PRODUCT MONOGRAPH

NAME

pms-CIPROFLOXACIN

(ciprofloxacin hydrochloride tablets, USP) ciprofloxacin 100 mg ciprofloxacin 250 mg ciprofloxacin 500 mg ciprofloxacin 750 mg

CONTRAINDICATIONS

pms-CIPROFLOXACIN (ciprofloxacin hydrochloride) tablets are contraindicated in patients who have shown hypersensitivity to ciprofloxacin or other quinolone antibacterial agents.

WARNINGS

Children

The safety of pms-CIPROFLOXACIN (ciprofloxacin hydrochloride tablets) in children has not yet been established. Damage to juvenile weight-bearing joints and lameness were observed both in rat and dog studies but not in weaned piglets (see TOXICOLOGY). Histopathological examination of the weight-bearing joints in immature dogs revealed permanent lesions of the cartilage. Consequently, ciprofloxacin should not be used in prepubertal patients. Experience in pubertal patients below 18 years of age is limited.

Pregnancy

The safety of ciprofloxacin in the treatment of infections in pregnant women has not yet been established. (See PRECAUTIONS).

General

Convulsions have been reported in patients receiving ciprofloxacin. Convulsions, increased class. Quinolones may also cause central nervous system (CNS) stimulation which may lead to tremors, restlessness, lightheadedness, confusion and hallucinations. If these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors that predispose to seizures (See ADVERSE REACTIONS).

PRECAUTIONS

General

Anaphylactic reactions including cardiovascular collapse have occurred rarely in patients receiving therapy with ciprofloxacin. These reactions may occur within the first 30 minutes following the first dose and may require epinephrine and other emergency measures. Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic necrosis with fatal outcome have also been reported to occur very rarely in patients receiving ciprofloxacin in combination with other drugs. The possibility that these reactions were related to ciprofloxacin cannot be excluded. Ciprofloxacin should be withdrawn at the first appearance of a skin rash or other signs of hypersensitivity. Tendon rupture (predominantly Achilles tendon) has been reported predominantly in the elderly on prior systemic treatment with glucocorticoids. At any sign of an tendonitis (i.e. painful swelling), the administration of ciprofloxacin should be discontinued, physical exercise avoided, and a physician consulted. Crystalluria related to ciprofloxacin has been reported only rarely in man because human urine is usually acidic. Crystals have been observed in the urine of laboratory animals, usually from alkaline urine. Patients receiving ciprofloxacin should be well hydrated and alkalinity of the urine should be avoided. The recommended daily dose should not be exceeded. Pseudomembranous colitis has been reported with virtually all antibacterial agents, including ciprofloxacin, and may range in severity from mild to life-threatening. It is important to consider this diagnosis in patients with diarrhoea subsequent to the administrations of antibacterial agents. Subsequent to diagnosis of pseudomembranous colitis, therapeutic measures should be initiated. Mild cases will usually respond to discontinuation of drug alone. In moderate to severe cases, consideration should be given to the management with fluids, electrolytes, protein supplementation and treatment with an antibacterial drug effective against Clostridium difficile. Ciprofloxacin has been shown to produce photosensitivity reactions. Patients taking ciprofloxacin should avoid direct exposure to excessive sunlight or UV-light. Therapy should be discontinued if photosensitization (ie. sunburn-like skin reactions) occurs. Prolonged use of ciprofloxacin may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is therefore essential, and if superinfection should occur during therapy, appropriate measures should be taken.

Pregnancy

The safety of ciprofloxacin in pregnancy has not yet been established. Ciprofloxacin should not be used in pregnant women unless the likely benefits outweigh the possible risk to the fetus. Ciprofloxacin has been shown to be non-embryotoxic and non-teratogenic in animal studies.

Nursing mothers

Ciprofloxacin is excreted in human milk. A decision should be made to discontinue nursing or to discontinue the administration of ciprofloxacin, taking into account the importance of the drug to the mother and the possible risk to the infant.

