5.1 Risk of Skin Irritation and Flu-Like Symptoms

Discontinue Terconazole Vaginal Cream and do not retreat, if skin irritation, fever, chills or flu-like symptoms are reported during use.

5.2 Hypersensitivity

There is no information regarding cross-hypersensitivity between terconazole and other azole antifungal agents. Monitor patients with a history of hypersensitivity to azoles.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse reactions that appear to be related to drug use and estimating their relative rates.

During a controlled clinical trial conducted in the United States, patients with vulvovaginal candidiasis were treated with Terconazole Vaginal Cream, 0.8% for 3 days (n=231) or Terazol®3 for 3 days (n=229) [see Clinical Studies (14)]. Table 1 lists the adverse reactions occurring in ≥2% of patients receiving Terconazole Vaginal Cream in the trial. The therapy-related discontinuation rate was 2.0% for Terconazole Vaginal Cream. The adverse reaction most frequently causing discontinuation of Terconazole Vaginal Cream therapy was vulvovaginal itching (0.7%).

Table 1: Adverse Reactions Occurring in ≥2% of Patients Receiving Terconazole Vaginal Cream in a Randomized, Double-Blind Active Controlled Trial

Other adverse reactions reported in less than 2% of patients receiving Terconazole Vaginal Cream was fever (1%).

Photosensitivity reactions were observed in some normal volunteers following repeated dermal application of terconazole 2.0% (not an approved strength) and 0.8% creams under conditions of filtered artificial ultraviolet light. Photosensitivity reactions were not observed in U.S. and foreign clinical trials in patients who were treated with other terconazole formulations (i.e., terconazole suppositories or vaginal cream, 0.8%).

8.1 Pregnancy

Risk Summary

There are no available data on Terconazole Vaginal Cream use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Available data from observational studies with terconazole use in pregnancy are insufficient to identify a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

In animal reproduction studies with oral terconazole, no adverse development effects were observed at clinically relevant systemic exposures (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

There was no evidence of malformations when terconazole was administered orally in rats, or rabbits.

There was a delay in fetal ossification at an oral dose of 10 mg/kg/day in rats. Higher doses resulted in decreased litter size, decreased number of viable young and reduced fetal weight in rats. There was also a delay in ossification and an increase incidence of skeletal variants.

The 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 30 times the mean peak plasma level (0.006 mcg/mL) seen in normal subjects after intravaginal administration of terconazole vaginal cream 0.8%. 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.

8.2 Lactation

Risk Summary

There are no data on the presence of terconazole in human milk, the effect on the breast-fed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Terconazole Vaginal Cream and any potential adverse effects on the breast-fed infant from Terconazole Vaginal Cream or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of Terconazole Vaginal Cream have not been established in female pediatric patients for the treatment of vulvovaginal candidiasis.

8.5 Geriatric Use

Clinical studies of Terconazole Vaginal Cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

12.1 Mechanism of Action

Terconazole is an antifungal agent [see Microbiology (12.4)].

12.3 Pharmacokinetics

Following intravaginal administration of Terconazole Vaginal Cream, 0.8% in adult females, absorption ranged from 5-8% in three hysterectomized subjects and 12-16% in two non-hysterectomized subjects with tubal ligations.

Following daily intravaginal administration of 0.8% terconazole 40 mg (0.8% cream x 5 g) for seven days to healthy female subjects, plasma concentrations were low and gradually rose to a daily peak (mean of 5.9 ng/mL or 0.006 mcg/mL) at 6.6 hours. Results from similar studies in female patients with vulvovaginal candidiasis indicate that the slow rate of absorption, the lack of accumulation, and the mean peak plasma concentration of terconazole was not different from that observed in healthy females. The absorption characteristics of terconazole vaginal cream, 0.8% in pregnant or non-pregnant patients with vulvovaginal candidiasis were also similar to those found in healthy subjects.

Following oral (30 mg) administration of 14C-labelled terconazole, the mean 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 mean elimination half-life of 52.2 hours (range 44-60). Excretion of radioactivity was both by renal (32-56%) and fecal (47- 52%) routes.

In vitro, terconazole is highly protein bound (94.9%) and the degree of binding is independent of drug concentration.

12.4 Microbiology

Mechanism of Action

Terconazole inhibits the enzyme cytochrome P450 14α-demethylase which leads to inhibition of ergosterol synthesis, an essential component of the fungal cell membrane

Activity in vitro

Terconazole exhibits fungicidal activity in vitro against Candida albicans.

Drug Resistance

Studies showed no development of resistance to terconazole during successive passages of C. albicans. However, the clinical significance of such an effect is not known.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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

Mutagenesis

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 (about 10 times the recommended intravaginal human dose based on body surface area comparisons) for a three-month period.