Norfloxacin (AA Pharma) Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ........................................................................................... 2

TABLE OF CONTENTS ............................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ..................................................................... 4

1 INDICATIONS .............................................................................................................. 4

1.1 Pediatrics ................................................................................................................... 4

1.2 Geriatrics ................................................................................................................... 4

2 CONTRAINDICATIONS ................................................................................................. 4

3 SERIOUS WARNINGS AND PRECAUTIONS BOX. ........................................................... 5

4 DOSAGE AND ADMINISTRATION ................................................................................. 5

4.1 Dosing Considerations .............................................................................................. 5

4.2 Recommended Dose and Dosage Adjustment ......................................................... 5

4.4 Administration .......................................................................................................... 6

4.5 Missed Dose .............................................................................................................. 6

5 OVERDOSAGE ............................................................................................................. 7

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 7

7 WARNINGS AND PRECAUTIONS .................................................................................. 7

7.1 Special Populations ................................................................................................. 10

7.1.1 Pregnant Women .................................................................................................... 10

7.1.2 Breast-feeding ......................................................................................................... 10

7.1.3 Pediatrics ................................................................................................................. 11

7.1.4 Geriatrics ................................................................................................................. 11

8 ADVERSE REACTIONS................................................................................................ 11

8.2 Clinical Trial Adverse Reactions .............................................................................. 11

8.5 Post-Market Adverse Reactions .............................................................................. 13

9 DRUG INTERACTIONS ............................................................................................... 14

9.2 Drug Interactions Overview .................................................................................... 14

9.4 Drug-Drug Interactions ........................................................................................... 14

9.5 Drug-Food Interactions ........................................................................................... 16

9.6 Drug-Herb Interactions. .......................................................................................... 16

9.7 Drug-Laboratory Test Interactions.......................................................................... 16

10 CLINICAL PHARMACOLOGY ....................................................................................... 17

10.1 Mechanism of Action .............................................................................................. 17

10.2 Pharmacodynamics ................................................................................................. 17

10.3 Pharmacokinetics .................................................................................................... 18

11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 23

12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 23

PART II: SCIENTIFIC INFORMATION ...................................................................................... 24

13 PHARMACEUTICAL INFORMATION ........................................................................... 24

14 CLINICAL TRIALS ....................................................................................................... 24

14.2 Comparative Bioavailability Studies ....................................................................... 24

15 MICROBIOLOGY ....................................................................................................... 25

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 30

PATIENT MEDICATION INFORMATION ................................................................................. 35

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

NORFLOXACIN (norfloxacin tablets) is indicated for:

• 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:

  • Escherichia coli
  • Klebsiella pneumonia
  • unspecified Klebsiella spp.
  • unspecified Enterobacter spp.
  • unspecified Citrobacter spp.
  • Proteus mirabilis
  • Staphylococcus aureus
  • Streptococcus faecalis
  • Pseudomonas aeruginosa
• The treatment of adults with gonococcal urethritis, or cervicitis due to penicillinase producing and non-penicillinase producing Neisseria gonorrhoeae.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of NORFLOXACIN and other antibacterial drugs, NORFLOXACIN should be used only to treat 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.

1.1 Pediatrics

Pediatrics (<18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of NORFLOXACIN in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use. See 7.1.3 Pediatrics.

1.2 Geriatrics

Geriatrics (≥67 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness. See 7.1.4 Geriatrics.

2 CONTRAINDICATIONS

NORFLOXACIN (norfloxacin tablets) is contraindicated in:

• Patients with known hypersensitivity to NORFLOXACIN, or to other quinolone antibacterial agents or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

• Fluoroquinolones, including NORFLOXACIN, have been associated with disabling and potentially persistent adverse reactions which to date include, but are not limited to: tendonitis, tendon rupture, peripheral neuropathy and neuropsychiatric effects.

• Quinolones have been associated with prolongation of the QT interval on the

  electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsades de pointes have been reported in patients taking norfloxacin. (see 7 WARNINGS AND PRECAUTIONS: Cardiovascular).

• Fluoroquinolones, including norfloxacin, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid norfloxacin in patients with a known history of myasthenia gravis (see 7 WARNINGS AND PRECAUTIONS: Musculoskeletal).

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• In cases of uncomplicated acute bacterial cystitis, limit the use of NORFLOXACIN to circumstances where no other treatment options are available. A urine culture should be obtained prior to treatment to ensure norfloxacin tablets susceptibility.
• Limit the use of NORFLOXACIN to patients where no other treatment options exist AND where norfloxacin tablets susceptibility is demonstrated, OR norfloxacin tablets susceptibility is highly likely, typically greater than or equal to 95%, based on local susceptibility patterns.
• Appropriate culture and susceptibility studies should be carried out prior to initiation of therapy with norfloxacin tablets and if clinically indicated during treatment. Therapy may be initiated before obtaining results of these tests (see 15 MICROBIOLOGY), however, modification of such treatment may be required once the results become available.

4.2 Recommended Dose and Dosage Adjustment

Adults

The recommended dosage of NORFLOXACIN (norfloxacin tablets) for urinary tract infections is one 400 mg tablet 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 three

(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. See 7.1.4 Geriatrics.

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 m² (0.50 mL/s/1.73 m² but greater than 6.6 mL/min/1.73 m² (0.11 mL/s/1.73 m²) the recommended dose is one 400 mg tablet once daily. See 7 WARNINGS AND PRECAUTIONS, Renal.

