Noroxin (Norfloxacin)

Norfloxacin is a fluoroquinolone anti-infective medication. In Canada, norfloxacin is used in adults to treat complicated and uncomplicated urinary tract infections and prostatitis caused by susceptible organisms, as well as uncomplicated gonorrhea.

Uses

Norfloxacin has also been used in adults to treat various gastrointestinal (GI) infections caused by susceptible organisms. Because only low serum concentrations of norfloxacin are reached after usual oral doses, its use is generally limited to genitourinary or GI tract infections. Before starting norfloxacin treatment, appropriate specimens should be collected to identify the causative organism, and in vitro susceptibility testing should be performed.

Norfloxacin may be started before these test results are available. If the clinical response is unsatisfactory, additional specimens should be obtained and susceptibility testing repeated.

Urinary Tract Infections and Prostatitis

Uncomplicated Urinary Tract Infections

Oral norfloxacin is prescribed for adults with uncomplicated urinary tract infections (UTIs) caused by susceptible bacteria, including Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae). Some clinicians recommend reserving norfloxacin for complicated UTIs, especially those involving multidrug-resistant bacteria, and advise against using it for uncomplicated infections unless first-line treatments are ineffective or not tolerated.

Studies suggest that a 7-10 day course of norfloxacin is as effective as co-trimoxazole and may cause fewer side effects. Norfloxacin has also shown similar effectiveness to amoxicillin for uncomplicated UTIs. Limited data suggest that 3 days of treatment may be enough, but more research is needed to assess relapse and recurrence rates.

Although norfloxacin can be effective, it is generally not a first choice for uncomplicated UTIs because of concerns about antibiotic resistance and possible side effects. It is mainly considered when other treatments have failed or resistance has been confirmed.

Complicated Urinary Tract Infections

Oral norfloxacin is used in adults to treat complicated UTIs caused by susceptible E. coli, K. pneumoniae, Proteus mirabilis (P. mirabilis), Pseudomonas aeruginosa (Ps. aeruginosa), Serratia marcescens (S. marcescens), or Enterococcus faecalis (E. faecalis). Oral norfloxacin has generally been effective in adults with chronic bacteriuria or complicated UTIs caused by susceptible organisms, including Ps. aeruginosa. In a limited number of patients, oral norfloxacin appeared to be as effective as injectable anti-infective therapy for nonbacteremic, hospital-acquired UTIs. However, more study is needed to compare the relative effectiveness of oral norfloxacin with the injectable anti-infectives usually used for complicated UTIs. Some clinicians suggest that norfloxacin may be especially useful for UTIs caused by organisms resistant to other anti-infectives (for example, beta-lactam antibiotics and aminoglycosides) and for chronic or complicated UTIs when injectable therapy is not warranted.

Prostatitis

Oral norfloxacin is used to treat prostatitis caused by E. coli.

Gonorrhea and Associated Infections

Oral norfloxacin is an alternative treatment for uncomplicated gonorrhea in adults, but in Canada, current practice generally centres on ceftriaxone-based treatment, with cefixime used in some situations. Although a single 800-mg dose of norfloxacin has shown activity, its role is limited because of treatment failures and the spread of fluoroquinolone-resistant Neisseria gonorrhoeae in Canada and internationally.

In Canada, uncomplicated gonorrhea is generally treated with ceftriaxone as first-line therapy, with limited alternatives used when needed. Treatment failures with norfloxacin have been reported, and fluoroquinolones are generally avoided for infections acquired in regions where resistance is known or suspected.

While studies suggest that norfloxacin may be as effective as intramuscular (IM) spectinomycin for certain strains, its effectiveness for pharyngeal infections remains uncertain. In Canadian practice, careful attention to local resistance patterns is essential, and ceftriaxone-based treatment is generally preferred for gonorrhea to help preserve effectiveness and limit resistance.

