PRODUCT MONOGRAPH

CIPRO(r) (Ciprofloxacin Hydrochloride Tablets) 250 mg, 500 mg, 750 mg U.S.P. CIPRO(r) I.V. (Ciprofloxacin Injection) 10 mg/mL in Water for Injection Bayer Standard CIPRO(r) I.V. MINIBAGS (Ciprofloxacin Injection) 2 mg/mL in 5% Dextrose Bayer Standard CIPRO(r) ORAL SUSPENSION (Ciprofloxacin Oral Suspension) 10 g/100 mL Bayer Standard

CONTRAINDICATIONS

CIPRO(r) (ciprofloxacin hydrochloride tablets), CIPRO(r) I.V. (ciprofloxacin injection) and CIPRO(r) Oral Suspension (ciprofloxacin oral suspension) 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 CIPRO(r) (ciprofloxacin hydrochloride tablets), CIPRO(r) I.V. (ciprofloxacin injection) and CIPRO(r) Oral Suspension (ciprofloxacin oral suspension) in pediatric patients and adolescents (under the age of 18 years), pregnant women and nursing women has not yet 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, clozapine). 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 hypersensitivity 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 fluids, 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 dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-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.

Gastrointestinal

Clostridium difficile-associated disease

Clostridium difficile-associated disease (CDAD) has been reported with the use of many antibacterial agents, including ciprofloxacin. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of the colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over 2 months after the administration of antibacterial agents. Treatment with antibacterial agents may alter the normal flora of the colon and many permit overgrowth of Clostridium difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy. If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Drugs that inhibit peristalsis may delay clearance of Clostridium difficile and its toxins, and therefore should not be used in the treatment of CDAD. Surgical evaluation should be instituted as clinically indicated since surgical intervention may be required in certain severe cases. (See ADVERSE REACTIONS.)

PRECAUTIONS

SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF CIPRO(r) I.V. 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 (generally Achilles tendon) has been reported predominantly in the elderly on prior systemic treatment with glucocorticoids. At any sign of tendonitis (ie, painful swelling, inflammation), a physician should be consulted and the antibiotic treatment should be discontinued. Care should be taken to keep the affected extremity at rest and avoid any inappropriate exercise (as the risk for tendon rupture might increase otherwise). Ciprofloxacin should not be used in patients with a clear history of tendon disorders related to quinolone treatment because they may be at risk of developing tendon disorders again when re-exposed to a fluoroquinolone. 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 CIPRO(r) and CIPRO(r) I.V. 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 CIPRO(r), CIPRO(r) I.V. and CIPRO(r) Oral Suspension in pregnancy have not yet been established. CIPRO(r), CIPRO(r) I.V. and CIPRO(r) Oral Suspension should not be used in pregnant women unless the likely benefits outweigh the possible risk to the fetus. (See WARNINGS.) CIPRO(r), CIPRO(r) I.V. and CIPRO(r) Oral Suspension have 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 CIPRO(r), CIPRO(r) I.V. and CIPRO(r) Oral Suspension, 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, CIPRO(r), CIPRO(r) I.V. and CIPRO(r) Oral Suspension 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 prescribed, 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.

Sucrose load for oral suspension formulation

As the oral suspension contains sucrose, it is unsuitable for patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency. (See PHARMACEUTICAL INFORMATION.)

Dextrose load for intravenous solution formulation

Ciprofloxacin infusion solution (bags) contain glucose. This should be taken into account in patients with diabetes mellitus. Glucose content is 5 g for the 100 mL bag and 10 g for the 200 mL bag. (See PHARMACEUTICAL INFORMATION).

Drug Interactions

Caffeine

Caffeine has been shown to interfere with the metabolism and pharmacokinetics of ciprofloxacin. Excessive caffeine intake should be avoided.

Clozapine

Following concomitant administration of 250 mg ciprofloxacin for 7 days, serum concentrations of clozapine and n-desmethylclozapine were increased by 29% and 31%, respectively (see WARNINGS).

Cyclosporine

Some quinolones, including ciprofloxacin, have been associated with transient increases in serum creatinine levels in patients who are concomitantly receiving cyclosporine.

Duloxetine

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.

Ferrous Sulfate

Oral ferrous sulfate at therapeutic doses decreases the bioavailability of oral ciprofloxacin, therefore concomitant therapy is not advised.

Food and Dairy Products

Although, ciprofloxacin may be taken with meals that include milk, simultaneous administration with dairy products alone, or with calcium-fortified products should be avoided, since decreased absorption is possible. It is recommended that ciprofloxacin be administered at least 2 hours before or 2 hours after substantial calcium intake (>800 mg). (See DOSAGE AND ADMINISTRATION.)

Glyburide

In particular cases, concurrent administration of ciprofloxacin and glyburide can intensify the action of glyburide (hypoglycemia).

Histamine H2-receptor Antagonists Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin.

Lidocaine

It was demonstrated in healthy subjects that concomitant use of lidocaine with ciprofloxacin, a moderate inhibitor of CYP450 1A2 isozyme, reduces clearance of intravenous lidocaine by 22%. Ciprofloxacin may increase the systemic toxicity of lidocaine.

Methotrexate

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.

Metoclopramide

Metoclopramide accelerates the absorption of ciprofloxacin (oral), resulting in a shorter time to reach maximum plasma concentrations. No effect was seen on the bioavailability of ciprofloxacin.