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.

Weight (kg) x (140-age)

Males:

72 x serum creatinine (mg/100 mL)

Females: 0.85 x above value.

To convert to international units multiply result by 0.01667.

The administration of norfloxacin tablets to anuric patients is not recommended.

Pediatrics

The safety and efficacy of norfloxacin tablets in prepubertal children have not been established. Norfloxacin tablets should not be used in patients in whom epiphyseal closure has not occurred. See 7.1.3 Pediatrics.

4.4 Administration

NORFLOXACIN tablets should be taken orally with a glass of water at least 1 hour before, or 2 hours after a meal or milk ingestion.

4.5 Missed Dose

If the patient misses a dose, inform the patient to skip the missed dose and take the next dose at the regular dosing schedule.

5 OVERDOSAGE

There has not been any case of overdose with norfloxacin tablets reported to date; consequently neither the signs nor the symptoms of overdosage have been identified.

In the event of recent acute overdosage, 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 tablets is not dialysable.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

NORFLOXACIN 400 mg tablets are white, oval, biconvex, film-coated tablets, scored and engraved "400" on one side, other side plain. Available in bottles of 100, 500 and 1000s.

7 WARNINGS AND PRECAUTIONS

See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

Cardiovascular

Some quinolones have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. During post-marketing surveillance, extremely rare cases of torsades de pointes, have been reported in patients taking norfloxacin tablets These reports generally involve patients who had other concurrent medical conditions and the relationship to norfloxacin tablets has not been established. Among drugs known to cause prolongation of the QT interval, the risk of arrhythmias may be reduced by avoiding use in the presence of hypokalemia, significant bradycardia, or concurrent treatment with class Ia or

class III antiarrhythmic agents.

Aortic Aneurysm and Aortic Dissection: Epidemiologic studies report an increased risk of aortic aneurysm and dissection after intake of fluoroquinolones, particularly in the older population.

Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or in presence of other risk factors for aortic aneurysm and dissection (e.g., Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet’s disease, hypertension, atherosclerosis).

In case of sudden severe abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.

Endocrine and Metabolism

Blood Glucose Disturbances: Fluoroquinolones, including NORFLOXACIN have been associated with disturbances of blood glucose, including symptomatic hyperglycemia and hypoglycemia, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin. In these patients, careful monitoring of blood glucose is recommended. SEVERE CASES OF HYPOGLYCEMIA RESULTING IN COMA OR DEATH HAVE BEEN REPORTED. If a hypoglycemic reaction occurs, discontinue NORFLOXACIN immediately and initiate appropriate therapy.

Hematologic

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 tablets. See 8.2 Clinical Trial Adverse Reactions, Blood and lymphatic system disorders.

Musculoskeletal

As with other quinolones, tendinitis and/or tendon rupture have been observed rarely in patients taking norfloxacin tablets, especially when corticosteroids are taken concomitantly. If a patient develops symptoms of tendinitis and/or tendon rupture, norfloxacin tablets should be discontinued immediately and the patient advised to seek appropriate medical management. See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

Quinolones, including norfloxacin, may exacerbate the signs of myasthenia gravis and lead to life threatening weakness of the respiratory muscles. Caution should be exercised when using quinolones, including NORFLOXACIN, in patients with myasthenia gravis. See 8.2 Clinical Trial Adverse Reactions, Musculoskeletal and connective tissue disorders.

Neurologic

NORFLOXACIN (norfloxacin tablets) should be used with caution in patients with a history of convulsions.

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 tablets; however, a causal relationship to norfloxacin tablets has not been established.

Central Nervous System Adverse Reactions: Fluoroquinolones, including NORFLOXACIN have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (including pseudotumor cerebri), tremors, and light-headedness. As with other fluoroquinolones, NORFLOXACIN should be used with caution in patients with a known or suspected central nervous system (CNS) disorder that may predispose them to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose them to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction). If these reactions occur in patients receiving NORFLOXACIN, discontinue NORFLOXACIN immediately and institute appropriate measures.

Psychiatric

Psychiatric Adverse Reactions: Fluoroquinolones, including NORFLOXACIN have been associated with an increased risk of psychiatric adverse reactions, including: toxic psychoses, hallucinations, or paranoia; depression, or suicidal thoughts; anxiety, agitation, restlessness, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; and memory impairment. Cases of attempted or completed suicide have been reported, especially in patients with a medical history of depression, or an underlying risk factor for depression. These reactions may occur following the first dose. If these reactions occur in patients receiving NORFLOXACIN, discontinue NORFLOXACIN, and institute appropriate measures.

Ophthalmologic

If vision disorder occurs in association with the use of NORFLOXACIN, consult an eye specialist immediately. A modest increase in risk of developing retinal detachment was found in association with the use of fluoroquinolones in some observational studies; however, a causal relationship to the drug has not been clearly established.

Renal

Since norfloxacin tablets is eliminated primarily by the kidney, NORFLOXACIN should be used with caution and at a reduced dosage in patients with impaired renal function. See 4.2 Recommended Dose and Dosage Adjustment, Impaired Renal Function. Norfloxacin tablets 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 m² (0.5 mL/s/1.73 m²) or less.