GI Infections

Norfloxacin has been effective when used in adults to treat gastroenteritis caused by susceptible strains of enterotoxigenic E. coli, Aeromonas hydrophila, Plesiomonas shigelloides, Salmonella, Shigella boydii, Shigella (Sh.) dysenteriae, Sh. flexneri, Sh. sonnei, Vibrio cholerae, or Vibrio (V.) parahaemolyticus. Although some strains of Helicobacter pylori (formerly Campylobacter pylori or C. pyloridis) are susceptible to norfloxacin in vitro, the drug has been ineffective in eradicating the organism in vivo and has had little effect on gastritis symptoms in a limited number of patients with nonulcer dyspepsia.

Cholera

Norfloxacin has been effective when used in the treatment of cholera. Although tetracyclines are generally the anti-infectives of choice for cholera when used along with fluid and electrolyte replacement, alternative agents for infections caused by tetracycline-resistant V. cholerae include co-trimoxazole, fluoroquinolones, or furazolidone. In one study in adults with severe cholera and dehydration, norfloxacin was more effective than co-trimoxazole in reducing stool output and shortening the duration of diarrhea, fluid requirements, and vibrio excretion.

Shigella Infections

Oral norfloxacin is used to treat shigellosis caused by susceptible Shigella. In severe cases, anti-infective treatment is generally recommended in addition to fluid and electrolyte replacement because these medications appear to shorten both the duration of diarrhea and the period of fecal excretion of Shigella. A fluoroquinolone (for example, ciprofloxacin, norfloxacin, or ofloxacin) or ceftriaxone is considered a treatment of choice for shigellosis when the isolate's susceptibility is unknown. Azithromycin has also been recommended, and co-trimoxazole or ampicillin may be effective if the strain is known to be susceptible. In one controlled study in adults with acute shigellosis, an 800-mg oral dose of norfloxacin was as effective as 5 days of co-trimoxazole therapy.

Travelers' Diarrhea

Norfloxacin is effective for short-term treatment and prevention of travelers' diarrhea in adults travelling to high-risk areas. These infections are mainly caused by enterotoxigenic E. coli, but other pathogens such as Shigella and Salmonella can also be involved. Treatment depends on how severe the illness is. Mild cases may only need oral rehydration, while moderate to severe cases may benefit from anti-infective medications, which can shorten the illness.

Fluoroquinolones such as norfloxacin, ciprofloxacin, levofloxacin, and ofloxacin are commonly used for treatment. Azithromycin is an alternative for children and pregnant women, especially in regions with high Campylobacter resistance. Co-trimoxazole can also be used, but resistance is a concern.

For Canadian travellers, routine preventive use of anti-infectives is generally discouraged because of resistance risks and side effects. Although preventive antibiotics have shown effectiveness in controlled studies, they are usually reserved for selected high-risk individuals. Instead, travellers should focus on prevention, such as safe food and water practices, to lower the risk of diarrhea.

Mechanism of Action

Norfloxacin is usually bactericidal. Like other fluoroquinolone anti-infectives, norfloxacin inhibits deoxyribonucleic acid (DNA) synthesis in susceptible organisms by inhibiting type II DNA topoisomerases (DNA gyrase and topoisomerase IV). In vitro studies, particularly susceptibility tests, indicate that the antibacterial activity of norfloxacin is reduced in the presence of urine, especially acidic urine.

The clinical importance of this in vitro effect has not yet been determined. However, because norfloxacin concentrations in urine are usually much higher than the norfloxacin minimum inhibitory concentrations (MICs) for most urinary tract pathogens, this effect is probably not clinically important. Norfloxacin has an activity spectrum similar to that of many other fluoroquinolones, such as ciprofloxacin and ofloxacin. Norfloxacin is active in vitro against gram-negative aerobic bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa.