Drug interactions

Concurrent administration of ciprofloxacin with theophylline may lead to an elevated plasma concentration and prolongation of elimination half-life of theophylline. This may result in increased risk of theophylline-related adverse reactions. If concomitant use cannot be avoided, plasma concentrations of theophylline should be monitored and dosage adjustments made as appropriate. Ciprofloxacin has been shown to interfere with the metabolism and pharmacokinetics of caffeine. Excessive caffeine intake should be avoided. Some quinolones, including ciprofloxacin, have been associated with transient increases in serum creatinine levels in patients who are concomitantly receiving cyclosporine. Quinolones have been reported to increase the effects of the oral anticoagulant warfarin and its derivatives. During concomitant administration of these drugs, the prothrombin time or other appropriate coagulation tests should be closely monitored. Probenecid blocks renal tubular secretion of ciprofloxacin and has been shown to produce an increase in the level of ciprofloxacin in the serum. Concomitant administration of a nonsteroidal anti-inflammatory drug (fenbufen) with a quinolone (enoxacin) has been reported to increase the risk of CNS stimulation and convulsive seizures. Antacids containing aluminum or magnesium hydroxide have been shown to reduce the absorption of ciprofloxacin. Concurrent administration with these agents should be avoided. Administration of sucralfate prior to ciprofloxacin resulted in a 30% reduction in absorption of ciprofloxacin. Concurrent administration with ciprofloxacin should be avoided. Oral ferrous sulfate at therapeutic doses decreases the bioavailability of oral ciprofloxacin, therefore concomitant therapy is not advised. The use of calcium supplement and highly buffered drugs such as antiretrovirals reduces the absorption of ciprofloxacin, therefore concomitant administration is not advised. In particular cases, concurrent administration of ciprofloxacin and glyburide can intensify the action of glyburide (hypoglycemia).

Renal impairment

Since ciprofloxacin is eliminated primarily by the kidney, ciprofloxacin should be used with caution and at a reduced dosage in patients with impaired renal function. (See DOSAGE AND ADMINISTRATION).

Hepatic impairment

In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics were observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, however, have not been fully elucidated. An increased incidence of nausea, vomiting, headache and diarrhoea were observed in this patient population.

PHARMACOLOGY

ANIMAL PHARMACOLOGY

Effects on histamine release

Ciprofloxacin was administered intravenously to 9 anaesthetized dogs (initially with thiopental sodium at 25 mg/kg I.V., followed by continuous infusion of a mixture of fentanyl 0.04 mg/kg/hr and dehydrobenzperidol 0.25 mg/kg/hr) at a single dose of 3, 10 or 30 mg/kg. Ciprofloxacin treatment resulted in circulatory changes similar to those caused by histamine release. These were reductions in blood pressure, cardiac output and maximum rate of pressure increase in the left ventricle (dp/dt max), and increase in heart rate. This histamine-liberating effect was counteracted by the simultaneous intravenous administration of 0.01 mg/kg pyrilamine maleate. No signs of histamine liberation were observed on conscious animals.

In vitro

experiments on isolated rat mast cells also indicate that ciprofloxacin at concentrations of

0.1 to 100 mg/L has histamine-liberating properties.

Bronchodilatory Effects

Ciprofloxacin was tested on isolated guinea-pig trachea at concentrations of 0.0001 to 10 mg/L. It produced a dose-related small but significant relaxation of respiratory airway smooth muscle. It has, however, no effect on leukotriene D4 and histamine-induced contractions at these doses.

CNS Effects

Ciprofloxacin was administered orally to 4 groups of 1 cat each under chloralose-urethane anaesthesia at doses of 0, 10, 20, and 100 mg/kg. No effects were observed on neuromuscular transmission, flexor reflex, or blood pressure.

Gastrointestinal Effects

Ciprofloxacin was administered orally to 4 groups of 20 mice each at doses of 0, 10, 30 and 100 mg/kg, 40 minutes prior to a 15% charcoal suspension. No effect was observed in intestinal charcoal transit time. When given to 3 groups of 20 rats each at doses of 0, 30 or 100 mg/kg, no gastric lesions were observed on sacrificing the animals after 5 hours. When given intraduodenally to 3 groups of 8 rats each at doses of 0, 10 and 100 mg/kg, no increase in basal gastric acid secretion was observed on perfusion of the stomach.

