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All about: Factive

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Generic Name: gemifloxacin mesylate
Dosage Form: Tablets

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Factive and other antibacterial drugs, Factive should be used only to treat infections that are proven or strongly suspected to be caused by bacteria.

Factive Description

Factive (gemifloxacin mesylate) is a synthetic broad-spectrum antibacterial agent for oral administration. Gemifloxacin, a compound related to the fluoroquinolone class of antibiotics, is available as the mesylate salt in the sesquihydrate form. Chemically, gemifloxacin is (R,S) - 7 - [(4Z) - 3 - (aminomethyl) - 4 - (methoxyimino) - 1 - pyrrolidinyl] - 1 - cyclopropyl - 6 - fluoro - 1,4 - dihydro - 4 - oxo - 1,8 - naphthyridine - 3 - carboxylic acid.

The mesylate salt is a white to light brown solid with a molecular weight of 485.49. Gemifloxacin is considered freely soluble at neutral pH (350 μg/mL at 37°C, pH 7.0).  Its empirical formula is C18H20FN5O4•CH4O3S and its chemical structure is:

Each white to off-white, oval, film-coated Factive tablet has breaklines and GE 320 debossed on both faces and contains gemifloxacin mesylate equivalent to 320 mg gemifloxacin. The inactive ingredients are crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, and titanium dioxide.

Factive - Clinical Pharmacology

Pharmacokinetics

The pharmacokinetics of gemifloxacin are approximately linear over the dose range from 40 mg to 640 mg. There was minimal 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.

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%-84%).  Following repeat oral doses of 320 mg to healthy subjects, the mean ± SD maximal gemifloxacin plasma concentrations (Cmax) and systemic drug exposure (AUC(0-24)) were 1.61 ± 0.51 μg/mL (range 0.70-2.62 μg/mL) and 9.93 ± 3.07 μg•hr/mL (range 4.71-20.1 μg•hr/mL), respectively.  In patients with respiratory and urinary tract infections (n=1423), similar estimates of systemic drug exposure were determined using a population pharmacokinetics analysis (geometric mean AUC(0-24), 8.36 μg•hr/mL; range 3.2 – 47.7 μg•hr/mL.

The pharmacokinetics of gemifloxacin were not significantly altered when a 320 mg dose was administered with a high-fat meal.  Therefore Factive tablets may be administered without regard to meals.

Distribution

In vitro binding of gemifloxacin to plasma proteins in healthy subjects is approximately 60 to 70% and is concentration independent.  After repeated doses, the in vivo plasma protein binding in healthy elderly and young subjects ranged from 55% to 73% and was unaffected by age.  Renal impairment does not significantly affect the protein binding of gemifloxacin.  The blood-to-plasma concentration ratio of gemifloxacin was 1.2:1.  The geometric mean for Vdss/F is 4.18 L/kg (range, 1.66 – 12.12 L/kg).

Gemifloxacin is widely distributed throughout the body after oral administration.  Concentrations of gemifloxacin in bronchoalveolar lavage fluid exceed those in the plasma.  Gemifloxacin penetrates well into lung tissue and fluids.  After five daily doses of 320 mg gemifloxacin, concentrations in plasma, bronchoalveolar macrophages, epithelial lining fluid and bronchial mucosa at approximately 2 hours were as in Table 1:

Table 1. Gemifloxacin Concentrations in Plasma and Tissues (320 mg Oral Dosing)
Tissue Concentration Ratio compared with
(mean ± SD) plasma (mean±SD)
Plasma 1.40 (0.442) μg/mL ---
Bronchoalveolar Macrophages 107 (77) μg/g 90.5 (106.3)
Epithelial Lining Fluid 2.69 (1.96) μg/mL 1.99 (1.32)
Bronchial Mucosa 9.52 (5.15) μg/g 7.21 (4.03)

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 metabolites formed are minor (<10% of the administered oral dose); the principal ones are N-acetyl gemifloxacin, the E-isomer of gemifloxacin and the carbamyl glucuronide of gemifloxacin.  Cytochrome P450 enzymes do not play an important role in gemifloxacin metabolism, and the metabolic activity of these enzymes is not significantly inhibited by gemifloxacin.