The drug is also active in vitro against many gram-positive aerobic bacteria, including penicillinase-producing, nonpenicillinase-producing, and oxacillin-resistant staphylococci (previously known as methicillin-resistant staphylococci). However, many strains of streptococci are relatively resistant to the drug. Obligate anaerobic bacteria are generally resistant to norfloxacin.

The drug has some in vitro activity against Chlamydia, Mycoplasma, and some Mycobacterium, but it is inactive against fungi and viruses.

Pharmacokinetics

• Absorption: Norfloxacin is rapidly absorbed from the GI tract, although food can delay absorption. Peak plasma concentrations occur within 1-2 hours after a dose, and 30-50% of the dose is absorbed. Antacids containing magnesium or aluminum reduce its bioavailability.
• Distribution: Norfloxacin is widely distributed in various tissues, including the kidneys, liver, and prostatic tissue. Biliary concentrations can be much higher than serum levels, and the drug crosses the placenta. However, it is not detected in breast milk after a 200-mg dose.
• Elimination: The half-life in adults with normal renal function is 2.3-4 hours, and it increases with renal impairment. About 30% of a dose is excreted unchanged in the urine within 24-48 hours. Norfloxacin undergoes minimal metabolism, producing less active metabolites.

Norfloxacin is eliminated mainly through the kidneys, and dose adjustments may be needed in patients with impaired renal function.

Administration

Norfloxacin is taken by mouth. It should be taken with a glass of water at least 1 hour before or at least 2 hours after a meal or after drinking milk or other dairy products. Patients taking norfloxacin should stay well hydrated and drink plenty of fluids. To reduce the chance of interference with GI absorption, patients should be told not to take antacids containing magnesium or aluminum, sucralfate, metal cations such as iron or zinc (including multivitamin products containing zinc), or buffered didanosine preparations at the same time as norfloxacin or within 2 hours of a norfloxacin dose.

Dosage

Dosage forms of norfloxacin:

• Co Norfloxacin 400 mg Tablet;
• Novo-Norfloxacin 400 mg Tablet;
• Pms-Norfloxacin 400 mg Tablet;
• Apo-Norflox 400 mg Tablet;
• Noroxin 400 mg tablet.

Because of the risk of crystalluria, the manufacturer recommends that the usual dose of 400 mg twice daily should not be exceeded in adults with normal renal function.

Drug-Drug Interactions

This medication may interact with some drugs.

