PRODUCT MONOGRAPH

CO CIPROFLOXACIN

TABLETS

(Ciprofloxacin Tablets USP)

mg, 500 mg, 750 mg Ciprofloxacin as Ciprofloxacin Hydrochloride

Antibacterial Agent

Cobalt Pharmaceuticals Inc. Date of Preparation:

Kitimat Road January 29, 2004

Mississauga, Ontario Date of Revision: L5N 2B8

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PRODUCT MONOGRAPH

CO CIPROFLOXACIN

TABLETS

(Ciprofloxacin Tablets USP) 250 mg, 500 mg, 750 mg Ciprofloxacin as Ciprofloxacin Hydrochloride

CONTRAINDICATIONS

CO CIPROFLOXACIN

(Ciprofloxacin Hydrochloride) tablets are contraindicated in patients who have shown hypersensitivity to ciprofloxacin or other quinolone antibacterial agents.

WARNINGS

Children

The safety of CO 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, CO CIPROFLOXACIN Tablets should not be used in prepubertal patients.27 Experience in pubertal patients below 18 years of age is limited.

Pregnancy

The safety of CO CIPROFLOXACIN Tablets 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 intracranial pressure, and toxic psychosis have been reported in patients receiving drugs in this 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).

General

PRECAUTIONS

Anaphylactic reactions including cardiovascular collapse have occurred rarely in patients receiving therapy with CO CIPROFLOXACIN (Ciprofloxacin Hydrochloride) tablets. 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, eosinphilia, 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 or 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. 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. 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. Prolonged use of CO CIPROFLOXACIN Tablets 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 CO CIPROFLOXACIN Tablets in pregnancy have not yet been established.

CO CIPROFLOXACIN

Tablets 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-tertogenic in animal studies.

Nursing Mothers

Ciprofloxacin is excreted in human milk. A decision should be made to discontinue nursing or to discontinue the administrtion of CO CIPROFLOXACIN Tablets, taking into account the importanceof the drug to the mother and the possible risk to the infant.

Drug Interactions

Concurrent administration of ciprofloxacin with theophyline 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.24 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 adminstration 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 Tablets 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, CO CIPROFLOXACIN Tablets 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 diarrhea were observed in this patient population.

SYMPTOMS AND TREATMENT OF OVERDOSE

In the event of acute, excessive oral over dosage, reversible renal toxicity, arthralgia, myalgia and CNS symptoms have been reported. Therefore, apart from routine emergency measures, it is recommended to monitor renal function and to administer magnesium- or calcium-containing antacids which reduce the absorption of ciprofloxacin and to maintain adequate hydration. Based on information obtained from subjects with chronic renal failure, only a small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal dialysis.

DOSAGE AND ADMINISTRATION

The determination of dosage for any particular patient must take into consideration the severity and nature of the infection, the susceptibility of the causative organism, the integrity of the patient's host-defence mechanisms, and the status of renal function.

Oral Administration

CO CIPROFLOXACIN

(Ciprofloxacin Hydrochloride) tablets may be taken before or after meals. Absorption is faster on an empty stomach. Patients should be advised to drink fluids liberally and not take antacids containing magnesium or aluminum.

Adults

The recommended dosages of oral CO CIPROFLOXACIN Tablets are:

e.g., hospital-acquired pneumonia, osteomyelitis Depending on the severity of the infections, as well as the clinical bacteriological responses, the average treatment period should be approximately 7 to 14 days. Generally, treatment should last 3 days beyond the disappearance of clinical symptoms or until cultures are sterile. Patients with osteomyelitis may require treatment for a minimum of 6 to 8 weeks and up to 3 months. With acute cystitis in females a 3 to 5 day treatment may be sufficient. With infectious diarrhea a five-day treatment may be sufficient. Typhoid fever should be treated for 14 days. Acute sinusitis should be treated for 10 days with 500 mg q 12h. Chronic bacterial prostatitis should be treated for 28 days with 500 mg q 12h.

