PART I: HEALTH PROFESSIONAL INFORMATION 4

SUMMARY PRODUCT INFORMATION 4 INDICATIONS AND CLINICAL USE 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 11 DRUG INTERACTIONS 15 DOSAGE AND ADMINISTRATION 18 OVERDOSAGE 19 ACTION AND CLINICAL PHARMACOLOGY 19 STORAGE AND STABILITY 23 DOSAGE FORMS, COMPOSITION AND PACKAGING 23

PART II: SCIENTIFIC INFORMATION 24

PHARMACEUTICAL INFORMATION 24 CLINICAL TRIALS 25 DETAILED PHARMACOLOGY 26 MICROBIOLOGY 30 TOXICOLOGY 34 REFERENCES 38

PART III: CONSUMER INFORMATION. 40

FACTIVE(tm)

gemifloxacin mesylate

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics DOSAGE AND ADMINISTRATION.

For a brief discussion, see

and

Pediatrics (< 18 years of age):

WARNINGS AND PRECAUTIONS, Special Populations,

For a brief discussion, see

Pediatrics.

CONTRAINDICATIONS

• Gemifloxacin mesylate is contraindicated in patients with a history of hypersensitivity to gemifloxacin, fluoroquinolone antibiotic agents, or any of the product components. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Serious hypersensitivity and/or anaphylactic reactions have been reported in patients receiving quinolone therapy, including FACTIVE(tm) (see WARNINGS AND PRECAUTIONS, Hypersensitivity).

General

THE SAFETY AND EFFECTIVENESS OF FACTIVE(tm) IN CHILDREN, ADOLESCENTS (LESS THAN 18 YEARS OF AGE), PREGNANT WOMEN, AND NURSING WOMEN HAVE NOT BEEN ESTABLISHED WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women, Nursing Women Pediatrics

(see

and

subsections).

Prescribing FACTIVE(tm) in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Carcinogenesis and Mutagenesis

Long-term studies in animals to determine the carcinogenic potential of gemifloxacin have not been conducted. Gemifloxacin was clastogenic in vitro mouse lymphoma, human chromosome aberration, and in vivo rat micronucleus assays. The clinical significance of these clastogenic findings is not known. Gemifloxacin was not mutagenic in Ames Salmonella mutation, rat unscheduled DNA synthetis and mouse micronucleus assays (see TOXICOLOGY).

Cardiovascular

QT Interval Prolongation

Gemifloxacin may prolong the QT interval in some patients. Gemifloxacin should be avoided in patients with a history of prolongation of the QTc interval, patients with uncorrected electrolyte disorders (hypokalemia or hypomagnesemia), and patients receiving Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic agents. Gemifloxacin should be used with caution when given concurrently with these drugs, as well as in patients with ongoing proarrhythmic conditions, such as clinically significant bradycardia or acute myocardial ischemia. Pharmacokinetic studies between gemifloxacin and drugs that prolong the QTc interval such as erythromycin, antipsychotics and tricyclic antidepressants have not been performed. No cardiovascular morbidity or mortality attributable to QTc prolongation occurred with gemifloxacin treatment in over 6775 patients, including 653 patients concurrently receiving drugs known to prolong the QTc interval and 5 patients with hypokalemia. In clinical trials with gemifloxacin, a small mean increase in the QTc interval was observed but this was not statistically different from the comparator group. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher. QTc prolongation may lead to an increased risk for ventricular arrhythmias including torsades de pointes. The maximal change in the QTc interval occurs approximately 5-10 hours following oral administration of gemifloxacin.

Gastrointestinal

Pseudomembranous Colitis

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including gemifloxacin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who experience diarrhea subsequent to the administration of any antibacterial agent. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is the primary cause of "antibiotic-associated colitis." After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

Hepatic/Biliary/Pancreatic

Hepatic

Liver enzyme elevations (increased ALT and/or AST) occurred at similar rates (0.5% and 0.4%, respectively) in patients receiving gemifloxacin 320 mg daily relative to comparator antimicrobial agents. In patients who received gemifloxacin at doses of 480 mg per day or greater there was an increased incidence of elevations in liver enzymes (see ADVERSE REACTIONS). There were no clinical symptoms associated with these liver enzyme elevations. The liver enzyme elevations resolved following cessation of therapy. The recommended dose of gemifloxacin 320 mg daily should not be exceeded and the recommended length of therapy should not be exceeded (see DOSAGE AND ADMINISTRATION).

Hypersensitivity

Serious hypersensitivity and/or anaphylactic reactions have been reported in patients receiving fluoroquinolone therapy, including FACTIVE(tm). Hypersensitivity reactions reported in patients receiving fluoroquinolone therapy have occasionally been fatal. These reactions may occur following the first dose. 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. Gemifloxacin should be discontinued immediately at the appearance of any sign of an immediate Type I hypersensitivity skin rash or any other manifestation of a hypersensitivity reaction; the need for continued fluoroquinolone therapy should be evaluated (see WARNINGS AND PRECAUTIONS, Skin, Rash and ADVERSE REACTIONS). As with other drugs, 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/or some due to uncertain etiology, have been reported in patients receiving therapy with antibiotics, including gemifloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations usually include new onset of fever and one or more of the following: 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; anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.

Musculoskeletal and Connective Tissue

Chondrotoxic Effects

Fluoroquinolones, including gemifloxacin, have been shown to cause arthropathy in immature animals. The relevance of these findings to humans is unknown (see TOXICOLOGY).

Tendon Effects

Tendonitis and ruptures of the shoulder, hand, Achilles tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving fluoroquinolones. Gemifloxacin 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 tendonitis or tendon rupture has been confidently excluded. Tendon rupture may occur either during or after treatment. Elderly patients, athletes, and patients taking corticosteroids are more prone to tendonitis.

Neurologic

Neuropathy

In clinical studies with gemifloxacin, central nervous system (CNS) effects have been reported infrequently. As with other fluoroquinolones, gemifloxacin should be used with caution in patients with CNS diseases such as epilepsy, or in patients predisposed to convulsions. Although not seen in gemifloxacin clinical trials, convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving other fluoroquinolones. (See WARNINGS AND PRECAUTIONS, Psychiatric). If these reactions occur in patients receiving gemifloxacin, the drug should be discontinued and appropriate measures should be instituted.

Peripheral Neuropathy

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

Psychiatric

In clinical studies with gemifloxacin, central nervous system (CNS) effects have been reported. Although not seen in gemifloxacin clinical trials, convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving other fluoroquinolones. CNS stimulation, which may lead to tremors, restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, insomnia, and rarely suicidal thoughts or acts may also be caused by other fluoroquinolones. If these reactions occur in patients receiving gemifloxacin, the drug should be discontinued and appropriate measures instituted.

