A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Factive Indications, Dosage, Storage, Stability - Gemifloxacin mesylate
Factive Indications, Dosage, Storage, Stability - Gemifloxacin mesylate
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 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 noncomparative
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.
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
5).
|
Table 5
|
|
INDICATION
|
DOSE
|
DURATION
|
|
Acute bacterial exacerbation of chronic bronchitis
|
One 320 mg tablet daily
|
5 days
|
|
Community-acquired pneumonia (of mild to moderate severity)
|
One 320 mg tablet daily
|
7 days
|
The recommended dose and duration of FACTIVE should not
be exceeded (see Table 2).
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 6 provides dosage guidelines for use in patients with
renal impairment:
|
Table 6. RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
|
|
Creatinine Clearance(mL/min)
|
Dose
|
|
>40
|
See Usual Dosage
|
|
³ 40
|
160 mg q24h
|
Patients requiring routine hemodialysis or continuous
ambulatory peritoneal dialysis (CAPD) should receive 160 mg q24h.
When only the serum creatinine concentration is known,
the following formula may be used to estimate creatinine clearance.
|
Men: Creatinine Clearance (mL/min) =
|
Weight (kg) x (140 - age)
|
|
72 x serum creatinine (mg/dL)
|
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 67707-320-05
|
|
320 mg Unit of Use (CR*) 7's
|
NDC 67707-320-07
|
|
320 mg Hospital Pack (NCR**) 30's
|
NDC 67707-320-30
|
|
*Child Resistant
|
|
** Not 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 behaviour
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
mM.
Gemifloxacin, like many other quinolones, tends to crystallise
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 7 below.
|
Table 7. 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)
|
Community Acquired Pneumonia (CAP)
The clinical program to evaluate the efficacy of gemifloxacin
in the treatment of community acquired pneumonia in adults consisted of
three double-blind, randomized, actively-controlled clinical studies (studies
011, 012, and 049) and one open, actively-controlled study (study 185).
In addition, two uncontrolled studies (studies 061 and 287) were conducted.
Three of the studies, pivotal study 011 and the uncontrolled studies,
had a fixed 7-day duration of treatment for FACTIVE. Pivotal 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 are shown in Table
8:
|
Table 8. Clinical Response at Follow-Up (Test of
Cure): CAP Studies with a Fixed 7 Day Duration of Treatment
|
|
Drug Regimen
|
Success Rate % (n/N)
|
Treatment Difference (95% CI)*
|
|
Study 011
|
|
FACTIVE 320 mg x 7 days
|
88.7% (102/115)
|
1.1 (-7.3, 9.5)
|
|
Amoxicillin/clavulanate500 mg/125 mg tid x 10 days
|
87.6% (99/113)
|
|
Study 061
|
|
FACTIVE 320 mg x 7 days
|
91.7%(154/168)
|
(86.1, 95.2)
|
|
Study 287
|
|
FACTIVE 320 mg x 7 days
|
89.8% (132/147)
|
(84.9, 94.7)
|
|
* For uncontrolled studies, the 95% CI around the
success rate is shown
|
The combined bacterial eradication rates for patients
treated with a fixed 7-day treatment regimen of FACTIVE are shown in Table
9:
|
Table 9. Bacterial Eradication by Pathogen for Patients
Treated with FACTIVE in Studies with a Fixed 7-day Duration of Treatment
|
|
Pathogen
|
n/N
|
%
|
|
S. pneumoniae
|
68/77
|
88.3
|
|
M. pneumoniae
|
21/22
|
95.5
|
|
H. influenzae
|
30/35
|
85.7
|
|
C. pneumoniae
|
13/14
|
92.9
|
|
K. pneumoniae*
|
11/13
|
84.6
|
|
M. catarrhalis
|
10/10
|
100
|
* Subjects with Klebsiella pneumoniae included
in this table were from non-comparative studies 061 and 287. 10 of these
subjects had mild disease, 2 had moderate disease, and 1 had severe disease.
Both failures were in subjects with mild disease (one of these had a bacteriologic
recurrence).
FACTIVE was also effective in the treatment of CAP due
to PRSP (penicillin MIC of ³2 mg/mL).
Of 11 patients with PRSP treated for 7 days, 100% achieved clinical and
bacteriological success at follow-up. Two of these subjects were classified
as having severe disease and were bacteremic.
Cutaneous Manifestations (Rash)
In clinical trials of 6,775 patients, the incidence of
rash was higher in patients receiving gemifloxacin than in those receiving
comparator drugs (see PRECAUTIONS
and ADVERSE REACTIONS). 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). (See Table 2).
To further characterize gemifloxacin-associated rash,
a clinical pharmacology study was conducted. The study enrolled 1,011
healthy female volunteers less than 40 years of age. Subjects were randomized
to receive either FACTIVE 320 mg po daily or ciprofloxacin 500 mg po twice
daily for 10 days. The objective of the study was to assess the characteristics
of rash. The majority of rashes in subjects receiving FACTIVE were maculopapular
and of mild to moderate severity; 7% of the rashes were reported as severe,
and severity appeared to correlate with the extent of the rash. In 68%
of the subjects reporting a severe rash and approximately 25% of all those
reporting rash, >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. There were no documented
cases of hypersensitivity syndrome or findings suggestive of angioedema
or other serious cutaneous reactions.
The majority of rash events (81.9%) occurred on days
8 through 10 day of the planned 10 day course of gemifloxacin; 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 gemifloxacin were treated
with ciprofloxacin or placebo; 5.9% developed rash when treated with ciprofloxacin
and 2.0% developed rash when treated with placebo. The characteristics
of rash in subjects receiving ciprofloxacin following gemifloxacin were
similar to those described in subjects who only received ciprofloxacin.
The cross sensitization rate to other fluoroquinolones was not evaluated
in this clinical study. There was no evidence of sub-clinical sensitization
to gemifloxacin (i.e. subjects who had not developed a rash to gemifloxacin
in the first part of the study were not at higher risk of developing a
rash to gemifloxacin 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.
REFERENCES
1. National Committee for Clinical Laboratory
Standards. Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria that Grow Aerobically—Sixth Edition. Approved Standard NCCLS
Document M7-A6, Vol. 23, No. 2, NCCLS, Wayne, PA, January 2003.
2. National Committee for Clinical Laboratory
Standards. Performance Standards for Antimicrobial Disk Susceptibility
Tests—Eighth Edition. Approved Standard NCCLS Document A2-A8, Vol. 23,
No. 1, NCCLS Wayne, PA, January 2003.
Updated Sep 18, 2003
top
