PRODUCT MONOGRAPH

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CIPROFLOXACIN INTRAVENOUS INFUSION, BP

Ciprofloxacin 2 mg/mL in 5.5 % Dextrose Sterile Antibacterial Agent Apotex Inc. 150 Signet Drive Weston, Ontario M9L 1T9 Date of Preparation: January 8, 2008 Submission Control No: 119108

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 8 DRUG INTERACTIONS 12 DOSAGE AND ADMINISTRATION 15 OVERDOSAGE 18 ACTION AND CLINICAL PHARMACOLOGY 18 STORAGE AND STABILITY 21 DOSAGE FORMS, COMPOSITION AND PACKAGING 21

PART II: SCIENTIFIC INFORMATION 22

PHARMACEUTICAL INFORMATION 22 DETAILED PHARMACOLOGY 23 MICROBIOLOGY 35 TOXICOLOGY 41 REFERENCES 44

PART III: CONSUMER INFORMATION 47

CIPROFLOXACIN INTRAVENOUS INFUSION, BP

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Ciprofloxacin Injection

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Ciprofloxacin is 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 AND PRECAUTIONS

Serious Warnings and Precautions

$Drug interactions with theophylline (see DRUG INTERACTIONS)

General

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. Intravenous infusion should be administered by slow infusion over a period of 60 minutes. Local IV 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 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.

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.

Dextrose load for intravenous solution formulation

The 5.5% dextrose w/v intravenous solution is unsuitable for patients with rare glucose- galactose malabsorption. (See PHARMACEUTICAL INFORMATION).

Carcinogenesis and Mutagenesis

See animal data in Toxicology section.

Endocrine and Metabolism

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.

Hepatic/Biliary/Pancreatic

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 SCIENTIFIC INFORMATION - DETAILED PHARMACOLOGY)

Neurologic

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.)

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 diarrhea 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.

Renal

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

Sensitivity/Resistance

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.

Skin

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.

Special Populations

Pregnant Women:

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

Nursing 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, taking into account the importance of the drug to the mother and the possible risk to the infant.

Pediatrics (< 18 years of age): SCIENTIFIC INFORMATION TOXICOLOGY

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. Damage to juvenile weight-bearing joints and lameness were observed both in rat and dog studies but not in weaned piglets. Histopathological examination of the weight-bearing joints in immature dogs revealed permanent lesions of the cartilage. (See

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)

Geriatrics: SCIENTIFIC INFORMATION DETAILED PHARMACOLOGY

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

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)

DRUG INTERACTIONS

Overview

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. Caffeine has been shown to interfere with the metabolism and pharmacokinetic 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). 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 AND PRECAUTIONS.) 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.

Drug-Drug Interactions

Table # 1- Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Severity and nature of the infection Susceptibility of the causative organism Integrity of the patient's host-defense mechanisms Status of patients's renal function.

Recommended Dose and Dosage Adjustment

Ciprofloxacin should be administered by IV infusion over a period of 60 minutes. Slow infusion into a large vein will minimize patient discomfort and reduce the risk of venous irritation.

Adults

The recommended adult dosages of Ciprofloxacin Intravenous Infusion, BP are:

Table 2: Recommended Adult dosages of Ciprofloxacin Intravenous Infusion, BP

*1) Clinical success was demonstrated with a limited number of patients switched to oral therapy: (ciprofloxacin 500 mg PO ql2h plus metronidazole 500 mg PO q6h) during day 3, 4 or 5 of therapy when able to take oral

medication and having shown an initial clinical response to the intravenous therapy.

1. See Metronidazole Product Monograph for Prescribing Information including cautionary statements.

2. For information on ciprofloxacin plus metronidazole combination therapy, see ACTION AND CLINICAL PHARMACOLOGY, SCIENTIFIC INFORMATION - DETAILED PHARMACOLOGY, and ADVERSE REACTION

sections of the Ciprofloxacin Product Monograph.

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 IV/PO 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 IV/PO 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 SCIENTIFIC INFORMATION - DETAILED 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.

Table 3: Maximum Daily Dose with Stated Creatinine Clearance or Serum Creatinine

Maximum daily dose, not to be exceeded when either creatinine clearance or serum creatinine are in the ranges stated.

Hemodialysis

Only a small amount of ciprofloxacin (<10%) is removed from the body after hemodialysis or peritoneal dialysis. For hemodialysis patients, please follow dosing recommendations as described in Table 3. On dialysis days, the dose should be administered after dialysis. 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

Impaired Hepatic Function

No dosage adjustment is required.

Pediatric Use

The safety and efficacy of Ciprofloxacin Intravenous Infusion, BP in individuals less than 18 years of age has not been established. Ciprofloxacin Intravenous Infusion, BP should not be used in pediatric patients and adolescents. (See WARNINGS AND PRECAUTIONS)

Administration

Intermittent Intravenous Infusion

Ciprofloxacin Intravenous Infusion, BP should be administered only by intravenous infusion over a period of 60 minutes. The drug should not be given by rapid injection. Slow infusion of a dilute solution into a large vein will minimize patient discomfort and reduce the risk of venous irritation. If Ciprofloxacin Intravenous Infusion, BP is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each drug. Only Ciprofloxacin Intravenous Infusion, BP contains ciprofloxacin at 2.0 mg/mL and should be administered "as is". As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit.

