Ciprofloxacin (Sivem Pharmaceuticals, 250 mg, 500 mg, 750 mg) Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes .................................................................................................. 2

Table of Contents .................................................................................................................. 2

Part 1: Healthcare Professional Information........................................................................... 4

1 Indications ................................................................................................................. 4

1.1 Pediatrics ................................................................................................................. 7

1.2 Geriatrics ................................................................................................................. 7

2 Contraindications ....................................................................................................... 7

3 Serious Warnings and Precautions Box ....................................................................... 7

4 Dosage and Administration ........................................................................................ 8

4.1 Dosing Considerations ............................................................................................ 8

4.2 Recommended Dose and Dosage Adjustment ....................................................... 8

4.4 Administration ...................................................................................................... 10

4.5 Missed Dose .......................................................................................................... 10

5 Overdose ................................................................................................................. 10

6 Dosage Forms, Strengths, Composition, and Packaging ............................................. 11

7 Warnings and Precautions ........................................................................................ 11

7.1 Special Populations ............................................................................................... 16

7.1.1 Pregnancy .......................................................................................................... 16

7.1.2 Breastfeeding .................................................................................................... 16

7.1.3 Pediatrics ........................................................................................................... 16

7.1.4 Geriatrics ........................................................................................................... 16

8 Adverse Reactions .................................................................................................... 17

8.1 Adverse Reaction Overview .................................................................................. 17

8.2 Clinical Trial Adverse Reactions ............................................................................ 17

8.3 Less Common Clinical Trial Adverse Reactions ..................................................... 17

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data .............................................................................................................. 19

8.5 Post-Market Adverse Reactions ............................................................................ 19

9 Drug Interactions ..................................................................................................... 20

9.1 Serious Drug Interactions ..................................................................................... 20

9.2 Drug Interactions Overview .................................................................................. 20

9.3 Drug-Behaviour Interactions ................................................................................. 21

9.4 Drug-Drug Interactions ......................................................................................... 21

9.5 Drug-Food Interactions ......................................................................................... 27

9.6 Drug-Herb Interactions ......................................................................................... 27

9.7 Drug-Laboratory Test Interactions........................................................................ 27

10 Clinical Pharmacology .............................................................................................. 27

10.1 Mechanism of Action ............................................................................................ 27

10.3 Pharmacokinetics .................................................................................................. 27

11 Storage, Stability, and Disposal ................................................................................. 34

Part 2: Scientific Information ............................................................................................... 35

13 Pharmaceutical Information ..................................................................................... 35

14 Clinical Trials ......................................................................................................... 37

14.2 Comparative Bioavailability Studies ..................................................................... 37

15 Microbiology ............................................................................................................ 37

16 Non-Clinical Toxicology ............................................................................................ 41

17 Supporting Product Monographs .............................................................................. 44

Patient Medication Information .......................................................................................... 45

Part 1: Healthcare Professional Information

1 Indications

CIPROFLOXACIN (ciprofloxacin tablets) may be indicated for the treatment of patients with the following infections caused by susceptible strains of the indicated microorganisms:

Respiratory Tract Infections

Acute exacerbation of chronic bronchitis caused by:

Haemophilus influenzae

Moraxella catarrhalis

Acute pneumonia caused by:

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Klebsiella pneumoniae

Proteus mirabilis

Pseudomonas aeruginosa

Staphylococcus aureus

Acute sinusitis caused by:

Haemophilus influenzae

Moraxella catarrhalis

CIPROFLOXACIN should not be prescribed to patients with acute bacterial exacerbations of simple/uncomplicated chronic obstructive pulmonary disease (i.e., patients who have chronic obstructive pulmonary disease without underlying risk factors).¹

CIPROFLOXACIN is not indicated for acute bronchitis.

Due to the nature of the underlying conditions which usually predispose patients to Pseudomonas infections of the respiratory tract, bacterial eradications may not be achieved in patients who display clinical improvement despite evidence of in vitro sensitivity. In patients requiring subsequent courses of therapy, CIPROFLOXACIN should be used alternately with other antipseudomonal agents. Some strains of Pseudomonas aeruginosa may develop resistance during treatment. Therefore, susceptibility testing should be performed periodically during therapy to detect the emergence of bacterial resistance.

Urinary Tract Infections

Upper and lower urinary tract infections, such as complicated and uncomplicated cystitis, pyelonephritis, and pyelitis caused by:

Citrobacter diversus

¹ Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease - 2008 update - highlights for primary care. O'Donnell et al. Can Respir J 2008; 15(Suppl A):1A-8A.