1. Antacids. Antacids containing magnesium hydroxide or aluminum hydroxide may reduce the absorption of oral norfloxacin, so these drugs should not be taken at the same time. Patients should be instructed not to take antacids at the same time as norfloxacin or within 2 hours of a norfloxacin dose. The mechanism of this interaction has not been fully clarified. However, studies using ciprofloxacin suggest that antacids containing magnesium and aluminum ions may bind to quinolones and form insoluble complexes in the GI tract.
2. Antifungal Agents. Norfloxacin is inactive against fungi when used alone. However, some in vitro studies involving Candida suggest that it may enhance the antifungal activity of agents such as amphotericin B, flucytosine, ketoconazole, miconazole, and nystatin. However, reports of this interaction are conflicting. In at least one in vitro study, norfloxacin did not affect the antifungal activity of amphotericin B. Further study is needed to assess the antifungal effect when norfloxacin is used together with an antifungal agent.
3. Aminoglycosides. The antibacterial activities of norfloxacin and aminoglycosides may be additive or partly synergistic in vitro against gram-negative bacteria such as Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, and Proteus. However, synergy appears to be unpredictable, and indifference or antagonism has also been reported when norfloxacin was used with an aminoglycoside against Enterobacteriaceae or Ps. aeruginosa.
4. Coumarin Anticoagulants. Starting oral norfloxacin in patients stabilized on warfarin has led to prolonged prothrombin time in several patients and, in at least one patient, increased prothrombin time and fatal pontine hemorrhage. The mechanism of this interaction is not known. However, norfloxacin may displace anticoagulants from serum albumin-binding sites. Norfloxacin should be used cautiously in patients taking a coumarin anticoagulant, and prothrombin time or another appropriate clotting test should be monitored closely.
5. Cyclosporine. Concomitant use of cyclosporine and norfloxacin has increased serum cyclosporine concentrations. Therefore, the manufacturer recommends monitoring cyclosporine serum concentrations and adjusting the dose as needed in patients taking both drugs.
6. Didanosine. Didanosine chewable/dispersible buffered tablets, buffered powder for oral solution, or pediatric powder for oral solution prepared as an admixture with antacid may interfere with the oral absorption of norfloxacin. To reduce the chance of interaction, patients should be told not to take didanosine preparations at the same time as norfloxacin or within 2 hours of a norfloxacin dose.
7. Iron, Multivitamins, and Mineral Supplements. Oral multivitamins and mineral supplements containing divalent or trivalent cations such as iron or zinc may interfere with the oral absorption of norfloxacin, leading to lower serum and urine concentrations of the quinolone. Therefore, these multivitamins and/or mineral supplements should not be taken at the same time as norfloxacin or within 2 hours of a norfloxacin dose.
8. Nitrofurantoin. In vitro, nitrofurantoin antagonizes the antibacterial activity of norfloxacin. Because this antagonism could also occur in vivo, norfloxacin and nitrofurantoin should not be used at the same time.
9. Other Anti-infectives. In vitro, chloramphenicol, rifampin, or tetracycline can inhibit the bactericidal activity of norfloxacin. In one in vitro study, the combination of norfloxacin with chloramphenicol or tetracycline was antagonistic against all Salmonella isolates tested. In another in vitro study using strains of Ps. aeruginosa resistant to aminoglycosides and carbenicillin, the antibacterial activities of imipenem and norfloxacin were synergistic or partly synergistic against about one-third of strains tested and indifferent against about two-thirds; antagonism did not occur. In vitro studies using gram-positive and gram-negative bacteria indicate that neither synergism nor antagonism occurs when norfloxacin is used with a beta-lactam antibiotic such as ampicillin, cefotaxime, or cefoxitin.
10. Probenecid. Concomitant administration of probenecid substantially decreases urinary excretion of norfloxacin, possibly by blocking renal tubular secretion of the anti-infective. However, serum concentrations and the half-life of norfloxacin are generally not affected.
11. Sucralfate. Concomitant administration of sucralfate may interfere with the oral absorption of norfloxacin, resulting in lower serum and urine concentrations of the quinolone. If concomitant use is necessary, the manufacturer and published studies indicate that sucralfate should not be taken at the same time as norfloxacin; separating norfloxacin by at least 2 hours before sucralfate has been shown to avoid a significant pharmacokinetic interaction.
12. Xanthine Derivatives. Concomitant use of some quinolones, such as ciprofloxacin and norfloxacin, in patients taking theophylline has increased plasma theophylline concentrations and decreased drug clearance. This may increase the risk of theophylline-related side effects. Concomitant administration of norfloxacin and an extended-release theophylline preparation in a limited number of individuals produced slight increases in serum theophylline concentrations compared with some other quinolone derivatives. In other studies, concomitant administration of norfloxacin in patients stabilized on theophylline resulted in, at most, an 18% increase in plasma theophylline concentrations and a decrease in theophylline clearance of 5-28%. Some clinicians suggest that the interaction between norfloxacin and theophylline may not be clinically important in most patients. However, theophylline-related side effects have been reported in patients receiving norfloxacin at the same time. Therefore, some clinicians suggest that norfloxacin should be used cautiously in patients taking theophylline. The manufacturer of norfloxacin states that consideration should be given to monitoring plasma theophylline concentrations, and theophylline dosage should be adjusted as required. Some quinolones, such as ciprofloxacin, have also been reported to alter the pharmacokinetics of caffeine, and the possibility of exaggerated or prolonged caffeine effects during concomitant use with a quinolone should be considered.
13. Oral contraceptives. Plasma concentrations of oral contraceptive steroids were unchanged by norfloxacin.