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

Reproductive Health: Female and Male Potential

• Teratogenic Risk

  Reproduction studies have been carried out in the mouse, rat, rabbit, and monkey. Norfloxacin tablets 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 tablets was given by the oral route but not by the subcutaneous route. The clinical significance of the study results observed in rabbits and monkeys is not known. See 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology.

Sensitivity/Resistance

Development of Drug Resistant Bacteria: Prescribing NORFLOXACIN in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.

Skin

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

7.1 Special Populations

7.1.1 Pregnant Women

The safety of norfloxacin tablets in the treatment of infections in pregnant women is not established; consider its use only if the anticipated benefits to the mother justify the potential risks to the fetus. Following a single dose of 200 mg norfloxacin tablets, concentrations in umbilical cord serum ranged from non detectable levels to 0.5 mg/L and in amniotic fluid from non detectable levels to 0.92 mg/L. The pharmacokinetics of norfloxacin tablets in pregnant patients have not been investigated. See 7 WARNINGS AND PRECAUTIONS, Reproductive Health: Female and Male Potential.

7.1.2 Breast-feeding

Norfloxacin tablets 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 norfloxacin tablets is to be administered to a breast-feeding woman.

7.1.3 Pediatrics

Pediatrics (<18 years of age): The safety of NORFLOXACIN (norfloxacin tablets) in children is unknown. Norfloxacin tablets should not be given to patients in whom epiphyseal closure has not occurred. In two animal species (dogs and rabbits) in which norfloxacin tablets 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.

7.1.4 Geriatrics

Geriatrics (≥67 years of age): Alterations in dosage are not recommended. See 4.2 Recommended Dose and Dosage Adjustment, Geriatrics and 10.3 Pharmacokinetics, Special Populations and Conditions, Geriatrics.

When norfloxacin tablets was administered to 4 females and 2 males, 67 to 74 years old, with normal renal function for their age, [i.e., creatinine clearance of 91 ± 14 mL/min/1.73m² (1.52 ± 0.2 mL/s/1.73 m²)], the plasma half-life of the drug was only slightly prolonged.

8 ADVERSE REACTIONS

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

NORFLOXACIN (norfloxacin tablets) 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.

Table 2 – Adverse Reactions Reported with Norfloxacin Tablets Clinical Trials

8.5 Post-Market Adverse Reactions

The following additional adverse reactions have been reported since the drug was marketed:

Blood and lymphatic system disorders: Hemolytic anemia, thrombocytopenia. Abnormal adverse reactions observed rarely in clinical trials include leukopenia, eosinophilia, neutropenia.

Ear and labyrinth disorders: Tinnitus.

On very rare occasions, the following have been reported: transient hearing loss.

Eye disorders: Conjunctivitis, eye pain/irritation, visual disturbances.

On very rare occasions, the following have been reported: nystagmus, hemophthalmia.

General disorders and administration site conditions: Asthenia/fatigue.

On very rare occasions, the following have been reported: fever.

Gastrointestinal disorders: Constipation, flatulence, pseudomembranous colitis, dysgeusia, pancreatitis (rare).

On very rare occasions, the following have been reported: dry mouth.

Hepatobiliary disorders: Hepatitis, jaundice, including cholestatic jaundice.

Immune system disorders: Anaphylaxis, angioedema.

Investigations: Abnormal adverse reactions observed rarely in clinical trials include elevation of ALAT (SGPT), ASAT (SGOT), alkaline phosphatase, bilirubin, increased BUN, serum creatinine, and LDH, elevated creatine kinase (CK), and decreased hematocrit.

Musculoskeletal and connective tissue disorders: Tendon rupture, possible exacerbation of myasthenia gravis, arthritis, myalgia.

Nervous system disorders: Convulsions, paresthesia, polyneuropathy including Guillain-Barre syndrome, tremors, myoclonus, somnolence.

On very rare occasions, the following have been reported: hypertonia, ataxia, dysarthria, dysphasia.

Psychiatric disorders: Confusion, psychic disturbances including psychotic reactions.

Respiratory thoracic and mediastinal disorders: On very rare occasions, the following have been reported: dyspnea.

Renal and urinary disorders: Interstitial nephritis.

Abnormal adverse reactions observed rarely in clinical trials include proteinuria.

On very rare occasions, the following have been reported: renal failure.

Reproductive system and breast disorders: Vaginal candidiasis.

Skin and subcutaneous tissue disorders: photosensitivity, Stevens-Johnson syndrome, toxic

epidermal necrolysis, exfoliative dermatitis, erythema multiforme, pruritus, urticaria.

On very rare occasions, the following have been reported: periorbital erythema.

Vascular disorders: Vasculitis.

Others

Although the following adverse reactions were not observed in these clinical trials with norfloxacin tablets, they have been reported following treatment with other quinolone antibacterial agents:

Blood and lymphatic system disorders: Hemolytic anemia in patients with latent or actual defects in glucose-6-phosphate dehydrogenase (G6PD) activity.

Cardiac disorders: Palpitation.

Ear and labyrinth disorders: Vertigo.

Eye disorders: Overbrightness of light, change in colour perception, difficulty in focusing, decrease in visual acuity and double vision.

Gastrointestinal disorders: Soreness of the gums, metallic taste.

General disorders and administration site conditions: Swelling of the extremities, edema.

Hepatobiliary disorders: Cholestasis.

Metabolism and nutrition disorders: Metabolic acidosis.

Musculoskeletal and connective tissue disorders: Joint stiffness.