Citrobacter freundii

Enterobacter cloacae

Escherichia coli

Klebsiella pneumoniae

Klebsiella oxytoca

Morganella morganii

Proteus mirabilis

Pseudomonas aeruginosa

Serratia marcescens

Staphylococcus aureus

Staphylococcus epidermidis

Staphylococcus saprophyticus

Streptococcus faecalis

Acute uncomplicated cystitis:

in females caused by Escherichia coli

In cases of uncomplicated acute bacterial cystitis, limit the use of CIPROFLOXACIN to circumstances where no other treatment options are available. A urine culture should be obtained prior to treatment to ensure ciprofloxacin susceptibility.

Chronic Bacterial Prostatitis

Caused by:

Escherichia coli

Skin and Soft Tissue Infections

Caused by:

Enterobacter cloacae

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Proteus vulgaris

Pseudomonas aeruginosa

Staphylococcus aureus

Staphylococcus epidermidis

Streptococcus pyogenes

Bone and Joint Infections

Caused by:

Enterobacter cloacae

Pseudomonas aeruginosa

Serratia marcescens

Staphylococcus aureus

Infectious Diarrhea (when antibacterial therapy is indicated)

Caused by:

Campylobacter jejuni

Escherichia coli (enterotoxigenic strains)

Shigella dysenteriae

Shigella flexneri

Shigella sonnei

Meningococcal Carriers

Treatment of asymptomatic carriers of Neisseria meningitidis to eliminate meningococci from the nasopharynx. A minimal inhibitory concentration (MIC) determination on the isolate from the index case should be performed as soon as possible. Ciprofloxacin is not indicated for the treatment of meningococcal meningitis.

Typhoid Fever (enteric fever)

Caused by:

Salmonella paratyphi

Salmonella typhi

Uncomplicated Gonorrhea

Cervical/urethral/rectal/pharyngeal infections caused by Neisseria gonorrhoea. Because co-infection with Chlamydia trachomatis is common, consideration should be given to treating presumptively with an additional regimen that is effective against C. trachomatis.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPROFLOXACIN, and other antibacterial drugs, CIPROFLOXACIN should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Limit the use of CIPROFLOXACIN to patients where no other treatment options exist AND where ciprofloxacin susceptibility is demonstrated, OR ciprofloxacin susceptibility is highly likely, typically greater than or equal to 95%, based on local susceptibility patterns.

Appropriate culture and susceptibility tests should be performed prior to initiating treatment in order to isolate and identify organisms causing the infection and to determine their susceptibilities to ciprofloxacin. Therapy with CIPROFLOXACIN may be initiated before results of these tests are known. However, modification of this treatment may be required once results become available or if there is no clinical improvement. Culture and susceptibility testing performed periodically during therapy will provide information on the possible emergence of bacterial resistance. If anaerobic organisms are suspected to be contributing to the infection, appropriate therapy should be administered.

1.1 Pediatrics

The safety and efficacy of ciprofloxacin in individuals less than 18 years of age have not been established. CIPROFLOXACIN is not recommended for children under the age of 18 years (see 7.1.3 Pediatrics).

1.2 Geriatrics

Elderly patients should receive a dose dependent on the severity of their illness and their creatinine clearance (see 4.2 Recommended Dose and Dosage Adjustment, Impaired Renal Function for dose modification based on creatinine clearance or serum creatinine).

2 Contraindications

• CIPROFLOXACIN is contraindicated in patients who have shown hypersensitivity to ciprofloxacin, or other quinolone antibacterial agents or any of the excipients. For a complete listing, see 6 Dosage Forms, Strengths, Composition, and Packaging.
• Concurrent administration of ciprofloxacin and agomelatine (currently not marketed in Canada) is contraindicated since it may result in an undesirable increase in agomelatine exposure (see 9 Drug Interactions).
• 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) (see 9 Drug Interactions).

3 Serious Warnings and Precautions Box

4 Dosage and Administration

4.1 Dosing Considerations

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.

CIPROFLOXACIN may be taken before or after meals. Absorption is faster on an empty stomach.

Patients should be advised to drink fluids liberally and avoid taking dairy products or antacids containing magnesium or aluminum.

4.2 Recommended Dose and Dosage Adjustment

Adults

The recommended dosages of CIPROFLOXACIN are:

Table 1 - Recommended Dosages for CIPROFLOXACIN

* e.g., hospital-acquired pneumonia, osteomyelitis

Depending on the severity of the infections, as well as the clinical and 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 q12h. Chronic bacterial prostatitis should be treated for 28 days with 500 mg q12h.

Special Populations:

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 10.3 Pharmacokinetics). 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 of CIPROFLOXACIN. However, monitoring of serum drug levels provides the most reliable basis for dosage adjustments.

Table 2 - Maximum Daily Dose with Stated Creatinine Clearance or Serum Creatinine

Maximum daily doses are 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 2. 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 (mcmol/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 in individuals less than 18 years of age have not been established. CIPROFLOXACIN should not be used in pediatric patients and adolescents (see 7.1.3 Pediatrics).

