PRODUCT MONOGRAPH

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CIPROFLOXACIN INTRAVENOUS INFUSION

(Ciprofloxacin Injection) 2 mg/mL in 5 % Dextrose BP Standard

CONTRAINDICATIONS

CIPROFLOXACIN INTRAVENOUS INFUSION (ciprofloxacin injection) are contraindicated in patients who have shown hypersensitivity to ciprofloxacin or other quinolone antibacterial agents or any of the excipients. Concurrent administration of ciprofloxacin and tizanidine is contraindicated since it may result in an undesirable increase in serum tizanidine concentrations. This can be associated with clinically relevant tizanidine-induced side effects (hypotension, somnolence, drowsiness).

WARNINGS

The safety of CIPROFLOXACIN INTRAVENOUS INFUSION in pediatric patients and adolescents (under the age of 18 years), pregnant women and nursing women has not yet been established. PRECAUTIONS: Pediatric Use, Pregnancy, and Nursing Women

(See

.) 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.

CNS and Psychiatric Effects

Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also cause central nervous system (CNS) stimulation which may lead to tremors, restlessness, lightheadedness, confusion, hallucinations, depression, nervousness, agitation, insomnia, anxiety, paranoia, nightmares and rarely, suicidal thoughts or acts. In rare cases, depression or psychosis can progress to self- endangering behaviour. These reactions may occur following the first dose. 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 or lower the seizure threshold. (See ADVERSE REACTIONS.)

Cytochrome P450

Ciprofloxacin is known to be a moderate inhibitor of the CYP450 1A2 enzymes. Care should be taken when other drugs are administered concomitantly which are metabolized via the same enzymatic pathway (e.g., theophylline, methylxanthines, caffeine, duloxetine). Increased plasma concentrations associated with drug specific side effects may be observed due to inhibition of their metabolic clearance by ciprofloxacin. (See CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions.)

Hypersensitivity

Serious hypersensitvity and/or anaphylactic reactions have been reported in patients receiving quinolone therapy, including ciprofloxacin. These reactions may occur within the first 30 minutes following the first dose and may require epinephrine and other emergency measures. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath and acute respiratory distress), dyspnea, urticaria, itching and other serious skin reactions. Ciprofloxacin should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluid, antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated. Serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain etiology, have been reported in patients receiving therapy with all antibiotics. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: fever, rash or severe dermatological reactions (e.g., toxic epidermal necrolysis, Steven-Johnson Syndrome), vasculitis, arthralgia, myalgia, serum sickness, allergic pneumonitis, interstitial nephritis, acute renal insufficiency or failure, hepatitis, jaundice, acute hepatic necrosis or failure, hepatic necrosis with fatal outcome, anemia including hemolytic and aplastic, thrombocytopenia including thrombotic thrombocytopenic purpura, leukopenia, agranulocytosis, pancytopenia, and/or other hematologic abnormalities.

Pseudomembranous Colitis

Pseudomembranous colitis has been reported with virtually all antibacterial agents, including ciprofloxacin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients with diarrhoea subsequent to the administration 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 C. difficile.

PRECAUTIONS

SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF CIPROFLOXACIN AND

THEOPHYLLINE

. These reactions include cardiac arrest, seizure, status epilepticus and respiratory failure. Similar serious adverse events have been noted with administration of theophylline alone; however, the possibility that ciprofloxacin may potentiate these reactions cannot be eliminated. If concomitant use cannot be avoided, the plasma levels of theophylline should be monitored and appropriate dosage adjustments should be made.

Tendon rupture (predominantly achilles tendon) has been reported predominantly in the elderly on prior systemic treatment with glucocorticoids. At any sign of 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. 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 (i.e., sunburn-like skin reactions) occurs. Intravenous infusion should be administered by slow infusion over a period of 60 minutes. Local i.v. reactions have been reported with the intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is 30 minutes or less, or if small veins of the hand are used. Prolonged use of ciprofloxacin injection 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 injection in pregnancy have not yet been established. CIPROFLOXACIN INTRAVENOUS INFUSION should not be used in pregnant women unless the likely benefits outweigh the possible risk to the fetus. (See WARNINGS.) Ciprofloxacin has been shown to be non-embryotoxic and non-teratogenic in animal studies.

Nursing Women

Ciprofloxacin is excreted in human milk. Because of the potential for serious adverse reactions in infants nursing from women taking ciprofloxacin, a decision should be made to discontinue nursing or to discontinue the administration of CIPROFLOXACIN INTRAVENOUS INFUSION, taking into account the importance of the drug to the mother and the possible risk to the infant. (See WARNINGS.)