Renal

Alteration of the dosage regimen is necessary for patients with impairment of renal function (creatinine clearance <= 40 mL/min including hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) patients) (see DOSAGE AND ADMINISTRATION). Adequate hydration should be maintained for patients receiving gemifloxacin to prevent the formation of highly concentrated urine.

Skin

Rash

Gemifloxacin therapy should be discontinued in patients developing a rash while on treatment (see ADVERSE REACTIONS). In clinical studies, the overall rate of drug-related rash was 2.8%. The most common form of rash associated with gemifloxacin was described as maculopapular and mild to moderate in severity; 0.3% was described as urticarial in appearance. Rash usually appeared 8 to 10 days after start of therapy; 60% of the rashes resolved within 7 days, and 80% resolved within 14 days. Approximately 10% of those patients developing rash had a rash described as of severe intensity. Histology was evaluated in a clinical pharmacology study and was consistent with an uncomplicated exanthematous skin reaction and showed no evidence of phototoxicity, vasculitis, or necrosis. There were no documented cases in the clinical trials of more serious skin reactions known to be associated with significant morbidity or mortality. Rash was more commonly observed in patients less than 40 years of age, especially females and post-menopausal females taking hormone replacement therapy. The incidence of rash also correlated with longer treatment duration (> 7 days). Prolonging duration of therapy beyond 7 days causes the incidence of rash to increase significantly in all subgroups except men over the age of 40 (see Table 1).

For further information on studies conducted to examine rash, see DETAILED PHARMACOLOGY, Human Pharmacology, Rash.

Photosensitivity

Photosensitivity reactions have been reported very rarely in clinical trials with FACTIVE(tm) (gemifloxacin mesylate). In a study of the skin response to ultraviolet and visible radiation conducted in 40 healthy volunteers, the minimum erythematous dose (MED) was assessed following administration of either gemifloxacin 160 mg once daily, gemifloxacin 320 mg once daily, or placebo for 7 days. In this study, gemifloxacin 320 mg once daily had a potential for producing delayed photosensitivity skin reactions (see ADVERSE REACTIONS). As with all drugs of this class, it is recommended that patients avoid unnecessary exposure to strong sunlight or to artificial UV rays (e.g., sunlamps, solariums), and should be advised of the appropriate use of broad spectrum sun block when in bright sunlight. Treatment should be discontinued if a photosensitivity reaction is suspected.

Special Populations

Pregnant Women:

The safety of gemifloxacin in pregnant women has not been established. Gemifloxacin should not be used in pregnant women unless the potential benefit to the mother outweighs the risk to the fetus.

Administration of gemifloxacin throughout organogenesis caused fetal growth retardation in mice (oral dosing at 450 mg/kg/day), rats (oral dosing at 600 mg/kg/day) and rabbits (intravenous dosing at 40 mg/kg/day) at AUC levels which were approximately 2-, 4-, and 3-fold those in women given oral doses of 320 mg. The overall no-effect level in pregnant animals was approximately 0.8 to 3-fold clinical exposure (see TOXICOLOGY).

Nursing Women:

Safety of gemifloxacin in nursing mothers has not been established. It is not known if gemifloxacin is excreted in human milk. Therefore, gemifloxacin should not be used in nursing women unless the potential benefit to the mother outweighs the risk to the infant. If the nursing mother is treated with gemifloxacin, the breast milk should be expressed and discarded during treatment.

Gemifloxacin is excreted in the breast milk of rats (see TOXICOLOGY).

Pediatrics (< 18 years of age)

: The safety and effectiveness of gemifloxacin in children and adolescents less than 18 years of age have not been established.

Fluoroquinolones, including gemifloxacin, cause arthropathy and osteochondrosis in immature animals (see WARNINGS AND PRECAUTIONS, General and TOXICOLOGY).

Geriatrics (>= 65 years of age)

: Of the total number of subjects in clinical studies of gemifloxacin, 30% (2064) were 65 years of age and over, while 12% (779) were 75 years of age and over. No overall difference in effectiveness was observed between geriatrics and younger subjects. The adverse event rates were similar to or lower than those for younger subjects with the exception of the incidence of rash, which was lower for geriatric patients compared to patients less than 40 years of age.

Monitoring and Laboratory Tests

Post-marketing reports of increases in the International Normalized Ratios (INR), Prothrombin Time (PT) and/or clinical episodes of bleeding in patients have been noted with the use of quinolones, including gemifloxacin, and warfarin or its derivatives. In addition, infectious disease and its accompanying inflammatory process, age and general status of the patient are risk factors for increased anticoagulation activity. Therefore, the PT, INR or other suitable coagulation test should be closely monitored if a quinolone antimicrobial, including gemifloxacin, is administered concomitantly with warfarin or its derivatives. (See DRUG INTERACTIONS).

DRUG INTERACTIONS

Overview

Results of in vitro inhibition studies indicate that hepatic cytochrome P450 (CYP450) enzymes do not play an important role in gemifloxacin metabolism. Therefore gemifloxacin should not cause significant in vivo pharmacokinetic interactions with other drugs that are metabolized by CYP450 enzymes. As with all other quinolones, iron antacids with multivitamins containing metal cations significantly reduced bioavailability of gemifloxacin.

Drug-Drug Interactions

Drug-Food Interactions

FACTIVE(tm) (gemifloxacin mesylate) can be taken with or without food.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

FACTIVE(tm) (gemifloxacin mesylate) can be taken with or without food and should be swallowed whole with a liberal amount of liquid. The recommended dosage of FACTIVE(tm) for the treatment of ABECB is one 320 mg tablet daily for 5 days. Extending therapy may increase the incidence of rash, especially for women under 40 years of age.

Special Populations

Patients with Impaired Renal Function

Dose adjustment in patients with creatinine clearance > 40 mL/min is not recommended. Modification of the dosage is recommended for patients with creatinine clearance

WARNINGS AND PRECAUTIONS, Renal; ACTION AND CLINICAL PHARMACOLOGY,

<= 40 mL/min. To determine recommended dosing regimen for renally impaired patients which would provide equivalent drug exposures for which clinical efficacy has been demonstrated a clinical safety study and population pharmacokinetic analysis was used. The safety and efficacy of gemifloxacin at 160 mg once daily dosage for patients with decreased creatinine clearance (<= 40 mL/min) has not been studied. (See

Special Populations and Conditions, Renal Insufficiency; DETAILED PHARMACOLOGY, Human Pharmacology, Effect of Renal Impairment).

Table 5

provides dosage guidelines for use in patients with renal impairment; however, monitoring of serum drug levels provides the most reliable basis for dosage adjustment.

Patients requiring routine hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) should receive 160 mg once daily. When only the serum creatinine concentration is known, the following formula may be used to estimate creatinine clearance. Men: Creatinine Clearance (mL/min) = Weight (kg) x (140 - age) 72 x serum creatinine (mg/dL) Women: 0.85 times the value calculated for men

Patients with Impaired Hepatic Function Geriatrics

No dosage adjustment is recommended.