4.4 Administration

Ciprofloxacin should be administered at least 2 hours before or 6 hours after antacids and mineral supplements containing magnesium or aluminum, as well as sucralfate, didanosine chewable/buffered tablets or pediatric powder, metal cations such as iron, and multivitamin preparations with zinc (see 9.4 Drug-Drug Interactions).

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 6 hours after substantial calcium intake (>800 mg) (see 9.4 Drug-Drug Interactions and 9.5 Drug-Food Interactions).

4.5 Missed Dose

If a dose is missed, it should be taken anytime but not later than 6 hours prior to the next scheduled dose. If less than 6 hours remain before the next dose, the missed dose should not be taken and treatment should be continued as prescribed with the next scheduled dose. Double doses should not be taken to compensate for a missed dose.

5 Overdose

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.

The administration of activated charcoal as soon as possible after oral overdose may prevent excessive increase of systemic ciprofloxacin exposure.

6 Dosage Forms, Strengths, Composition, and Packaging

Table 3 - Dosage Forms, Strengths, and Composition

CIPROFLOXACIN 250 mg tablet: White round film-coated tablet with breaking notch on one side. Embossed "cip" on top and "250" on the bottom of the breaking notch. Bottles of 100.

CIPROFLOXACIN 500 mg tablet: White oblong film-coated tablet with breaking notch on both sides. Embossed "cip" on one side of breaking notch and "500" on the other side, on one side of the tablet only. Bottles of 100.

CIPROFLOXACIN 750 mg tablet: White oblong film-coated tablet with breaking notch on both sides. Embossed "cip" on one side of breaking notch and "750" on the other side, on one side of the tablet only. Bottles of 50.

Composition

Medicinal Ingredient: 250 mg, 500 mg, or 750 mg ciprofloxacin as ciprofloxacin hydrochloride. Nonmedicinal ingredients: microcrystalline cellulose, sodium starch glycolate, povidone, silica colloidal anhydrous, stearic acid, magnesium stearate, croscarmellose sodium, hypromellose, polyethyelene glycol, titanium oxide and talc.

7 Warnings and Precautions

See 3 Serious Warnings and Precautions Box.

General

The use of ciprofloxacin with other drugs may lead to drug-drug interactions. For established or potential drug interactions, see 9 Drug Interactions.

Ciprofloxacin is not recommended for treatment of pneumococcal infections due to inadequate efficacy against Streptococcus pneumoniae.

Cardiovascular

Ciprofloxacin has been shown to prolong the QT interval of the electrocardiogram in some patients. In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Precaution should be taken when using ciprofloxacin with concomitant drugs that can result in prolongation of the QT interval (e.g., class IA or III antiarrhythmics) or in patients with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia) (see 9.4 Drug-Drug

Interactions and 8.5 Post-Market Adverse Reactions).

Kounis syndrome (see Immune and 8.5 Post-Market Adverse Reactions).

Aortic Aneurysm and Aortic Dissection

Epidemiologic studies report an increased risk of aortic aneurysm and aortic dissection after intake of fluoroquinolones, particularly in the older population. Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or in presence of other risk factors for aortic aneurysm and aortic dissection (e.g., Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet’s disease, hypertension, atherosclerosis).

In case of sudden severe abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.

Endocrine and Metabolism

Blood Glucose Disturbances

Fluoroquinolones, including ciprofloxacin have been associated with disturbances of blood glucose, including symptomatic hyperglycemia and hypoglycemia, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin. In these patients, careful monitoring of blood glucose is recommended. Severe cases of hypoglycemia resulting in coma or death have been reported. If a hypoglycemic reaction occurs, discontinue CIPROFLOXACIN immediately and initiate appropriate therapy (see 8.3 Less Common Clinical Trial Adverse Reactions and 9.4 Drug-Drug Interactions).

Gastrointestinal

Clostridium difficile-associated disease

Clostridium difficile-associated disease (CDAD) has been reported with the use of many antibacterial agents, including ciprofloxacin (see 8.5 Post-Market Adverse Reactions). 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 may 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 C. 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 C. difficile. Drugs that inhibit peristalsis may delay clearance of C. 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.

Hepatic/Biliary/Pancreatic

Cases of hepatic necrosis and life-threatening hepatic failure have been reported with ciprofloxacin. In the event of any signs and symptoms of hepatic disease (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), treatment should be discontinued (see 8.3 Less Common Clinical Trial Adverse Reactions).

There can be an increase in transaminases, alkaline phosphatase, or cholestatic jaundice, especially in patients with previous liver damage, who are treated with CIPROFLOXACIN (see 8.3 Less Common Clinical Trial Adverse Reactions and 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data).

Immune

Serious hypersensitivity and/or anaphylactic reactions have been reported in patients receiving fluoroquinolone therapy, including ciprofloxacin (see 8.3 Less Common Clinical Trial Adverse Reactions). 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.