Definitive clinical studies have not been completed for severe infections other than in the respiratory tract.

The duration of treatment depends upon the severity of infection. Generally ciprofloxacin should be continued for at least 3 days after the signs and symptoms of infection have disappeared. The usual duration is 7 to 14 days. However, for severe and complicated infections more prolonged therapy may be required. Bone and joint infections may require treatment for 4 to 6 weeks or longer.

Sequential P.O. Therapy:

In patients receiving intravenous ciprofloxacin, oral ciprofloxacin may be considered when clinically indicated at the discretion of the physician. Clinical studies evaluating the use of sequential P.O. therapy in septicemia, however, have not been completed.

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 (see HUMAN PHARMACOLOGY). 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 following table provides a guideline for dosage adjustment. However, monitoring of serum drug levels provides the most reliable basis for dosage adjustments. Only a small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal dialysis.

Maximum daily dose, not to be exceeded when either creatinine clearance or serum creatinine are in the ranges stated. When only the serum creatinine concentration 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: Creatinine Clearance mL/sec = Males: Weight (kg) x (140 - age) 49 x serum creatinine (:mol/L) Females: 0.85 x the above value In traditional units mL/min= Males: Weight (kg) x (140 - age) 72 x serum creatinine (mg/100 mL) Females: 0.85 x the above value

Children

The safety and efficacy of CO CIPROFLOXACIN Tablets in children has not been established.

CO CIPROFLOXACIN

Tablets should not be used in prepubertal patients (see WARNINGS).

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE

Proper Name:

Ciprofloxacin hydrochloride

Chemical Name:

1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl )

-3- quinolinecarboxylic acid hydrochloride monohydrate

Structural Formula:

O

HCl

. H2O

N N

HN

Molecular Formula: C17H18FN3O3HCl H20

Molecular Weight:

385.8

Description:

Ciprofloxacin hydrochloride is a pale yellow crystalline powder.

Solubilities in common solvents:

Sparingly soluble in Water. Slightly soluble in methanol, very slightly soluble in ethanol, practically insoluble in acetone, in ethyl acetate, and in methylene chloride.

pH solubility profile:

pH Solubility

1. 12 mg/mL

2. 36 mg/mL

3. 39 mg/mL

4. 42 mg/mL

5. 36 mg/mL

6. 38 mg/mL

7. 38 mg/mL

8. 38 mg/mL

pH and pKa values:

pH of a 2.5 % solution in water is 3.0 - 4.5 The pKa1 is 6.1 and the pKa2 is 8.7

Melting Point:

318 - 320 degC

COMPOSITION

Ciprofloxacin Hydrochloride Microcrystalline Cellulose Corn (Maize) Starch Crospovidone Purified Water Pregelatinised (Maize) Starch Colloidal Silicon Dioxide (Colloidal Anhydrous Silica) Magnesium Stearate Polyvinyl Alcohol Titanium Dioxide Polyethyleneglycol Talc

STABILITY AND STORAGE RECOMMENDATIONS

Store between 15degC and 30degC

AVAILABILITY OF DOSAGE FORMS

Coated Tablets

CO CIPROFLOXACIN

(Ciprofloxacin each white to off-white round, biconvex, film-coated Hydrochloride) Tablets 250 mg tablet, embossed " " on one side and " " on the

other side, contains ciprofloxacin hydrochloride equivalent to 250 mg ciprofloxacin. PVC/PE/PVDC film and aluminium foil unit dose blisters of 10's cartons of 100 (tablets), HDPE bottles of 100's and 500's.

CO CIPROFLOXACIN

Tablets 500 mg each white to off-white , capsule shaped, biconvex,

film-coated tablet, embossed "CR 500" on one side and " " on the other side, contains ciprofloxacin hydrochloride equivalent to 500 mg ciprofloxacin. PVC/PE/PVDC film and aluminium foil unit dose blisters of 10's cartons of 100 (tablets), HDPE bottles of 100's and 500's.