No dosage adjustment is recommended.

Missed Dose

If a dose of gemifloxacin mesylate is missed, the patient should take the dose as soon as possible and then return to their normal scheduled dose. However, if a dose is skipped, the patient should not double the next dose.

OVERDOSAGE

ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency

Any signs or symptoms of overdosage should be treated symptomatically. No specific antidote is known. In the event of acute oral overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage; the patient should be carefully observed and treated symptomatically, with appropriate hydration maintained. ECG monitoring is recommended due to the possible prolongation of the QT interval. FACTIVE(tm) (gemifloxacin mesylate) is not effectively removed from the body by hemodialysis. (See

).

Toxic signs after administration of a single high oral dose (400 mg/kg) of gemifloxacin to rodents included ataxia, lethargy, piloerection, and tremor. The minimum lethal intravenous doses in rats and mice were 160 and 80 mg/kg, respectively. Mortality occurred at oral gemifloxacin doses of 1600 mg/kg in rats and 320 mg/kg in mice.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

FACTIVE(tm) (gemifloxacin mesylate) is a synthetic broad-spectrum antibacterial agent that belongs to the fluoroquinolone class of antibiotics. Fluoroquinolones are antibacterial agents that act through inhibition of the bacterial type II topoisomerase enzymes, DNA gyrase and topoisomerase IV, both of which are essential for bacterial growth. DNA gyrase, encoded by gyrA and gyrB genes, catalyses ATP-dependent DNA supercoiling during DNA replication. Topoisomerase IV (specified by parC and parE genes) facilitates the separation of replicating DNA.

Pharmacodynamics

Resistance

The main mechanism of fluoroquinolone resistance is due to mutations in DNA gyrase and/or topoisomerase IV. Resistance to gemifloxacin develops slowly via multistep mutations and efflux in a manner similar to other fluoroquinolones. The frequency of spontaneous mutation is low (10-7 to < 10-10). Although cross-resistance has been observed between gemifloxacin and other fluoroquinolones, some microorganisms which are resistant to other fluoroquinolones may be susceptible to gemifloxacin.

Pharmacokinetics

The pharmacokinetics of gemifloxacin are approximately linear over the dose range 40 to 640 mg. There was negligible accumulation of gemifloxacin following multiple oral doses up to 640 mg a day for 7 days (mean accumulation < 20%). Following repeat oral administration of 320 mg gemifloxacin once daily, steady-state is achieved by the third day of dosing.

Figure 1. Mean Plasma Concentration - Time Profiles of Gemifloxacin 320 mg Single and Repeat Dose

Absorption and Bioavailability:

Gemifloxacin, given as an oral tablet, is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations of gemifloxacin were observed between 0.5 and 2 hours following oral tablet administration and the absolute bioavailability of the 320 mg tablet averaged approximately 71% (95% CI: 60% to 84%). Following repeated oral doses of 320 mg gemifloxacin doses to healthy subjects, the mean

+- SD maximal gemifloxacin plasma concentration (Cmax) and systemic drug exposure (AUC(0-24)) values were 1.61 +- 0.51 mcg/mL (range 0.70-2.62 mcg/mL) and 9.93 +- 3.07 mcg *h/mL (range 4.71-20.1 mcg *h/mL), respectively. (See DETAILED PHARMACOLOGY) The pharmacokinetics of gemifloxacin were not significantly altered when a 320 mg dose was administered with a high fat meal. Therefore, gemifloxacin may be administered with or without food.

Distribution:

The apparent steady-state mean volume of distribution is approximately

3.54 L/kg. In vitro binding of gemifloxacin to plasma proteins is low (approximately 60 to 70%) and is concentration independent. After repeated doses, the ex vivo plasma protein binding in healthy subjects ranged from 55% to 73% and was unaffected by age. Renal impairment does not significantly affect the protein binding of gemifloxacin. Gemifloxacin is widely distributed throughout the body after oral administration. Concentrations of gemifloxacin in bronchoalveolar lavage fluid and nasal secretions exceed those in the plasma. Gemifloxacin penetrates well into lung tissue and fluids. After five daily doses of 320 mg, gemifloxacin concentration in plasma, bronchial mucosa, epithelial lining fluid and bronchoalveolar macrophages at approximately 2 hours were as in Table 6.

Metabolism: Gemifloxacin is metabolized to a limited extent by the liver. The unchanged compound is the predominant drug-related component detected in plasma (approximately 65%) up to 4 hours after dosing. All available evidence indicates that cytochrome P450 enzymes play no appreciable role in the metabolism of gemifloxacin. Gemifloxacin neither inhibits nor induces cytochrome P450-associated enzyme activities at high in vitro concentrations or at high doses in laboratory species.

Excretion:

Gemifloxacin and its metabolites are eliminated via dual routes of excretion. Following oral administration of gemifloxacin to healthy subjects, a mean (+- SD) of 61 +- 9.5% of the dose was excreted in the feces and 36 +- 9.3% in the urine, as unchanged drug and metabolites. The plasma and urinary elimination half-lives are approximately 8 and 15 hours, respectively.

Special Populations and Conditions

Pediatrics (< 18 years of age):

The pharmacokinetics of gemifloxacin have not been studied in pediatric subjects.

Geriatrics (>= 65 years of age):

In adult subjects, the pharmacokinetics of gemifloxacin are not affected by age.

Gender:

There are no significant differences between gemifloxacin pharmacokinetics in males and females when differences in body weight are taken into account. Population pharmacokinetic studies indicate that following an administration of 320 mg gemifloxacin, AUC values were approximately 10% higher in healthy female subjects compared to males. Males and females had mean AUC values of 7.98 mcg *h/mL (range 3.21-

42.71 mcg *h/mL) and 8.80 mcg *h/mL (range 3.33-47.73 mcg *h/mL), respectively. No gemifloxacin dosage adjustment based on gender is recommended.

Race:

The pharmacokinetics of gemifloxacin are not affected by race.

Hepatic Insufficiency: The pharmacokinetics following a single 320 mg dose of gemifloxacin were studied in patients with mild (Child-Pugh Class A) to moderate (Child- Pugh Class B) liver disease. There was a mean increase of approximately 30% in AUC(0-inf) and a mean increase in Cmax of 25% in these patients compared to healthy volunteers. These differences were not clinically significant. There was no change in plasma elimination half-life. The pharmacokinetics of a single 320 mg dose of gemifloxacin were also studied in patients with severe hepatic impairment (Child-Pugh Class C). There was a mean increase in AUC(0-inf) of 45% and a mean increase in Cmax of 41% in these patients compared to healthy volunteers. These mean pharmacokinetic increases are not considered to be clinically significant. There was no significant change in plasma elimination half-life in the mild, moderate or severe hepatic impairment patients. No dosage adjustment is recommended in patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment (see DOSAGE AND ADMINISTATION). Renal Insufficiency: Results from population pharmacokinetic and clinical pharmacology studies with repeated 320 mg doses indicate that the clearance of gemifloxacin is reduced and the plasma elimination is prolonged, leading to an average increase in AUC values of approximately 70% in patients with renal insufficiency. In the pharmacokinetic studies, gemifloxacin Cmax was not significantly altered in subjects with renal insufficiency. Dose adjustment in patients with creatinine clearance > 40 mL/min is not required. Dosage should be adjusted in patients with creatinine clearances <= 40 mL/min, including hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) patients (see DOSAGE AND ADMINISTRATION). Hemodialysis removes approximately 20 to 30% of an oral dose of gemifloxacin from plasma.

