TERAZOL 3 Vaginal Suppositories are white to off-white suppositories for intravaginal administration containing 80 mg of the antifungal agent terconazole, cis  -1-[ p -[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, in triglycerides derived from coconut and/or palm kernel oil (a base of hydrogenated vegetable oils) and butylated hydroxyanisole.

TERCONAZOLE

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Terconazole, a triazole derivative, is a white to almost white powder with a molecular weight of 532.47. It is insoluble in water; sparingly soluble in ethanol; and soluble in butanol.

Microbiology:   Terconazole exhibits fungicidal activity in vitro against Candida albicans. The MIC values for terconazole against most species of lactic acid bacteria typically found in the human vagina were >/=128 mcg/mL, therefore, these beneficial bacteria are not affected by drug treatment. The exact pharmacologic mode of action of terconazole is uncertain; however, it may exert its antifungal activity by the disruption of normal fungal cell membrane permeability. No resistance to terconazole has developed during successive passages of C. albicans.

Human Pharmacology: Following intravaginal administration of terconazole in humans, absorption ranged from 5-8% in three hysterectomized subjects and 12-16% in two non-hysterectomized subjects with tubal ligations. Following oral (30 mg) administration of 14 C-labelled terconazole, the half-life of elimination from the blood for the parent terconazole was 6.9 hours (range 4.0-11.3). Terconazole is extensively metabolized; the plasma AUC for terconazole compared to the AUC for total radioactivity was 0.6%. Total radioactivity was eliminated from the blood with a half-life of 52.2 hours (range 44-60). Excretion of radioactivity was both by renal (32-56%) and fecal (47-52%) routes.

Photosensitivity reactions were observed in some normal volunteers following repeated dermal application of terconazole 2.0% and 0.8% creams under conditions of filtered artificial ultraviolet light.

Photosensitivity reactions have not been observed in U.S. and foreign clinical trials in patients who were treated vaginally with terconazole suppositories or cream.

TERAZOL 3 Vaginal Suppositories are indicated for the local treatment of vulvovaginal candidiasis (moniliasis). As TERAZOL 3 Vaginal Suppositories are effective only for vulvovaginitis caused by the genus Candida, the diagnosis should be confirmed by KOH smears and/or cultures.

CONTRAINDICATIONS

Patients known to be hypersensitive to terconazole or to any components of the suppository.

None.

PRECAUTIONS

General:   Discontinue use and do not retreat with terconazole if sensitization, irritation, fever, chills or flu-like symptoms are reported during use. The base contained in the suppository formulation may interact with certain rubber or latex products, such as those used in vaginal contraceptive diaphragms, therefore concurrent use is not recommended.

If there is lack of response to TERAZOL 3 Vaginal Suppositories, appropriate microbiological studies (standard KOH smear and/or cultures) should be repeated to confirm the diagnosis and rule out other pathogens.

Drug Interactions:   The therapeutic effect of TERAZOL 3 Vaginal Suppositories is not affected by oral contraceptive usage.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis:   Studies to determine the carcinogenic potential of terconazole have not been performed.

Mutagenicity:   Terconazole was not mutagenic when tested in vitro for induction of microbial point mutations (Ames test), or for inducing cellular transformation, or in vivo for chromosome breaks (micronucleus test) or dominant lethal mutations in mouse germ cells.

Impairment of Fertility: No impairment of fertility occurred when female rats were administered terconazole orally up to 40 mg/kg/day.

Pregnancy:   Pregnancy Category C

There was no evidence of teratogenicity when terconazole was administered orally up to 40 mg/kg/day (25 × the recommended intravaginal human dose) in rats, or 20 mg/ kg/day in rabbits, or subcutaneously in rats up to 20 mg/kg/ day. Dosages at or below 10 mg/kg/day produced no embryotoxicity; however, there was a delay in fetal ossification at 10 mg/kg/day in rats. There was some evidence of embryotoxicity in rabbits and rats at 20-40 mg/kg. In rats this was reflected as a decrease in litter size and number of viable young and reduced fetal weight. There was also delay in ossification and an increased incidence of skeletal variants.

The no-effect oral dose of 10 mg/kg/day resulted in a mean peak plasma level of terconazole in pregnant rats of 0.176 mcg/mL which exceeds by 44 times the mean peak plasma level (0.004 mcg/mL) seen in normal subjects after intravaginal administration of terconazole. This assessment does not account for possible exposure of the fetus through direct transfer of terconazole from the irritated vagina to the fetus by diffusion across amniotic membranes.

Since terconazole is absorbed from the human vagina, it should not be used in the first trimester of pregnancy unless the physician considers it essential to the welfare of the patient.

Nursing Mothers:   It is not known whether terconazole is excreted in human milk. Animal studies have shown that rat off-spring exposed via the milk of treated (40 mg/kg/orally) dams showed decreased survival during the first few post-partum days. Because many drugs are excreted in human milk, and because of the potential for adverse reaction in nursing infants from terconazole, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use:   Safety and efficacy in children have not been established.

ADVERSE REACTIONS

During controlled clinical studies conducted in the United States, 284 patients with vulvovaginal candidiasis were treated with terconazole 80 mg vaginal suppositories. Based on comparative analyses with placebo (295 patients) the adverse experiences considered adverse reactions most likely related to terconazole 80 mg vaginal suppositories were headache (30.3% vs 20.7% with placebo) and pain of the female genitalia (4.2% vs 0.7% with placebo). Adverse reactions that were reported but were not statistically significantly different from placebo were burning (15.2% vs 11.2% with placebo) and body pain (3.9% vs 1.7% with placebo). Fever (2.8% vs 1.4% with placebo) and chills (1.8% vs 0.7% with placebo) have also been reported. The therapy-related dropout rate was 3.5% and the placebo therapy-related dropout rate was 2.7%. The adverse drug experience on terconazole most frequently causing discontinuation was burning (2.5% vs 1.4% with placebo) and pruritus (1.8% vs 1.4% with placebo).

DOSAGE AND ADMINISTRATION

One TERAZOL 3 Vaginal Suppository (80 mg terconazole) is administered intravaginally once daily at bedtime for three consecutive days. Before prescribing another course of therapy, the diagnosis should be reconfirmed by smears and/or cultures and other pathogens commonly associated with vulvovaginitis ruled out. The therapeutic effect of TERAZOL 3 Vaginal Suppositories is not affected by menstruation.

HOW SUPPLIED

TERAZOL 3 (terconazole) Vaginal Suppositories 80 mg are available as 2.5 g, elliptically shaped white to off-white suppositories in packages of three (NDC 0062-5351-01) with a vaginal applicator. Store at Controlled Room Temperature 15°-30°C (59°-86°F)

Caution: Federal (USA) law prohibits dispensing without a prescription.

631-11-303-7                             REVISED March 1995

PRODUCT PHOTO(S):

NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.

The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drug' identity should be verified by chemical analysis.

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