Mint-Ciprofloxacin Product Monograph

Clinical Trials

A comparative, randomized, single dose, 2 way crossover bioavailability studies was performed under fasting conditions in healthy adult male volunteers. A summary of the pharmacokinetic parameters is given in the table below:

†Cipro^® is manufactured by Bayer Inc. and was purchased in Canada. ^$ Expressed as arithmetic (CV %) only.

INDICATIONS AND CLINICAL USES

Oral Administration

MINT-Ciprofloxacin (ciprofloxacin hydrochloride) 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

Streptococcus pneumoniae

Acute pneumonia caused by:

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Klebsiella pneumoniae

Proteus mirabilis

Pseudomonas aeruginosa

Staphylococcus aureus

Streptococcus pneumoniae

Acute sinusitis caused by:

Haemophilus influenzae

Moraxella catarrhalis

Streptococcus pneumoniae

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, MINT-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

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 Eschericia coli

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. An 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.

CONTRAINDICATIONS

MINT-Ciprofloxacin (ciprofloxacin hydrochloride) is contraindicated in patients who have shown hypersensitivity to ciprofloxacin or other quinolone antibacterial agents or any of the excipient.

Concurrent administration of ciprofloxacin and tizanidine is contraindicated since it may result in an undesirable increase in serum tizanidine concentrations. This can be associated with clinically relevant tizanidine-induced side effects (hypotension, somnolence, drowsiness).

WARNINGS

The safety of MINT-Ciprofloxacin (ciprofloxacin hydrochloride) in pediatric patients and adolescents (under the age of 18 years), pregnant women and nursing women has not yet been established. (See PRECAUTIONS: Pediatric Use, Pregnancy, and Nursing Women) Damage to juvenile weight-bearing joints and lameness were observed both in rat and dog studies but not in weaned piglets (see TOXICOLOGY). Histopathological examination of the weight-bearing joints in immature dogs revealed permanent lesions of the cartilage.

CNS and Psychiatric Effects

Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also cause central nervous system (CNS) stimulation which may lead to tremors, restlessness, lightheadedness, confusion hallucinations, depression, nervousness, agitation, insomnia, anxiety, paranoia, nightmares and rarely, suicidal thought 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 will 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 predispose to seizures and lower the seizure threshold. (See ADVERSE

REACTIONS)

Cytochrome P450

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

PRECAUTIONS, Drug Interactions)

Hypersensitivity

Serious hypersensitivity and/or anaphylactic reactions have been reported in patient 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 sever 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.

Pseudomembranous Colitis

Pseudomembranous colitis has been reported with virtually all antibacterial agents, including ciprofloxacin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients with diarrhoea subsequent to the administration of antibacterial agents. Subsequent to diagnosis of pseudomembranous colitis, therapeutic measures should be initiated. Mild cases with 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 antibacterial drug effective against C.

difficile.

PRECAUTIONS

Tendon rupture (predominantly achilles tendon) has been reported predominantly in the elderly on prior systemic treatment with glucocorticoids. At any sign of tendonitis (i.e., painful swelling), the administration of ciprofloxacin should be discontinued, physical exercise avoided, and a physician consulted.

Crystalluria related to ciprofloxacin has been reported only rarely in man because human urine is usually acidic. Crystals have been observed in the urine of laboratory animals, usually from alkaline urine. Patients receiving ciprofloxacin should be well hydrated and alkalinity of the urine should be avoided. The recommended daily dose should not be exceeded.

Ciprofloxacin has been shown to produce photosensitivity reactions. Patients taking ciprofloxacin should avoid direct exposure to excessive sunlight or UV-light. Therapy should be discontinued if photosensitization (ie. sunburn-like skin reactions) occurs.

Prolonged use of MINT-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.

Pregnancy

The safety of MINT-Ciprofloxacin in pregnancy have not yet been established. MINT-

Ciprofloxacin should not be used in pregnant women unless the likely benefits outweigh the possible risk to the fetus. (See WARNINGS) MINT-Ciprofloxacin have been shown to be non-embryotoxic and non-teratogenic in animal studies.

Nursing Women

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

Pediatric Use

The safety and efficacy of ciprofloxacin in the pediatric population less than 18 years of age have not been established. Quinolones, including ciprofloxacin, causes anthropathy and

osteochondrosis in juvenile animals of several species (See WARNINGS, TOXICOLOGY).

Elderly

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

Renal Impairment

Since ciprofloxacin is eliminated primarily by the kidney, MINT-Ciprofloxacin should be used with caution and at a reduced dosage in patients with impaired renal function. (See DOSAGE

AND ADMINISTRATION, HUMAN PHARMACOLOGY)

Hepatic Impairment

In preliminary studies in patients with stable chronic liver cirrhosis, (with mild to moderate hepatic impairment) no significant changes in ciprofloxacin pharmacokinetics were observed.