STORAGE AND STABILITY

Store between 15-25degC. Protect from light.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Composition

FACTIVE(tm) (gemifloxacin mesylate) tablets contain gemifloxacin mesylate equivalent to 320 mg gemifloxacin. Non-medicinal ingredients: crospovidone, hydroxypropyl methylcellulose, magnesium stearate (vegetable origin), microcrystalline cellulose, polyethylene glycol, povidone, and titanium dioxide.

Availability of Dosage Forms

FACTIVE(tm) (gemifloxacin mesylate) is available as white to off-white, oval, film-coated tablets with breaklines and GE 320 debossed on both tablet faces. Each tablet contains gemifloxacin mesylate equivalent to 320 mg gemifloxacin. FACTIVE(tm) is available in 5-tablets blisters.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Gemifloxacin mesylate Chemical name: (R,S)-7-(3-aminomethyl-4-Z-methoxyimino-1-pyrrolidinyl)- 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid methanesulfonate Molecular formula: C18H20FN5O4 *CH4O3S Molecular mass: Mesylate salt: 485.49 Free base: 389.39 Structural formula:

F CH3O

O

CO2H

N N N N

. CH3SO 3H

H2N Physicochemical properties: Gemifloxacin mesylate is a white to light brown solid. Gemifloxacin mesylate solubility in water at 37degC varies from very slightly soluble at pH 7.0 (350 mcg/mL) to freely soluble at pH 1.4 (163 mg/mL). The pKa values of gemifloxacin mesylate are 6.4 and 9.0 for the carboxylic acid and for the primary amine respectively. Melting of gemifloxacin mesylate shows an onset temperature of 193degC.

CLINICAL TRIALS

Study Demographics and Trial Design

Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB)

Study Results

Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB)

The primary efficacy parameter in studies 068, 070 and 212 was the clinical response at follow-up (days 13 to 24). The results of the clinical response at follow-up for the principal ABECB studies demonstrate that FACTIVE(tm) 320 mg p.o. once daily for 5 days was at least as effective as the comparators given for 7 days. The results are shown in Table 8 below.

DETAILED PHARMACOLOGY

Human Pharmacology

Human Pharmacokinetics

Gemifloxacin is administered as a racemic mixture and the enantiomers have similar microbiological activity. No gross differences have been observed in the pharmacokinetics of (+) and (-) enantiomers of gemifloxacin following either oral or intravenous administration. Absorption: Absorption of gemifloxacin is rapid but limited by the extent of absorption. The Cmax is between 0.5 and 2 hours following administration of 320 mg gemifloxacin and gemifloxacin concentrations generally decline in a biexponential manner, with a terminal phase half-life of approximately 5 to 9 hours. The terminal phase half-life is independent of dose. Following oral administration of 320 mg gemifloxacin, AUC and Cmax data exhibit low intra-subject (C.V.s of 25% and 23%, respectively) and inter-subject (C.V.s of 27% and 30%, respectively) variability. Following repeat administration of gemifloxacin, there is virtually no accumulation of gemifloxacin at doses up to 640 mg once daily in young subjects and up to 480 mg once daily in the elderly. It has been demonstrated that the effect of a high fat breakfast on the bioavailability of the commercial formulation of gemifloxacin is of no clinical relevance at doses of 320 mg and 640 mg. Based on these data, gemifloxacin can be administered without regard to food. In patients with respiratory and urinary tract infections (n=1423), systemic drug exposure (geometric mean AUC(0-24)) determined using a population pharmacokinetics analysis was 8.36 mcg *h/mL (range 3.2-47.7 mcg *h/mL). Distribution: Gemifloxacin is widely distributed into tissues. The geometric mean for Vdss/F is 4.18 L/kg (range 1.66-12.12 L/kg). Following intravenous dosing, steady state volume of distribution for gemifloxacin is, on average, 3.54 L/kg, which exceeds total body water in man (0.60 L/kg). Total systemic plasma clearance of gemifloxacin is, on average, 0.4 (L/h)/kg. Based on a blood-to-plasma ratio of 1.2:1 and that approximately 50% of the dose is renally cleared, hepatic clearance is likely to be approximately 15% of liver blood flow [circa. 1.24 (L/h)/kg] in man. It can therefore be concluded that gemifloxacin has a moderate clearance in man and undergoes negligible first-pass metabolism.

Metabolism:

Gemifloxacin is not extensively metabolised and is excreted predominantly unchanged following either oral or intravenous routes of administration. All metabolites formed are less than 10% of the administered dose; the principal ones are N-acetyl gemifloxacin, the E-isomer of gemifloxacin and the carbamyl glucuronide of gemifloxacin. Biotransformation pathways appear to be independent of the dose route. Gemifloxacin is also the predominant drug-related component in plasma up to 12 hours after dosing. The involvement of cytochrome P450 enzymes in the metabolism of gemifloxacin is negligible.

Excretion

: Gemifloxacin is eliminated as unchanged drug and metabolites via the feces and urine. The mean (+- SD) renal clearance following repeat doses of 320 mg is approximately

11.6 +- 3.9 L/h (range 4.6-17.6 L/h), which indicates that active renal secretion is involved in the elimination of gemifloxacin. After an oral administration of 320 mg gemifloxacin, the elimination half-life of radioactivity is similar to that for parent and would suggest negligible accumulation of any metabolite on repeat dosing. There was considerable between-subject variability in the extent of formation of N-acetyl-gemifloxacin, with AUC values representing between 3% and 74% of parent AUC. This variability was consistent with formation by the polymorphically expressed NAT2. Since the circulating metabolites are present at lower concentrations than parent and are considerably less potent than parent compound, they are not expected to contribute to the pharmacological activity of gemifloxacin.