OVERDOSAGE

In the event of acute, excessive overdosage, 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.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Ciprofloxacin, a synthetic fluoroquinolone, has in vitro activity against a wide range of gram- negative and gram-positive microorganisms. Its bactericidal action is achieved through inhibition of topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination. Ciprofloxacin retained some of its bactericidal activity after inhibition of RNA and protein synthesis by rifampin and chloramphenicol, respectively. These observations suggest ciprofloxacin may possess two bactericidal mechanisms, one mechanism resulting from the inhibition of DNA gyrase and a second mechanism which may be independent of RNA and protein synthesis. The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines. Therefore, microorganisms resistant to these classes of drugs may be susceptible to ciprofloxacin. Conversely, microorganisms resistant to fluoroquinolones may be susceptible to these other classes of antimicrobial agents. (See SCIENTIFIC INFORMATION - MICROBIOLOGY.) There is no cross-resistance between ciprofloxacin and the mentioned classes of antibiotics.

Pharmacodynamics

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.

Pharmacokinetics

Table #4 Summary of Ciprofloxacin's Pharmacokinetic Parameters in Healthy Volunteers

General: Ciprofloxacin and metronidazole have been studied in combination and serum levels of ciprofloxacin are not significantly altered by metronidazole at the doses studied. Serum levels of metronidazole when administered orally at a dose of 500 mg q6h in combination with ciprofloxacin 500 mg PO ql2h are: AUC0 6 156.3 mg.h/L, Cmax 31.3 mg/L and tmax 1.71 hours. Serum levels of metronidazole when administered intravenously at a dose of 500 mg IV q6h in combination with ciprofloxacin 400 mg IV ql2h are: AUC0 6 153.0 mg.h/L, Cmax 33.6 mg/L and tmax 1.0 hours. (See DOSAGE AND ADMINISTRATION and SCIENTIFIC INFORMATION - DETAILED PHARMACOLOGY) Following infusion of 400 mg IV Ciprofloxacin every eight hours in combination with 50 mg/kg IV piperacillin sodium every 4 hours, mean serum ciprofloxacin concentrations were 3.02 g/mL at 30 minutes and 1.18 g/mL between 6-8 hours after the end of infusion. The mean serum ciprofloxacin concentration given alone at 400 mg IV every eight hours was 3.67 g/mL at 30 minutes and 1.16 g/mL at 6 hours after the end of infusion.

Absorption:

Following an intravenous infusion of ciprofloxacin, the mean maximum serum concentrations were achieved at the end of infusion. Pharmacokinetics of ciprofloxacin were linear over the dose range up to 400 mg administered intravenously. Comparison of the pharmacokinetic parameters for a bid and tid i.v. dose regimen indicated no evidence of drug accumulation for ciprofloxacin and its metabolites. A 60-minute i.v. infusion of 200 mg ciprofloxacin or the oral administration of 250 mg ciprofloxacin both given every 12 hours produced an equivalent area under the serum concentration time curve (AUC). A 60-minute infusion of 400 mg ciprofloxacin every 12 hours was bioequivalent to a 500 mg oral dose every 12 hours with regard to AUC. The 400 mg i.v. dose administered over 60 minutes every 12 hours resulted in a Cmax similar to that observed with a 750 mg oral dose. A 60-minute infusion of 400 mg ciprofloxacin every 8 hours is equivalent with respect to AUC to 750 mg oral regimen given every 12 hours.

Distribution:

The protein binding of ciprofloxacin is low (20-30%), and the substance is present in plasma largely in a non-ionized form. Ciprofloxacin can diffuse freely into the extravascular space. The large steady-state volume of distribution of 2-3 L/kg body weight shows that ciprofloxacin penetrates in tissues resulting in concentrations which clearly exceed the corresponding serum levels.

Metabolism: Small concentrations of four metabolites have been reported: Desethyleneciprofloxacin (M1), sulphociprofloxacin (M2), oxociprofloxacin (M3) and formylciprofloxacin (M4). M1 to M3 display antibacterial activity comparable to or inferior to that of nalidixic acid. M4, with the smallest quantity, is largely equivalent to norfloxacin in its antimicrobial activity.

Excretion:

Ciprofloxacin is largely excreted unchanged both renally and to a smaller extent non-renally. Renal clearance is between 0.18-0.3 L/h/kg and the total body clearance between 0.48-0.60 L/h/kg. Ciprofloxacin undergoes both glomerular filtration and tubular secretion.

Non-renal clearance of ciprofloxacin is mainly due to active transintestinal secretion as well as metabolization. 1% of the dose is excreted via the biliary route. Ciprofloxacin is present in the bile in high concentrations.

Special Populations and Conditions

Geriatrics:

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.

Hepatic Insufficiency:

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 IV 200 mg, there was no difference in pharmacokinetics between patients with stable chronic cirrhosis (with mild to moderate hepatic impairment) and healthy volunteers.

Renal Insufficiency:

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.

STORAGE AND STABILITY

Minibags:

Protect from light, excessive heat and freezing.

Store at controlled room temperature 15deg-25degC (56deg-77degF). Use promptly when pouch is opened. As with all parenteral drug products, injections/intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration, whenever solution and container permits. Solutions showing haziness, particulate matter, precipitate or leakage should not be used. Discard unused portion.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Minibags:

each mL contains 2 mg of ciprofloxacin in ready-to-use minibags of 100 mL and 200 mL.

The minibags are made of polyvinyl chloride (PVC) and an over pouch to protect from moisture.