Excretion

Gemifloxacin and its metabolites are excreted 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 mean (±SD) renal clearance following repeat doses of 320 mg was approximately 11.6 ± 3.9 L/hr (range 4.6-17.6 L/hr), which indicates active secretion is involved in the renal excretion of gemifloxacin.  The mean (±SD) plasma elimination half-life at steady state following 320 mg to healthy subjects was approximately 7 ± 2 hours (range 4-12 hours).

Special Populations

Pediatric

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

Geriatric

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 indicated that following administration of 320 mg gemifloxacin, AUC values were approximately 10% higher in healthy female patients compared to males.  Males and females had mean AUC values of 7.98 μg•hr/mL (range, 3.21 – 42.71 μg•hr/mL) and 8.80 μg•hr/mL (range, 3.33 – 47.73 μg•hr/mL), respectively.  No gemifloxacin dosage adjustment based on gender is necessary.

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 in AUC (0-inf) of 34% and a mean increase in Cmax of 25% in these patients with hepatic impairment compared to healthy volunteers.

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 subjects with hepatic impairment compared to healthy volunteers.

These average 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 ADMINISTRATION.)

Renal Insufficiency

Results from population pharmacokinetic and clinical pharmacology studies with repeated 320 mg doses indicate 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. Modification of the dosage is recommended for patients with creatinine clearance ≤40 mL/min. (See DOSAGE AND ADMINISTRATION.) Hemodialysis removes approximately 20 to 30% of an oral dose of gemifloxacin from plasma.

Photosensitivity Potential

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, ciprofloxacin 500 mg b.i.d., or placebo for 7 days.  At 5 of the 6 wavelengths tested (295-430 nm), the photosensitivity potential of gemifloxacin was not statistically different from placebo.  At 365 nm (UVA region), gemifloxacin showed a photosensitivity potential similar to that of ciprofloxacin 500 mg b.i.d. and the photosensitivity potential for both drugs were statistically greater than that of placebo. Photosensitivity reactions were reported rarely in clinical trials with gemifloxacin (0.039%). (See ADVERSE REACTIONS.)

Drug-Drug Interactions

Antacids/Di- and Trivalent Cations

The systemic availability of gemifloxacin is significantly reduced when an aluminum- and magnesium- containing antacid is concomitantly administered (AUC decreased 85%; Cmax decreased 87%).  Administration of an aluminum- and magnesium- containing antacid or ferrous sulfate (325 mg) at 3 hours before or at 2 hours after gemifloxacin did not significantly alter the systemic availability of gemifloxacin. Therefore, aluminum- and/or magnesium- containing antacids, ferrous sulfate (iron), multivitamin preparations containing zinc or other metal cations, or Videx® (didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be taken within 3 hours before or 2 hours after taking Factive tablets.

Calcium carbonate (1000 mg) given either 2 hr before or 2 hr after gemifloxacin administration showed no notable reduction in gemifloxacin systemic availability.  Calcium carbonate administered simultaneously with gemifloxacin resulted in a small, not clinically significant, decrease in gemifloxacin exposure [AUC (0-inf) decreased 21% and Cmax decreased].

Sucralfate

When sucralfate (2 g) was administered 3 hours prior to gemifloxacin, the oral bioavailability of gemifloxacin was significantly reduced (53% decrease in AUC; 69% decrease in Cmax).  When sucralfate (2 g) was administered 2 hours after gemifloxacin, the oral bioavailability of gemifloxacin was not significantly affected; therefore Factive should be taken at least 2 hours before sucralfate. (See PRECAUTIONS.)

In Vitro Metabolism

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.

Theophylline

Gemifloxacin 320 mg at steady-state did not affect the repeat dose pharmacokinetics of theophylline (300 to 400 mg b.i.d. to healthy male subjects).