Effect of Renal Impairment

: Based on the results from a specific study to investigate the effect of renal impairment on the pharmacokinetics of gemifloxacin and on the population pharmacokinetic analysis of Phase III data, dosage adjustment is not considered necessary in patients with creatinine clearance > 40 mL/min. Below 40 mL/min increases in AUC approach and exceed 50% as renal function decreases and therefore, a halving of dose to

160 mg once daily would be recommended for patients with creatinine clearance <= 40 mL/min, including hemodialysis and CAPD patients. Following single oral administration of 160 mg gemifloxacin, there was a trend for reduced renal clearance and increased elimination half-life with decreased creatinine clearance. The overall reduction in oral clearance resulted in increased mean AUC values for patients with renal impairment particularly those with creatinine clearance <= 40 mL/min. There were no clear trends in Cmax in renally impaired patients relative to subjects with normal renal function. Gemifloxacin was not notably cleared from patients after four hours of hemodialysis. Dialytic clearance accounted for only approximately 13% of oral clearance. For patients with creatinine clearance <= 40 mL/min, including hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) patients, it would be recommended that the clinical dose of gemifloxacin be halved (i.e., 160 mg once daily). Effect of Hepatic Impairment: Based on the pharmacokinetic results obtained in patients with mild to moderate hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY), dosage adjustment is not considered necessary in patients with mild or moderate hepatic impairment (Child-Pugh A and B). AUC(0-inf) and Cmax for gemifloxacin were 40-45% higher, on average in subjects with severe hepatic impairment (Child-Pugh C), when compared to healthy subjects. Half-life was only slightly longer in subjects with severe hepatic impairment, compared to healthy subjects (9.7 h vs 8.1 h). Thus, no marked difference in the extent of accumulation upon repeat dosing is expected. These findings are similar to those seen in mild and moderate hepatic impairment (Child-Pugh A and B). Reducing the dose by half to 160 mg in severe hepatic impairment would probably result in a significant proportion of this population being underdosed, putting severely ill patients with respiratory tract infection at risk of treatment failure. Therefore, dosage adjustment based on pharmacokinetic considerations is not considered necessary in patients with severe hepatic impairment (Child-Pugh C).

Rash

In clinical trials of 6,775 patients, the incidence of rash was higher in patients receiving gemifloxacin than in those receiving comparator drugs (see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS). Rash was more commonly observed in patients less than 40 years of age, especially females and post-menopausal females taking hormone replacement therapy. The incidence of rash also correlated with longer treatment duration (> 7 days, see Table 1). To further characterize gemifloxacin-associated rash, a clinical pharmacology study was conducted. The study enrolled 1,011 healthy female volunteers less than 40 years of age. Subjects were randomized to receive either gemifloxacin 320 mg p.o. daily or ciprofloxacin 500 mg p.o. twice daily for 10 days. The objective of the study was to assess the characteristics of rash. The majority of rashes in subjects receiving gemifloxacin were maculopapular and of mild to moderate severity; 7% of the rashes were reported as severe, and severity appeared to correlate with the distribution of the rash. In 68% of the subjects reporting a severe rash and approximately 25% of all those reporting rash, over 60% of the body surface area was involved; the characteristics of the rash were otherwise indistinguishable from those subjects reporting a mild rash. The histopathology was consistent with the clinical observation of uncomplicated exanthematous morbilliform eruption. There were no documented cases of hypersensitivity syndrome or findings suggestive of angioedema or other serious cutaneous reactions. The majority of rash events (81.9%) occurred on days 8 through 10 of the planned 10-day course of gemifloxacin; 2.7% of rash events occurred within one day after the first dose was administered. The median duration of rash was 6 days. The rash resolved without treatment in the majority of subjects. Approximately 19% received antihistamines and 5% received steroids, although the therapeutic benefit of these therapies is uncertain. In the second part of this study after a 4 to 6 week wash out period, subjects developing a rash on gemifloxacin were treated with ciprofloxacin or placebo; 5.9% developed rash when treated with ciprofloxacin and 2.0% developed rash when treated with placebo. The characteristics of rash in subjects receiving ciprofloxacin following gemifloxacin were similar to those described in subjects who only received ciprofloxacin. The cross sensitization rate to other fluoroquinolones was not evaluated in this clinical study. There was no evidence of sub-clinical sensitization to gemifloxacin (i.e., subjects who had not developed a rash to gemifloxacin in the first part of the study were not at higher risk of developing a rash to gemifloxacin with a second exposure). There was no relationship between the incidence of rash and systemic exposure (Cmax and AUC) to either gemifloxacin or its major metabolite, N-acetyl gemifloxacin.

Animal Pharmacology

Cardiovascular

Quinolones have been associated with prolongation of the electrocardiographic QT interval in dogs. Gemifloxacin produced no effect on the QT interval in dogs dosed orally to provide about 4 times human therapeutic plasma concentrations at Cmax, and transient prolongation after intravenous administration at more than 4 times human plasma levels at Cmax. In the cardiac IKr (hERG) channel inhibition assay, gemifloxacin produced a concentration-dependent inhibition with IC50 of 259.6 micromole. In cardiovascular safety pharmacology studies, with telemetry-monitored conscious dogs, prolongation of the QRS interval by 6-15 msec was the only finding following single oral doses of 50-200 mg/kg; no effect was observed at 40 mg/kg (Cmax 3.78 mcg/mL; AUC 44.8 mcg *h/mL). The rate compensated QT interval (QTc) was unaffected at 200 mg/kg orally (Cmax 6.76 mcg/mL; AUC 69.7 mcg *h/mL). In dogs dosed 30 mg/kg intravenously (Cmax 10 mcg/mL; AUC 38.9 mcg *h/mL), mean arterial pressure rose 27 mmHg during a 30-minute infusion and fell to 12 mmHg below baseline after its completion. The QTc increased by up to 45 msec shortly after the infusion ended, and returned to near baseline 25 minutes later. The duration of the QRS complex increased to 42% above the predose mean. There was no effect on ECG at 10 mg/kg intravenously (Cmax 3.66 mcg/mL AUC 12.8 mcg *h/mL). Gemifloxacin at a concentration of 100 micromolar, approximately 30 times the clinical Cmax at the 320 mg oral dose, resulted in a 9% increase in action potential duration (APD90) in isolated dog Purkinje fibres. A concentration of 10 micromolar gemifloxacin had no effect on the APD90.

Central Nervous System

Some quinolones have been reported to have proconvulsant properties that are potentiated by the concurrent administration of non-steroidal anti-inflammatory drugs (NSAIDs). Gemifloxacin alone had effects in tests of behavior or CNS interaction typically at doses of at least 160 mg/kg. No convulsions or death occurred in mice after gemifloxacin administration alone (100 mg/kg) or in combination with 400 mg/kg 4-bipehnylacetic acid (4-BPA), the active metabolite of the NSAID fenbufen.

Antigenicity and Histamine Response

In a guinea-pig active anaphylaxis test, sensitization to an intravenous gemifloxacin challenge was achieved by subcutaneous administration but not oral administration. In a mouse/rat passive cutaneous anaphylaxis test (IgE mediated), conjugation was necessary to induce an IgE mediated skin response. Similarly, in a mouse passive hemagglutination test, an IgG/IgM response was induced by intraperitoneal injection of conjugated gemifloxacin, but not of unconjugated gemifloxacin or with oral administration.