Multivalent Cations

Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation- containing products such as magnesium/aluminum antacids, polymeric phosphate binders such as sevelamer, sucralfate, Videx(r) (didanosine) chewable/buffered tablets or pediatric powder, mineral supplements or products containing calcium, iron, or zinc may substantially interfere with the absorption of the quinolone, resulting in serum and urine levels considerably lower than desired. Ciprofloxacin should be administered at least 2 hours before or 6 hours after these preparations.

NSAID

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.

Probenecid

Probenecid blocks renal tubular secretion of ciprofloxacin and has been shown to produce an increase in the level of ciprofloxacin in the serum.

Ropinirole

In a clinical study it was shown that concomitant use of ropinirole with ciprofloxacin, a medium inhibitor of the CYP450 1A2 isozyme, resulted in increases in the Cmax and AUC of ropinirole of 60 and 84%, respectively. Ciprofloxacin may increase the systemic toxicity of ropinirole.

Theophylline

Concurrent administration of ciprofloxacin with theophylline may lead to 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.

Tizanidine

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.)

Warfarin

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.

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/dtmax), 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 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 CIPRO(r) 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. 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. (See Table 11.) With oral administration, a 500 mg dose, given as 10 mL of the 5% suspension (containing 250 mg ciprofloxacin/5 mL) is bioequivalent to the 500 mg tablet. A 10 mL volume of the 5% suspension (containing 250 mg ciprofloxacin/5 mL) is bioequivalent to a 5 mL volume of the 10% suspension (containing 500 mg ciprofloxacin/5 mL). (See Table 10.)

Table 10: Summary Table of the Comparative Bioavailability Data Ciprofloxacin Oral Suspension vs.

Tablet, Geometric Mean and Arithmetic Mean (CV%) *, Single Doses in Healthy Volunteers

arithmetic mean only

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 2). The pharmacokinetics of ciprofloxacin were linear over the dose range of 200 mg and 400 mg administered intravenously (see Table 11). 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 11: 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 12: 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.36

Figure 1

Mean Ciprofloxacin Serum Concentration After Single Oral Doses

Figure 2

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

Table 13: 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 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%. 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 14: 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 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 15) were compared to 6 patients (3 male, 3 female, age: 63 +- 6 years) with renal impairment (see Group II, Table 15) and to 5 patients (2 male, 3 female, age: 63 +- 6 years) with end-stage renal failure, treated by haemodialysis (see Group III, Table 15). 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 15).

Table 15: Mean Pharmacokinetic Parameters for Ciprofloxacin Following a Single 250 mg Oral Dose in Healthy Volunteers and in Patients with Renal Insufficiency

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 16, 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 16 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 16 shows the pharmacokinetic results for the group dosed two hours before hemodialysis.

Table 16: 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

0-4 r

0-4 r

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 CIPRO(r) 750 mg every 12 hours for a total of nine doses followed by a 1 week washout and then a 30 minute infusion of CIPRO(r) I.V. 200 mg, there was no difference in pharmacokinetics between patients with stable chronic cirrhosis (with mild to moderate hepatic impairment) and healthy volunteers.

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.

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 decreases 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, Videx(r) (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.

Clozapine

Following concomitant administration of 250 mg ciprofloxacin for 7 days, serum concentrations of clozapine and n-desmethylclozapine were increased by 29% and 31%, respectively (see WARNINGS).

Lidocaine

It was demonstrated in healthy subjects that concomitant use of lidocaine with ciprofloxacin, a moderate inhibitor of CYP450 1A2 isozyme, reduces clearance of intravenous lidocaine by 22%. Ciprofloxacin may increase the systemic toxicity of lidocaine.

Ropinirole

In a clinical study it was shown that concomitant use of ropinirole with ciprofloxacin, a medium inhibitor of the CYP450 1A2 isozyme, resulted in increases in the Cmax and AUC of ropinirole of 60 and 84%, respectively. Ciprofloxacin may increase the systemic toxicity of ropinirole.

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 17

summarizes the results of tissue and fluid penetration of ciprofloxacin in man.

Table 17: Distribution of Ciprofloxacin in Human Tissue/Fluid

TOXICOLOGY

Acute Toxicity

Chronic Toxicity

Subacute Tolerability Studies over 4 Weeks

Oral administration

: Doses up to and including 100 mg/kg were tolerated without damage by rats. Pseudoallergic reactions due to histamine release were observed in dogs.

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

Oral administration

: All doses up to and including 500 mg/kg were tolerated without damage by rats. In monkeys, crystalluria and changes in the renal tubules were observed in the highest-dose group (135 mg/kg).

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 erythrocyte counts and hemoglobin values.

Chronic Tolerability Studies over 6 Months

Oral administration

: Doses up to and including 500 mg/kg and 30 mg/kg were tolerated without damage by rats and monkeys, respectively. Changes in the distal renal tubules were again observed in some monkeys in the highest-dose group (90 mg/kg).

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 or 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 Hamster 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 vivo test systems gave negative results: Rat Hepatocyte DNA Repair Assay Micronucleus Test (Mice) Dominant Lethal Test (Mice) Chinese Hamster Bone Marrow

Special Tolerability Studies

It is known 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 Tolerabilitv

: 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 occured 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 tolerabilitv 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 animals (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. Ciprofloxacin treatment had no effect on the morphological structures of the retina and on electroretinographic findings.

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