The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, and stable chronic cirrhosis (with severe hepatic impairment) however, have not been fully elucidated. An increased incidence of nausea, vomiting, headache and diarrhea were observed in this patient population (see HUMAN PHARMACOLOGY).

Ability to Drive and Operate Machinery

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

Drug Interactions

Concurrent administration of ciprofloxacin with theophylline may lead to an elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (see ADVERSE REACTIONS) If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.

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

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

Quinolones have been reported to increase the effects of the oral anticoagulant warfarin and its derivatives. During concomitant administration of these drugs, the prothrombin time or other appropriate coagulation tests should be closely monitored.

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

Concomitant administration of a nonsteroidal anti-inflammatory drug (fenbufen) with a quinolone (enoxacin) has been reported to increase the risk of CNS stimulation and convulsive seizures.

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

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 of 2 hours after substantial calcium intake (>800 mg). (See DOSAGE AND

ADMINISTRATION)

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

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

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

Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin, potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate associated toxic reactions. Therefore, patient under methotrexate therapy should be carefully monitored with concomitant ciprofloxacin therapy is indicated.

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

In a clinical study in healthy subjects there was an increase in tizanidine serum concentrations

(C_max 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 CONTRADICATIONS, WARNINGS)

In Clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in an increase of AUC and C_max of duloxetine. Although no clinical data are available on a possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration.

ADVERSE REACTIONS

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

Adverse events, possibly, probably or highly probably related to ciprofloxacin occurred in 1395

(8.8%) of patients. The adverse reactions according to treatment (oral) show that the incidence of adverse reactions was 8.0% for the group treated orally, 17% for the group treated with ciprofloxacin I.V. and 15.3% for the group treated sequentially. The difference between the oral and i.v. group relates to adverse vascular reactions which are known to be associated with i.v.

administration.

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%).

Events possibly, probably drug-related occurring at a frequency of less than 1% with ciprofloxacin oral 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. The following have 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, anorexia, dry mouth, dyspepsia, dysphagia, enlarged abdomen, flatulence, gastrointestinal moniliasis, jaundice, stomatitis, vomiting, abnormal liver function test. The following have been reported rarely: moniliasis (oral), cholestatic jaundice and pseudomembranous colitis. The following have been reported very rarely: constipation, esophagitis, gastrointestinal haemorrhage, 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.

Hemic and Lymphatic: agranulocytosis, anaemia, eosinophilia, granulocytopenia, leukocytopenia, leukocytosis, pancytopenia. The following have been reported very rarely:

altered prothrombin levels, haemolytic anaemia, marrow depression (life threatening), pancytopenia (life threatening), thrombocytopenia, thrombocytosis.

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 (punctured skin hemorrahages), pruritus, serum sickness-like reaction, Stevens-Johnson syndrome, 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), epidermal necrolysis (Lyell Syndrome).

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

Musculoskeletal: The following have been reported rarely: achiness, arthralgia (joint pain), joint disorder (joint swelling), pain in the extremities, partial or complete tendon rupture

(predominantly achilles tendon), tendonitis (predominantly achillotendonitis), myalgia (muscular pain). The following have been reported very rarely: myasthenia (exacerbation of symptoms of myasthensia gravis).

There have been 54 reports of arthropathies with ciprofloxacin. Ten of these reports involved children. Arthralgia was usually the first symptom which led to rapid assessment and withdrawal of the drug. No irreversible arthropathies have been observed.

Nervous System: agitation, confusion, convulsion, dizziness, hallucinations, headache, hypesthesia, increased sweating, insomnia, somnolence, tremor (trembling). The following have been reported rarely: paresthesia (peripheral paralgesia). The following have been reported very rarely: abnormal dreams (nightmares), anxiety, apathy, ataxia, depersonalization, depression, diplopia, hemiplegia, hyperesthesia, hypertonia, increase of intracranial pressure, meningism, migraine, nervousness, neuritis, paresthesia, polyneuritis, sleep disorder, twitching, grand mal convulsions, abnormal (unsteady) gait, psychosis, intracranial hypertension. 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, rash, maculopapular rash. The following have been reported rarely: photosensitivity reaction. The following have been reported very rarely: alopecia, angioedema, fixed eruption, photosensitive dermatitis, petechia, urticaria.

Special Senses: abnormal vision (visual disturbances), taste perversion, tinnitus. The following have been reported rarely: transitory deafness (especially at higher frequencies), taste loss

(impaired taste). The following have been reported very rarely: chromatopsia, colour blindness, conjunctivitis, corneal opacity, diplopia, ear pain, eye pain, parosmia (impaired smell), anosmia

(usually reversible on discontinuation).

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.

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.