Hepatic, Renal and Phototoxicity

See TOXICOLOGY for information on Hepatic Toxicity, Renal Toxicity and Phototoxicity.

MICROBIOLOGY

Gemifloxacin has in vitro activity against a wide range of Gram-negative and Gram- positive microorganisms including atypical (i.e., Chlamydia pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae) organisms. Gemifloxacin is bactericidal with minimum bactericidal concentrations (MBCs) generally within a two-fold dilution of the minimum inhibitory concentrations (MICs). Gemifloxacin acts by inhibiting DNA synthesis through the inhibition of DNA gyrase and topoisomerase IV (TOPO IV), which are essential for bacterial growth. Streptococci showing double mutations in both DNA gyrase and TOPO IV are resistant to most fluoroquinolones. Gemifloxacin is a dual acting quinolone capable of targeting both enzyme systems at therapeutically relevant drug levels and has MIC values that are still in the susceptible range for some strains of these double mutants. The mechanism of action of quinolones, including gemifloxacin, is different from that of beta-lactams, macrolides, aminoglycosides, or tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to gemifloxacin and other quinolones. There is no known cross-resistance between gemifloxacin and the above-mentioned classes of antimicrobials. No antagonism has been observed in in vitro studies when gemifloxacin is combined with other antimicrobial agents such as beta-lactams, aminoglycosides or macrolides. The in vitro activity of gemifloxacin against clinical isolates is summarized in Table 9.

Susceptibility Tests

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 gemifloxacin powder. The MIC values should be interpreted according to the following criteria: For testing, Haemophilus influenzaea and Haemophilus parainfluenzaea

For testing Staphylococcus aureus and Streptococcus pneumoniaeb

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration 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 a high dosage of drug can be used. This category also provides a buffer zone that 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 gemifloxacin powder should provide MIC values as presented in Table 10.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of susceptibility of bacteria to antimicrobial agents. One such standardized procedure requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg gemifloxacin to test the susceptibility of microorganisms to gemifloxacin. Interpretation involves correlation of the diameters obtained in the disk test with the minimum inhibitory concentrations (MICs) for gemifloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg gemifloxacin disk against non-fastidious aerobic organisms, Streptococcus species, and Haemophilus species should be interpreted according to the criteria presented in Table 11.

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 gemifloxacin. 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 mcg gemifloxacin disk should provide zone diameters as presented in Table 12 in the following laboratory QC strains.

TOXICOLOGY

Several of the effects seen in toxicology studies have also been observed with other quinolones including crystal nephropathy, juvenile arthropathy, phototoxicity and effects on hepatobiliary, cardiovascular and CNS body systems.

Single Dose Toxicity

The maximum non-lethal single oral doses were 320 mg/kg in male mice, 236 mg/kg in female mice, 1600 mg/kg in male rats, and < 1600 mg/kg in female rats. The maximum tolerated oral dose in dogs was 360 mg/kg. The maximum non-lethal single intravenous doses were 70 mg/kg in male mice, 80 mg/kg in female mice, and 120 mg/kg in rats (both sexes). The maximum tolerated intravenous dose in dogs was 30 mg/kg.

Repeat Dose Studies

Rats

The principal finding in rat oral repeat-dose studies was crystal nephropathy, which was evident in a 7-day dose-ranging study in both sexes at 800 mg/kg/day; no effect was observed at 200 mg/kg/day. Raman spectroscopy identified the crystals in the kidney as drug-related material. The same finding was observed in a 28-day study in male rats at all doses (>= 48 mg/kg/day; Cmax 1.8 mcg/mL; AUC 7.7 mcg *h/mL) and in female rats at 600 mg/kg/day (Cmax 14.9 mcg/mL; AUC 100 mcg *h/mL). Reversibility of these findings was demonstrated following a 14-day treatment-free period, except in males receiving 600 mg/kg/day. In a 3-month study, gemifloxacin was well tolerated but resulted in a dose-related crystal nephropathy in males at 72 and 168 mg/kg/day with associated changes in blood chemistry and urine parameters. There were no nephrotoxic effects at 24 mg/kg/day in males or at any dose in females (up to 168 mg/kg/day), although crystalluria was noted in both sexes at 72 mg/kg/day and above. Crystal nephropathy is considered to be due to poor solubility at the alkaline pH of rat urine; female rat urine is more acidic than that of males mirroring renal sensitivity to gemifloxacin.

Dogs

A consistent finding in dogs given gemifloxacin orally for up to six months was cholangitis/pericholangitis, accompanied by hepatocellular degeneration and single cell necrosis. The lowest effect dose was 24 mg/kg/day for 13 weeks (mean Cmax 1.1 mcg/mL, AUC 7.6 mcg *h/mL for combined sexes). These findings were associated with deposits of crystals containing drug-related material in bile canaliculi and bile ducts, consistent with gemifloxacin's solubility in bile being exceeded during its 'first pass' through the liver. This initial hepatic load is best represented by the oral dose given, rather than by drug concentrations in the post-hepatic circulation. There were no hepatic findings in dogs given 96 mg/kg/day for 28 days (mean Cmax 4.1 mcg/mL; AUC 29.2 mcg *h/mL for combined sexes), or 8 mg/kg/day for 6 months (mean Cmax 0.64 mcg/mL; AUC 3.0 mcg *h/mL), compared with an adult human dosage of approximately < 6 mg/kg/day for 5-7 days (Cmax 1.6 mcg/mL; AUC 9.9 mcg *h/mL). Elevated plasma enzyme activities, most consistently ALT and alkaline phosphatase, but also GGT and AST, acted as markers of the liver histopathology and returned to normal values following a four week off-dose period. Increased liver enzyme activities in plasma and hepatocyte degeneration and necrosis have been seen with other quinolones. Arthropathy, characterized by degeneration of articular cartilage, occurred in dogs 26-32 weeks of age that were given at least 192 mg/kg/day gemifloxacin for 28 days (Cmax 6.7 mcg/mL; AUC 56.3 mcg *h/mL). No effects on joints were detected in a 3-month study in older dogs (doses up to 160 mg/kg/day).

Phototoxicity

Photosensitization to ultraviolet light (UVA) occurred in hairless mice given a single oral dose of 160 mg/kg but did not occur at 80 mg/kg gemifloxacin. There was no evidence of phototoxicity at 100 mg/kg/day in a standard hairless mouse model, after 13 weeks of oral administration with exposure to simulated sunlight (UVA + UVB)

Photococarcinogenicity

Gemifloxacin at oral doses of up to 100 mg/kg/day did not potentiate the skin tumorigenicity of simulated sunlight in hairless mice treated 5 days per week (radiation and gemifloxacin) for 40 weeks. The daily dose of UV radiation used in this study was approximately 1/3 of the minimal dose of UV radiation that would induce erythema in untanned (Caucasian) human skin, and induced tumors in nearly all untreated exposed mice. At 100 mg/kg/day, approximate gemifloxacin levels in plasma were Cmax 1.4 mcg/mL; AUC 3.1 mcg *h/mL, and in skin were Cmax 7.4 mcg/mL; AUC 21.2 mcg *h/mL.