CO CIPROFLOXACIN

Tablets 750 mg each white to off-white , capsule shaped, biconvex,

film-coated tablet, embossed "CR 750" on one side and " " on the other side, contains ciprofloxacin hydrochloride equivalent to 750 mg ciprofloxacin. PVC/PE/PVDC film and aluminium foil unit dose blisters of 10's cartons of 100 (tablets), HDPE bottles of 50's and 100's.

MICROBIOLOGY

The in vitro activity of ciprofloxacin against clinical isolates of gram-positive and gram-negative aerobic and anaerobic bacteria is shown in Table 1. Susceptibility was determined by both agar and broth dilution tests, pH 7.1 - 7.4, using inoculum sizes ranging from 104 to 105 colony forming units per mL.

Most strains of Pseudomonas cepacia, some strains of Pseudomonas maltophilia and most anaerobic bacterial (including Bacteroides fragilis and Clostridium difficile but excluding Clostridium perfringens) are resistant to ciprofloxacin.

Table 1: Cumulative Percent of Strains Inhibited at the Indicated Concentration of Ciprofloxacin

Table 1: Cumulative Percent of Strains Inhibited at the Indicated Concentration of Ciprofloxacin

Table 1: Cumulative Percent of Strains Inhibited at the Indicated Concentration of Ciprofloxacin

Table 1: Cumulative Percent of Strains Inhibited at the Indicated Concentration of Ciprofloxacin

The minimum inhibitory concentrations (MICs) of ciprofloxacin against aerobic bacteria are not significantly affected by changes in inoculum size in the range of 5 x 103 to 5 x 106 cfu/spot. Five bacterial species, Staphylococcus aureus K734, Staphylococcus epidermidis H846, Streptococcus faecalis 7149, Escherichia coli 2345, and Proteus mirabilis 2349 were tested for MICs with inoculum size of 5 x 103 to 5 x 106. Streptococcus faecalis showed a four-fold increase while the remainder showed only a two to three-fold increase (Table 2). There were no differences between MICs determined in Mueller Hinton and Isosensitest broth. MIC values 8 to 16 fold higher were seen when these organisms were tested in Mueller Hinton broth at pH 4.8 compared to values obtained at pH 7.3 (Table 2). This reduction in antibacterial activity suggests a significant pH effect. Some studies have demonstrated that increasing the concentration of magnesium in the medium used for in vitro testing reduces the antibacterial activity of ciprofloxacin. Neither zinc nor calcium supplementation had the same effect. The mechanism by which magnesium antagonizes the activity of ciprofloxacin is unclear.3

Table 2: Effect of Culture Medium Composition, pH and Inoculum Size On Antibacterial Activity of Ciprofloxacin

1. Mueller Hinton broth (BBL) 5 x 105 cfu/mL.

2. No difference between the MIC's determined in Mueller Hinton (BBL) and Isosensitest broth (Oxiod).

Development of Resistance

The mechanism of resistance development ot ciprofloxacin is unclear. Plasmid-mediated resistance does not occur. Chromosomal mutation influencing DNA gyrase and/or the cell membrane may confer resistance.

28,29

A progressive increase in MIC of ciprofloxacin was demonstrated in a bacterial strain of E. coli Neuman by daily passage in subinhibitory concentrations of the drug. MICs were determined by Isosensitest Broth Dilution Test, 105 cfu/mL inoculum. The MIC of the parent strain of E. coli was 0.03 mg/L. After three passages, the MIC increased to 0.25 mg/L and with five passages resulted in a MIC of 0.50 mg/L. Mutants having reduced susceptibility to ciprofloxacin emerged at a relatively low incidence in vitro (see Table 3).

Table 3: Frequency of resistance to ciprofloxacin

(2 clinical isolates of eight species from human urine - 0.1 mL of an overnight culture in Trypticase Soy Broth plated onto Trypticase Soy Agar containing ciprofloxacin at concentrations 4 and 8 times the MIC, incubated 35degC for 18 hours.)