Digoxin

Gemifloxacin 320 mg at steady-state did not affect the repeat dose pharmacokinetics of digoxin (0.25 mg once daily to healthy elderly subjects).

Oral Contraceptives

The effect of an oral estrogen/progesterone contraceptive product (once daily for 21 days) on the pharmacokinetics of gemifloxacin (320 mg once daily for 6 days) in healthy female subjects indicates that concomitant administration caused an average reduction in gemifloxacin AUC and Cmax of 19% and 12%. These changes are not considered clinically significant. Gemifloxacin 320 mg at steady-state did not affect the repeat dose pharmacokinetics of an ethinylestradiol/levonorgestrol oral contraceptive product (30 μg/150 μg once daily for 21 days to healthy female subjects).

Cimetidine

Co-administration of a single dose of 320 mg gemifloxacin with cimetidine 400 mg four times daily for 7 days resulted in slight average increases in gemifloxacin AUC(0-inf) and Cmax of 10% and 6%, respectively.  These increases are not considered clinically significant.

Omeprazole

Co-administration of a single dose of 320 mg gemifloxacin with omeprazole 40 mg once daily for 4 days resulted in slight average increases in gemifloxacin AUC(0-inf) and Cmax of 10% and 11%, respectively.  These increases are not considered clinically significant.

Warfarin

Administration of repeated doses of gemifloxacin (320 mg once daily for 7 days) to healthy subjects on stable warfarin therapy had no significant effect on warfarin-induced anticoagulant activity (i.e., International Normalized Ratios for Prothrombin Time). (See PRECAUTIONS: Drug Interactions.)

Probenecid

Administration of a single dose of 320 mg gemifloxacin to healthy subjects who also received repeat doses of probenecid (total dose = 4.5 g) reduced the mean renal clearance of gemifloxacin by approximately 50%, resulting in a mean increase of 45% in gemifloxacin AUC(0-inf) and a prolongation of mean half-life by 1.6 hours.  Mean gemifloxacin Cmax increased 8%.

Microbiology

Gemifloxacin has in vitro activity against a wide range of Gram-negative and Gram-positive microorganisms.  Gemifloxacin is bactericidal with minimum bactericidal concentrations (MBCs) generally within one dilution of the minimum inhibitory concentrations (MICs).  Gemifloxacin acts by inhibiting DNA synthesis through the inhibition of both DNA gyrase and topoisomerase IV (TOPO IV), which are essential for bacterial growth. Streptococcus pneumoniae showing mutations in both DNA gyrase and TOPO IV (double mutants) are resistant to most fluoroquinolones. Gemifloxacin has the ability to inhibit both enzyme systems at therapeutically relevant drug levels in S. pneumoniae (dual targeting), and has MIC values that are still in the susceptible range for some of these double mutants.

The mechanism of action of quinolones, including gemifloxacin, is different from that of macrolides, beta-lactams, 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.

The main mechanism of fluoroquinolone resistance is due to mutations in DNA gyrase and/or TOPO 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 resistant to other fluoroquinolones may be susceptible to gemifloxacin.

Gemifloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic gram-positive microorganisms

Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP])*,*MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are strains resistant to two or more of the following antibiotics: penicillin, 2nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

Aerobic gram-negative microorganisms

Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae (many strains are only moderately susceptible)
Moraxella catarrhalis

Other microorganisms

Chlamydia pneumoniae
Mycoplasma pneumoniae

The following data are available, but their clinical significance is unknown.

Gemifloxacin exhibits in vitro minimal inhibitory concentrations (MICs) of 0.25 μg/mL or less against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of gemifloxacin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials:

Aerobic gram-positive microorganisms

Staphylococcus aureus (methicillin-susceptible strains only)
Streptococcus pyogenes

Aerobic gram-negative microorganisms

Acinetobacter lwoffii
Klebsiella oxytoca
Legionella pneumophila
Proteus vulgaris

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 method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of gemifloxacin powder.  The MICs should be interpreted according to the following criteria:

a This interpretive standard is applicable only to broth microdilution susceptibility testing with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)1.
For testing Enterobacteriaceae:
MIC (μg/mL) Interpretation
≤0.25 Susceptible (S)
0.5 Intermediate (I)
≥1.0 Resistant (R)
For testing Haemophilus influenzae and Haemophilus parainfluenzae a:
MIC (μg/mL) Interpretation
≤0.12 Susceptible (S)

