FACTIVE: Package Insert and Label Information (Page 4 of 7)

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 %
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

* insufficient number of patients in this category for a meaningful analysis

(See PRECAUTIONS).

Laboratory Changes: The percentages of patients who received multiple doses of FACTIVE and had a laboratory abnormality are listed below. It is not known whether these abnormalities were related to FACTIVE or an underlying condition.

Clinical Chemistry: increased ALT (1.7%), increased AST (1.3%), increased creatine phosphokinase (0.7%), increased alkaline phosphatase (0.4%), increased total bilirubin (0.4%), increased potassium (0.3%), decreased sodium (0.2%), increased blood urea nitrogen (0.3%), decreased albumin (0.3%), increased serum creatinine (0.2%), decreased calcium (0.1%), decreased total protein (0.1%), decreased potassium (0.1%), increased sodium (0.1%), increased lactate dehydrogenase (<0.1%) and increased calcium (<0.1%).

CPK elevations were noted infrequently: 0.7% in FACTIVE patients vs. 0.7% in the comparator patients.

Hematology: increased platelets (1.0%), decreased neutrophils (0.5%), increased neutrophils (0.5%), decreased hematocrit (0.3%), decreased hemoglobin (0.2%), decreased platelets (0.2%), decreased red blood cells (0.1%), increased hematocrit (0.1%), increased hemoglobin (0.1%), and increased red blood cells (0.1%).

In clinical studies, approximately 7% of the FACTIVE treated patients had elevated ALT values immediately prior to entry into the study. Of these patients, approximately 15% showed a further elevation of their ALT at the on-therapy visit and 9% showed a further elevation at the end of therapy visit. None of these patients demonstrated evidence of hepatocellular jaundice. For the pooled comparators, approximately 6% of patients had elevated ALT values immediately prior to entry into the study. Of these patients, approximately 7% showed a further elevation of their ALT at the on-therapy visit and 4% showed a further elevation at the end of therapy visit.

In a clinical trial where 638 patients received either a single 640 mg dose of gemifloxacin or 250 mg BID of ciprofloxacin for 3 days, there was an increased incidence of ALT elevations in the gemifloxacin arm (3.9%) vs. the comparator arm (1.0%). In this study, two patients experienced ALT elevations of 8 to 10 times the upper limit of normal. These elevations were asymptomatic and reversible.

Post-Marketing Adverse Reactions: The majority of the post-marketing adverse events reported were cutaneous and most of these were rash. Some of these cutaneous adverse events were considered serious. The majority of the rashes occurred in women and in patients under 40 years of age.

The following are additional adverse reactions reported during the post-marketing use of FACTIVE. Since these reactions are reported voluntarily from a population of uncertain size, it is impossible to reliably estimate their frequency or establish a causal relationship to FACTIVE exposure:

  • peripheral neuropathy that may be irreversible;
  • anaphylactic reaction, erythema multiforme, skin exfoliation, facial swelling;
  • exacerbation of myasthenia gravis;
  • hemorrhage, increased international normalized ratio (INR), retinal hemorrhage;
  • peripheral edema;
  • renal failure;
  • prolonged QT, supraventricular tachycardia, syncope, transient ischemic attack;
  • photosensitivity/phototoxicity reaction (See PRECAUTIONS.);
  • antibiotic-associated colitis;
  • tendon rupture.

OVERDOSAGE

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. Hemodialysis removes approximately 20 to 30% of an oral dose of gemifloxacin from plasma.

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

DOSAGE AND ADMINISTRATION

FACTIVE can be taken with or without food and should be swallowed whole with a liberal amount of liquid. The recommended dose of FACTIVE is 320 mg daily, according to the following table (Table 4).Table 4. Recommended Dosage Regimen of FACTIVE

The clinical decision regarding the use of a 5 or 7 day regimen should be guided by results of the initial sputum culture.

INDICATION DOSE / DURATION
Acute bacterial exacerbation of chronic bronchitisOne 320 mg tablet daily for 5 days
Community-acquired pneumonia (of mild to moderate severity)
due to known or suspected S. pneumoniae, H. influenzae, M. pneumoniae, or C. pneumoniae infection One 320 mg tablet daily for 5 days
due to known or suspected MDRSP*, K. pneumoniae, or M. catarrhalis infection One 320 mg tablet daily for 7 days

*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 (MIC 2 µg/mL), 2nd generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

The recommended dose and duration of FACTIVE should not be exceeded (see Table 2).