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

Adverse reactions noted during therapy with ciprofloxacin and metronidazole in clinical trials were similar to those already noted during therapy with ciprofloxacin alone with the following additions:

Cardiovascular: peripheral edema

Digestive: colitis, gastritis, tongue discoloration

Hemic and Lymphatic: coagulation disorder, thrombocythemia

Skin: fungal dermatitis, pustular rash, sweating

Metabolic: healing abnormal, hypernatremia,

Nervous: dementia

Urinary: kidney tumour necrosis, urinary incontinence.

The following additional adverse events, in alphabetical order, regardless of incidence or relationship to drug, have been reported during clinical trials and from worldwide post-marketing experience in patients given ciprofloxacin (includes all formulations, all dosages, all drug-therapy durations, and in all indications): arrhythmia, atrial flutter, bleeding diathesis, bronchospasm, C. difficile associated diarrhea, candiduria, cardiac murmur, cardiopulmonary arrest, cardiovascular, collapse, cerebral thrombosis, chills, delirium, drowsiness, dysphasia, edema (conjunctivae, hands, lips, lower extremities, neck), epistaxis, exfoliative dermatitis, fever, gastrointestinal bleeding, gout (flare up), gynecomastia, hearing loss, hemoptysis, hemorrhagic cystitis, hyperpigmentation, joint stiffness, lightheadedness, lymphadenopathy, manic reaction, myoclonus, nystagmus, pain (arm, breast, epigastric, foot, jaw, neck, oral mucosa), paranoia, phobia, pleural effusion, polyuria, postural hypotension, pulmonary embolism, purpura, QT prolongation (frequency < 1 per million), renal calculi, respiratory arrest, respiratory distress, restlessness, rhabdomyolysis, torsades de pointes (frequency < 1 per million), toxic psychosis, unresponsiveness, urethral bleeding, urination (frequent), ventricular ectopy, ventricular fibrillation (frequency < 1 per million), ventricular tachycardia (frequency <

1 per million), vesicles, visual acuity (decreased) and visual disturbances (flashing lights, change in colour perception, overbrightness of lights).

SYMPTOMS AND TREATMENT OF OVERDOSE

In the event of acute, excessive oral 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.

DOSAGE AND ADMINISTRATION

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

Oral Administration

MINT-Ciprofloxacin (ciprofloxacin hydrochloride) may be taken before or after meals.

Absorption is faster on an empty stomach. Patients should be advised to drink fluids liberally and not take antacids containing magnesium or aluminum.

MINT-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, Videx^®

(didanosine) chewable/buffered tablets or pediatric powder, metal cations such as iron and multivitamin preparations with zinc. (See PRECAUTIONS, Drug Interactions)

Although MINT-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 MINT-Ciprofloxacin be administered at least 2 hours before or 2 hours after substantial calcium intake. (>800 mg). (See

PRECUATIONS, Drug Interactions)

Adults

The recommended dosages of MINT-Ciprofloxacin are:

Table 1: Recommended Dosages for Oral 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 q 12h. Chronic bacterial prostatitis should be treated for 28 days with 500 mg q 12h.

Impaired Renal Function

Ciprofloxacin is eliminated primarily by renal excretion. However, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine (see

HUMAN PHARMACOLOGY). This alternate pathway of drug elimination appears to compensate for the reduced renal excretion of patients with renal impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with severe renal dysfunction. The following table provides a guideline for dosage adjustment. However, monitoring of serum drug levels provides the most reliable basis for dosage adjustments.

Table 2: 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 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 (μmol/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 has not been established. Ciprofloxacin should not be used in pediatric patients and adolescents. (See

WARNINGS)

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE

Proper Name: Ciprofloxacin hydrochloride

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

Structural Formula:

Molecular Formula: C₁₇H₁₈FN₃0₃ HC1 H₂0

Molecular Weight: 385.8

Description: Ciprofloxacin hydrochloride is a pale yellow crystalline powder.

It is sparingly 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 3 x 10^-4 M solution of 25°C.

COMPOSITION

Tablets

Ciprofloxacin Hydrochloride

Microcrystalline Cellulose

Starch (corn)

Sodium Starch Glycolate

Colloidal Silicon Dioxide

Talc

Magnesium Stearate

Hypromellose

Titanium Dioxide

Polyethylene Glycol

STABILITY AND STORAGE RECOMMENDATIONS

Tablets: Store at room temperature 15°- 30°C.

AVAILABILITY OF DOSAGE FORMS

MINT-Ciprofloxacin 250 mg Tablets: White to off-white, round, film-coated tablets, debossed with “RX709" on one side and plain on the other side. Bottles of 100s.

MINT-Ciprofloxacin 500 mg Tablets: White to off-white, caplet shaped, film-coated tablets, debossed with “RX710" on one side and plain on the other side. Bottles of 100s.

