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| Description |
| Clinical
Pharmacology |
| Indication
and Usage |
| Contraindications |
| Clinical
Studies |
| Warnings |
| Precautions |
| Adverse
Reactions |
| Dosage
and Administration |
| How Supplied |
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| Description |
| Gynazole·1
(butoconazole nitrate) vaginal cream, 2% contains butoconazole nitrate 2%, an
imidazole derivative with antifungal activity. Its chemical name is
(±)-1-[4-(p-chlorophenyl)-2-[(2,6-dichlorophenyl) thio]butyl] imidazole
mononitrate, and it has the following chemical structure: |
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| Butoconazole
nitrate is a white to off-white crystalline powder with a molecular weight of
474.79. It is sparingly soluble in methanol; slightly soluble in chloroform,
methylene chloride, acetone, and ethanol; very slightly soluble in ethyl
acetate; and practically insoluble in water. It melts at about 159°C with
decomposition. |
| Gynazole·1
contains 2% butoconazole nitrate in a cream of edetate disodium, glyceryl
monoisostearate, methylparaben, mineral oil, polyglyceryl-3 oleate, propylene
glycol, propylparaben, colloidal silicon dioxide, sorbitol solution, purified
water, and microcrystalline wax. |
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| CLINICAL
PHARMACOLOGY |
| Following
vaginal administration of butoconazole nitrate vaginal cream, 2% to 3 women,
1.7% (range 1.3 - 2.2%) of the dose was absorbed on average. Peak plasma levels
(13.6 - 18.6 ng radioequivalents/mL of plasma) of the drug and its metabolites
are attained between 12 and 24 hours after vaginal administration. |
| Microbiology |
| The exact
mechanism of the antifungal action of butoconazole nitrate is unknown; however,
it is presumed to function as other imidazole derivatives via inhibition of
steroid synthesis. Imidazoles generally inhibit the conversion of lanosterol to
ergosterol, resulting in a change in fungal cell membrane lipid composition.
This structural change alters cell permeability and, ultimately, results in the
osmotic disruption or growth inhibition of the fungal cell. |
| Butoconazole
nitrate is an imidazole derivative that has fungicidal activity in vitro
against Candida spp. and has been demonstrated to be clinically
effective against vaginal infections due to Candida albicans. Candida
albicans has been identified as the predominant species responsible
for vulvovaginal candidiasis. |
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| INDICATIONS
AND USAGE |
| Gynazole·1
(butoconazole nitrate) vaginal cream, 2% is indicated for the local treatment
of vulvovaginal candidiasis (infections caused by Candida). The
diagnosis should be confirmed by KOH smears and/or cultures (see CLINICAL
STUDIES). |
| Note:
Gynazole·1 is safe and effective in non-pregnant women; however, the safety
and effectiveness of this product in pregnant women has not been established.
(See PRECAUTIONS: Pregnancy.)
|
| Contraindications |
| Gynazole·1
is contraindicated in patients with a history of hypersensitivity to any of the
components of the product. |
| CLINICAL
STUDIES |
Vulvovaginal
Candidiasis: Two studies were conducted that compared 2% butoconazole
nitrate cream with clotrimazole tablets. There were 322 enrolled patients, 161
received 2.0% butoconazole vaginal cream and 161 patients inserted the 500-mg
clotrimazole vaginal tablet. At the second follow-up visit (30 days
post-therapy), 118 patients in the butoconazole group and 116 in the
clotrimazole group were evaluable for efficacy analysis, respectively. All of
these patients had infection caused by Candida albicans.
The efficacy of the study drugs was assessed by evaluating clinical, mycologic
and therapeutic cure rates, which are summarized in Table 1.
The therapeutic cure is defined by a complete resolution of signs and symptoms
of vaginal candidiasis (clinical cure) along with a negative KOH
examination and negative culture for Candida spp. (microbiologic
eradication) at the long term follow-up. The therapeutic cure rate was 67% in
the butoconazole group and 61% in the clotrimazole group.
|
| Table
1 |
 |
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| WARNINGS |
This cream
contains mineral oil. Mineral oil may weaken latex or rubber products such as
condoms or vaginal contraceptive diaphragms; therefore, use of such products
within 72 hours following treatment with Gynazole·1 is not recommended.