Nervous system disorders: Signs and symptoms of increased intracranial pressure in infants and children which usually disappeared rapidly with no sequelae when treatment was discontinued.

Psychiatric disorders: Restlessness; toxic psychosis (rare).

Reproductive system and breast disorders: Perineal burning.

Skin and subcutaneous tissue disorders: Bullae.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

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

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 3 - Established or Potential Drug-Drug Interactions

C = Case Study; T = Theoretical.

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions.

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Norfloxacin is a quinolone carboxylic acid antibacterial agent for oral administration. Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal.

At the molecular level, three specific actions have been attributed to norfloxacin in the inhibition of E.coli cells:

1. 1. Inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase,
2. 2. Inhibition of the relaxation of supercoiled DNA,
3. 3. Promotion of double-stranded DNA breakage.

10.2 Pharmacodynamics

ANIMAL PHARMACOLOGY

Central Nervous System

Norfloxacin (0.1 to 1.0 g/kg p.o.) showed no significant influences on behavior or in various pharmacological tests of central nervous system activity in either mice or rats. Similarly, norfloxacin (10 mg/kg i.v.) produced no changes in the central nervous system of rabbits implanted with recording electrodes.

Peripheral Nervous System

Intravenous administration of norfloxacin (10 mg/kg) modestly reduced (30%) contractions of the cat nictitating membrane elicited by both pre- and post-ganglionic nerve stimulation. Nerve stimulated contractions of the rabbit tibialis muscle, however, were unaffected by similar doses of norfloxacin.

Using in vitro smooth muscle preparations (guinea pig ileum and trachea), norfloxacin (100 to 300 mg/L) exhibited no anticholinergic, antiserotonergic or antihistaminergic activity. Likewise, norfloxacin did not alter the intrinsic muscle tone of the above preparations. In the isolated rat vas deferens, norfloxacin did alter responses to norephinephrine (slightly enhancing low concentrations and reducing high concentrations) though no alteration in epinephrine responses were observed in the guinea pig ileum and trachea. Norfloxacin (100 mg/L) slightly reduced the amplitude of spontaneous contractions of the pregnant and nonpregnant rat uterus and rabbit ileum in vitro. However, in vivo norfloxacin (10 mg/kg i.v.) was without significant effect on spontaneous contractions of the stomach, intestine, bladder and uterus of rabbits.

Similarly, gastrointestinal motility in mice was unaffected by 1.0 g/kg p.o. of norfloxacin.

Cardiovascular and Respiratory Systems

Norfloxacin (1.0 mg bolus) slightly increased (10 ± 3%) coronary flow and decreased heart rate (7 ± 2%) while modestly depressing contractile force (45 ± 4%) of isolated, perfused guinea pig hearts. In the isolated rabbit ear artery, a similar 1 mg bolus of norfloxacin produced a weak, transient decrease followed by an increase in blood flow. In vivo, norfloxacin administered intravenously increased by about 20%, the respiratory rate in urethane anesthetized rabbits (30 mg norfloxacin/kg) and barbiturate anesthetized dogs (10 mg norfloxacin/kg). In these animals blood pressure tended to be reduced without significant changes in heart rate. The decrease of blood pressure in rabbits (approximately 15%) and particularly dogs, was marked by considerable animal variation (3/6 dogs had decreases of 90 to 100 mmHg). Infusion of norfloxacin (180 mg/hour i.v.) produced an elevation in the respiratory rate (60% increase) with a decrease (about 10%) in blood pressure and no change in heart rate in dogs. In urethane anesthetized rats, a reduction of about 20% in blood pressure was caused by norfloxacin (200 mg/kg i.v.). This reduction was inhibited by diphenhydramine but unaffected by atropine, propranolol or phentolamine. Oral administration of norfloxacin (1.0 g/kg) did not alter the blood pressure of unanesthetized rats.

Other Systems

Norfloxacin (1.0 g/kg p.o.) did not change blood sugar levels or coagulation time in rats and did not exhibit any anti-inflammatory activity in rats. Similarly, norfloxacin (300 mg/kg p.o.) was unable to prevent cold stress-induced ulcers in rats. Subcutaneous administration of norfloxacin (200 mg/kg) significantly reduced by about 90% gastric acid secretion while doses as high as 1.0 g/kg p.o. failed to alter bile secretion in rats. Norfloxacin (1.0 g/kg p.o.) significantly reduced urinary volume (30% decrease) over 24 hours and reduced urinary Na⁺ excretion (ca. 25%) and significantly increased urinary K⁺ excretion (ca. 30%) over this time period. None of these effects were observed at doses of 100 mg/kg p.o.

10.3 Pharmacokinetics

Absorption

Animal Pharmacokinetics

The absorption, distribution, and excretion of norfloxacin has been studied in rats, dogs, monkeys, mice and rabbits. Absorption is rapid in all species following oral administration, ranging from 10 to 12% in rats, mice and rabbits to 20 to 25% in monkeys and 70% in beagle dogs. Serum levels of norfloxacin measured for 0.5 to 4 hours after oral drug administration to monkeys (25 mg/kg) ranged from 0.3 to 2.35 mcg/mL.

Human Pharmacology

In 15 healthy fasting male volunteers aged 22 to 52 years (mean age: 34.1 ± 9.2 years), the mean peak serum concentrations of norfloxacin was 0.8 ± 0.3 (0.4 to 1.5) and 1.5 ± 0.6 (0.6 to 2.7) mg/L occurring within 1 to 1.5 hours of oral administration of 200 mg and 400 mg doses, respectively.