MINT-Ciprofloxacin 750 mg Tablets: White to off-white, caplet shaped, film-coated tablets, debossed with “RX711" on one side and plain on the other side. Bottles of 100s.

MICROBIOLOGY

The in vitro activity of ciprofloxacin against clinical isolates of gram-positive and gram-negative aerobic and anaerobic bacteria is shown in Table 3. 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. Susceptibility was determined by agar and broth dilution tests, pH 7.1-7.4, using inoculum sizes ranging from 10⁴ to 10⁵ colony forming units per mL.

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. There is no cross-resistance between ciprofloxacin and the mentioned classes of antibiotics.

Most strains of Pseudomonas cepacia, some strains of Pseudomonas maltophilia and most anaerobic bacteria (including Bacteroides fragilis and Clostridium difficile but excluding

Clostridium perfringens) are resistant to ciprofloxacin.

Table 3: Cumulative Percent of Strains Inhibited at the Indicated Concentration of Ciprofloxacin mg/L

Genera or Species (Number of

Strains)

0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64

Acinetobacter antiratus -42 2 12 19 52 86 95 98 100 Actinomyces spp. -3 33.3 100 Branhamella catarrhalis -28 4 43 100 Campylobacter jejuni -100 64 95 97 100 Chlamydia trachomatis -10 70 100 Clostridium spp. -8 10.0 55.0 75.0 95.0 100 Clostridium perfringens -12 8.3 83.3 100 Citrobacter freundii -19 88 94 100 Citrobacter diversus -3 66 100 Citrobacter spp. -4 100 Enterobacter aerogenes -5 50 83 100 Enterobacter agglomerans -2 100 Enterobacter cloaceae -49 61 86 96 100 Escherichia coli -203 84 92 93 96 98 99 100 Flavobacterium brevie -3 66 100 Fusobacterium spp. -8 25.0 50.0 75.0 87.5 100 Haemophilus ducreyi -72 100 Haemophilus influenzae

beta-lactamase positive

-50 90 100

Klebsiella oxytoca -32 78 97 100 Klebsiella pneumonia -40 21 72 85 90 97 100

Table 3: Cumulative Percent of Strains Inhibited at the Indicated Concentration of Ciprofloxacin mg/L

Genera or Species (Number of

Strains)

0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64

Klebsiella species -24 33 88 92 96 100 Morganella morganii -12 92 100 Moraxella spp. -5 20 40 60 80 100 Neisseria gonorrhoeae

beta-lactamase negative

-15 13 73 87 100

Propionibacterium spp. -42 2.4 28.6 88.1 92.9 100 Proteus mirabilis -57 28 88 93 98 100 Proteus vulgaris -3 100 Providencia alcalifaciens -6 33 66 100 Providencia rettgeri -5 80 100 Providencia stuartii -16 6 25 38 50 56 75 100 Pseudomonas aeruginosa -187 1 2 7 41 65 83 89 96 98 100 Pseudomonas aeruginosa

(Fibrocystic mucoid strain)

3 20 43 63 80 100

Pseudomonas aeruginosa

(Fibrocystic non-mucoid strain)

13 50 93 100

Pseudomonas aeruginosa

(Bacteremic non-cystic strain)

• -(30)

  3 57 88 100

Pseudomonas cepacia -10 50 100 Pseudomonas fluorescens -8 50 75 100 Pseudomonas maltophilia -11 9 36 55 64 82 91 100 Salmonella spp. -81 33 68 96 100

Table 3: Cumulative Percent of Strains Inhibited at the Indicated Concentration of Ciprofloxacin mg/L

Genera or Species (Number of

Strains)

0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64

Serratia marcescens -12 50 100 Shigella spp. -59 97 98 98 100 Shigella sonnei -45 100 Staphylococcus aureus -101 2 5 15 52 95 100 Staphylococcus epidermidis -64 5 6 28 84 95 100 Streptococcus faecalis -39 31 87 100 Streptococcus pneumoniae -51 9 27 100 Ureaplasma urealyticum -10 20 50 100 The minimum inhibitory concentrations (MICs) of ciprofloxacin against aerobic bacteria are not significantly affected by changes in inoculum size in the range of 5 X 10³ to 5 X 10⁶ cfu/spot.

Five bacterial species, Staphylococcus aureus K734, Staphylococcus epidermidis H846,

Streptococcus faecalis 7149, Escherichia coli 2345, and Proteus mirabilis 2349 were tested for

MICs with inoculum size of 5 X 10³ to 5 X 10⁶. Streptococcus faecalis showed a four-fold increase while the remainder showed only a two to three-fold increase (Table 4). There were no differences between MICs determined in Mueller Hinton and Isosensitest broth.

