Factive Information
Factive () Warning:
Factive ()
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 ()-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 37ºC, pH 7.0). Its empirical formula is CHFNO•CHOS 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
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.
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 .
Pediatric:
Geriatric:
Gender:
Hepatic Insufficiency:
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 .)
Hemodialysis removes approximately 20 to 30% of an oral dose of gemifloxacin from plasma.
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 BID, 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 BID 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 )
It is difficult to ascribe relative photosensitivity/phototoxicity among various fluoroquinolones during actual patient use because other factors play a role in determining a subject’s susceptibility to this adverse event such as: a patient’s skin pigmentation, frequency and duration of sun and artificial ultraviolet light (UV) exposure, wearing of sun screen and protective clothing, the use of other concomitant drugs and the dosage and duration of fluoroquinolone therapy. (See and )
Antacids/Di- and Trivalent Cations
®
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].
Theophylline
Digoxin
Oral Contraceptives
Cimetidine
Omeprazole
Probenecid
MICROBIOLOGY
Gemifloxacin has 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. 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 (dual targeting), and has MIC values that are still in the susceptible range for some of these double mutants. However, the presence of double mutants was not evaluated in clinical trials; therefore, the clinical significance of these data are unknown.
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 to
Gemifloxacin has been shown to be active against most strains of the following microorganisms, both and in clinical infections as described in the section.
Aerobic Gram-positive microorganisms
Streptococcus pneumoniae
*
*
Aerobic Gram-negative microorganisms
Other microorganisms
The following data are available,
Gemifloxacin exhibits 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
Aerobic Gram-negative microorganisms
Susceptibility Tests
Dilution techniques:
1
For testing :
For testing and :
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.
For testing :
b
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:
d
S. pneumoniae
Diffusion Techniques:
2
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 μg gemifloxacin disk should be interpreted according to the following criteria:
For testing :
For testing and :
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.
For testing :
f
2
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 μg gemifloxacin disk should provide the following zone diameters in these laboratory quality control strains:
h
S. pneumoniae
2
Factive () Indications And Usage
Factive () is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed below. (See and )
*MDRSP: multi-drug resistant , includes isolates previously known as PRSP (penicillin-resistant ), 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.
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.
Factive () Contraindications
Factive () is contraindicated in patients with a history of hypersensitivity to gemifloxacin, fluoroquinolone antibiotic agents, or any of the product components.
Factive () Warnings
Pharmacokinetic studies between gemifloxacin and drugs that prolong the QTc interval such as erythromycin, antipsychotics, and tricyclic antidepressants have not been performed. Factive () 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 Factive () treatment in over 8119 patients, including 707 patients concurrently receiving drugs known to prolong the QTc interval and 7 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.
Factive () 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 and .)
Other serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including Factive () . These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted (See and ).
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of , and surgical evaluation should be instituted as clinically indicated.
Factive () Precautions
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 ). 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 and .)
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 and )
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 )
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 )
Alteration of the dosage regimen is necessary for patients with impairment of renal function (creatinine clearance ≤40 mL/min). (See )
Adequate hydration of patients receiving Factive () should be maintained to prevent the formation of a highly concentrated urine.
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 )
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 )
Concomitant administration of Factive () with probenecid resulted in a 45% increase in systemic exposure to gemifloxacin. (See .)
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 .)
Carcinogenesis:
Photocarcinogenesis:
Impairment of Fertility:
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 , , and ).
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).
Factive () 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%.
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 )
In clinical trials of acute bacterial exacerbation of chronic bronchitis (ABECB) and community acquired pneumonia (CAP), the incidences of rash were as follows ():
(See ).
Factive () 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.
Factive () 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 ().
The clinical decision regarding the use of a 5 or 7 day regimen should be guided by results of the initial sputum culture.
The recommended dose and duration of Factive () should not be exceeded (see ).
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.
Women: 0.85 x the value calculated for men
Factive () 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 67707-320-05320 mg Unit of Use (CR*) 7's NDC 67707-320-07
*Child Resistant
Factive () 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 I (hERG) channel inhibition assay, having an IC 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.