Pediatric Use

The safety and efficacy of ciprofloxacin in the pediatric population less than 18 years of age have not been established. Quinolones, including ciprofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. (See WARNINGS, TOXICOLOGY.)

Elderly

Ciprofloxacin is substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. (See HUMAN PHARMACOLOGY.)

Renal Impairment

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

Hepatic Impairment

In preliminary studies in patients with stable chronic liver cirrhosis (with mild to moderate hepatic impairment), no significant changes in ciprofloxacin pharmacokinetics were observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency and stable chronic cirrhosis (with severe hepatic impairment), however, have not been fully elucidated. An increased incidence of nausea, vomiting, headache and diarrhea were observed in this patient population. (See HUMAN PHARMACOLOGY.)

Ability to Drive and Operate Machinery

Even when ciprofloxacin is taken exactly as prescibed, it can affect the speed of reaction to such an extent that the ability to drive or to operate machinery is impaired. This applies particularly in combination with alcohol.

Dextrose load for intravenous solution formulation

The 5% dextrose w/v intravenous solution is unsuitable for patients with rare glucose-galactose malaborption. (See PHARMACEUTICAL INFORMATION).

Drug Interactions

Concurrent administration of ciprofloxacin with theophylline may lead to an elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See ADVERSE REACTIONS.) If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate. Caffeine has been shown to interfere with the metabolism and pharmacokinetics of ciprofloxacin. 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. In particular cases, concurrent administration of ciprofloxacin and glyburide can intensify the action of glyburide (hypoglycemia). Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin. Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin, potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated. In a clinical study in healthy subjects there was an increase in tizanidine serum concentrations (Cmax increase: 7-fold, range: 4 to 21-fold; AUC increase: 10-fold, range: 6 to 24-fold) when given concomitantly with ciprofloxacin. Associated with the increased serum concentrations was a potentiated hypotensive and sedative effect. Tizanidine must not be administered together with ciprofloxacin. (See CONTRAINDICATIONS, WARNINGS.) In clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in an increase of AUC and Cmax of duloxetine. Although no clinical data are available on a possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration.

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

The relative bioavailability of oral ciprofloxacin, given as a tablet, is between 70 and 80 percent compared to an equivalent dose of IV ciprofloxacin. Following a 60-minute intravenous infusion of 200 mg and 400 mg ciprofloxacin to 13 healthy male volunteers (18 - 40 years), the mean maximum serum concentrations achieved were 2.14 and 4.60 mg/L respectively; the concentrations at 12.0 hours were 0.11, 0.23 mg/L respectively (see Figure 1). The pharmacokinetics of ciprofloxacin were linear over the dose range of 200 mg and 400 mg administered intravenously (see Table 6). At steady-state, the serum elimination half-life was approximately 5-6 hours and the total clearance around 35 L/hr was observed. Comparison of the pharmacokinetic parameters following the 1st and 5th iv dose on a 12h regimen indicated no evidence of drug accumulation. An intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours, for 6 doses, to 12 healthy male volunteers (18-40 years) has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by a 500 mg oral dose given every 12 hours. The 400 mg iv dose administered over 60 minutes every 12 hours resulted in a Cmax similar to that observed with a 750 mg oral dose. An infusion of 200 mg ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250 mg oral dose every 12 hours. Pharmacokinetics were dose proportioned with no significant changes in clearance or half-life occurring over this dose range (see below).

Table 6

Pharmacokinetic Parameters Of Ciprofloxacin Following Single Doses In Healthy Volunteers Oral/IV

IV parameters following a 60-minute infusion period

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

Table 7

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

Note: Following the repeated dosing of metronidazole 500 mg IV tid, the peak and minimum mean plasma metronidazole concentrations, at steady-state, were 26 ug/mL and 12 ug/mL respectively.35

Figure 1

Mean Serum Ciprofloxacin Serum Concentration (mg/L) vs Time after A Single Intravenous Dose Administered over 60 Minutes

TIME RELATIVE TO START OF DOSE (HOURS)

• 200 mg IV + 400 mg IV

Table 8

Mean Urinary Excretion of Ciprofloxacin

Note: IV dose administered over 30 minutes.

