FACTIVE (Page 5 of 12)

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, rash occurred more often with FACTIVE than with therapy with comparator agents (2.7% vs. 0.6%). Increasing incidence of rash was associated with younger age (especially below 40), female gender, use of hormone replacement therapy and longer durations of therapy (see Table 2). Urticarial reactions, some of which were not classified as rash, were more common in FACTIVE patients than in comparator patients (0.6% vs. 0.2%). FACTIVE should be discontinued in patients developing a rash or urticaria 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 & Age (yr) Category

Duration of FACTIVE Therapy

5 days

7 days

10 days**

14 days**

Female < 40

10/399 (2.5%)

49/407 (12.0%)

20/131 (15.3%)

7/31 (22.6%)

Female ≥ 40

30/1438 (2.1%)

34/887 (3.8%)

19/308 (6.2%)

10/126 (7.9%)

Male < 40

6/356 (1.7%)

26/453 (5.7%)

7/74 (9.5%)

3/39 (7.7%)

Male ≥ 40

10/1503 (0.7%)

26/984 (2.6%)

9/345 (2.6%)

3/116 (2.6%)

Totals

56/3696 (1.5%)

135/2732 (4.9%)

55/858 (6.4%)

23/312 (7.4%)


**exceeds the recommended duration of therapy (see DOSAGE AND ADMINISTRATION)
The most common form of rash associated with FACTIVE was described as maculopapular and mild to moderate in severity. Eighty percent of rashes resolved within 14 days. Approximately 10% of the rashes (0.5% of all patients) were described as of severe intensity and approximately 10% of those with rash were treated with systemic steroids. There were no documented cases in the clinical trials of more serious skin reactions known to be associated with significant morbidity or mortality.

Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with use of quinolones after sun or UV light exposure. Therefore excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs. (See ADVERSE REACTIONS and ADVERSE REACTIONS/ Post-Marketing Adverse Reactions.)

Hepatic Effects: Liver enzyme elevations (increased ALT and/or AST) occurred at similar rates in patients receiving FACTIVE 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 FACTIVE 320 mg daily should not be exceeded and the recommended length of therapy should not be exceeded. (See DOSAGE AND ADMINISTRATION.)

Renal Effects: 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 FACTIVE should be maintained to prevent the formation of a highly concentrated urine.

Information for Patients
Patients should be counseled:

  • to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue FACTIVE treatment. The risk of serious tendon disorders with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart and lung transplants;

  • that fluoroquinolones like FACTIVE may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems;

  • 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 and hives. Rash occurs more commonly in those under 40, especially women and in women on hormone replacement therapy. The incidence of rash increases with duration more than 5 days and particularly longer than 7 days. Patients should discontinue FACTIVE 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 diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible;

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

  • 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 convulsions have been reported in patients receiving quinolones. Patients should notify their physician before taking FACTIVE if they have a history of convulsions, seizures, or epilepsy;

  • that other central nervous system problems such as tremors, restlessness, lightheadedness, confusion and hallucinations may occur rarely;

  • that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients should contact their physician; (See CLINICAL PHARMACOLOGY: Photosensitivity Potential);

  • that increases of the International Normalized Ratio (INR), or prothrombin time (PT), and/or clinical episodes of bleeding have been noted with concurrent administration of warfarin or its derivatives, and FACTIVE. Patients should notify their physicians if they are taking warfarin or its derivatives;

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

  • 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.

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).

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