Food-Drug Interactions

Norfloxacin has several food-drug interactions that can affect its absorption and effectiveness. In particular, dairy products such as milk and yogurt should be avoided at the same time as norfloxacin, as they can reduce absorption by about 50% when taken together. In addition, antacids or supplements containing minerals such as calcium, iron, or magnesium should not be taken within 2 hours of norfloxacin, as they can also interfere with its bioavailability.

Side Effects

Oral norfloxacin is generally well tolerated at the doses used to treat urinary tract infections, and its side effects are similar to those reported with other quinolone anti-infectives such as ciprofloxacin and ofloxacin.

Norfloxacin is a fluoroquinolone antibacterial drug with properties similar to ciprofloxacin, although it is less potent in vitro.

Norfloxacin inhibits cytochrome P450 1A2 (CYP1A2) and can therefore increase the effects of other drugs by reducing their clearance.

Organs and Systems

• Sensory systems: A corneal ulcer associated with deposits of norfloxacin in the right eye has been reported in a 40-year-old man with right trigeminal and facial nerve palsies and reduced tear secretion. He stopped using norfloxacin ophthalmic solution and recovered.
• Psychological, psychiatric. Hallucinations have been reported with norfloxacin.
• Hematologic. Eosinophilia occurred in a 35-year-old man with alcoholic cirrhosis taking norfloxacin 400 mg twice daily (bid) for prophylaxis of spontaneous bacterial peritonitis.
• Gastrointestinal. In a prospective study of women with urinary tract infections treated with pivmecillinam 400 mg twice daily for 3 days or norfloxacin 400 mg twice daily for 3 days, 36% of the pivmecillinam group and 39% of the norfloxacin group reported adverse events. Gastrointestinal symptoms were the most common. Among patients who took norfloxacin, 4.3% developed vaginal candidiasis.
• Liver. Acute hepatitis has been reported with norfloxacin.
• Pancreas. Norfloxacin can cause pancreatitis.
• Urinary tract. Acute interstitial nephritis, probably related to norfloxacin, has been reported.
• Musculoskeletal. Myalgia has been attributed to norfloxacin.

Side effects have been reported in about 3.5-10% of patients taking norfloxacin and were severe enough to require stopping treatment in 1% or fewer patients.

The most common side effects reported during clinical trials involved the GI tract or central nervous system (CNS). However, in post-marketing experience, rash has been the side effect reported most often.

Side effects have occurred in about 7% of patients receiving a single 800-mg oral dose of norfloxacin to treat uncomplicated gonorrhea. Dizziness, nausea, and abdominal cramping were reported most often with this single-dose regimen, occurring in 2-3.5% of patients. Diarrhea, vomiting, loss of appetite, constipation, indigestion, headache, tingling in the fingers, hyperhidrosis, lower hemoglobin and hematocrit, and a decreased platelet count have also been reported. Increased aspartate aminotransferase (AST) (SGOT) concentrations were reported in 1% or fewer patients receiving the single-dose regimen.

GI Effects

Nausea is one of the most common side effects of norfloxacin. It has been reported in about 1-4% of patients taking the drug. Other GI side effects reported in 1% or fewer patients include abdominal pain, cramping, loose stools, diarrhea, vomiting, loss of appetite, indigestion, difficulty swallowing, altered taste, stomatitis, dry mouth, a bitter taste, heartburn, digestive problems, constipation, flatulence, and anal itching.

Effects on Fecal Flora

Norfloxacin selectively affects normal bowel flora, reducing gram-negative aerobic bacteria while largely leaving anaerobic and gram-positive flora intact. Normal bacterial counts typically return to baseline within 1-2 weeks after stopping the drug. Although norfloxacin has limited activity against Clostridium difficile, pseudomembranous colitis has rarely been reported, suggesting that high fecal concentrations of the drug may help protect against this condition. More research is needed to clarify the relationship between fluoroquinolone use and C. difficile-associated colitis.

