FACTIVE (Page 5 of 9)

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, post-marketing reports of increases in the INR, or PT, and/or clinical episodes of bleeding in patients have been noted with the use of quinolones, including FACTIVE, 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 FACTIVE, 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.

Mutagenesis: Gemifloxacin was not mutagenic in 4 bacterial strains (TA 98, TA 100, TA 1535, TA 1537) used in an Ames Salmonella reversion assay. It did not induce micronuclei in the bone marrow of mice following intraperitoneal doses of up to 40 mg/kg and it did not induce unscheduled DNA synthesis in hepatocytes from rats which received oral doses of up to 1600 mg/kg. Gemifloxacin was clastogenic in vitro in the mouse lymphoma and human lymphocyte chromosome aberration assays. It was clastogenic in vivo in the rat micronucleus assay at oral and intravenous dose levels (≥800 mg/kg and ≥40 mg/kg, respectively) that produced bone marrow toxicity. Fluoroquinolone clastogenicity is apparently due to inhibition of mammalian topoisomerase activity which has threshold implications.

Impairment of Fertility: Gemifloxacin did not affect the fertility of male or female rats at AUC levels following oral administration (216 and 600 mg/kg/day) that were approximately 3- to 4-fold higher than the AUC levels at the clinically recommended dose.

Pregnancy:

Teratogenic Effects.

Pregnancy Category C. 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 (IV 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 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 approximately 0.8 to 3-fold clinical exposure.

The safety of FACTIVE in pregnant women has not been established. FACTIVE should not be used in pregnant women unless the potential benefit to the mother outweighs the risk to the fetus. There are no adequate and well-controlled studies in pregnant women.

Nursing Mothers:

Gemifloxacin is excreted in the breast milk of rats. There is no information on excretion of gemifloxacin into human milk. Therefore, FACTIVE should not be used in lactating women unless the potential benefit to the mother outweighs the risk.

Pediatric Use:

Safety and effectiveness 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.)

Geriatric Use:

Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as FACTIVE. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing FACTIVE to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue FACTIVE and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (See Boxed Warning, WARNINGS, and ADVERSE REACTIONS/Post-Marketing Adverse Event Reports).

Of the total number of subjects in clinical studies of FACTIVE, 29% (2314) were 65 and over, while 11% (865) were 75 and over. No overall difference in effectiveness was observed between these subjects and younger subjects; the adverse event rate for this group was similar to or lower than that for younger subjects with the exception that the incidence of rash was lower in geriatric patients compared to patients less than 40 years of age.

Elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, FACTIVE should be avoided in patients taking drugs that can result in prolongation of the QT interval (e.g., Class IA or Class III antiarrhythmics) or in patients with risk factors for torsades de pointes (e.g., known QT prolongation, uncorrected hypokalemia).

ADVERSE REACTIONS

In clinical studies, 8119 patients received daily oral doses of 320 mg FACTIVE. In addition, 1797 healthy volunteers and 81 patients with renal or hepatic impairment received single or repeat doses of gemifloxacin in clinical pharmacology studies. The majority of adverse reactions experienced by patients in clinical trials were considered to be of mild to moderate severity.

FACTIVE was discontinued because of an adverse event (determined by the investigator to be possibly or probably related to drug) in 2.0% of patients, primarily due to rash (0.8%), nausea (0.3%), diarrhea (0.3%), urticaria (0.2%) and vomiting (0.2%). Comparator antibiotics were discontinued because of an adverse event at an overall comparable rate of 2.1%, primarily due to diarrhea (0.5%), nausea (0.4%), vomiting (0.3%), rash (0.3%), abdominal pain (0.2%) and vertigo (0.2%).

The most commonly reported adverse events with a frequency of ≥2% for patients receiving 320 mg FACTIVE versus comparator drug (beta-lactam antibiotics, macrolides or other fluoroquinolones) are as follows: diarrhea 5.0% vs. 6.2%; rash 3.5% vs. 1.1%; nausea 3.7% vs. 4.5%; headache 4.2% vs. 5.2%; abdominal pain 2.2% vs. 2.2%; vomiting 1.6% vs. 2.0%; and dizziness 1.7% vs. 2.6%.

Adverse Events with a Frequency of Less than 1%

Additional drug-related adverse events (possibly or probably related) in the 8119 patients, with a frequency of >0.1% to ≤1% included: abdominal pain, anorexia, constipation, dermatitis, dizziness, dry mouth, dyspepsia, fatigue, flatulence, fungal infection, gastritis, genital moniliasis, genital pruritus, hyperglycemia, increased alkaline phosphatase, increased ALT, increased AST, increased creatine phosphokinase, insomnia, leukopenia, pruritus, somnolence, taste perversion, thrombocythemia, urticaria, vaginitis, and vomiting.

Other adverse events reported from clinical trials which have potential clinical significance and which were considered to have a suspected relationship to the drug, that occurred in ≤0.1% of patients were: abnormal urine, abnormal vision, anemia, arthralgia, asthenia, back pain, bilirubinemia, dyspnea, eczema, eosinophilia, facial edema, flushing, gastroenteritis, granulocytopenia, hot flashes, increased GGT, increased non-protein nitrogen, leg cramps, moniliasis, myalgia, nervousness, non-specified gastrointestinal disorder, pain, pharyngitis, photosensitivity/phototoxicity reactions, pneumonia, thrombocytopenia, tremor, vertigo. (See PRECAUTIONS.)

In clinical trials of acute bacterial exacerbation of chronic bronchitis (ABECB) and community acquired pneumonia (CAP), the incidences of rash were as follows (Table 3):

Table 3. Incidence of Rash by Clinical Indication in Patients Treated with FACTIVE
ABECB (5 days) N = 2284 CAP (5 days) N = 256 CAP (7 days) N = 643
n/N % n/N % n/N %
* insufficient number of patients in this category for a meaningful analysis
Totals 27/2284 1.2 1/256 0.4 26/643 4.0
Females, < 40 years NA* 1/37 2.7 8/88 9.1
Females, ≥ 40 years 16/1040 1.5 0/73 0 5/214 2.3
Males, < 40 years NA* 0/65 0 5/101 5.0
Males, ≥ 40 years 11/1203 0.9 0/81 0 8/240 3.3

(See PRECAUTIONS).

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