Factive () Clinical Studies
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 below.
To evaluate the safety and efficacy of a 5-day course of Factive () , 510 outpatient and hospitalized adults with clinically and radiologically determined mild to moderate community-acquired pneumonia were clinically evaluated in a double-blind, randomized, prospective, multicenter study comparing Factive () 320 mg for five days to Factive () 320 mg for seven days (Study OP-634-001).
Clinical success rates in the clinically evaluable population were 95.0% in the 5 day group and 92.1% in the 7 day group.
The microbiological efficacy of the 5-day regimen was documented for pathogens listed in Table 8 below.
Previous clinical studies evaluated the efficacy of Factive () in a 7-day treatment of CAP in adults. This clinical program consisted of three double-blind, randomized, actively-controlled clinical studies (studies 011, 012, and 049) and one open-label, actively-controlled study (study 185). In addition, two uncontrolled studies (studies 061 and 287) were conducted. Three of the studies, controlled study 011 and the uncontrolled studies, had a fixed 7-day duration of treatment for Factive () . Controlled study 011 compared a 7-day course of Factive () with a 10-day treatment course of amoxicillin/clavulanate (1g/125 mg TID) and clinical success rates were similar between treatment arms. The results of comparative studies 049, 185, and 012 were supportive although treatment duration could have been 7 to 14 days. The results of the clinical studies with a fixed 7-day duration of Factive () are shown in .
The combined bacterial eradication rates for patients treated with a fixed 7-day treatment regimen of Factive () are shown in .
Factive () was also effective in the treatment of CAP due to multi-drug resistant (MDRSP*). Of 35 patients with MDRSP treated for 7 days, 29 (82.9%) achieved clinical and bacteriological success at follow-up. The clinical and bacteriological success for the 35 patients with MDRSP isolates are shown in .
*MDRSP: multi-drug resistant , includes isolates previously known as PRSP (penicillin-resistant ), 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.
Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in below.
To further characterize gemifloxacin-associated rash, which in early clinical studies appeared to be associated with age less than 40 and female gender, a clinical pharmacology study was conducted. The study enrolled 1,011 healthy female volunteers less than 40 years of age. Subjects were randomized in a 5:1 ratio to receive either Factive () 320 mg PO daily (819 subjects) or ciprofloxacin 500 mg PO twice daily for 10 days (164 subjects). This study was designed to enroll subjects at a high risk for rash (women 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. Approximately 11% of the rashes were described as being “urticaria-like”. There were no documented cases of hypersensitivity syndrome or findings suggestive of angioedema or other serious cutaneous reactions.
The majority of rashes (81.9%) occurred on days 8 through 10 of the planned 10 day course of Factive () ; 2.7% of rash events occurred within one day of the start of dosing. 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 Factive () were treated with ciprofloxacin (n=136) or placebo (n=50); 5.9% developed rash when treated with ciprofloxacin and 2.0% developed rash when treated with placebo. The cross sensitization rate to other fluoroquinolones was not evaluated in this clinical study. There was no evidence of sub-clinical sensitization to Factive () on a second exposure (i.e., subjects who had not developed a rash to Factive () in the first part of the study were not at higher risk of developing a rash to Factive () 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.
Factive () References
1. Clinical and Laboratory Standards Institute. -Seventh Edition. Clinical and Laboratory Standards Institute document M7-A7, Vol. 26, No. 2, CLSI, Wayne, PA, January 2006.
2. Clinical and Laboratory Standards Institute. -Ninth Edition. Clinical and Laboratory Standards Institute document M2-A9, Vol. 26, No. 1, CLSI, Wayne, PA, January 2006.
DATE OF REVISION October 2008© Oscient Pharmaceuticals Corporation 2008Factive () is a registered trademark of LG Life Sciences.
Manufactured for:Oscient PharmaceuticalsWaltham, MA 02451-1478 USA
Licensed from LG Life Sciences, Ltd. Seoul, Korea
Read the Medication Guide that comes with Factive () before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment.