Cases of acute myocardial ischemia with or without myocardial infarction as part of a hypersensitivity reaction (Kounis syndrome) have also been reported (see 8.5 Post-Market Adverse Reactions). In the event of Kounis syndrome while on treatment with CIPROFLOXACIN, discontinue CIPROFLOXACIN immediately.

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.

Monitoring and Laboratory Tests

Ciprofloxacin in vitro potency may interfere with the Mycobacterium spp. culture test by suppression of mycobacterial growth, causing false negative results in specimens from patients currently taking ciprofloxacin.

Musculoskeletal

Myasthenia Gravis

Fluoroquinolones, including CIPROFLOXACIN, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid CIPROFLOXACIN in patients with a known history of myasthenia gravis (see 8.5 Post-Market Adverse Reactions).

Tendinitis and Tendon Rupture

Tendinitis and tendon rupture (predominantly Achilles tendon), sometimes bilateral, may occur with CIPROFLOXACIN, even within the first 48 hours of treatment. Rupture of the shoulder, hand and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving fluoroquinolones, including ciprofloxacin (see 8.3 Less Common Clinical Trial Adverse Reactions and 8.5 Post-Market Adverse Reactions). CIPROFLOXACIN should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart, or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. CIPROFLOXACIN should be discontinued if the patient experiences pain, swelling, inflammation, or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-fluoroquinolone antimicrobial drug.

CIPROFLOXACIN should not be used in patients with a history of tendon disease/disorder related to previous fluoroquinolone treatment.

Neurologic

Central Nervous System Adverse Reactions

Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (including pseudotumor cerebri), tremors, and light-headedness. Cases of status epilepticus have also been reported. As with other fluoroquinolones, CIPROFLOXACIN should be used with caution in patients with a known or suspected central nervous system (CNS) disorder that may predispose them to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose them to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction). If these reactions occur in patients receiving CIPROFLOXACIN, discontinue CIPROFLOXACIN immediately and institute appropriate measures (see 8.3 Less Common Clinical Trial Adverse Reactions).

Peripheral Neuropathy

Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and/or weakness have been reported in patients receiving fluoroquinolones, including ciprofloxacin.

Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition (see 8.5 Post-Market Adverse Reactions).

Psychiatric Adverse Reactions

Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of psychiatric adverse reactions, including: toxic psychoses, hallucinations, or paranoia; depression, or suicidal thoughts; anxiety, agitation, restlessness, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; and memory impairment. Cases of attempted or completed suicide have been reported, especially in patients with a medical history of depression, or an underlying risk factor for depression. These reactions may occur following the first dose. If these reactions occur in patients receiving CIPROFLOXACIN, discontinue CIPROFLOXACIN and institute appropriate measures (see 8.3 Less Common Clinical Trial Adverse Reactions and 8.5 Post-Market Adverse Reactions).

Ophthalmologic

If vision disorder occurs in association with the use of CIPROFLOXACIN, consult an eye specialist immediately.

Renal

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.

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 4.2 Recommended Dose and Dosage Adjustment, Special Populations and 10.3 Pharmacokinetics).

Sensitivity/Resistance

Development of Drug-Resistant Bacteria

Prescribing CIPROFLOXACIN in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.

Overgrowth of Non-Susceptible Organisms

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.

Skin

Phototoxicity

Ciprofloxacin has been shown to produce photosensitivity reactions. Moderate to severe phototoxicity reactions have been observed in patients exposed to direct sunlight or ultraviolet light while receiving drugs in this class. Excessive exposure to sunlight or ultraviolet light should be avoided. Therapy should be discontinued if phototoxicity occurs (e.g., sunburn-like skin reactions).

7.1 Special Populations

7.1.1 Pregnancy

The safety of ciprofloxacin in pregnancy has not yet been established. CIPROFLOXACIN should not be used in pregnant women unless the likely benefits outweigh the possible risk to the fetus. Ciprofloxacin has been shown to be non-embryotoxic and non-teratogenic in animal studies (see 16 Non-Clinical Toxicology, Reproductive and developmental toxicology).

7.1.2 Breastfeeding

The safety of ciprofloxacin in nursing women has not been established. 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.

7.1.3 Pediatrics

The safety and efficacy of ciprofloxacin in the pediatric population less than 18 years of age have not been established. Fluoroquinolones, 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 (see 16 Non-Clinical Toxicology). Histopathological examination of the weight-bearing joints in immature dogs revealed permanent lesions of the cartilage. CIPROFLOXACIN are not recommended for use in pediatric patients and adolescents.

7.1.4 Geriatrics

Ciprofloxacin is substantially excreted by the kidney, and the risk of adverse reactions may be greater in elderly patients with impaired renal function (see 10.3 Pharmacokinetics).

8 Adverse Reactions

8.1 Adverse Reaction Overview

The following sections summarize the safety information derived from clinical trials and post-market use of ciprofloxacin.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequences of adverse reactions observed in the clinical trials may not reflect frequences observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

Ciprofloxacin is generally well tolerated. During worldwide clinical investigation (1991), 16,580 courses of ciprofloxacin treatment were evaluated for drug safety.