Cross Resistance

Cross-resistance with other quinolones has been observed. Although limited data shows that nalidixic-resistant organisms are less susceptible to ciprofloxacin, achievable serum levels of ciprofloxacin are generally above the increased MICs seen in these less susceptible organisms. A study of the activity of ciprofloxacin against selected organisms which were resistant to antimicrobial agents having other mechanisms of action (e.g. beta-lactam and aminoglycoside antibiotics) showed that they were sensitive to ciprofloxacin (see Table 4) and that their MICs were generally within the range observed for other microorganisms of the same species (compared to Table 1). Similarly, organisms resistant to ciprofloxacin might be sensitive to antimicrobial agents having other mechanisms of action.

Table 4: Activity of Ciprofloxacin Against Selelcted Bacteria Resistant to $-Lactams and Aminoglycosides

Table 4: Activity of Ciprofloxacin Against Selelcted Bacteria Resistant to $-Lactams and Aminoglycosides

The MIC's of piperacillin and cefoperazone were > 128 mg/L for all organisms. (Clinical isolates from urine - Both agar and broth dilution tests were used, 105 inoculum on Mueller Hinton Agar or broth.)

Combination with other Anti-infectives

In general, combinations of ciprofloxacin with beta-lactam or aminoglycoside antibiotics were neither antagonistic nor synergistic when evaluated by the microdilution checkerboard method. The few instances of synergy that were observed did not show any predictable pattern (Table 5).

Table 5: Combination of Ciprofloxacin with Aminoglycosides Checkerboard Assay

FIC = Fraction Inhibitory Concentration

Susceptibility Testing

The standard Kirby-Bauer disc susceptibility test (using 5:g ciprofloxacin discs) and the dilution susceptibility test should be interpreted using the following criteria:

A report of " Intermediate susceptibility" suggests that the organism may be susceptible if the infection is confined to tissues and fluids ( e.g. urine), in which high antibiotic levels are attained. The Quality Control strains should have the following assigned daily ranges for ciprofloxacin:

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 0.04mg/kg/hr and dehydrobenzperidol 0.25 mg/kg/hr) at a single dose of 3, 10 or 30mg/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 quinea-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 doses of 0, 10, 30, and 100 mg/kg, 40 minutes prior to a 15% charcoal suspension. No effects 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 30mg/kg group in comparison to controls. At 60 minutes post dose, the serum triglycerides 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 per cent compared to an equivalent dose of IV ciprofloxacin. 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+-9.4kg), ciprofloxacin was absorbed rapidly and extensively from the gastrointestinal tract. 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. 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)

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

Figure 1: Mean Ciprofloxacin Serum Concentration After Single Oral Doses

Table 8: Mean Urinary Excretion of Ciprofloxacin

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 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 feces 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 feces, accounting for 45% and 25% of the dose, respectively. Total (urine and feces) 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 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

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 ciprfloxacin 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).

Table 10: Mean Pharmacokinetic Parameters for Ciprofloxacin Following a Single 250 mg Oral Dose in Healthy Volunteers and in Patients with Renal Insufficiency

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 ciprfloxacin (500 mg) orally resulted in about 50% reduction in the ciprfloxacin 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. 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

*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, haematological, 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 males and 60 females per group) by a stomach tube, in doses of 0, 10, 30, 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

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 had 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. Caesarean 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 of 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, or 100 mg/kg/day. Treatment of the dams commenced on the 16th day of gestation. Caesarean sections were performed on 50 percent 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 12 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 on 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 12 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 12: Mutagenicity Studies Summary

Joint and Oculotoxicity

Investigation 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 was 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 opthalmoscopic and histopathological 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 wee tolerated without any harmful effects. Ciprofloxacin caused no discernible opthalmoscopic or histopathological damage to the eye. In the 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 cartilage 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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