Photocomutagenicity

UV radiation (750 mJ/cm2) did not potentiate the clastogenic effect of up to 250 mcg/mL gemifloxacin in CHO cells in vitro.

Carcinogenicity

Long term studies in animals to determine the carcinogenic potential of gemifloxacin have not been conducted.

Mutagenicity

Gemifloxacin was not mutagenic in an Ames bacterial mutation assay where 4 strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537) were tested, a mouse micronucleus assay (up to 40 mg/kg i.p.) and a rat unscheduled DNA synthesis assay (up to 1600 mg/kg p.o. ). Gemifloxacin was clastogenic in vitro in mouse lymphoma and human chromosome aberration assays, and in vivo in the rat micronucleus assay at doses that produced bone marrow toxicity (>= 800 mg/kg p.o. and >= 40 mg/kg i.v. ). Fluoroquinolone clastogenicity has been associated with inhibition of mammalian topoisomerase activity, for which there is evidence of threshold dependency.

Impairment of Fertility

Gemifloxacin did not affect the fertility of male or female rats given oral doses of up to 216 and 600 mg/kg/day, providing AUC levels that were approximately 3- to 4-fold higher than the AUC levels at the clinically recommended dose.

Teratogenicity

Gemifloxacin treatment during organogenesis caused fetal growth retardation in mice (oral dosing at 450 mg/kg/day), rats (oral dosing at 600 mg/kg/day) and rabbits (i.v. dosing at 40 mg/kg/day) at AUC levels which were 2-, 4- and 3-fold those in women given oral doses of 320 mg. In rats, this growth retardation appeared to be reversible in a pre- and postnatal development study (mice and rabbits were not studied for the reversibility of this effect). Treatment of pregnant rats only at 8-fold clinical exposure (based upon AUC comparisons) caused fetal brain and ocular malformations in the presence of maternal toxicity. The overall no-effect exposure level in pregnant animals was 0.8 to 3-fold clinical exposure.

REFERENCES

1. Appelbaum, PC. Resistance among Streptococcus pneumoniae: Implications for drug selection. Clin Infect Dis. June 2002; 34 (12): 1613-1620.

2. Ball P, Wilson R, Mandell L, Brown J, Henkel T and the 069 Clinical Study Group.

Efficacy of gemifloxacin in acute exacerbations of chronic bronchitis: a randomized, double-blind comparison with trovafloxacin. J Chemother. 2001; 13: 288-298. Berry V, Page R, Satterfield J, Singley C, Straub R, Woodnutt G. Comparative in vivo activity of gemifloxacin in a rat model of respiratory tract infection. J Antimicrob Chemother. Apr 2000; 45 Suppl 1: 79-85. Boswell FJ, Andrews JM, Jevons G, Wise R. Comparison of the in vitro activities of several new fluoroquinolones against respiratory pathogens and their abilities to select fluoroquinolone resistance. J Antimicrob Chemother. Oct 2002; 50(4): 495-502. Brenwald NP, Applebaum P, Davies T, Gill MJ. Evidence for efflux pumps, other than PmrA, associated with fluoroquinolone resistance in Streptococcus pneumoniae. Clin Microbiol Infect. Feb 2003; 9(2): 140-143. Davies TA, Kelly LM, Hoellman DB, Ednie LM, Clark CL, Bajaksouzian S, et al. Activities and postantibiotic effects of gemifloxacin compared to those of 11 other agents against Haemophilus influenzae and Moraxella catarrhalis. Antimicrob Agents Chemother. Mar 2000; 44(3): 633-639. Davy M, Allen A, Bird N, Rost KL, Fuder H. Lack of effect of gemifloxacin on the steady-state pharmacokinetics of theophylline in healthy volunteers. Chemotherapy. Nov-Dec 1999; 45(6): 478-484. File T, Schlemmer B, Garau J, Lode H, Lynch S, Young C. Gemifloxacin versus amoxicillin-clavulanate in the treatment of acute exacerbations of chronic bronchitis. J Chemother. 2000; 12: 314-325. Garcia-Garrote F, Cercenado E, Matin-Pedroviejo J, Cuevas O, Bouza E. Comparative in vitro activity of the new quinolone gemifloxacin (SB265805) with other fluoroquinolones against respiratory tract pathogens. J Antimicrob Chemother. May 2001; 47(5): 681- 684. Gillespie SH, Voelker LL, Dickens A. Evolutionary barriers to quinolone resistance in

Streptococcus pneumoniae

. Microb Drug Resist. Summer 2002; 8 (2): 79-84.

Goldstein EJ. Review of the in vitro activity of gemifloxacin against gram-positive and gram-negative anaerobic pathogens. J Antimicrob Chemother. Apr 2000: 45 Suppl 1: 55- 65. Koeth LM, Jacobs MR, Bajaksouzian S, Zilles A, Lin G, Appelbaum PC. Comparative in vitro activity of gemifloxacin to other fluoroquinolones and non-quinolone agents against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in the United States in 1999-2000. Int J Antimicrob Agents. Jan 2002; 19(1): 33-37. Morrissey I, George JT. Bacterial activity of gemifloxacin and other quinolones against

Streptococcus pneumoniae

. J Antimicrob Chemother. Apr 2000; 45 Suppl 1; 107-110.

Naigi K, Davies TA, Dewasse BE, Jacobs MR, Appelbaum PC. Single- and multi-step resistance selection study of gemifloxacin compared with trovafloxacin, ciprofloxacin, gatifloxacin and moxifloxacin in Streptococcus pneumoniae. J Antimicrob Chemother. Sep 2001; 48(3): 365- 374. Vousden M, Allen A, Lewis A, Ehren N. Lack of pharmacokinetic interaction between gemifloxacin and digoxin in healthy elderly volunteers. Chemotherapy. Nov-Dec 1999; 45(6): 485-490. Vousden M, Ferguson J, Richards J, Bird N, Allen, A. Evaluation of phototoxic potential of gemifloxacin in healthy volunteers compared with ciprofloxacin. Chemotherapy. Nov- Dec 1999; 45(6): 512-520. Wilson R, Langan C, Ball P, Bateman K, Pypstra R. Oral gemifloxacin once daily for 5 days compared with sequential therapy with i.v. ceftriaxone/oral cefuroxime (maximum of 10 days) in the treatment of hospitalized patients with acute exacerbations of chronic bronchitis. Respir Med. Mar 2003: 97(3): 242-249. Wilson R, Schentag JJ, Ball P, Mandell L. A comparison of gemifloxacin and clarithromycin in acute exacerbations of chronic bronchitis and long-term clinical outcomes. Clin Ther. Apr 2002; 24(2): 639-652. Wise R, Andrews JM. The in vitro activity and tentative breakpoint of gemifloxacin, a new fluoroquinolone. J Antimicrob Chemother. Nov 1999; 44(5): 679-688. Zhanel GG, Palatnick L, Nichol KA, Bellyou T, Low DE, Hoban DJ. Antimicrobial Resistance in Respiratory tract Streptococcus pneumoniae Isolates: results of the Canadian Respiratory Organism Susceptibility Study, 1997-2002. Antimicrob Agents Chemother. June 2003; 47(6): 1867-1874. IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

PrFACTIVE(tm)

gemifloxacin mesylate

This leaflet is part III of a three-part "Product Monograph" published when FACTIVE(tm) was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about FACTIVE(tm). Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

FACTIVE(tm) is used to treat a certain type of bacterial lung infection called bronchitis. FACTIVE(tm) does not treat viral

infections (e.g., the common cold).