MIC values 8 to 16 fold higher were seen when these organisms were tested in Mueller Hinton broth at pH 4.8 compared to values obtained at pH 7.3 (Table 4). This reduction in antibacterial activity suggests a significant pH effect.

Some studies have demonstrated that increasing the concentration of magnesium in the medium used for in vitro testing reduces the antibacterial activity of ciprofloxacin. Neither zinc nor calcium supplementation had the same effect. The mechanism by which magnesium antagonizes the activity of ciprofloxacin is unclear.

Table 4: Effect of Culture Medium Composition, pH and Inoculum Size On

Antibacterial Activity of Ciprofloxacin

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

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

Development of Resistance

Resistance to ciprofloxacin in vitro develops slowly via multiple-step mutation. Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between <1x10^-9 to

1 x 10^-6. The prevalence of resistance may vary geographically and with time for selected species. Local information on resistance is desirable, particularly when treating severe infections.

Susceptibility Testing

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum 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. The

MIC values should be interpreted according to the following criteria:

For testing Enterobacteriaceae, Enterococcus species, and Staphylococcus species.

MIC (μg/mL) Interpretation

≤ 1 Susceptible (S)

2 Intermediate (I) ≥ 4 Resistant (R)

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. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide the following MIC values:

Microorganism Zone Diameter(mm)

Enterococcus faecalis ATCC 29212 0.25 – 2.0 Escherichia. coli ATCC 25922 0.004 - 0.015 Staphylococcus aureus ATCC 25923 0.12 - 0.5

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 µg 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 µg ciprofloxacin disk should be interpreted according to the following criteria:

Zone Diameter (mm) Interpretation

≥ 21 Susceptible (S)

16 - 20 Intermediate (I)

≤ 15 Resistant (R)

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5 µg ciprofloxacin disk should provide the following zone diameters in these laboratory test quality control strains:

Table 5: Daily Ranges for Ciprofloxacin for Quality Control Samples

PHARMACOLOGY

ANIMAL PHARMACOLOGY

Effects on histamine release

Ciprofloxacin was administered intravenously to 9 anaesthetized dogs (initially with thiopental sodium at 25 mg/kg i.v., followed by continuous infusion of a mixture of fentanyl 0.04 mg/kg/hr and dehydrobenzperidol 0.25 mg/kg/hr) at a single dose of 3, 10 or 30 mg/kg. Ciprofloxacin treatment resulted in circulatory changes similar to those caused by histamine release. These were reductions in blood pressure, cardiac output and maximum rate of pressure increase in the left ventricle (dp/dt max), and increase in heart rate. This histamine-liberating effect was counteracted by the simultaneous intravenous administration of 0.01 mg/kg pyrilamine maleate.

No signs of histamine liberation were observed on conscious animals.

In-vitro experiments on isolated rat mast cells also indicate that ciprofloxacin at concentrations of 0.1 to 100 mg/L has histamine liberating properties.

Bronchodilatory Effects

Ciprofloxacin was tested on isolated guinea-pig trachea at concentrations of 0.0001 to 10 mg/L.

It produced a dose-related small but significant relaxation of respiratory airway smooth muscle.

It has, however, no effect on leukotriene D4 and histamine-induced contractions at these doses.

CNS Effects

Ciprofloxacin was administered orally to 4 groups of 1 cat each under chloralose-urethane anaesthesia at doses of 0, 10, 20 and 100 mg/kg. No effects were observed on neuromuscular transmission, flexor reflex, or blood pressure.

Gastrointestinal Effects

Ciprofloxacin was administered orally to 4 groups of 20 mice each at doses of 0, 10, 30, and 100 mg/kg, 40 minutes prior to a 15% charcoal suspension. No effect was observed in intestinal charcoal transit time. When given to 3 groups of 20 rats each at doses of 0, 30 or 100 mg/kg, no gastric lesions were observed on sacrificing the animals after 5 hours.

When given intraduodenally to 3 groups of 8 rats each at doses of 0, 10 and 100 mg/kg, no increase in basal gastric acid secretion was observed on perfusion of the stomach.

Effect on Blood Glucose and Serum Triglycerides

Four groups of six fasting rats each were given intravenous injections of 0, 3, 10, and 30 mg/kg respectively. A slight but significant increase in blood glucose concentrations 60 minutes and

240 minutes post dose was observed in the 3 and 10 mg/kg groups but not in the 30 mg/kg group in comparison to controls.

At 60 minutes post dose, the serum triglyceride concentrations were slightly but significantly reduced in all three groups. This effect was not dose-related. At 120 minutes, the concentration was slightly elevated in the 30 mg/kg group.