The incidence of adverse reactions was 8.0%. In orally treated patients enrolled in clinical trials, the most frequently reported events, possibly, probably drug-related were: nausea (1.3%), and diarrhea (1.0%).

Most of the adverse events reported in orally treated patients were described as only mild or moderate in severity.

8.3 Less Common Clinical Trial Adverse Reactions

Events possibly or probably drug-related occurring at a frequency of less than 1% with ciprofloxacin treatment during clinical trials and subsequent post-marketing surveillance are as follows:

Body as a Whole: back pain, chest pain, pain, pain in extremities, moniliasis.

Cardiovascular System: palpitation, phlebitis, tachycardia, thrombophlebitis (at infusion site). The following has been reported rarely (≥0.01% <0.1%): hypotension. The following have been reported very rarely (<0.01%): angina pectoris, atrial fibrillation, cardiac arrest, cerebrovascular disorder, electrocardiogram abnormality, hot flashes, hypertension, kidney vasculitis, myocardial infarct, pericarditis, pulmonary embolus, substernal chest pain, syncope (fainting), vasodilation (hot flashes).

Digestive: abdominal pain, decreased appetite and food intake, dry mouth, dyspepsia, dysphagia, enlarged abdomen, flatulence, gastrointestinal moniliasis, jaundice, stomatitis, taste perversion, vomiting, abnormal liver function test. The following have been reported rarely: taste loss (impaired taste), moniliasis (oral), cholestatic jaundice, and pseudomembranous colitis. The following have been reported very rarely: constipation, esophagitis, gastrointestinal hemorrhage, glossitis, hepatomegaly, ileus, increased appetite, intestinal perforation, life-threatening pseudomembranous colitis with possible fatal outcome, liver damage, melena, pancreatitis, tenesmus, tooth discoloration, toxic megacolon, ulcerative stomatitis.

Ear and Labyrinth Disorders: tinnitus. The following have been reported rarely: transitory deafness (especially at higher frequencies). The following have been reported very rarely: ear pain.

Eye Disorders: abnormal vision (visual disturbances). The following have been reported very rarely: chromatopsia, colour blindness, conjunctivitis, corneal opacity, diplopia, eye pain.

Hemic and Lymphatic: agranulocytosis, anaemia, eosinophilia, granulocytopenia, leukocytopenia, leukocytosis, pancytopenia. The following have been reported rarely: abnormal prothrombin level, thrombocytopenia, thrombocytosis. The following have been reported very rarely: haemolytic anaemia, bone marrow depression (life-threatening), pancytopenia (life- threatening).

Hypersensitivity: rash. The following have been reported rarely: allergic reaction, anaphylactic/anaphylactoid reactions including facial, vascular and laryngeal edema, drug fever, haemorrhagic bullae and small nodules (papules) with crust formation showing vascular involvement (vasculitis), hepatitis, interstitial nephritis, petechiae (punctuate skin hemorrhages), pruritus, serum sickness-like reaction, Stevens-Johnson Syndrome (potentially life-threatening) (see 7 Warnings and Precautions, Immune). The following have been reported very rarely: shock (anaphylactic; life-threatening), pruritic rash, erythema multiforme (minor), erythema nodosum, major liver disorders including hepatic necrosis, (very rarely progressing to life threatening hepatic failures), toxic epidermal necrolysis (Lyell Syndrome, potentially life-threatening).

Metabolic and Nutritional Disorder: creatinine increased. The following have been reported rarely: edema (face), hyperglycemia, hypoglycemia.

Musculoskeletal: The following have been reported rarely in patients of all ages: achiness, arthralgia (joint pain), joint disorder (joint swelling), pain in the extremities, partial or completed tendon rupture (shoulder, hand or Achilles tendon), tendinitis (predominantly achillotendinitis), myalgia (muscular pain). The following have been reported very rarely: myasthenia (exacerbation of symptoms of myasthenia gravis) (see 7 Warnings and Precautions, Musculoskeletal).

Nervous System: agitation, confusion, convulsion, dizziness, hallucinations, headache, hypesthesia, increased sweating, insomnia, somnolence, tremor (trembling). The following has been reported rarely: paresthesia (peripheral paralgesia), abnormal dreams (nightmares), anxiety, seizures (including status epilepticus), depression (potentially culminating in self-injurious behavior, such as suicidal ideations/thoughts and attempted or completed suicide) (see 7 Warnings and Precautions, Neurologic). The following have been reported very rarely: anosmia (usually reversible on discontinuation), apathy, ataxia, depersonalization, diplopia, hemiplegia, hyperesthesia, hypertonia, increase of intracranial pressure, meningism, migraine, nervousness, neuritis, paresthesia, parosmia (impaired smell), polyneuritis, sleep disorder, twitching, grand mal convulsions, abnormal (unsteady) gait, psychotic reactions (potentially culminating in self-injurious behavior, such as suicidal ideations / thoughts and attempted or completed suicide), intracranial hypertension (including pseudotumor cerebri). In some instances these reactions occurred after the first administration of ciprofloxacin. In these instances, ciprofloxacin has to be discontinued and the doctor should be informed immediately.