What it does:

FACTIVE(tm) is an antibiotic. It kills many types of bacteria in the lung by interfering with bacterial enzymes to help stop bacterial

growth and the infection.

When it should not be used:

• Do not take FACTIVE(tm) if you are allergic to any ingredient in the drug or to any antibiotic called "quinolone". See "What the important nonmedicinal

ingredients are."

Do not take FACTIVE(tm) if you are receiving Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic agents.

What the medicinal ingredient is:

The medicinal ingredient is gemifloxacin mesylate.

What the important nonmedicinal ingredients are:

FACTIVE(tm) tablets contain: crospovidone, hydroxypropyl methylcellulose, magnesium stearate (vegetable origin),

microcrystalline cellulose, polyethylene glycol, povidone, titanium

dioxide.

What dosage forms it comes in:

FACTIVE(tm) is available as 320 mg tablets of gemifloxacin (as gemifloxacin mesylate) in a package of 5 tablets per blister.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Serious hypersensitivity and/or anaphylactic reactions have been reported in patients receiving quinolone therapy, including FACTIVE(tm).

BEFORE you use FACTIVE(tm) talk to your doctor or pharmacist if:

you are taking any other medications with FACTIVE(tm), including over-the-counter medications and dietary supplements.

you are allergic to quinolone drug or any other non- medicinal ingredient in FACTIVE(tm).

you have a history of convulsions. Convulsions have been reported in patients receiving certain antibiotics called quinolones.

• you are pregnant, planning to become pregnant, or are breast feeding. The effects of FACTIVE(tm) on unborn children and nursing infants are unknown.

• you have kidney problems. You may require a lower dose

and special monitoring during therapy.

you or any family member have a rare heart condition known as congenital prologation of the QTc interval (lengthened heartbeat). FACTIVE(tm) may produce changes in the electrocardiogram (QTc interval prolongation).

you have low potassium or magnesium levels.

you have slow heart beat called bradycardia.

you have recently had a heart attack.

you are on diuretics, e.g., furosemide, hydrochlorothiazide.

you are taking quinidine, procainamide, amidodorane or sotalol.

you are taking drug for abnormal heart rhythm

(antiarrhythmics).

you are taking erythromycin, antipsychotic, and tricyclic antidepressant, warfarin or coumadin.

FACTIVE(tm) has not been studied in children under the age of 18. Quinolones may cause joint problems (arthropathy) in children.

FACTIVE may be associated with allergic (hypersensitivity) reactions, even after a single dose. Stop taking the drug at the first sign of rash or other signs of the allergic reaction and tell your doctor.

Contact your doctor if the following develop while taking FACTIVETM:

1. diarrhea

2. peripheral neuropathy (nerve damage) with symptoms such as tingling, prickling, pain and weakness.

3. depression, paranoia, rarely suicidal thoughts.

INTERACTIONS WITH THIS MEDICATION

Drugs that may interact with FACTIVE(tm) include:

Antacids: Do not take the following medicines within 3 hours before FACTIVE(tm) or 2 hours after FACTIVE(tm). They may interfere with the absorption of FACTIVE(tm) and may prevent it from working properly: IMPORTANT: PLEASE READ

• antacids containing magnesium and/or aluminum or any medications containing calcium carbonate

• products containing ferrous sulfate (iron)

• multivitamin preparations containing zinc or other metals

• VIDEX(r) (didanosine) chewable/buffered tablets or the pediatric powder for oral solution

Sucralfate:

FACTIVE(tm) should be taken at least 2 hours before sucralfate.

Warfarin: there have been reports of increased episodes of bleeding when warfarin and FACTIVE(tm) are taken together. Patients should notify their physicians if they are taking warfarin or its derivatives.

PROPER USE OF THIS MEDICATION

tenderness or rupture of a tendon. Rest and avoid exercise until you have seen a doctor.

Phototoxicity, the damage of skin by light, has been reported with certain antibiotics (quinolones) and the incidence has been low for FACTIVE(tm). Avoid excessive sunlight or artificial ultraviolet light (e.g., tanning beds). Contact your doctor if sunburn or a skin eruption occurs.

Usual adult dose:

The recommended dosage of FACTIVE(tm) for the treatment of bronchitis is one 320 mg tablet daily for 5 days. Take FACTIVE(tm) at the same time each day, with or without meals. Swallow the tablet whole with liberal amounts of liquid. Do not chew the tablet.

Overdose:

Contact your doctor or pharmacist if you have taken more than the recommended dose.

Missed Dose:

If you miss a dose, take it as soon as you remember unless it is almost time for the next dose. In that case, skip the missed dose

and take the next one as directed. Do not take two doses at once.

Although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by FACTIVE(tm).

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

FACTIVE(tm) is generally well tolerated. The most common side effects with FACTIVE(tm) include diarrhea, rash, nausea, headache, vomiting, stomach pain, dizziness, and a change in the way things taste in your mouth.

FACTIVE(tm) may be associated with serious allergic reactions, even after a single dose. Discontinue the drug and contact your doctor if allergic symptoms occur such as rapid pulse, difficulty in breathing, hives, swelling of the throat and tongue.

FACTIVE(tm) may cause dizziness; if this occurs, do not operate an automobile or machinery or engage in activities requiring mental alertness or coordination.

Discontinue FACTIVE(tm) and contact your doctor if you feel pain,

This is not a complete list of side effects. For any unexpected effects while taking FACTIVE(tm), contact your doctor or pharmacist.

HOW TO STORE IT

FACTIVE(tm) tablets should be stored between 15 and 25degC. Keep out of reach of children. IMPORTANT: PLEASE READ

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax 866-678-6789 By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at: http://www.abbott.ca or by contacting the sponsor, Abbott Laboratories, Limited, at:

1-800-699-9948.

This leaflet was prepared by Abbott Laboratories, Limited. Last revised: August 1, 2007