Nervous System Effects

Headache has been reported in up to 3% of patients, and dizziness in up to 2% of patients taking norfloxacin. Other nervous system side effects occurring in up to 1% of patients include lightheadedness, asthenia, drowsiness, tiredness, depression, insomnia, anxiety, irritability, nervousness, euphoria, confusion or disorientation, abnormal dreams, hallucinations, personality changes, psychotic reactions, ataxia, paresthesia, and polyneuropathy including Guillain-Barre syndrome. Seizures, myoclonus, and tremors have been reported rarely in patients taking norfloxacin. Other severe CNS side effects, including increased intracranial pressure and toxic psychosis, have been reported with some other fluoroquinolones (e.g., ciprofloxacin).

Dermatologic and Sensitivity Reactions

Eosinophilia has been seen in up to 1.8% of patients taking norfloxacin, with rash, fever, and itching reported in up to 1% of cases. Severe hypersensitivity reactions, including anaphylaxis, angioedema, and toxic epidermal necrolysis, have occurred, sometimes after the first dose. The manufacturer advises stopping norfloxacin at the first sign of a rash or hypersensitivity and giving appropriate treatment for severe reactions. Norfloxacin can also cause photosensitivity, so caution with sun exposure is needed during treatment.

Genitourinary Effects

Increased serum creatinine and blood urea nitrogen (BUN) concentrations have rarely been reported in patients taking norfloxacin, along with cases of interstitial nephritis and renal failure. Although a direct causal link has not been firmly established, acute renal failure was reported in an older adult patient. Crystalluria can occur with higher doses (800-1600 mg) and urine pH levels between 6.5-7.8. However, it has not been linked to kidney toxicity in humans. Patients are advised to avoid excessive doses and maintain adequate fluid intake to reduce the risk of crystalluria.

Musculoskeletal Effects

Achilles, shoulder, and hand tendon ruptures requiring surgical repair or causing prolonged disability have been reported in patients taking fluoroquinolones, including norfloxacin. Patients who develop tendon pain, inflammation, or rupture should stop the drug right away. In addition, fluoroquinolones may worsen myasthenia gravis, leading to severe respiratory muscle weakness. Although tendonitis and tendon rupture are rare, they can happen within days to months after starting treatment, especially in older adults or people taking corticosteroids. Animal studies indicate that fluoroquinolones can cause cartilage erosion and joint problems, raising concerns about their use in humans and in immature animals.

Hepatobiliary Effects

Hepatitis, jaundice (including cholestatic jaundice), and increased serum concentrations of AST (SGOT), alanine aminotransferase (ALT) (SGPT), and alkaline phosphatase have been reported in less than 2% of patients taking norfloxacin. Increased serum lactate dehydrogenase (LDH) concentrations have been reported rarely.

Hematologic Effects

Decreased leukocyte or neutrophil counts have been reported in about 2% of patients taking norfloxacin; thrombocytopenia has also been reported. In one patient, there was some evidence that leukopenia resulted from an immunologic rather than a toxic mechanism. Decreased hemoglobin concentration, decreased hematocrit, and hemolytic anemia have occurred rarely. Prolongation of prothrombin time occurred in at least one patient taking norfloxacin.

Other Adverse Effects

Back pain, hyperhidrosis, and symptomatic hypoglycemia have been reported in patients taking norfloxacin. Tinnitus and temporary hearing loss have also been reported rarely in patients taking the drug. Diplopia and weakness have been reported. Although other visual disturbances have been reported with some fluoroquinolones (e.g., ciprofloxacin), these side effects have not been reported with norfloxacin, and animal studies using the drug have not shown evidence of ocular toxicity.