Effect on Blood Glucose and Serum triglycerides

Four groups of six fasting rats each were given intravenous injections of 0, 3, 10 and 30 mg/kg respectively. A slight but significant increase in blood glucose concentrations 60 minutes and 240 minutes post dose was observed in the 3 and 10 mg/kg groups but not in the 30 mg/kg group in comparison to controls. At 60 minutes post dose, the serum triglyceride concentrations were slightly but significantly reduced in all three groups. This effect was not dose-related. At 120 minutes, the concentration was slightly elevated in the 30 mg/kg group.

HUMAN PHARMACOLOGY

Pharmacokinetics and absorption

Following oral administration of single doses of 250 mg, 500 mg and 750 mg of ciprofloxacin respectively to groups of 3 healthy male volunteers (age: 22.8 +- 3.5 years, weight 68.5 +- 9.4 kg), ciprofloxacin was absorbed rapidly and extensively from the gastrointestinal tract (Figure 1). Maximum serum concentrations (Cmax) increased dose-proportionally and were attained 1 to 2 hours after oral dosing. The total areas under the serum concentration - time curves (AUC) were also increased in proportion to dose (Figure 1). Mean concentrations 12 hours after dosing with 250 mg, 500 mg, or 750 mg were 0.1, 0.2, and 0.4 mg/L, respectively. The serum elimination half- lives (t1/2) were between 4 and 6 hours. (Table 6). Pharmacokinetics were dose proportional with no significant changes in clearance or half-life occurring over this dose range (see Table 6 below).

Table 6

Pharmacokinetic parameters of Ciprofloxacin Following Single Oral Doses In Healthy Volunteers

Similar values were obtained following the oral administration of multiple doses every 12 hours for 7 days (Table 7).

Table 7

Mean Pharmacokinetic Parameters of Ciprofloxacin and Metronidazole at Steady State in Healthy Volunteers

Following the repeated dosing of metronidazole 55 mg IV tid, the peak and minimum mean plasma metronidazole concentrations, at steady-state, were 26 :g/mL and 12 :g/mL respectively.

Figure 1

Mean Ciprofloxacin Serum Concentration After Single Oral Doses

Metabolism and Excretion

Ciprofloxacin is largely excreted unchanged both renally and to a small extent, extrarenally (Table 8).

Table 8

Mean Urinary Excretion of Ciprofloxacin

Small concentrations of 4 metabolites have been reported: Desethyleneciprofloxacin (M1) (1.8%), sulphociprofloxacin (M2) (5.0%), oxociprofloxacin (M3)(9.6%) and formylciprofloxacin (M4) (0.1%). Following the oral administration of a single 259 mg dose of 14C-labelled ciprofloxacin to six healthy male volunteers (age: 25.0 +- 1.46 years, weight 70.0 +- 3.39 kg), approximately 94% of the dose was recovered in the urine and faeces over five days. Most of the radioactivity was recovered in the urine (55.4%). Unchanged ciprofloxacin was the major radioactive moiety identified in both urine and faeces, accounting for 45% and 25% of the dose, respectively. Total (urine and faeces) excretion of all metabolites was 18.8%.

FACTORS INFLUENCING THE PHARMACOKINETICS

Age (Elderly)

In 4 females and 6 males, (age 67 +- 4 years, weight 65 +- 6 kg) with normal renal function for their age, given a single oral dose of 250 mg, maximum ciprofloxacin serum concentrations and areas under the serum concentration time curves were significantly higher than in 10 male younger volunteers (age 24 +- 3 years, weight: 72 +- 9 kg). The time to peak serum concentrations, overall elimination half-life an urinary recovery of ciprofloxacin were similar in both age groups (Table 9).

Table 9

Impaired renal Function

Since ciprofloxacin is eliminated primarily by the kidney, a change in pharmacokinetics is to be expected depending on the degree of impairment of renal function. The pharmacokinetics of ciprofloxacin following a single oral dose of 250 mg in 6 patients (5 male, 1 female, age: 51 +- 9 years) with normal renal function (see Group I, Table 10) were compared to 6 patients (3 male, 3 female, age: 63 +- 6 years) with renal impairment (see Group II, table 10) and to 5 patients (2 male, 3 female, age: 63 +- 6 years) with end-stage renal failure, treated by haemodialysis (see Group III, Table 10). Patients with renal insufficiency had significantly increased AUCs, prolonged (about 2-fold) elimination half-lives, and decreased renal clearances. Haemodialysis resulted in a minimal decrease in plasma levels. From the dialysate concentrations, it can be estimated that no more than 2% of the dose was removed by dialysis over 4 hours, which was less than the amount lost in the urine over 24 hours in patients of Group II (see Table 10). Results of studies in patients on peritoneal dialysis and on hemodialysis show that very little ciprofloxacin is removed by dialysis.

