recovered unchanged in urine. The renal clearance of drug was 154 mL/min (2.57 mL/s). The maximum plasma concentration was approximately 2 mg/L, occurring 1.3 hours after drug administration. The plasma half-life of norfloxacin in these individuals was 4 hours.

Probenecid: The 12-hour urinary excretion of norfloxacin following a 200 mg dose was diminished from 28% of the dose to 14% of the dose by the coadministration of probenecid.

Serum protein binding: At a serum concentration of 2.5 mg/L the human serum protein binding is 10 to 15%.

Norfloxacin is found in the liver, gallbladder, gallbladder bile, bile in common bile duct, bile, prostate, kidney.

Indications And Clinical Uses: The treatment of upper and lower urinary tract infections, specifically complicated and uncomplicated cystitis, pyelitis and pyelonephritis caused by susceptible strains of the following microorganisms: E. coli, K. pneumoniae, unspecified Klebsiella spp., unspecified Enterobacter spp., unspecified Citrobacter spp., P. mirabilis, S. aureus, S. faecalis, P. aeruginosa.

The treatment of adults with gonococcal urethritis, or cervicitis due to penicillinase-producing and nonpenicillinase- producing N. gonorrhea.

Appropriate culture and susceptibility studies should be carried out prior to initiation of therapy with norfloxacin and if clinically indicated during treatment. Therapy may be initiated before obtaining results of these tests, however, modification of such treatment may be required once the results become available.

Contra-Indications: In patients with known hypersensitivity to norfloxacin, to any component of this product or other quinolone antibacterial agents.

Manufacturers’ Warnings In Clinical States: Children: Safety in children is unknown. Adults: Norfloxacin should not be given to patients in whom epiphyseal closure has not occurred. In 2 animal species (dogs and rabbits) in which norfloxacin was administered to young animals, lameness and lesions (i.e., blister formation and eventual erosion) of the articular cartilage of the weight-bearing joints were observed. In young dogs this occurred following a single dose several times the recommended human dose. These changes were not observed in dogs 6 months of age or older. Similar changes in animals have been observed with other structurally related drugs.

Norfloxacin should be used with caution in individuals with a history of convulsions or known factors that predispose to seizures. Convulsions have been reported rarely in patients receiving norfloxacin; however, a causal relationship to norfloxacin has not been established.

Pregnancy: Safety in the treatment of infections in pregnant women is not established.

Precautions: General: Norfloxacin should be used with caution in patients with a history of convulsions.

During therapy, patients should be reminded to drink sufficient amounts of fluids to maintain adequate hydration in order to avoid possible development of crystalluria.

As with other quinolones, tendinitis and/or tendon rupture have been observed rarely in patients taking norfloxacin, especially when corticosteroids are taken concomitantly. If a patient develops symptoms of tendinitis and/or tendon rupture, norfloxacin should be discontinued immediately and the patient advised to seek appropriate medical management.

Rarely, hemolytic reactions have been reported in patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity who take quinolone antibacterial agents, including norfloxacin (see Adverse Effects).

Photosensitivity reactions have been observed in patients exposed to sunlight while receiving quinolone antibiotics. While taking norfloxacin, excessive exposure to sunlight should be avoided and therapy discontinued if photosensitivity should occur.

Pregnancy: Safety in the treatment of infections in pregnant women is not established; consider its use only if the anticipated benefits to the mother justifies the potential risks to the fetus. Following a single dose of 200 mg norfloxacin concentrations in umbilical cord serum ranged from nondetectable levels to 0.5 mg/L and in amniotic fluid from nondetectable levels to 0.92 mg/L. The pharmacokinetics of norfloxacin in pregnant patients have not been investigated.

Reproduction studies have been carried out in the mouse, rat, rabbit and monkey. Norfloxacin did not show any teratogenic effects in these studies. In the monkey, however, an increased incidence of embryonic loss has been observed at a dosage of 10 times the human dose which results in peak plasma levels approximately 2 to 3 times that in humans. In the rabbit, embryonic loss was observed when norfloxacin was given by the oral route but not by the s.c. route. The clinical significance of the study results observed in rabbits and monkeys is not known.

Lactation: Norfloxacin was not detected in human milk following a single 200 mg dose. However, because this dose was low (half the recommended single dose) and as many drugs are secreted in human milk, caution should be exercised if it is to be administered to a nursing woman.

Geriatrics: Alterations in dosage are not recommended (see Dosage and Pharmacology). When norfloxacin was administered to 4 females and 2 males, 67 to 74 years old, with normal renal function for their age, i.e., creatinine clearance 91±14 mL/min/1.73 m(1.52 mL/s/1.73 m, the plasma half-life of the drug was only slightly prolonged.

Drug Interactions: Since urinary excretion of norfloxacin is diminished by concomitant administration of probenecid, norfloxacin should not be administered concomitantly with probenecid.

Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been rare reports of theophylline-related adverse reactions in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required.

Elevated serum levels of cyclosporine have been reported with concomitant use with norfloxacin. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly.

Norfloxacin may 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.

Multivitamins, products containing iron or zinc, antacids or sucralfate should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin because they may interfere with absorption resulting in lower serum and urine levels of norfloxacin.

Norfloxacin has been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of its plasma half-life.

Antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin.

Renal Impairment: Since norfloxacin is eliminated primarily by the kidney, it should be used with caution and at a reduced dosage in patients with impaired renal function (see Dosage). Norfloxacin is not recommended for anuric patients.

There is insufficient data on which to have a dosage recommendation for the treatment of gonorrhea in patients with a creatinine clearance of 30 mL/min/1.73 m(0.5 mL/s/1.73 m or less.

Adverse Reactions: Norfloxacin is generally well tolerated. In controlled clinical trials involving 1 528 patients, the overall incidence of drug-related adverse reactions was approximately 3%. The following adverse reactions were reported: Gastrointestinal: nausea 2%, dyspepsia 0.3%, flatulence 0.3%, heartburn 0.3%, abdominal pain 0.3%, vomiting 0.2%, diarrhea 0.2%, anorexia 0.1%.

Nervous System: headache 1.6%; dizziness/lightheadedness 1.2%; drowsiness

Musculoskeletal: tendinitis 0.1%, arthralgia 0.1%.

Hypersensitivity: rash 0.4%; erythema 0.2%; urticaria 0.1%; pruritus 0.1%.

The following additional adverse reactions have been reported since the drug was marketed: Musculoskeletal: tendon rupture, possible exacerbation of myasthenia gravis.

Body as a Whole/Site Unspecific: asthenia/fatigue.

Hypersensitivity: anaphylaxis, interstitial nephritis, angioedema, vasculitis, urticaria, arthritis, myalgia.

Ocular: conjunctivitis, eye pain/irritation.

Skin: photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, pruritus.

Gastrointestinal: constipation, flatulence, pseudomembranous colitis, pancreatitis (rare), hepatitis.

Nervous System/Psychiatric: convulsions, confusion, paresthesia, polyneuropathy including Guillain-Barr© syndrome, psychic disturbances including psychotic reactions, somnolence.

Hematologic: hemolytic anemia, thrombocytopenia.

Special Senses: tinnitus.

Genitourinary: vaginal candidiasis.

Laboratory: Abnormal adverse reactions observed rarely in clinical trials include leukopenia, eosinophilia, neutropenia, proteinuria and elevation of ALT, AST, alkaline phosphatase, bilirubin, increased BUN, serum creatinine, and LDH, and decreased hematocrit.

On very rare occasions, the following have been reported: hypertonia, renal failure, dyspnea, ataxia, dysarthria, dysphasia, hemophthalmia, nystagmus, periorbital erythema, fever, dry mouth, transient hearing loss.

Others: Although the following adverse reactions were not observed in these clinical trials, they have been reported following treatment with other quinolone antibacterial agents: hemolytic anemia in patients with latent or actual defects in glucose-6-phosphate dehydrogenase (G6PD) activity; overbrightness of light, change in color perception, difficulty in focusing, decrease in visual acuity and double vision; restlessness; bullae; palpitation; soreness of the gums; joint stiffness; swelling of the extremities; metallic taste; toxic psychosis (rare); perineal burning; vertigo; edema; cholestasis; metabolic acidosis; (signs and symptoms of increased intracranial pressure in infants and children which usually disappeared rapidly with no sequelae when treatment was discontinued).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There has not been any case of overdose with norfloxacin reported to date; consequently, neither the signs nor the symptoms of overdosage have been identified.

In the event of recent acute overdose, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration should be maintained to avoid the possible development of crystalluria. Norfloxacin is not dialyzable.

Dosage And Administration: Adults: For urinary tract infections, 400 mg twice a day taken with a glass of water at least 1 hour before, or 2 hours after a meal or milk ingestion for 7 to 10 days.

For women with uncomplicated acute cystitis, the duration of therapy can be reduced to 3 days.

For adults with gonococcal urethritis or cervicitis, the recommended dosage of norfloxacin is two 400 mg tablets (800 mg) given as a single dose.

Geriatrics: The recommended dosage of norfloxacin in elderly patients with normal renal function for their age is the same as given for adults above.

Impaired Renal Function: Norfloxacin may be used in the treatment of patients with renal insufficiency who do not require hemodialysis.

In patients with a glomerular filtration rate of less than 30 mL/min/1.73 m(0.50 mL/s/1.73 m but greater than 6.6 mL/min/1.73 m(0.11 mL/s/1.73 m the recommended dose is 400 mg once daily (see Precautions).

When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function: Males:

Weight (kg)x(140-age) / 72xserum creatinine (mg/100 mL)

Females: 0.85xabove value

To convert to international units multiply results by 0.01667.

The administration to anuric patients is not recommended.

Children: Safety and efficacy of norfloxacin in prepubertal children have not been established. Norfloxacin should not be used in patients in whom epiphyseal closure has not occurred (see Warnings).

Availability And Storage: Each oval-shaped, white, film-coated compressed tablet, scored on one side and engraved MSD 705 on the other, contains: norfloxacin 400 mg. Nonmedicinal ingredients: carnauba wax, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose and titanium dioxide. Gluten- and tartrazine-free. Bottles of 30 and 100. Store at 15 to 30°C in tightly closed containers, protected from heat, moisture and direct light. (Shown in Product Recognition Section)

NOROXIN® MSD Norfloxacin Antibacterial Agent

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