The current absence of data on resistant strains precludes defining any results other than “Susceptible”.  Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

bThese interpretive standards are applicable only to broth microdilution susceptibility tests using cation–adjusted Mueller-Hinton broth with 2-5% lysed horse blood.
For testing Streptococcus pneumoniae b:
MIC (μg/mL) Interpretation
≤0.12 Susceptible (S)
0.25 Intermediate (I)
≥0.5 Resistant (R)

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 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 concentration 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 the following MIC values:

Microorganism MIC Range (μg/mL)
c This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution procedure using Haemophilus Test Medium (HTM)1.
d This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a broth microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.
Enterococcus faecalis ATCC 29212 0.016-0.12
Escherichia coli ATCC 25922 0.004-0.016
Haemophilus influenzae ATCC 49247c 0.002-0.008
Streptococcus pneumoniae ATCC 49619d 0.008-0.03

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 procedure2 requires the use of standardized inoculum concentrations.  This procedure uses paper disks impregnated with 5μg gemifloxacin to test the susceptibility of microorganisms to gemifloxacin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5μg gemifloxacin disk should be interpreted according to the following criteria:

e This interpretive standard is applicable only to disk diffusion susceptibility testing with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium (HTM).2
For testing Enterobacteriaceae:
Zone Diameter (mm) Interpretation
≥20 Susceptible (S)
16-19 Intermediate (I)
≤15 Resistant (R)
For testing Haemophilus influenzae and Haemophilus parainfluenzae e:
Zone Diameter (mm) Interpretation
≥18 Susceptible (S)

The current absence of data on resistant strains precludes defining any results other than “Susceptible”.  Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

f These zone diameter standards apply only to tests performed using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood incubated in 5% CO2.
For testing Streptococcus pneumoniae f:
Zone Diameter (mm) Interpretation
≥23 Susceptible (S)
20-22 Intermediate (I)
≤19 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 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 5μg gemifloxacin disk should provide the following zone diameters in these laboratory quality control strains:

g  This quality control range is applicable to only H. influenzae ATCC 49247 tested by a disk diffusion procedure using Haemophilus Test Medium (HTM)2.
h  This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a disk diffusion procedure using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood and incubated in 5% CO2.
Microorganism Zone Diameter (mm)
Escherichia coli ATCC 25922 29-36
Haemophilus influenzae ATCC 49247g 30-37
Streptococcus pneumoniae ATCC 49619h 28-34

Indications and Usage for Factive

Factive is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed below. (See DOSAGE AND ADMINISTRATION and CLINICAL STUDIES.)

Acute bacterial exacerbation of chronic bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis.

Community-acquired pneumonia (of mild to moderate severity) caused by Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]) *, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae, or Klebsiella pneumoniae **.

*MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are strains resistant to two or more of the following antibiotics: penicillin, 2nd generation cephalosporins, e.g. cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

** In clinical trials, there were 13 subjects with Klebsiella pneumoniae, primarily from non-comparative studies. Ten subjects had mild disease, two had moderate disease, and one had severe disease. There were two clinical failures in subjects with mild disease (one subject with bacteriologic recurrence).

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

Contraindications

Gemifloxacin is contraindicated in patients with a history of hypersensitivity to gemifloxacin, fluoroquinolone antibiotic agents, or any of the product components.

Warnings

THE SAFETY AND EFFECTIVENESS OF Factive IN CHILDREN, ADOLESCENTS (LESS THAN 18 YEARS OF AGE), PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS: Pediatric Use, Pregnancy and Nursing Mothers subsections.)

QT Effects

Fluoroquinolones 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.

Pharmacokinetic studies between gemifloxacin and drugs that prolong the QTc interval such as erythromycin, antipsychotics, and tricyclic antidepressants have not been performed. 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. 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.