The mean elimination half-life of norfloxacin was approximately 3 hours. Therefore, as was noted in another group of 26 healthy male (23) and female (3) volunteers aged 19 to 50 years (mean: 28.6 ± 9.1 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.

Pharmacokinetic information for healthy normal volunteers is given in Table 6

Distribution

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

Tissue Concentrations: Concurrent norfloxacin concentrations in serum, tissues and body fluids are given in Table 4

Table 4: Norfloxacin Concentrations in Human Tissues and Body Fluids

+ One 400 mg tablet at time zero the evening before surgery and again 11 hr later.

* One 400 mg tablet given between 21 hr and 22 hr the night before surgery and a second 400 mg tablet one hour before surgery.

** The serum levels in 2 out of 3 patients were higher than expected and consequently kidney concentrations may also have been higher than expected.

Elimination and Metabolism

Animal Pharmacokinetics: In rats, dogs and monkeys, 8%, 39% and17% of respective oral doses of norfloxacin were excreted in urine, chiefly as unchanged drug (>75%), but also as various combinations of six metabolites, all with modifications in the piperazine ring.

Human Pharmacology: Following oral administration to 15 healthy fasting male volunteers, aged 22 to 52 years (mean: 34.1 ± 9.2 years), 25 to 30% of a norfloxacin dose was recovered unchanged in urine within 48 hours (see Table 5).

Table 5: Mean Urinary Excretion of Norfloxacin

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 mcg/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 of norfloxacin is absorbed. After a single 400 mg dose, mean antimicrobial activities equivalent to 164 ± 202, 338 ± 220, 632 ± 688, and 126 ± 123 mcg of norfloxacin/g of feces were recovered over 0 to 12, 12 to 24, 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 ± 71 mL/min (range: 161 to 424) [4.58 ± 1.18 mL/s range: 2.68 to 7.07)].

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 (see Table 5).

Special Populations and Conditions

• 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 years old with normal renal function for their age i.e., creatinine clearance 91 ± 14 mL/min/1.73 m² (1.52 ± 0.23 mL/s/1.73 m²), 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 (see Table 5). 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 (see Table 6).

Table 6: Comparison of Pharmacokinetic Parameters Between Healthy Elderly Volunteers and

Healthy Younger Volunteers Following a Single 400 mg Oral Dose

• Renal insufficiency: Excretion of norfloxacin in patients with creatinine clearance (C_cr)

  greater than 30 mL/min/1.73 m² (0.50 mL/s/1.73 m², was similar to that of healthy volunteers. In patients with C_cr less than 30 mL/min/1.73 m² (0.50 mL/s/1.73 m²) but greater than 6.6 mL/min/1.73 m² (0.11 mL/s/1.73 m²), less than 10% of an oral dose was excreted in urine. The mean elimination half-life of norfloxacin in serum increased to 6.5 hours in these patients (see Table 7).

Table 7: Mean Pharmacokinetic Parameters for Norfloxacin Following a Single 400 mg Oral Dose in Healthy Volunteers and in Patients with Varying Degrees of Renal Insufficiency

*Harmonic mean

• 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.

11 STORAGE, STABILITY AND DISPOSAL

Store at room temperature 15°C to 30°C. Keep container tightly closed. Protect from light.

NORFLOXACIN should never be disposed of in household trash. Disposal via a pharmacy take back program is recommended.

12 SPECIAL HANDLING INSTRUCTIONS

None.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: norfloxacin

Chemical name: 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-

3-quinoline carboxylic acid.

Molecular formula and molecular mass: C₁₆ H₁₈ F N₃ O₃ and 319.34 g/mol

Structural formula:

Physicochemical properties: Norfloxacin is an odourless, white to pale yellow crystalline powder with a bitter taste and a melting point of 220 to 224⁰C. It is very slightly soluble in water, in methanol, and in ethyl acetate; slightly soluble in acetone and in alcohol; freely soluble in acetic acid; sparingly soluble in chloroform; and insoluble in ether.

14 CLINICAL TRIALS

14.2 Comparative Bioavailability Studies

A comparative bioavailability study was performed using healthy human volunteers. The rate and extent of absorption of norfloxacin following administration of a single (one 400 mg tablet) dose of NORFLOXACIN and NOROXIN^® were measured and compared. The results are ummarsummarized as follows:

Table 8 - Summary Table of the Comparative Bioavailability Data

*Arithmetic means (CV%).

**Based on the least squares estimate.

†Noroxin^® is manufactured by Merck, Sharp & Dohme, Div. of Merck Frosst Canada, and was purchased in Canada.

15 MICROBIOLOGY

The in vitro activity of norfloxacin tablets against clinical isolates of gram-positive and gram-negative aerobic bacteria is shown in Table 9. Susceptibility was determined by both agar and broth dilution tests, pH 7.1 to 7.4, using inoculum sizes ranging from 10⁴ to 10⁵ colony-forming units (cfu) per mL. Norfloxacin tablets lacks useful activity against Actinomyces spp., Fusobacterium spp., Bacteroides spp., and Clostridium spp., other than C. perfringens. The minimal inhibitory concentrations (MICs) of norfloxacin against aerobic bacteria are not significantly affected by culture medium composition or by changes in inoculum size in the range 10³ to 10⁶ cfu/spot (Table 10). In one study with 37 enterobacteria in Mueller-Hinton agar, increases in MIC values of norfloxacin at 10⁸ cfu/spot were 2- to 4-fold higher than at 10⁶ cfu/spot.