HUMAN PHARMACOLOGY

Pharmacokinetics

The relative bioavailability of oral ciprofloxacin, given as a tablet, is between 70 and 80 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)

Pharmacokinetics were dose proportioned with no significant changes in clearance or half-life occurring over this dose range (see below)

Table 6: Pharmacokinetic Parameters Of Ciprofloxacin Following Single Doses

In Healthy Volunteers Oral

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

Table7: Mean Pharmacokinetic Parameters of Ciprofloxacin and Metronidazole at Steady State in Healthy Volunteers

Table 8: Mean Urinary Excretion of Ciprofloxacin

Metabolism and Excretion

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

Small concentrations of 4 metabolites have been reported: Desethyleneciprofloxacin (M₁)

(1.8%), sulphociprofloxacin (M₂) (5.0%), oxociprofloxacin (M₃) (9.6%) and formylciprofloxacin

(M₄) (0.1%).

Following the oral administration of a single 259 mg dose of ¹⁴C-labelled ciprofloxacin to six healthy male volunteers (age: 25.0 ± 1.46 years, weight: 70.0 ± 3.39 kg), approximately 94% of the dose was recovered in the urine and feces over five days. Most of the radioactivity was recovered in the urine (55.4%). Unchanged ciprofloxacin was the major radioactive moiety identified in both urine and feces, accounting for 45% and 25% of the dose, respectively. Total

(urine and feces) excretion of all metabolites was 18.8%.

FACTORS INFLUENCING THE PHARMACOKINETICS

Age (Elderly)

In 4 females and 6 males, (age: 67 ± 4 years, weight: 65 ± 6 kg) with normal renal function for their age, given a single oral dose of 250 mg, maximum ciprofloxacin serum concentrations and areas under the serum concentration time curves were significantly higher than in 10 male younger volunteers (age: 24 ± 3 years, weight: 72 ± 9 kg). The time to peak serum concentrations, overall elimination half-life and urinary recovery of ciprofloxacin were similar in both age groups.

Table 9: Comparison of pharmacokinetic parameters between healthy elderly and healthy younger volunteers

Impaired Renal Function

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 patient 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 10) were compared to 6 patients (3 male, 3 female, age: 63 ± 6 years) with renal impairment (see Group II,

Table 10) and to 5 patients (2 male, 3 female, age: 63 ± 6 years) with end-stage renal failure, treated by haemodialysis (see Group III, Table 10). Patients with renal insufficiency had significantly increased AUCs, prolonged (about 2-fold) elimination half-lives, and decreased renal clearances.

Haemodialysis resulted in a minimal decrease in plasma levels. From the dialysate concentrations, it can be estimated that no more than 2% of the dose was removed by dialysis over 4 hours, which was less than the amount lost in the urine over 24 hours in patients of Group

II (see Table 10).

Table 10: Mean Pharmacokinetic Parameters for Ciprofloxacin Following a Single 250 mg

Oral Dose in Healthy Volunteers and in Patients with Renal Insufficiency

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 I.V.

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

Food

The administration of ciprofloxacin with food delayed absorption, as shown by an increase of approximately 50% in time to peak concentrations, but did not cause other changes in the pharmacokinetics of ciprofloxacin.

Drug Interactions

Theophylline

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

Caffeine

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

Multivalent Cations

Absorption of ciprofloxacin is significantly reduced by concomitantly administration of multivalent cation-containing products such as magnesium/aluminum antacids sucralfate, Videx^®

(didanosine) chewable/buffered tablets or pediatric powder, mineral supplements or products contain calcium, iron or zinc.

Probenecid

Co-administration of probenecid (1000 mg) with ciprofloxacin (500 mg) orally resulted in about

50% reduction in the ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation.

Serum Protein Binding

Serum protein binding of ciprofloxacin is between 19 to 40%, which is not likely to be high enough to cause significant protein binding interactions with other drugs.

Tissue Concentrations

In one study, the apparent volume of distribution (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.

Table 11 summarizes the results of tissue and fluid penetration of ciprofloxacin in man.

Table 11: Distribution of Ciprofloxacin in Human Tissue/Fluid

TOXICOLOGY

Acute Toxicity

Species Mode of administration LD50 (mg/kg)

Mouse p.o. approx 5000

Rat p.o approx 5000

Rabbit p.o. approx 2500

Mouse i.v. approx 290

Rat i.v. approx 145

Rabbit i.v. approx 125

Dog i.v. approx 250

Chronic Toxicity

Subacute Tolerability Studies over 4 weeks

Oral administrations: Doses up to and including 100 mg/kg were tolerated without damaged 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 administrations: 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 there 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 haemoglobin values.