Recurrent vaginal yeast infections, especially those that are difficult to
eradicate, can be an early sign of infection with the human immunodeficiency
virus (HIV) in women who are considered at risk for HIV infection.
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| PRECAUTIONS |
General:
If clinical symptoms persist, tests should be repeated to rule out
other pathogens, to confirm the original diagnosis, and to rule out other
conditions that may predispose a patient to recurrent vaginal fungal
infections.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis: Long term studies in animals have not been performed to
evaluate the carcinogenic potential of this drug.
Mutagenicity: Butoconazole nitrate was not mutagenic when
tested in the Ames bacterial test, yeast, chromosomal aberration assay in CHO
cells, CHO/HGPRT point mutation assay, mouse micronucleus, and rat dominant
lethal assays.
Impairment of Fertility: No impairment of fertility was seen
in rabbits or rats administered butoconazole nitrate in oral doses up to 30
mg/kg/day (5 times the human dose based on mg/M2) or 100 mg/kg/day
(10 times the human dose based on mg/M2), respectively.
Pregnancy:
Pregnancy Category C
In pregnant rats administered 6 mg/kg/day of butoconazole nitrate
intravaginally during the period of organogenesis, there was an increase in
resorption rate and decrease in litter size; however, no teratogenicity was
noted. This dose represents a 130- to 353-fold margin of safety based on serum
levels achieved in rats following intravaginal administration compared to the
serum levels achieved in humans following intravaginal administration of the
recommended therapeutic dose of butoconazole nitrate.
Butoconazole nitrate has no apparent adverse effect when administered orally to
pregnant rats throughout organogenesis at dose levels up to 50 mg/kg/day (5
times the human dose based on mg/M2). Daily oral doses of 100, 300
or 750 mg/kg/day (10, 30 or 75 times the human dose based on mg/M2 respectively)
resulted in fetal malformations (abdominal wall defects, cleft palate), but
maternal stress was also evident at these higher dose levels. There were,
however, no adverse effects on litters of rabbits who received butoconazole
nitrate orally, even at maternally stressful dose levels (e.g., 150 mg/kg, 24
times the human dose based on mg/M2).
Butoconazole nitrate, like other azole anti-fungal agents, causes dystocia in
rats when treatment is extended through parturition. However, this effect was
not apparent in rabbits treated with as much as 100 mg/kg/day orally (16 times
the human dose based on mg/M2).
There are, however, no adequate and well-controlled studies in pregnant women.
Gynazole·1 should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Nursing Mothers: It is not known whether this drug is excreted
in human milk. Because many drugs are excreted in human milk, caution should be
exercised when butoconazole nitrate is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in children have not
been established.
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| ADVERSE
REACTIONS |
| Of the 314
patients treated with Gynazole·1 for 1 day in controlled clinical trials, 18
patients (5.7%) reported complaints such as vulvar/vaginal burning, itching,
soreness and swelling, pelvic or abdominal pain or cramping, or a combination
of two or more of these symptoms. In 3 patients (1%) these complaints were
considered treatment-related. Five of the 18 patients reporting adverse events
discontinued the study because of them. |
| DOSAGE
AND ADMINISTRATION |
| The
recommended dose of Gynazole·1 is one applicatorful of cream (approximately 5
grams of the cream) intravaginally. This amount of cream contains approximately
100 mg of butoconazole nitrate. |
| HOW
SUPPLIED:
Gynazole·1 (butoconazole nitrate) vaginal cream, 2% is available in cartons
containing one single-dose prefilled disposable applicator (NDC 64011- 001-08). |
| |
| Store at
25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). (See USP Controlled
Room Temperature). Avoid heat above 30°C (86°F). U.S. Patent Nos. 4,078,071,
4,551,148, 4,636,202 and 5,266,329
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Manufactured
for Ther-rx Corporation
by KV Pharmaceutical Co.
St. Louis, MO 63044
P4249 08/03 |
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| Important Gynazole•1 Information |
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| Fast Relief |
| FOR LESS |
Give your patients
$15 off their next prescription of
Gynazole•1 |
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