Precautions and Contraindications

Norfloxacin is contraindicated in patients with a history of hypersensitivity to the drug or other quinolones, because it can cause severe hypersensitivity reactions, sometimes after the first dose. Patients should be told to stop the drug and contact their physician at the first sign of a rash or any symptoms of hypersensitivity.

Crystalluria may occur, especially with high doses, so patients should stay well hydrated and avoid taking more than the recommended dose. Caution is advised in people with CNS disorders, as norfloxacin may worsen conditions such as seizures and myasthenia gravis. Patients should also be aware that dizziness or lightheadedness can occur. They should avoid excessive sun exposure because of the risk of phototoxicity.

Pediatric Precautions

Because norfloxacin causes arthropathy in immature animals, the manufacturer states that the drug should not be used in children or adolescents younger than 18. Some clinicians state that the drug may be used cautiously in adolescents if skeletal growth is complete. In Canada, use of fluoroquinolones (e.g., ciprofloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, sparfloxacin) in patients younger than 18 years may be justified in selected circumstances, but only after careful assessment of the individual risks and benefits and discussion with parents or caregivers.

The AAP states that fluoroquinolones may be helpful when no other oral treatment is available (to avoid the use of an injectable agent) or when the child has an infection caused by multidrug-resistant gram-negative bacteria, such as certain strains of Pseudomonas or Mycobacterium. Possible uses of fluoroquinolones in pediatric patients therefore include treatment of urinary tract infections caused by P. aeruginosa or other multidrug-resistant gram-negative bacteria, chronic suppurative otitis media or malignant otitis externa, chronic osteomyelitis, exacerbation of cystic fibrosis, mycobacterial infection, or other gram-negative bacterial infections in immunocompromised patients when prolonged oral therapy is desired.

A single oral dose of norfloxacin 6 times the usual human dose caused lameness in immature dogs; histologic evaluation of the weight-bearing joints of these dogs revealed permanent cartilage lesions. Most other quinolones (e.g., ciprofloxacin, ofloxacin) also cause cartilage erosions in weight-bearing joints and other signs of arthropathy in immature animals of various species.

Mutagenicity and Carcinogenicity

Norfloxacin was not mutagenic in the dominant lethal test in mice. It did not cause chromosomal aberrations in hamsters or rats receiving doses 30-60 times the usual human dose. In vitro studies using microbial (i.e., Ames test) or mammalian (i.e., Chinese hamster fibroblasts, V-79 mammalian cell assay) cell systems have not shown norfloxacin to be mutagenic. Although norfloxacin was weakly positive in the Rec-assay for DNA repair, other mutagenicity assays, including more sensitive tests such as the V-79 mammalian cell assay, did not show evidence of mutagenicity. Results from the hepatocyte DNA repair assay have been equivocal. There was no evidence of carcinogenicity in rats receiving norfloxacin for 19 months, and there was no increase in neoplastic changes in rats receiving norfloxacin dosages 8-9 times the usual human dosage for up to 96 weeks.

Pregnancy, Fertility and Lactation

Norfloxacin is contraindicated in pregnant and breastfeeding women because of potential risks, including embryotoxicity seen in animal studies. It caused embryonic loss in cynomolgus monkeys at high doses and has been associated with slight maternal toxicity. Although no teratogenic effects were seen in various animal species at lower doses, the drug can cross the placenta. It may be excreted in breast milk, raising concerns for nursing infants. Given these risks and the availability of safer alternatives, norfloxacin should generally be avoided during pregnancy and breastfeeding.

Acute Toxicity

Limited information is available on the acute toxicity of norfloxacin. The oral median lethal dose (LD50) of the drug is greater than 4 g/kg in mice and rats. If acute overdose of norfloxacin occurs, the stomach should be emptied by inducing vomiting or by gastric lavage.

Supportive and symptomatic treatment should be started, and the patient should be monitored. Adequate hydration must be maintained to reduce the risk of crystalluria.