Table 10

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Food

The administration of ciprofloxacin with food delayed absorption, as shown by an increase of approximately 50% in time to peak concentrations, but did not cause other changes in the pharmacokinetics of ciprofloxacin.

Probenecid

Co-administration of probenecid (1000 mg) with ciprofloxacin (500 mg) orally resulted in about 50% reduction in the ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation.

Serum Protein Binding

Serum protein binding of ciprofloxacin is between 19 to 40%.

Tissue Concentrations

In one study, the apparent volume of distribution (Vdarea) of ciprofloxacin was estimated from the kinetic data recorded after oral doses and found to be approximately 3.5 L/kg, which suggests substantial tissue penetration. The distribution of ciprofloxacin was observed to be rapid in healthy volunteers receiving various single and multiple intravenous doses. Fitting the serum profile to a two-compartment model provides a distribution phase with a half-life between 0.2 and 0.4 hours. The volume of distribution at steady state (Vdss) and Vdarea were between 1.7 and 2.7 L/kg respectively. The volume of the central compartment was between 0.16 and 0.63 L/kg, which approximates the total volume of extracellular water. Single intravenous doses of 100, 150 and 200 mg ciprofloxacin were administered to nine healthy volunteers to determine the excretion and distribution of ciprofloxacin following intravenous administration and to assess the effect of dose size on pharmacokinetic parameters. Analysis with a three-compartmental pharmacokinetic model quantified approximate sizes and kinetics of distribution into two peripheral compartments. A rapidly equilibrating compartment (V2) with a high intercompartmental clearance rate, accounting for the rapid decline in ciprofloxacin concentrations in serum immediately following drug infusion, and a third, slowly equilibrating tissue compartment with relatively slow intercompartmental clearance. This would contribute to the prolonged terminal half-life (4 to 5 h) of ciprofloxacin IV. The results of this study were as follows: Volume of distribution at steady state (Vss) was determined to be between 2.0 and 2.9 L/kg. Volumes in each compartment were determined to be as follows: central compartment 0.2 - 0.4, peripheral V2 0.6 - 0.8 and peripheral V3 1.2 - 1.6 L/kg. Table 11 summarizes the results of tissue and fluid penetration of ciprofloxacin in man.

Table 11

Distribution of Ciprofloxacin in Human Tissue/Fluid

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TOXICOLOGY

Acute Toxicity

Table 12

Single Dose Toxicity of Ciprofloxacin

Dosages in the toxicology section are expressed in terms of ciprofloxacin. The dog regurgitated the substances to a large extent after high oral doses, so that neither symptoms of intoxication nor the LD50 could be determined. The symptoms observed in the other species consisted of reduced orientation and motility, tonic- clonic convulsions, and gasping for breath at high doses. Cyanosis and narrowed palpebral fissures were observed in mice and rats treated with 5000 mg/kg orally.

Short-term Toxicity

Groups of 10 male and 10 female Wistar rats each, strain BOR:WISW, were given ciprofloxacin hydrochloride in doses of 0, 5, 20, or 80 mg/kg/day intraperitoneally for 4 weeks. After administration of 80 mg/kg/day, evidence of mechanically caused nephropathy was found. This was associated with a slight effect on the kidney function (increased BUN). Crystal-like precipitates were found in the distal tubules and were probably responsible for the mechanical tubule obstruction. The urine sediment was found also to contain crystals. On the basis of morphological criteria, the crystalline precipitates in the tubule lumens and those in the urine sediment were regarded as identical. They were probably caused by the low solubility of the ciprofloxacin at neutral pH values. Groups of 2 male and 2 female beagles each were given ciprofloxacin hydrochloride orally in doses of 0, 40, or 80 mg/kg/day for 4 weeks. Ciprofloxacin was administered orally, in gelatin capsules. Both doses produced swelling of the soft tissue in the region of the head, reddening, and pruritus after the very first dose. This oral intolerability improved substantially after the administration of ciprofloxacin in lacquered capsules. All the other investigations, hematological, clinical chemistry and urine analyses did not reveal any ciprofloxacin-related alterations. Pathological-anatomical and histopathological examinations likewise did not reveal any damage. Groups of 2 male and 2 female Rhesus monkeys were given ciprofloxacin hydrochloride orally in doses of 0 or 15 mg/kg/day for 4 weeks. The appearance and behaviour of the animals, food and water intake, body weight developments, laboratory investigations, pathological-anatomical and histopathological examinations were all unaffected by treatment.