MICs of 4- and 33-fold higher were seen when representative enterobacteria were tested simultaneously in Diagnostic Sensitivity Test (DST) agar at pH 5.5 (MIC range= 0.12 to 32 mg/L), and at pH 7.2 (MIC = 0.015 to 4). This reduction in antibacterial activity suggests a pH effect (Table 10). In pooled human urine agar at pH 6.5, the observed MICs ranged from 0.06 to 16 mg/L. The magnesium content of urine could account for the reduced activity of norfloxacin and other quinolones in pooled human urine agar.

Generally, minimal bactericidal concentrations (MBCs) for norfloxacin are 1 to 4 times the MICs against susceptible bacteria. At these concentrations, norfloxacin is bactericidal, even with bacteria in their stationary phase of growth.

TABLE 9: CUMULATIVE PERCENT OF STRAINS INHIBITED AT THE INDICATED CONCENTRATION OF NORFLOXACIN

* Only three strains

** Includes 303 penicillinase-producing stains

TABLE 10: EFFECT OF CULTURE MEDIUM COMPOSITION, pH AND INOCULUM SIZE ON

ANTIBACTERIAL ACTIVITY OF NORFLOXACIN

^aTSA = trypticase soy agar (BBL); NA =nutrient agar (Difco); MH =Mueller Hinton agar (BBL); BHI = brain heart infusion (Difco); 10⁶ cfu, pH 7.3

^b Trypticase soy broth, 10⁵ cfu/mL;ND = not done

^cTSA = (BBL), pH 7.3

Development of Resistance

A progressive increase in MIC of norfloxacin was demonstrated in five bacterial isolates by daily passage in subinhibitory concentrations of drug (Table 11). Cross-resistance with other quinolone antibacterial agents has also been observed.

Table 11: Comparative Norfloxacin MIC of Parent and Derivative Strains

* Broth dilution test, inoculum 10⁶ cfu/mL, trypticase soy broth.

R3= parent strain after 3 transfers.

R5 = parent strain after 5 transfers.

The frequency with which resistant mutants arise varies among genera (Table 12), is greatest for P. aeruginosa and least for E. coli. In concentrations within two dilutions of the MIC, mutants of P. aeruginosa can be isolated rather frequently 10^-4 to 10^-6, whereas those of E. coli are relatively uncommon (10^-8). Increasing amounts of norfloxacin resulted in lower frequency of mutants (Table 12).

Table 12: Frequency of Norfloxacin-Resistant Mutants Among Various Species of

Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus

*Overnight cultures in trypticase soy broth (Oxoid) were plated in 10- and 100-fold dilutions on CLEO agar (Oxoid) containing various concentrations of norfloxacin.

ND =not detectable, frequency of resistant mutants <10^-10

Nalidixic acid-resistant urinary isolates have been reported to demonstrate higher MICs to norfloxacin than nalidixic acid-suspectible strains. In one study, nalidixic acid-resistant strains of enterobacteria (MIC 2 ≥ 128 mg/L) showed an MIC range for norfloxacin of 0.06 to 16 mg/L (Table 13), or 4 to 16 times that for the nalidixic acid-susceptible strains tested (MIC range of 0.015 to 1.0 mg/L). Thus, induced resistance to nalidixic acid was associated with cross-resistance to norfloxacin.

Table 13: Norfloxacin MICs Against Nalidixic Acid-Susceptible and -Resistant Urinary

Enterobacteria

The inoculum was applied with a multipoint inoculator, at approximately 10² cfu/spot. ^a MIC ≤ 32 mg/L

^b MIC ≥ 128 mg/L

Nalidixic acid-resistant organisms were inhibited by norfloxacin tablets at a concentration of 16 mg/L or less for approximately 90% of the isolates investigated. Norfloxacin tablets is active in vitro against Enterobacteriaceae and nonfermentative gram-negative bacilli (Pseudomonas aeruginosa, Acinetobacter spp.) resistant to ampicillin, carbenicillin, trimethoprim and aminoglycosides. Antagonism has been demonstrated in vitro between norfloxacin and nitrofurantoin.

Susceptibility Testing

The standard disc (1 to 3) susceptibility test [formerly, Kirby-Bauer] (using the 10 mcg norfloxacin disc of 6 mm diameter) or dilution susceptibility should be used.

Organisms should be tested with norfloxacin discs, since norfloxacin has been shown by in vitro tests to be active against genera and strains of bacteria known to be or determined to be resistant when nalidixic acid discs are used.

Table 14: Interpretation of Susceptibility Criteria of Norfloxacin (For Mild or Moderate Infections of the Urinary Tract)

These susceptibility criteria apply only to organisms isolated from urine (urinary tract).

There is a lack of clinical data to indicate if these same susceptibility criteria will be appropriate for the treatment of severe urinary tract infections suitable for oral therapy.

Proposed control limits for monitoring susceptibility tests are given in Table 15.