Metabolism and Excretion

Ciprofloxacin is largely excreted unchanged both renally and, to a small extent, extra-renally. 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 intravenous administration of a single 107 mg dose of 14C-labelled ciprofloxacin to six healthy male volunteers (age: 23.7 +- 1.89 years, weight: 80.2 +- 3.45 kg), 15% of unchanged ciprofloxacin was recovered in the feces, suggesting that hepatic extraction and biliary excretion is an extra-renal clearance pathway for ciprofloxacin. Direct evidence of biliary excretion of ciprofloxacin was obtained in 12 patients (age 28-58) with T-tube drainage. A peak biliary concentration of 16 mg/L was seen 4 hours after a single oral dose of ciprofloxacin 500 mg. After intravenous administration to a group of 9 healthy male volunteers (age: 26.8 +- 9.7 yrs, weight: 63.9 +- 6.4 kg), approximately 50% to 70% of the dose is excreted in the urine as unchanged drug. After a 200 mg IV dose, urine concentrations of ciprofloxacin usually exceed 200 ug/mL during the first two hours after dosing, and are generally greater than 10 ug/mL at 8 to 12 hours after dosing. The urinary excretion of ciprofloxacin is virtually complete by 24 hours after dosing. Approximately 15% of an IV dose is recovered from the feces within 5 days after dosing, which may arise from either biliary clearance or transintestinal elimination. Following intravenous administration, approximately 10% of the dose is recovered in the urine in the form of metabolites.

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 and urinary recovery of ciprofloxacin were similar in both age groups.

Table 9

Comparison of pharmacokinetic parameters between healthy elderly and healthy younger volunteers

Impaired Renal Function

Ciprofloxacin is eliminated primarily by renal excretion. However, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine. This alternate pathway of drug elimination appears to compensate for the reduced renal excretion of patients with renal impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with severe renal dysfunction. The pharmacokinetics of ciprofloxacin following multiple IV doses were compared in subjects with normal renal function and in subjects with various degrees of renal impairment (see Table 10, Groups 1-4). Patients with renal insufficiency had significantly increased concentrations of ciprofloxacin, M1 and M2 metabolites and decreased renal clearances. Results of studies in patients on peritoneal dialysis and on hemodialysis show that very little ciprofloxacin is removed by dialysis. An open-label crossover study was conducted in eight peritoneal dialysis patients. Patients received a single dose of i.v. ciprofloxacin on two separate occasions, once with frequent dialysis (fluid exchange done at 4, 8, 12 and 24 hours) and once with delayed dialysis (fluid exchange at 12 and 24 hours). Pharmacokinetic parameters for ciprofloxacin, M1 and M2 metabolites were not significantly different for frequent versus delayed dialysis, except that dialysate clearances for ciprofloxacin and M2 were higher when dialysis was done frequently. Group 5 in Table 10 shows the pharmacokinetic results for the frequent dialysis group. In an open-label crossover study, seven hemodialysis patients received a single dose of i.v. ciprofloxacin on two separate occasions, once immediately after hemodialysis, and once two hours before hemodialysis. The results demonstrated that the pharmacokinetic parameters were not significantly different between the two treatments for ciprofloxacin, M1 and M2 metabolites. Group 6 in Table 10 shows the pharmacokinetic results for the group dosed two hours before hemodialysis.

Table 10

Mean Pharmacokinetic Parameters for Ciprofloxacin and Metabolites M1 and M2 Following IV Dosing in Healthy Volunteers, Patients with Renal Insufficiency, Peritoneal Dialysis Patients, and Hemodialysis Patients

Hepatic Impairment

In studies in patients with stable chronic cirrhosis (with mild to moderate hepatic impairment), no significant changes in ciprofloxacin pharmacokinetics have been observed. In a study of 7 cirrhotic patients and healthy volunteers given ciprofloxacin 750 mg every 12 hours for a total of nine doses followed by a 1 week washout and then a 30 minute infusion of ciprofloxacin injection 200 mg, there was no difference in pharmacokinetics between patients with stable chronic cirrhosis (with mild to moderate hepatic impairment) and healthy volunteers.

Drug Interactions

Theophylline

Studies with immediate-release ciprofloxacin have shown that concomitant administration of ciprofloxacin with theophylline decreases the clearance of theophylline, resulting in elevated serum theophylline levels and increased risk of a patient developing CNS or other adverse reactions.

Caffeine

Ciprofloxacin decrease caffeine clearance and inhibits the formation of paraxanthine after caffeine administration.

Multivalent Cations

Absorption of ciprofloxacin is significantly reduced by concomitant administration of multivalent cation-containing products such as magnesium/aluminum antacids, sucralfate, didanosine chewable/buffered tablets or pediatric powder, mineral supplements or products containing calcium, iron or zinc.