Long-term toxicity

In a study on SPF rats, strain BOR:WISW, groups of 20 male and 20 female animals each were given ciprofloxacin hydrochloride in oral doses of 0, 20, 100 or 500 mg/kg/day for 6 months. Five animals from each group were sacrificed after 3 months and 15 animals per sex and per group were dosed for 6 months. No evidence of damage caused by ciprofloxacin was observed on clinical evaluation, or on the basis of haematological and clinical chemistry tests and urine analyses. The pathological-anatomical and histopathological examination likewise gave no indications of damage related to the use of ciprofloxacin and, in particular, no kidney damage was present. However, the acicular crystals described in the short-term rat study were found in the urine sediment of some animals on 500 mg/kg/dose.

REPRODUCTIVE TOXICITY

Fertility studies

Ciprofloxacin hydrochloride was administered to rats, strain Bor:WISW, (24 male and 60 females per group) by a stomach tube, in doses of 0, 10, 30 or 100 mg/kg/day. Treatment was commenced in the males 10 weeks before mating and in the females 3 weeks before mating and was continued in the females up to the 7th day of gestation. doses up to 100 mg/kg/day ciprofloxacin had no effects on fertility; the intrauterine and postnatal development of the young and the fertility of the F1 generation were likewise unimpaired by ciprofloxacin.

Embryotoxicity studies

1. Mouse

In a study on mice, strain BOC-NMRI, (25 per group), ciprofloxacin hydrochloride was given orally by stomach tube, in doses of 0, 10, 30 or 100 mg/kg/day from the 6th to the 15th day of gestation. Caesarean sections were performed on the 18th day of gestation. None of the doses tested caused either embryotoxic or teratogenic effects. The postnatal development of the offspring of all groups was also unaffected.

Rats

In a study on rats, strain Bor-WISW, (15 per group) oral doses of 0 or 100 mg/kg/day were administered from the 6th to the 15th day of gestation. Rats were allowed to litter normally. The result of this study also indicated that the dose of 100 mg/kg/day has no embryotoxic or teratogenic effects. In a parenteral study on rats, strain BOC-WISW, (25 per group) ciprofloxacin hydrochloride at doses of 0, 3, 10, or 30 mg/kg/day was administered intravenously from day 6 to day 15 of gestation. Caeserean sections were performed on the 20th day of gestation. In addition, 2 groups of animals were given doses of 0 or 30 mg/kg/day for the same period but were allowed to litter normally and to rear their young for a period of 3 weeks. it was found that all the doses tested had neither embryotoxic nor teratogenic effects. No effects on the postnatal development of the reared young were observed.

Rabbits

In a study on rabbits, strain CHBB:HM, (12 per group), ciprofloxacin hydrochloride was given orally in doses of 0, 10, 30 or 100 mg/kg/day. For each dose, the animals were divided into 3 subgroups each treated for periods for 5 days: one subgroup from day 6 to day 10, one subgroup from day 10 to day 14, and one subgroup from day 14 to day 18 of gestation. Caesarean sections were performed on the 29th day of pregnancy. The dose of 100 mg/kg impaired digestion as evidenced by development of diarrhea, constipation and reduced food or water intake and as a result influenced body weight development of the dams. Increased rates of resorption, lower numbers of foetuses and lower foetal weights were observed and believed to be due to maternal toxicity. There was no evidence of embryotoxicity or teratogenicity. In a parenteral study on rabbits, strain CHBB:HM, (12 per group), ciprofloxacin (lactate) at doses of 0, 2.5, 7 or 20 mg/kg/day was administered intravenously into an ear vein. Sequential treatment identical with that performed in the oral study was used. None of the doses tested caused maternal intolerance or any embryotoxic or teratogenic effects on the young.