Table 15: Control Limits for Monitoring Norfloxacin Susceptibility Tests

^*Trademark of American Type Culture Collection

16 NON-CLINICAL TOXICOLOGY

General Toxicology

Acute Toxicity

The six metabolites were also tested orally for their acute toxicity in rats and mice. The LD ₅₀ values were estimated to be greater than 2000 mg/kg.

Subacute Toxicity Studies

One month oral toxicity studies were carried out in rats (250, 500 and 1000 mg/kg/day, 10 males and 10 females per group), dogs (50, 100 and 200 mg/kg/day, one male and one female per group; or 25, 50 and 100 mg/kg b.i.d., 6 days per week, 3 males and 3 females per group) and monkeys (25, 50, 100 mg/kg, b.i.d., 6 days per week, 2 males per group). In all studies, similar size groups served as controls and received sterile distilled water.

A slight increase in urinary potassium excretion was seen in female rats dosed at 500 and 1000 mg/kg/day. There was, however, no concurrent decrease in serum potassium level. A slight enlargement of cecum was observed in 3 of 10 male rats at 1000 mg/kg/day. Liver glucose-6- phosphatase activity was slightly increased at all dose levels in the dog study in which norfloxacin tablets was given at doses of 25, 50 or 100 mg/kg b.i.d.

Chronic Toxicity Studies

A six-month oral toxicity study in rats at norfloxacin tablets doses of 0, 125, 250 and 500 mg/kg/day (10 rats/sex/group) revealed only minimal effects as evidenced by slight body weight retardation in male rats in the 250 and 500 mg/kg/day groups.

A similar study was carried out in rats (15 rats/sex/group) at norfloxacin tablets doses of 0, 50, 200 and 600 mg/kg/day orally. There was a slight, but not statistically significant, decrease in body weight gain at 600 mg/kg/day in males. In addition, crystalluria consisting of the dihydrate and the magnesium salt of norfloxacin occurred in rats from the 200 and 600 mg/kg/day groups. The crystalluria was most frequent in males given 600 mg/kg/day. A high incidence of cecal enlargement was seen at all dose levels. Gray feces were observed in all treated groups and a very slight but statistically significant decrease in serum proteins was observed in males dosed at 600 mg/kg/day.

Four chronic oral toxicity studies were performed to evaluate the potential toxicity of norfloxacin tablets in dogs following chronic administration for 20 weeks to 13 months. The doses used were: 0, 25, 50 and 100/200 mg/kg/day (the dose was increased due to lack of drug-induced effect, 6 days per week, 4 males and 4 females per group); 0, 50, 150 and 300 mg/kg/day (7 days per week, 3 males and 3 females per group); 0, 25, 50 and 100 mg/kg/day (7 days per week, 1 male and 1 female per group); 0, 50, 100 and 150 mg/kg/day (7 days per week, 4 males and 4 females per group). Crystalluria was evident in one of these studies where dogs were given the drug at 50, 150 and 300 mg/kg/day for 26 weeks. The incidence was dose related. Four dogs, (1 and 3 in the 150 mg and 300 mg/kg/day dosage groups respectively), were found dead or were sacrificed due to urinary obstruction

from drug crystals. It was postulated that crystalluria in dogs and rats is the result of low solubility of norfloxacin in alkaline urine. This was supported by the observation of a significant decrease in the incidence of crystalluria and the absence of urinary obstruction in dogs in a separate study at 50, 150 and 300 mg/kg/day orally to 3 dogs/sex/group for three months where the urine was acidified by the administration of ammonium chloride. The pH after urine acidification was generally 6.0 or below whereas the urinary pH of dogs where drug crystals were formed was between 6.86 and 8.28.

Other frequently observed changes in the 150 and 300 mg/kg/day groups consisted of a dose- related incidence of emesis, grey or clay-coloured feces (due to unabsorbed drug) and retardation of body weight gain. There were also changes in the hematologic and serum biochemical parameters (leukocytosis, elevated serum urea nitrogen and creatinine) that are compatible with uremia and pyelonephritis secondary to intrarenal or urethral obstruction.

Carcinogenicity

A 19-month chronic oral toxicity study was done in rats (50 per sex per group). The rats were autopsied after a 12 to 14 week withdrawal period. Norfloxacin tablets was given in the diet at 0.05 or 0.2% in the feed. The estimated drug intake was 18 to 35 mg/kg/day for the low dose group and 70 to 140 mg/kg/day for the high-dose group. No drug related neoplastic changes were reported as compared to control animals. The highest dose was below the maximum tolerated dose (approximately 600 mg/kg/day).

Genotoxicity

Norfloxacin tablets was negative in a dominant lethal test in mice (300 or 800 mg/kg administered as a single dose), an in vivo chromosome aberration test in rats (1000 mg/kg/day for 38 days) and hamsters (250 or 500 mg/kg, one dose), and various in vitro genotoxicity studies including an Ames test, chromosomal aberration test, sister chromatid exchange assay, unscheduled DNA synthesis assay and V-79 mammalian cell mutagenesis assay. Norfloxacin tablets was weakly positive in a test for DNA repair (rec assay), however, this was considered to be of questionable biological significance since a more sensitive test for DNA repair (V-79 mammalian cell mutagenesis assay) was negative.

Reproductive and Developmental Toxicology

Fertility

The effect of norfloxacin tablets on fertility was assessed in male and female mice. Norfloxacin tablets was administered orally at dosage levels of 0, 125, 250, 500 mg/kg/day (20 per sex per group) for 61 days before mating and during mating to male mice and for 15 days before mating until the sixth day of pregnancy to female mice. There were no treatment-related effects on the reproductive performances of the adults or differences in growth and characteristics of the fetuses.