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.

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving fluoroquinolone therapy.  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. 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. (See PRECAUTIONS and ADVERSE REACTIONS.)

Serious and occasionally fatal events, some due to hypersensitivity and/or some of uncertain etiology, have been reported in patients receiving fluoroquinolones.  These events may be severe and generally occur following the administration of multiple doses.  Clinical manifestations usually include new onset 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.

Peripheral Neuropathy

Rare 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.

Tendon Effects

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 quinolones.  Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially the elderly.  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 excluded.  Tendon rupture can occur during or after therapy with quinolones.

CNS Effects

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 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. 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.

Antibiotic Associated 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 present with 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. (See ADVERSE REACTIONS.)

Precautions

General

Prescribing Factive 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.

Rash

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 <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 (seeTable 2). Gemifloxacin therapy should be discontinued in patients developing a rash while on treatment.  (See ADVERSE REACTIONS and CLINICAL STUDIES.)

Table 2. Rash Incidence in Factive Treated Patients from the Clinical Studies Population* by Gender, Age, and Duration of Therapy
Gender & Duration of Gemifloxacin Therapy
Age (yr) 5 days 7 days 10 days** 14 days**
Category
*includes patients from studies of community-acquired pneumonia, acute bacterial exacerbation of chronic bronchitis, and other indications
**exceeds the recommended duration of therapy (see DOSAGE AND ADMINISTRATION)
Female < 40 5/242 (2.1%) 39/324 (12.0%) 20/131 (15.3%) 7/31 (22.6%)
Female ≥ 40 19/1210 (1.6%) 30/695 (4.3%) 19/308 (6.2%) 10/126 (7.9%)
Male < 40 4/218 (1.8%) 20/318 (6.3%) 7/74 (9.5%) 3/39 (7.7%)
Male ≥ 40 9/1321 (0.7%) 23/776 (3.0%) 9/345 (2.6%) 3/116 (2.6%)
Totals 37/2991 (1.2%) 112/2113 (5.3%) 55/858 (6.4%) 23/312 (7.4%)

Photosensitivity reactions have been reported very rarely in clinical trials with Factive. (See CLINICAL PHARMACOLOGY.)  However, as with all drugs of this class, it is recommended that patients avoid unnecessary exposure to strong sunlight or artificial UV rays (e.g., sunlamps, solariums), and should be advised of the appropriate use of broad spectrum sun block if in bright sunlight.  Treatment should be discontinued if a photosensitivity reaction is suspected.

Hepatic Effects: Liver enzyme elevations (increased ALT and/or AST) occurred at similar rates in patients receiving gemifloxacin 320 mg daily relative to comparator antimicrobial agents (ciprofloxacin, levofloxacin, clarithromycin/cefuroxime axetil, amoxicillin/clavulanate potassium, and ofloxacin).  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.)

Alteration of the dosage regimen is necessary for patients with impairment of renal function (creatinine clearance ≤40 mL/min). (See DOSAGE AND ADMINISTRATION.)

Adequate hydration of patients receiving gemifloxacin should be maintained to prevent the formation of a highly concentrated urine.

Information for Patients

Patients should be counseled:

  • that antibacterial drugs including Factive should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Factive is prescribed to treat a bacterial infection, patients should be told that 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 or other antibacterial drugs in the future;

  • that Factive has been associated with rash.  Patients should discontinue drug and call their healthcare provider if they develop a rash;

  • that Factive may be associated with hypersensitivity reactions, including anaphylactic reactions, even following a single dose; patients should immediately discontinue the drug at the sign of a rash or other allergic reaction and seek medical care;

  • that Factive may cause changes in the electrocardiogram (QTc interval prolongation);

  • that Factive should be avoided in patients receiving Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic agents;

  • that Factive should be used with caution in patients receiving drugs that affect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants;

  • to inform their physician of any personal or family history of QTc prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia;

  • to inform their physician of any other medications when taken concurrently with Factive, including over-the-counter medications and dietary supplements;