Other: The following have been reported rarely: asthenia (general feeling of weakness, tiredness), death.

Respiratory System: dyspnea. The following have been reported very rarely: hiccup, hyperventilation, increased cough, larynx edema, lung edema, lung hemorrhage, pharyngitis, stridor, voice alteration.

Skin/Appendages: pruritus, urticaria, rash, maculopapular rash. The following has been reported rarely: photosensitivity reaction, blistering. The following have been reported very rarely: alopecia, angioedema, fixed eruption, photosensitive dermatitis, petechia.

Urogenital System: albuminuria, hematuria. The following have been reported rarely: abnormal kidney function, acute kidney failure, dysuria, leukorrhea, nephritis interstitial, urinary retention, vaginitis, vaginal moniliasis.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data

Laboratory Values: increased alkaline phosphatase, ALT increased, AST increased, BUN (urea) increased, cholestatic parameters increased, Gamma - GT increased, lactic dehydrogenase increased, NPN increased, transaminases increased, decreased albuminuria, bilirubinemia, creatinine clearance decreased, hypercholesteremia, hyperuricemia, increased sedimentation rate. The following have been reported rarely: acidosis, increased amylase, crystalluria, electrolyte abnormality, haematuria, hypercalcemia, hypocalcemia and lipase increased.

8.5 Post-Market Adverse Reactions

The additional adverse events summarized in Table 4, in alphabetical order, regardless of incidence or relationship to drug, have been reported during clinical trials and/or from worldwide post-marketing experience in patients given ciprofloxacin (includes all formulations, all dosages, all drug-therapy durations, and in all indications).

Table 4 - Post-Market Adverse Reactions

In isolated instances, some serious adverse drug reactions may be long-lasting (> 30 days) and disabling; such as tendinitis, tendon rupture, musculoskeletal disorders, and other reactions affecting the nervous system including psychiatric disorders and disturbance of senses.

9 Drug Interactions

9.1 Serious Drug Interactions

9.2 Drug Interactions Overview

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 reported in patients receiving theophylline alone; the possibility that ciprofloxacin may potentiate these reactions cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments should be made as appropriate.

Cytochrome P450:

Ciprofloxacin is contraindicated in patients receiving concomitant treatment with agomelatine (currently not marketed in Canada) or tizanidine as this may lead to an undesirable increase in exposure to these drugs.

Ciprofloxacin is known to be an 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, zolpidem). Increased plasma concentrations associated with drug specific side effects may be observed due to inhibition of their metabolic clearance by ciprofloxacin.

9.3 Drug-Behaviour Interactions

Ability to Drive and Operate Machinery

Fluoroquinolones including ciprofloxacin may result in an impairment of the patient’s ability to drive or operate machinery due to CNS reactions. This applies particularly in combination with alcohol (see 8.3 Less Common Clinical Trial Adverse Reactions and 8.5 Post-Market Adverse Reactions).

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 5 - Established or Potential Drug-Drug Interactions

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

^aCurrently not marketed in Canada

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.

9.5 Drug-Food Interactions

Although ciprofloxacin may be taken with meals that include milk, simultaneous administration with dairy products alone (calcium intake > 800 mg), with calcium-fortified products, or mineral-fortified drinks, should be avoided since decreased absorption is possible. It is recommended that ciprofloxacin be administered at least 2 hours before or 6 hours after these preparations (see 9.4 Drug-Drug Interactions, and 4.1 Dosing Considerations).

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Ciprofloxacin in vitro potency may interfere with the Mycobacterium spp. culture test by suppression of mycobacterial growth, causing false negative results in specimens from patients currently taking CIPROFLOXACIN.

10 Clinical Pharmacology

10.1 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 13 Pharmaceutical Information, 15 Microbiology). There is no cross-resistance between ciprofloxacin and the mentioned classes of antibiotics.

10.3 Pharmacokinetics

(See 10 Clinical Pharmacology, Detailed Human Pharmacology)

Absorption:

Following oral administration of single doses of 250 mg, 500 mg, and 750 mg of ciprofloxacin tablets, ciprofloxacin is absorbed rapidly and extensively mainly from the small intestine, reaching maximum serum concentrations 1-2 hours later.

The absolute bioavailability is approximately 70% to 80%. Maximum serum concentrations (C_max) and total areas under serum concentration vs. time curves (AUC) increased in proportion to dose.

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.

Distribution:

The protein binding of ciprofloxacin is low (20% to 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. They were identified as 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.

