Terconazole Dailymed

Rx Only

Description

Terconazole 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-(1 H-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.

The structural formula of terconazole is as follows:

TERCONAZOLE C 26H 31Cl 2N 5O 3

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.

Clinical Pharmacology

Absorption

Following a single intravaginal application of a suppository containing 240 mg ¹⁴C-terconazole to healthy women, approximately 70% (range: 64 to 76%) of terconazole remains in the vaginal area during the suppository retention period (16 hours); approximately 10% (range: 5 to 16%) of the administered radioactivity was absorbed systemically over 7 days. Maximum plasma concentrations of terconazole occur 5 to 10 hours after intravaginal application of the cream or suppository. Systemic exposure to terconazole is approximately proportional to the applied dose, whether as the cream or suppository. The rate and extent of absorption of terconazole are similar in patients with vulvovaginal candidiasis (pregnant or non-pregnant) and healthy subjects.

Distribution

Terconazole is highly protein bound (94.9%) in human plasma and the degree of binding is independent of drug concentration over the range of 0.01 to 5.0 mcg/mL.

Metabolism

Systemically absorbed terconazole is extensively metabolized (>95%).

Elimination

Across various studies in healthy women, after single or multiple intravaginal administration of terconazole as the cream or suppository/ovule, the mean elimination half-life of unchanged terconazole ranged from 6.4 to 8.5 hours. Following a single intravaginal administration of a suppository containing 240 mg ¹⁴C-terconazole to hysterectomized or tubal ligated women, approximately 3 to 10% (mean ± SD: 5.7 ± 3.0%) of the administered radioactivity was eliminated in the urine and 2.0 to 6% (mean ± SD: 4.2 ± 1.6%) was eliminated in the feces during the 7-day collection period.

Multiple Dosing

There is no significant increase in maximum plasma concentration or overall exposure (AUC) after multiple daily applications of the cream for 7 days or suppositories for 3 days.

Photosensitivity reactions were observed in some normal volunteers following repeated dermal application of terconazole 2% 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 with terconazole suppositories or vaginal cream (0.4% and 0.8%).

Microbiology

Mechanism of action

Terconazole, an azole antifungal agent, inhibits fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylase enzyme. This enzyme functions to convert lanosterol to ergosterol. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell wall and may be responsible for the antifungal activity of terconazole. Mammalian cell demethylation is less sensitive to terconazole inhibition.

Activity

Terconazole exhibits antifungal activity in vitro against Candida albicans and other Candida species. The MIC values of terconazole against most Lactobacillus spp. typically found in the human vagina were ≥128 mcg/mL; therefore these beneficial bacteria are not affected by drug treatment.

Indications And Usage

Terconazole Vaginal Suppositories, 80 mg is indicated for the local treatment of vulvovaginal candidiasis (moniliasis). As this product is 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 of the components of the suppositories.

Warnings

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

Precautions

General

For vulvovaginal use only. Terconazole is not for ophthalmic or oral use. 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 or latex condoms; 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

The therapeutic effect of this product 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 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) 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 20 to 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 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 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.

Terconazole may be used during the second and third trimester if the potential benefit outweighs the possible risks to the fetus.

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 terconazole vaginal suppositories 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.

Adverse Reactions

Adverse Reactions from Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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 clinical practice.

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 have also been 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 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).

Post-marketing Experience

The following adverse drug reactions have been first identified during post-marketing experience with terconazole:. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General: Asthenia, Influenza-Like Illness consisting of multiple uled reactions including fever and chills, nausea, vomiting, myalgia, arthralgia, malaise

Immune: Hypersensitivity, Anaphylaxis, Face Edema

Nervous: Dizziness

Respiratory: Bronchospasm

Skin: Rash, Toxic Epidermal Necrolysis, Urticaria

To report SUSPECTED ADVERSE REACTIONS, contact Cosette Pharmaceuticals, Inc. at 1-800-922-1038 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.