Perinatal and Postnatal studies

Pregnant SPF rats, strain Mura:WIST, (50 per group) were given ciprofloxacin hydrochloride orally in doses of 0, 10, 30, 100 mg/kg/day. Treatment of the dams commenced on the 16th day of gestation. Caesarean sections were performed on 50% of the dams in each group on the 20th day of gestation. The remaining 50% of the dams in each group were allowed to litter naturally and to rear their young. Treatment was continued until the 21st day of lactation for this subgroup. None of the doses tested had any influence on the perinatal or postnatal development; no significant findings compared to the controls were found either in the Caesarean section groups or in the groups in which the young were reared. Female SPF rats, strain BOR:WIST, (50 per group) were given ciprofloxacin hydrochloride subcutaneously in doses of 0, 3, 10, or 30 mg/kg/day. Ciprofloxacin had no effect either on the late intrauterine development of the fetuses, the course of birth, postnatal development, or the fertility of the F1 generation. The histological examination of the joints of the young, performed at the end of the weaning period, did not reveal any damage to the articular cartilage.

MUTAGENICITY STUDIES

In-vitro

(See Table 13 for details)

The Salmonella / microsome test (the Ames test) was used to test for point-mutagenic effects. No mutagenicity could be attributed to ciprofloxacin using this standard test. To investigate the potential effect of mammalian DNA, the unscheduled DNA synthesis (UDS) test on rat (F-344) hepatocytes, the mouse lymphoma test and hamster V79 (HGPRT locus) assay were used. The UDS test and the mouse lymphoma test were positive. The hamster V79 assay was negative.

In-vivo

(See Table 13 for details)

The micronucleus test was used for microsomal mutations in somatic tissue, and the dominant lethal test, for potential influence on damage-susceptible germ-cell stages. No mutagenicity could be attributed to ciprofloxacin using these two standard tests. In-vivo UDS test, in F-344 rat, gave no indication of DNA repair following a four-hour exposure to ciprofloxacin.

Table 13 - Mutagenicity Studies Summary

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Joint and oculotoxicity

Investigations with rats, strain Bor:WISW, weaned piglets German Landschwin breed, and purebred beagle dogs were carried out for possible arthropathogenic and oculotoxic potential. Groups of 2 male and 2 female weaned piglets each were treated orally with ciprofloxacin hydrochloride for 16 successive days at doses of 0, 20, or 50 mg/kg/day. Autopsy was performed on the 17th day. An additional group received 50 mg/kg/day for 16 days and were kept for a 17 day treatment-free period before autopsy. Histopathological examinations did not show any alterations in the hip and knee joints. Groups of 10 male and 10 female juvenile Wistar rats, strain Bor:WISW, aged between 4 and 5 weeks were given ciprofloxacin hydrochloride once a day by a stomach tube in doses of 0, 100, 250, or 500 mg/kg/day over a period of 10 days. In addition to the central question of joint tolerability, specific ophthalmoscopic and histopathologic eye examinations were performed to assess the possibility of oculotoxicity. Ciprofloxacin induced marginal degenerative damage to the articular cartilage after the administration of the highest dose (500 mg/kg) and only in 1 of the 20 animals used. Doses up to 250 mg/kg/day were tolerated without any harmful effects. Ciprofloxacin caused no discernible ophthalmoscopic or histopathological damage to the eye. In a dog study, groups of 2 male and 2 female beagles each aged between 13 and 14 weeks were used. Ciprofloxacin hydrochloride was administered in gastric-juice-resistant gelatin capsules at doses of 0, 30, 70, or 100 mg/kg/day for 4 weeks. Histopathological examination revealed primary degenerative articular changes in the knee joint and hip joint cartilages at all doses tested. Severity of degenerative changes was dose-related with 100 mg/kg resulting in moderate primary degenerative articular cartilage changes in the knee-joint cartilage while 30 mg/kg resulted in slight focal degenerative change in the tibial knee-joint cartilage. No treatment-related ophthalmological changes were found.

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