Elimination:

Ciprofloxacin is largely excreted unchanged both renally and to a smaller extent non-renally. Renal clearance is between 0.18 to 0.3 L/h/kg and the total body clearance between 0.48 to 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 (≥ 65 years of age):

No dosage adjustment based on age alone is necessary for elderly patients. Compromised renal function may lead to increased drug exposure in this population group as ciprofloxacin is substantially excreted by the kidney.

• Hepatic Insufficiency:

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.

• Renal Insufficiency:

Ciprofloxacin is eliminated primarily by renal excretion. Patients with renal insufficiency had significantly increased AUCs, prolonged (about 2-fold) elimination half-lives, and decreased renal clearances.

Some modification of dosage is recommended, particularly for patients with severe renal dysfunction. Only a small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal dialysis (see 4.2 Recommended Dose and Dosage Adjustment, Impaired Renal Function).

Detailed 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 ± 9.4 kg), ciprofloxacin was absorbed rapidly and extensively from the gastrointestinal tract.

Maximum serum concentrations (C_max) 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 (t_½) were between 4 and 6 hours (see Table 6 and Figure 1).

Table 6 - Pharmacokinetic Parameters of Ciprofloxacin Following Single Doses In Healthy Volunteers

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

Table 7 - Mean Pharmacokinetic Parameters of Ciprofloxacin at Steady State in Healthy Volunteers

Figure 1: Mean Ciprofloxacin Serum Concentration After Single Oral Doses

Metabolism and Excretion

Ciprofloxacin is largely excreted unchanged both renally and, to a small extent, 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%.

Table 8 shows urinary recovery data from another trial where healthy subjects were administered a single dose of ciprofloxacin in tablet form (see Table 8).

Table 8 - Mean Urinary Excretion of Ciprofloxacin

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.

Tissue Concentrations

In one study, the apparent volume of distribution (Vd_area) 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 (Vd_SS) and Vd_area 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 second, 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 (V_SS) was determined to be between 2.0 and 2.9 L/kg. Volumes in each compartment were determined to be: central compartment 0.2 -0.4, peripheral V₂ 0.6 - 0.8 and peripheral V₃ 1.2 - 1.6 L/kg.

Table 9 summarizes the results of tissue and fluid penetration of ciprofloxacin in man.

Table 9 - Distribution of Ciprofloxacin in Human Tissue/Fluid

Bone 4

2.9 ± 2.2 2 - 4

Nasal Secretions 20 500 mg PO 1.4 ± 0.81

Special Populations

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.

Table 10 - Comparison of Pharmacokinetic Parameters between Healthy Elderly and Healthy Younger Volunteers Following Oral Administration of a Single 250 mg Tablet

tmax (hr)

1.2 ± 0.1

Renal Impairment

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 11) were compared to 6 patients (3 male, 3 female, age: 63 ± 6 years) with renal impairment (see Group II, Table 11) and to 5 patients (2 male, 3 female, age: 63 ± 6 years) with end-stage renal failure, treated by haemodialysis (see Group III, Table 11). 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 11).

Table 11 - Mean Pharmacokinetic Parameters for Ciprofloxacin Following Oral Administration of a Single 250 mg Tablet in Healthy Volunteers and in Patients with Renal Insufficiency

I > 1.0

(> 60)

1.0 (±

0.0) 4.4 (±0.2) 6.94 (±

0.97)

232.9 (± 44.8)

37.0 (± 3.7)

Hepatic Impairment

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

11 Storage, Stability, and Disposal

Store between 15 and 30°C.

Part 2: Scientific Information

13 Pharmaceutical Information

Drug substance

Non-proprietary name of the drug substance: Ciprofloxacin hydrochloride

Chemical Name: 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid hydrochloride monohydrate

Molecular formula and molecular mass: C₁₇H₁₈FN₃O₃ ^. HCl ^. H₂O, 385.8 g/mol

Structural Formula:

Physicochemical properties: Ciprofloxacin hydrochloride is a pale yellow crystalline powder. It is soluble in water. Its solubility in aqueous buffer of pH 7.4 at 21°C is 0.19 g/L, while the solubility is considerably higher at slightly acidic or slightly alkaline pH. At 140°C, water of crystallization is lost. At 307°C, decomposition takes place. The pH of ciprofloxacin hydrochloride is between 3 and 4.5 in a solution (1 in 40). The pK_a1 is 6.5 and pK_a2 is 8.9 determined using a 3x10^-4M solution of 25°C.

Drug substance

Non-proprietary name of the drug substance: Ciprofloxacin

Chemical Name: 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.

3-quinolinecarboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl).