Chronic Tolerability Studies over 6 months

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

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

Carcinogenicity

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

Reproduction Toxicology

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

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

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

Mutagenicity

Eight in vitro mutagenicity tests have been conducted with ciprofloxacin. Test results are listed below:

Salmonella: Microsomes Test (Negative)

E. coli: DNA Repair Assay (Negative)

Mouse Lymphoma Cell Forward Mutation Assay (Positive)

Chinese Hamster V₇₉ Cell HGPRT Test (Negative)

Syrian Hamster Embryo cell Transformation Assay (Negative)

Saccharomyces cerevisiae: Point Mutation Assay (Negative)

Mitotic Crossover and Gene Conversion Assay (Negative)

Rat Hepatocyte Primary Culture DNA Repair Assay (LIDS) (Positive)

Two of the eight tests were positive, but results of the following four in vivo test systems gave negative results:

Rat Hepatocyte DNA Repair Assay

Micronucleus Test (Mice)

Dominant Lethal Test (Mice)

Chinese Hamster Bone Marrow

Special Tolerability Studies

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

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

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

The precipitation of crystals in renal tubules doe 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 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 cause damage to the large, weight-bearing 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 has no effect on the morphological structures of the retina and on electroretinographic findings.

BIBLIOGRAPHY

1. 1. Aigner KR, Dalhoff A. Penetration activities of ciprofloxacin into muscle, skin and fat following oral administration. J Antimicrob Chemother 1986;18:644-645.
2. 2.

   Aldridge KE, Schiro DD, Tsai L, Janney A, Sanders CV, Marier RL. Ciprofloxacin

   (BAY o 9867) and in vitro comparison with other broad spectrum antibiotics. Curr Ther

   Res 1985;37(4):754-762.

3. 3. Auckenthaler R, Michea-Hamzehpour M, Pechere JC. In-vitro activity of newer quinolones against aerobic bacteria. J Antimicrob Chemother 1986;17(Suppl.B):29-39.
4. 4.

   Barry AL, Fass RJ, Anhalt JP, Neu HC, Thornsberry C, Tilton RC, Painter BG,

   Washinton JA. Ciprofloxacin disk susceptibility tests: interpretive zone size standards for

   5μg disks. J Clin Microbiol 1985;21(6):880-883.

5. 5. Bauernfeind A, Petermuller C. In vitro activity of ciprofloxacin, norfloxacin and nalidixic acid. Eur J Clin Microbiol 1983;2(2):111-115.
6. 6. Bayer A, Gajewska A, Stephens M, Marshal-Stark J, Pathy J. Pharmacokinetics of ciprofloxacin in the elderly, Respiration 1987;51:292-295.
7. 7.

   Beermann D, Scholl H, Wingender W, Forster D, Beubler E. Metabolism of ciprofloxacin in man. In Neu HC & Weuta H (Eds) 1st International Ciprofloxacin

   Workshop, Leverkusen 1985, pp. 141-146, Excerpta Medica, Amsterdam, 1986.

8. 8.

   Crump B, Wise R, Dent J. Pharmacokinetics and tissue penetration of ciprofloxacin.

   Antimicrob Agents Chemother 1983;24(5):784-786.

9. 9. Fass RJ. Efficacy and safety of oral ciprofloxacin for treatment of serious urinary tract infections Antimicrob Agents Chemother 1987;31:148-150.
10. 10. Fass RJ. Efficacy and safety of oral ciprofloxacin in the treatment of serious respiratory infections. Am J Med 1987;82 (Suppl 4A):202-207.
11. 11.

    Fass RF. Treatment of skin and soft tissue infections with oral ciprofloxacin. J

    Antimicrob Chemother 1986; 18 (Suppl.D):153-157.

12. 12.

    Fong IG, Ledbetter WH, Van en broucke C, Simbul M, Rahm V. Ciprofloxacin concentrations in bone and muscle after oral dosing. Antimicrob Agents Chemother

    1986;29:405-408.

13. 13.

    Gasser TC, Ebert SC, Graversen PHm, Madsen PO. Ciprofloxacin pharmacokinetics with normal and impaired renal function. Antimicrob Agents and Chemother 1987;31:709-

    712.

14. 14.

    Giamarellou H, Galanakis N, Dendrinos C, Stefanou J, Daphnis E. Evaluation of ciprofloxacin in the treatment of Pseudomonas aeruginosa infections. Eur J Clinical

    Microbiol 1986;5:232-235.

15. 15. Gonzalez MA, Moranchel AH, Duran S, Pichardo A, Magana JL. Multiple dose ciprofloxacin dose ranging and kinetics. Clin Pharmacol Ther 1985;37:633-637.
16. 16.

    Greenberg RNM, Kennedy DJ, Reilly PM, Luppen KL, Weinandt WJ. Treatment of bone, joint and soft tissue infections with oral ciprofloxacin. Antimicrob Agents

    Chemother 1987;31:151-155.

17. 17. Greenberg RNM, Tice AD, Marsh PK, Craven PC, Reilly PM. Randomized trial of ciprofloxacin compared with other antimicrobial therapy in the treatment of osteomyelitis. Am J Med 1987;82 (Suppl.4A):266-269.
18. 18.

