Terconazole warnings and precautions

# Warnings
Anaphylaxis and toxic epidermal necrolysis have been reported during terconazole therapy. TERAZOL therapy should be discontinued if anaphylaxis or toxic epidermal necrolysis develops.

# 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.

## Laboratory Tests
If there is lack of response to terconazole, appropriate microbiologic studies (standard KOH smear and/or cultures) should be repeated to confirm the diagnosis and rule out other pathogens.

## Drug Interactions
TERAZOL 7 (terconazole) Vaginal Cream 0.4% and TERAZOL 3 (terconazole) Vaginal Suppositories 80 mg
The therapeutic effect of these products is not affected by oral contraceptive usage.
TERAZOL 3 (terconazole) Vaginal Cream 0.8%
The levels of estradiol (E2) and progesterone did not differ significantly when 0.8% terconazole vaginal cream was administered to healthy female volunteers established on a low dose oral contraceptive.

## 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 for a three month period.

## Pregnancy
Teratogenic Effects: 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 of the suppository formulation, 50 the recommended intravaginal human dose of the 0.8% vaginal cream formulation, and 100 the intravaginal human dose of the 0.4% vaginal cream formulation) in rats, or 20 mg/kg/day in rabbits, or subcutaneously up to 20 mg/kg/day in rats.
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 2040 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 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 0.4% vaginal cream, by 30 times the mean peak plasma level (0.006 mcg/mL) seen in normal subjects after intravaginal administration of terconazole 0.8% vaginal cream, and by 17 times the mean peak plasma level (0.010 mcg/mL) seen in normal subjects after intravaginal administration of terconazole 80 mg vaginal suppository. This safety assessment does not account for possible exposure of the fetus through direct transfer to terconazole from the irritated vagina 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 this drug is excreted in human milk. Animal studies have shown that rat offspring exposed via the milk of treated (40 mg/kg/orally) dams showed decreased survival during the first few post-partum days, but overall pup weight and weight gain were comparable to or greater than controls throughout lactation. 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.

## Geriatric Use
Clinical studies of TERAZOL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.