TERATOLOGY

In mice, oral doses of 0, 125, 250 or 500 mg/kg/day (31 mice/group) given on days 6 to 15 of gestation did not have any adverse effect on the pregnant mother or F₁ or F₂ fetuses.

In rats, oral doses of 0, 50, 200 or 800 mg/kg/day (administered b.i.d. to 20 rats/group) given on days 6 to 17 of gestation did not adversely affect the progress or outcome of pregnancy.

Rabbits

In an oral teratology study, rabbits were given 0, 25, 50 or 100 mg/kg/day of norfloxacin tablets orally (12 or 13 rabbits per group) from day 6 to 18 of gestation. In this study, rabbits in the 100 mg/kg/day group showed decreased activity, reduced appetite, diarrhea and reduced body weight gain. Embryotoxicity (i.e., abortion and fetal resorption) was also observed at this dosage level. An additional study comparing the maternal and fetal toxicity of norfloxacin tablets administered orally at doses of 100 mg/kg/day with that administered subcutaneously at doses of 20 mg/kg/day (which resulted in approximately 5-fold higher maximum plasma drug levels) was carried out. There was no evidence of embryotoxicity in the group that received norfloxacin tablets at a dose of 20 mg/kg/day by the subcutaneous route. This suggested that the embryotoxicity of norfloxacin tablets in rabbits did not correlate with drug levels in blood.

Monkeys

In an oral teratology study in cynomolgus monkeys, norfloxacin tablets was given at doses of 0, 50, 100, 150 or 300/200 mg/kg/day (the dose was reduced because of emesis) in single or divided doses from days 20 to 50 gestation. There were at least 10 female monkeys in each group. Doses of 200 mg/kg/day and greater were maternotoxic and produced vomiting, reduced appetite, and body weight loss. In the 150 and 300/200 mg/kg/day groups, 3 of 10 and 11 of 16 monkeys lost their embryos. There was no evidence of a teratogenic effect in surviving fetuses. Doses of 100 mg/kg/day did not result in any increase in embryonic losses relative to controls.

Gestation and Postnatal Development

The effect of norfloxacin tablets during the gestation and postnatal period was studied in mice at doses of 0, 125, 250 and 500 mg/kg/day (21 mice per group). Female mice were dosed orally from day 15 of gestation to day 21 postpartum. No significant difference was observed with newborn of the treated groups as compared to controls.

Special Toxicology

Arthopathy

Three to five month old dogs were treated orally with norfloxacin tablets for seven days at doses of 0, 30, 60, 100, 250 or 500 mg/kg/day or for 99 days at a dose of 0 or 200 mg/kg/day (2 or 3 dogs per group). Similarly, 8 to 10 week old rabbits were treated orally for seven days at 0, 250 or 300 mg/kg/day or for 21 days at 0, 100 or 150 mg/kg/day (5 to 11 rabbits/group). Nalidixic acid (30, 60 and 100 mg/kg/day) and pipemidic acid (30, 60, 100, 200 and 500 mg/kg/day) were used as positive controls. Clinical signs of lameness appeared from the second day in dogs given doses greater than 60 mg/kg/day of norfloxacin tablets and persisted through the duration of the seven day study. Similar signs of lameness were seen in dogs given oral doses greater than 30 mg/kg/day of nalidixic acid and pipemidic acid.

No clinical signs of lameness were seen in rabbits treated with any of these test compounds. In dogs, lameness was associated with joint lesions that were characterized by increased amount of synovial fluid and blister formation and sometimes erosions on the articular cartilage. There was recovery from clinical signs within six to eight weeks after initiation of the study, but lesions remained.

In the rabbits, there was blister formation on the articular cartilage at doses of 250 mg/kg/day or greater for seven days. There were no clinical signs of lameness.

The arthropathogenic effects of norfloxacin tablets were limited to young animals. There was no evidence of lameness or gross changes in the joints of dogs that were 8 to 10 months of age at the start of the study and given oral doses of norfloxacin tablets up to 100 to 150 mg/kg/day for 22 weeks to 13 months.

Antigenicity

Antigenicity of norfloxacin tablets was studied by examining its potential to induce delayed hypersensitivity and anaphylactic reaction in guinea pigs (0.8% and 0.5% respectively) and specific antibodies in rabbits (30 mg/mL-1 mL, 2 injections). Norfloxacin tablets elicited no delayed hypersensitivity reaction on the skin of guinea pigs. Anaphylactic reaction was not observed in guinea pigs sensitized with norfloxacin tablets alone or a mixture of norfloxacin and Freund's complete adjuvant. Serum from guinea pigs sensitized with norfloxacin failed to induce passive cutaneous anaphylaxis in recipient guinea pigs. Specific antibodies against norfloxacin were not detected in sera of rabbits immunized with norfloxacin conjugated with bovine gammaglobulin and Freund's complete adjuvant.

Retina

No evidence of retinal toxicity was seen in cats given oral doses up to 200 mg/kg/day for two weeks as measured by electroretinogram and histopathology.

Auditory System

Norfloxacin tablets administered to rats at a rate of 500 mg/kg/day orally for six months did not have any adverse effect on the auditory or vestibular function or on the histology of the organ of Corti.