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%, which is not likely to be high enough to cause significant protein binding interactions with other drugs.

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

TOXICOLOGY

Acute Toxicity

Species Mode of Administration LD50

(mg/kg)

Chronic Toxicity

Subacute Tolerability Studies over 4 Weeks

Parenteral administration

: In the highest-dose group in each case (rats 80 mg/kg and monkeys 30 mg/kg), crystals containing ciprofloxacin were found in the urine sediment. There were also changes in individual renal tubules, with typical foreign-body reactions due to crystal-like precipitates. These changes are considered secondary inflammatory foreign-body reactions due to the precipitation of a crystalline complex in the distal renal tubule system.

Subchronic Tolerability Studies over 3 Months

Parenteral administration

: Although the changes in the renal tubules observed in rats were in some cases very slight, they were present in every dose group. In monkeys they were found only in the highest-dose group (18 mg/kg) and were associated with slightly reduced erthrocyte counts and hemoglobin values.

Chronic Tolerability Studies over 6 Months

Parenteral administration

: In monkeys slightly elevated urea and creatinine concentrations and changes in the distal renal tubules were recorded in the highest-dose group (20 mg/kg).

Carcinogenicity

In carcinogenicity studies in mice (21 months) and rats (24 months) with doses up to approximately 1000 mg/kg bw/day in mice and 125 mg/kg bw/day in rats (increased to 250 mg/kg bw/day after 22 weeks), there was no evidence of a carcinogenic potential at any dose level.

Reproduction Toxicology

Fertility studies in rats:

Fertility, the intrauterine and postnatal development of the young, and the fertility of F1 generation were not affected by ciprofloxacin.

Embryotoxicity studies

: These yielded no evidence of any embryotoxic or teratogenic action of ciprofloxacin.

Perinatal and postnatal development in rats

: No effects on the perinatal and postnatal development of the animals were detected. At the end of the rearing period histological investigations did not bring to light any sign of articular damage in the young.

Mutagenicity

Eight in vitro mutagenicity tests have been conducted with ciprofloxacin. Test results are listed below: Salmonella: Microsome Test (Negative)

E. coli

: DNA Repair Assay (Negative)

Mouse Lymphoma Cell Forward Mutation Assay (Positive) Chinese Hamster V79 Cell HGPRT Test (Negative) Syrian Hmaster Embryo Cell Transformation Assay (Negative)

Saccharomyces cerevisiae

: Point Mutation Assay (Negative) Mitotic Crossover and Gene Conversion Assay (Negative)

Rat Hepatocyte Primary Culture DNA Repair Assay (LIDS) (Positive) Two of the eight tests were positive, but results of the following four in vitro test sytems gave negative results: Rat Hepatocyte DNA Repair Assay Micronucleus Test (Mice) Dominant Lethal Test (Mice) Chinese Hamster Bone Marrow

Special Tolerability Studies

It is unknown from comparative studies in animals, both with the older gyrase inhibitors and the more recent ones, that this substance class produces a characteristic damage pattern. Kidney damage, cartilage damage in weight-bearing joints of immature animals, and eye damage may be encountered.

Renal Tolerability

: The crystallization observed in the animal studies occurred preferentially under pH conditions that do not apply in man.

Compared to rapid infusion, a slow infusion of ciprofloxacin reduces the danger of crystal precipitation. The precipitation of crystals in renal tubules does not immediately and automatically lead to kidney damage. In the animal studies, damage occurred only after high doses, with correspondingly high levels of crystalluria. For example, although they always caused crystalluria, even high doses were tolerated over 6 months without damage and without foreign-body reactions occurring in individual distal renal tubules. Damage to the kidneys without the presence of crystalluria has not been observed. The renal damage observed in animal studies must not, therefore, be regarded as a primary toxic action of ciprofloxacin on the kidney tissue, but as typical secondary inflammatory foreign-body reactions due to the precipitation of a crystalline complex of ciprofloxacin, magnesium, and protein.

Articular tolerability studies

: As it is also known for other gyrase inhibitors, ciprofloxacin causes damage to the large, weight-bearing joints in immature animals.

The extent of the cartilage damage varies according to age, species, and dose; the damage can be reduced by taking the weight off the joints. Studies with mature animal (rat, dog) revealed no evidence of cartilage lesions.

Retina tolerability studies

: Ciprofloxacin binds to the melanin containing structures including the retina. Potential effects of ciprofloxacin on the retina were assessed in various pigmented animal species. Ciprolfoxacin treatment had no effect on the morphological structures of the retina and on electroretinographic findings.

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