Molecular formula and molecular mass: C₁₇H₁₈FN₃0₃, 331.34 g/mol

Structural Formula:

Physicochemical properties: Ciprofloxacin is a pale yellow to white crystalline powder which is soluble in dilute (0.1 N) hydrochloric acid, practically insoluble in water, very slightly soluble in ethanol and methylene chloride and soluble in dilute acetic acid. Ciprofloxacin melts at about 255°C, with decomposition. pH of ciprofloxacin is 7.6 at 0.1 g/L water at 20°C. It has a pK_a1 of 6.5 and pK_a2 of 8.9 determined using a 3 x 10^-4 M solution at 25°C.

14 Clinical Trials

The clinical trial data on which the original indication was authorized is not available.

14.2 Comparative Bioavailability Studies

A randomized, single-dose (1 x 500 mg ciprofloxacin), three-way crossover comparative bioavailability study of CIPROFLOXACIN tablets (Sivem Pharmaceuticals ULC), Ciprobay® tablets (Bayer Inc., Germany), and Ciproxin® tablets (Bayer Inc., Switzerland) was conducted in healthy, adult, male subjects under fasting conditions. Comparative bioavailability data from 18 volunteers who completed the study, comparing CIPROFLOXACIN tablets (Sivem Pharmaceuticals ULC) and Ciprobay® tablets (Bayer Inc., Germany) is presented in the following table.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ CIPROFLOXACIN (ciprofloxacin as ciprofloxacin hydrochloride) tablets, 500 mg (Sivem Pharmaceuticals ULC)

² Ciprobay® (ciprofloxacin as ciprofloxacin hydrochloride) tablets, 500 mg (Bayer Inc., Germany)

³ Expressed as median (range) only

⁴ Expressed as the arithmetic mean (CV%) only

15 Microbiology

Mechanism of Action

The bactericidal action of ciprofloxacin results from inhibition of enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination.

Drug Resistance

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 and other fluoroquinolones. There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between <10^-9 to 1x 10^-6.

Activity in vitro and in vivo

Ciprofloxacin has in vitro activity against a wide range of gram-positive and gram negative microorganisms. Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal inhibitory concentration (MIC) by more than a factor of 2. Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections:

Aerobic gram-positive microorganisms

Enterococcus faecalis (Many strains are only moderately susceptible.)

Staphylococcus aureus (methicillin-susceptible strains only)

Staphylococcus epidermidis (methicillin-susceptible strains only)

Staphylococcus saprophyticus

Streptococcus pyogenes

Aerobic gram-negative microorganisms

The following in vitro data are available, but their clinical significance is unknown. Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 mcg/mL or less against most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of ciprofloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive microorganisms

Staphylococcus haemolyticus

Staphylococcus hominis

Aerobic gram-negative microorganisms

Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.

Susceptibility Tests

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted according to the criteria outlined in Table 12.

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg ciprofloxacin to test the susceptibility of microorganisms to ciprofloxacin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg ciprofloxacin disk should be interpreted according to the criteria outlined in Table 12. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Quality Control: Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. For dilution technique, standard ciprofloxacin powder should provide the MIC values according to criteria outlined in Table 13. For diffusion technique, the 5 mcg ciprofloxacin disk should provide the zone diameters outlined in Table 13.

16 Non-Clinical Toxicology

General toxicology

Acute toxicity:

Table 14 - LD₅₀ (mg/kg) across species

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.

Reproductive and developmental 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.

Genotoxicity

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 cerevisiæ: 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 toxicology

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 tolerability studies:

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

Compared to rapid infusion, a slow infusion of ciprofloxacin reduces the danger of crystal precipitation.

The precipitation of crystals in renal tubules does not immediately and automatically lead to kidney damage. In the animal studies, damage occurred only after high doses, with correspondingly high levels of crystalluria. For example, although they always caused crystalluria, even high doses were tolerated over 6 months without damage and without foreign-body reactions occurring in individual distal renal tubules.

Damage to the kidneys without the presence of crystalluria has not been observed. The renal damage observed in animal studies must not, therefore, be regarded as a primary toxic action of ciprofloxacin on the kidney tissue, but as typical secondary inflammatory foreign-body reactions due to the precipitation of a crystalline complex of ciprofloxacin, magnesium, and protein.

Articular tolerability studies:

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

The extent of the cartilage damage varies according to age, species, and dose; the damage can be reduced by taking the weight off the joints. Studies with mature 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.

Detailed Animal Pharmacology

Effects on Histamine Release:

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

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

0.1 to 100 mg/L has histamine liberating properties.

Bronchodilatory Effects:

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

Central Nervous System (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.

17 Supporting Product Monographs

1. 1. CIPRO® tablets, 250 mg, 500 mg, 750 mg, CIPRO® I.V. solution, 10 mg/mL, CIPRO® I.V. MINIBAGS solution 2 mg/mL, CIPRO® ORAL SUSPENSION 10 g/100 mL, control 120682, product monograph, Bayer Inc. (2008-06-05)
2. 2. CIPRO® ORAL SUSPENSION 10 g/100 mL, control 297788, product monograph, Bayer Inc. (2025-10-23)