Use in Renally Impaired Patients: 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. Table 5 provides dosage guidelines for use in patients with renal impairment.Table 5. Recommended Doses for Patients with Renal Impairment

Creatinine Clearance

(mL/min)

Dose
>40 See Usual Dosage
40 160 mg every 24 hours

Patients requiring routine hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) should receive 160 mg every 24 hours.

When only the serum creatinine concentration is known, the following formula may be used to estimate creatinine clearance.

Creatinine Clearance Formula
(click image for full-size original)

Creatinine Clearance Formula

Women: 0.85 x the value calculated for men

Use in Hepatically Impaired 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.

Use in Elderly: No dosage adjustment is recommended.

HOW SUPPLIED

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

320 mg Unit of Use (CR*) 5’s NDC 44001-321-05
320 mg Unit of Use (CR*) 7’s NDC 44001-321-07

*Child Resistant

Storage

Store at 25ºC (77ºF); excursions permitted to 15º-30ºC (59º-86ºF) [see USP Controlled Room Temperature]. Protect from light.

ANIMAL PHARMACOLOGY

Quinolones have been shown to cause arthropathy in immature animals. Degeneration of articular cartilage occurred in juvenile dogs given at least 192 mg/kg/day gemifloxacin in a 28-day study (producing about 6 times the systemic exposure at the clinical dose), but not in mature dogs. There was no damage to the articular surfaces of joints in immature rats given repeated doses of up to 800 mg/kg/day.

Some quinolones have been reported to have proconvulsant properties that are potentiated by the concomitant 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 occurred in mice given the active metabolite of the NSAID, fenbufen, followed by 80 mg/kg gemifloxacin.

Dogs given 192 mg/kg/day (about 6 times the systemic exposure at the clinical dose) for 28 days, or 24 mg/kg/day (approximately equivalent to the systemic exposure at the clinical dose) for 13 weeks showed reversible increases in plasma ALT activities and local periportal liver changes associated with blockage of small bile ducts by crystals containing gemifloxacin.

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. Gemifloxacin exhibited weak activity in the cardiac IKr (hERG) channel inhibition assay, having an IC50 of approximately 270 μM.

Gemifloxacin, like many other quinolones, tends to crystallize at the alkaline pH of rodent urine, resulting in a nephropathy in rats that is reversible on drug withdrawal (oral no-effect dose 24 mg/kg/day).

Gemifloxacin was weakly phototoxic to hairless mice given a single 200 mg/kg oral dose and exposed to UVA radiation. However, no evidence of phototoxicity was observed at 100 mg/kg/day dosed orally for 13 weeks in a standard hairless mouse model, using simulated sunlight.

CLINICAL STUDIES

Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB)

FACTIVE (320 mg once daily for 5 days) was evaluated for the treatment of acute bacterial exacerbation of chronic bronchitis in three pivotal double-blind, randomized, actively-controlled clinical trials (studies 068, 070, and 212). The primary efficacy parameter in these studies was the clinical response at follow-up (day 13 to 24). The results of the clinical response at follow-up for the principal ABECB studies demonstrate that FACTIVE 320 mg PO once daily for 5 days was at least as good as the comparators given for 7 days. The results are shown in Table 6 below.Table 6. Clinical Response at Follow-Up (Test of Cure): Pivotal ABECB Studies

Drug Regimen

Success Rate % (n/N)

Treatment Difference (95% CI)

Study 068

FACTIVE 320 mg x 5 days

86.0 (239/278)

1.2 (-4.7, 7.0)

Clarithromycin 500 mg BID x 7 days

84.8 (240/283)

Study 070

FACTIVE 320 mg x 5 days

93.6 (247/264)

0.4 (-3.9, 4.6)

Amoxicillin/clavulanate500 mg/125 mg TID x 7 days

93.2 (248/266)

Study 212

FACTIVE 320 mg x 5 days

88.2 (134/152)

3.1 (-4.7, 10.7)

Levofloxacin 500 mg x 7 days

85.1 (126/148)

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