    Honeybourne D, Wise R, Andrews JM. Ciprofloxacin penetration into lungs. Lancet

    1987;2031:1040.

19. 19.

    LeBel M, Bergeron MG, Vallee F, Fiset C, Chasse G. Pharmacokinetics &

    Pharmacodynamics of ciprofloxacin in cystic fibrosis patients. Antimicrob Agents

    Chemother 1986;30:260-266.

20. 20.

    Ledergerber B, Bettex JD, Joos B, Flepp M, Luethy R. Effect of standard breakfast on drug absorption and multiple-dose pharmacokinetics of ciprofloxacin. Antimicrob

    Agents Chemother 1985;27(3):350-352.

21. 21.

    Licitra CM, Brooks RG, Siegler BE. Clinical Efficacy and levels of ciprofloxacin in

    Tissue in patients with soft tissue infection. Antimicrob Agents Chemother 1987;31:805-

    807.

22. 22.

    Performance standards for antimicrobial susceptibility tests. 8^th ed. Wayne, PA: national

    Committee for Clinical Laboratory Standards; 2003.

23. 23.

    Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically.

    6^th ed. Wayna, PA: National Committee for Clinical Lablratory Standards; 2003.

24. 24.

    Ramirez-Ronda CH, Saavedra S, Rivera-Vazques CR. Comparative, double-blind study of oral ciprofloxacin and intravenous cefotaxime in skin and skin structure infections.

    Am J Med 1987;82 (Suppl. 4A):220-223.

25. 25.

    Raoof S, Wollschager C, Khan FA. Ciprofloxacin increases serum levels of theophylline.

    Am J Med 1987;84 (Suppl. 4A):115-118.

26. 26. Ratcliffe NT, Smith JT. Effects of magnesium on the activity of 4-quinolone antibacterial agents. J Pharm Pharmacol 1983; 35(Suppl):61P.
27. 27.

    Schacht P, Arcieri G, Branolte J, Bruck H, Chysky V. Worldwide Clinical Data on

    Efficacy and Safety of Ciprofloxacin. Infection, 1988;(Suppl.1), 16:29-43.

28. 28.

    Schluter G. Toxicology of ciprofloxacin. In Neu HC, Weuta H (Eds) 1st International

    Ciprofloxacin Workshop, Leverkusen 1985, pp. 291-296, Excerpta Medica, Amsterdam,

    1986.

29. 29.

    Smith JT. The mode of action of 4-quinolones and possible mechanisms of resistance. J

    Antimicrob Chemother 1986;18(Supp. D.):21-29.

30. 30.

    Wolfson JS, Hooper DC, The fluoroquinolones: Stuctures, Mechanisms of Action and

    Resistance, and Spectra of Activities in Vitro. Antimicrob Agents Chemother

    1985;28(4):581-586.

31. 31.

    Zeiler H-J. Evaluation of the In Vitro Bactericidal Action of Ciprofloxacin on Cells of

    Escherichia Coli in the Logarithmic and Stationary Phases of Growth. Antimicrob Agents

    Chemother 1985;28(4):524-527.

32. 32.

    Cox CE. Brief Report: Sequential Intravenous and Oral Ciprofloxacin versus

    Intravenous Ceftazidime in the Treatment of Complicated Urinary Tract Infections. Am

    J Med 1989; 87 (5a): 157S-159S.

33. 33.

    Menon L., Ernst JA, Sy ER, Flores D, Pacia A, Lorian V. Brief Report: Sequential

    Intravenous/Oral Ciprofloxacin Compared with Intravenous Ceftazidime in the Treatment of Lower Respiratory Tract Infections. Am J Med 1989; 87 (5a): 119S-120S.

34. 34. Data on file at Bayer Inc.
35. 35.

    Thorsteinsson SB., Bergan T., Johannesson G., Thorsteinsson HS, Rohwedder R.

    Tolerance of Ciprofloxacin at Injection Site, Systemic Safety and Effect of

    Electroencephalogram. Chemotherapy 1987;33:448-451.

36. 36.

    Honeybourne D., Andrews J.M., Ashby J.P., Lodwick R, Wise R. Evaluation of the penetration of ciprofloxacin and amoxycillin into the bronchial mucosa. From the

    Departments of Thoracic Medicine and Microbiology, Dudley Road Hospital,

    Birmingham, June 1, 1988.

37. 37.

    Houghton G, Thorne P.S., Smith J., Templeton R. et al. The Pharmacokinetics of

    Intravenous Metronidazole (single and multiple dosing). Royal Society of Medicine

    International Congress and Symposium Series No. 18.

38. 38. Product Monograph for Cipro® (Ciprofloxacin Hydrochloride Tablets) 250mg, 500mg and 750mg, Date of Revision: May 8, 2006.