  • to contact their physician if they experience palpitations or fainting spells while taking Factive;

  • that Factive may be taken with or without meals;

  • to drink fluids liberally;

  • not to take antacids containing magnesium and/or aluminum or products containing ferrous sulfate (iron), multivitamin preparations containing zinc or other metal cations, or Videx® (didanosine) chewable/buffered tablets or the pediatric powder for oral solution within 3 hours before or 2 hours after taking Factive tablets;

  • that Factive should be taken at least 2 hours before sucralfate;

  • that phototoxicity has been reported with certain quinolones. The potential for Factive to cause phototoxicity was low (3/7659) at the recommended dose in clinical studies. In keeping with good clinical practice, avoid excessive sunlight or artificial ultraviolet light (e.g., tanning beds). If a sunburn-like reaction or skin eruption occurs, contact your physician; (See CLINICAL PHARMACOLOGY: Photosensitivity Potential);

  • that Factive may cause dizziness; if this occurs, patients should not operate an automobile or machinery or engage in activities requiring mental alertness or coordination;

  • that they  should discontinue Factive therapy and inform their physician if they feel pain, tenderness or rupture of a tendon.  Patients should rest and avoid exercise until the diagnosis of tendonitis or tendon rupture has been excluded;

  • that convulsions have been reported in patients receiving quinolones; and they should notify their physician before taking this drug if there is a history of this condition.

Drug Interactions

Administration of repeat doses of Factive had no effect on the repeat dose pharmacokinetics of theophylline, digoxin or an ethinylestradiol/levonorgestrol oral contraceptive product in healthy subjects. (See CLINICAL PHARMACOLOGY: Drug-Drug Interactions.)

Concomitant administration of Factive and calcium carbonate, cimetidine, omeprazole, or an estrogen/progesterone oral contraceptive produced minor changes in the pharmacokinetics of gemifloxacin, which were considered to be without clinical significance. (See CLINICAL PHARMACOLOGY.)

Concomitant administration of Factive with probenecid resulted in a 45% increase in systemic exposure to gemifloxacin.  (See CLINICAL PHARMACOLOGY.)

Factive had no significant effect on the anticoagulant effect of warfarin in healthy subjects on stable warfarin therapy.  However, because some quinolones have been reported to enhance the anticoagulant effects of warfarin or its derivatives in patients, the prothrombin time or other suitable coagulation test should be closely monitored if a quinolone antimicrobial is administered concomitantly with warfarin or its derivatives.

Quinolones form chelates with alkaline earth and transition metals.  The absorption of oral gemifloxacin is significantly reduced by the concomitant administration of an antacid containing aluminum and magnesium. Magnesium- and/or aluminum-containing antacids, products containing ferrous sulfate (iron), multivitamin preparations containing zinc or other metal cations, or Videx® (didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be taken within 3 hours before or 2 hours after Factive. Sucralfate should not be taken within 2 hours of Factive. (See CLINICAL PHARMACOLOGY.)

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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

Photocarcinogenesis

Gemifloxacin did not shorten the time to development of UVR-induced skin tumors in hairless albino (Skh-1) mice; thus, it was not photocarcinogenic in this model.  These mice received oral gemifloxacin and concurrent irradiation with simulated sunlight 5 days per week for 40 weeks followed by a 12-week treatment-free observation period.  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 Caucasian humans.  The median time to the development of skin tumors in the hairless mice was similar in the vehicle control group (36 weeks) and those given up to 100 mg/kg gemifloxacin daily (39 weeks).  Following repeat doses of 100 mg/kg gemifloxacin per day, the mice had skin gemifloxacin concentrations of approximately 7.4 μg/g.  Plasma levels following this dose were approximately 1.4 μg /mL in the mice around the time of irradiation.  There are no data on gemifloxacin skin levels in humans, but the mouse plasma gemifloxacin levels are in the expected range of human plasma Cmax levels (0.7-2.6 μg /mL, with an overall mean of about 1.6 μg /mL) following multiple 320 mg oral doses.

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