Description: Terconazole is a triazole antifungal agent available for intravaginal use. It is structurally related to imidazole-derivative antifungal agents, although imidazoles have 2 nitrogens in the azole ring while terconazole and other triazoles have 3 nitrogens in the azole ring. Terconazole is usually fungicidal against Candida albicans. Although antifungal activity has been demonstrated against other fungi, it is indicated only for the treatment of vulvovaginal candidiasis. Treatment of vulvovaginal candidiasis with terconazole produces clinical cures in about 84�96% of patients; the relapse rate three to four weeks after therapy is 3�15%. Intravaginal terconazole appears to be at least as effective as intravaginal clotrimazole or miconazole for this indication. Terconazole was approved by the FDA in 1987. Mechanism of Action: The exact mechanism of action is unknown; however, terconazole may exert its antifungal activity by disrupting normal fungal cell membrane permeability. Terconazole and other triazole antifungal agents (e.g., itraconazole, fluconazole) inhibit cytochrome P450 14-alpha-desmethylase in susceptible fungi, which leads to the accumulation of lanosterol and other methylated sterols and a decrease in ergosterol concentration. This mechanism of action is similar to that of the imidazole-derivative antifungal agents (e.g., butoconazole, clotrimazole, miconazole). Terconazole is usually fungicidal against Candida albicans. Antifungal activity has also been demonstrated against other fungi. Results of in vitro susceptibility tests are method dependent; however, terconazole is generally active in vitro against Trichophyton mentagrophytes, T. rubrum, T. tonsurans, T. verrucosum, and Epidermophyton floccosum. Most susceptible strains of these dermatophytes are inhibited in vitro by terconazole concentrations of 10 �g/ml or less. Higher concentrations of 100 �g/ml are usually required for in vitro inhibition of Microsporum audouinii and M. canis. In vitro, concentrations of 10�100 �g/ml inhibit C. albicans, C. glabrata, C. krusei, C. parapsilosis, C. pseudotropicalis, C. stellatoidea, and C. tropicalis. The MIC values for terconazole against most species of lactic acid bacteria typically found in the human vagina are >= 128 �g/ml; therefore, these beneficial bacteria are not affected by drug treatment. Pharmacokinetics: Terconazole is administered intravaginally. Following intravaginal administration, absorption ranges 5�16%, with absorption appearing to be greater in nonhysterectomized women than in hysterectomized women. The amount absorbed is proportional to the dose, and absorption is similar in women with or without vulvovaginal candidiasis. Mean peak plasma terconazole concentrations are 4 ng/ml following administration of single or multiple doses of the 0.4% vaginal cream and 10.4 ng/ml following a single 80 mg vaginal suppository. Peak plasma concentrations averaged 6 ng/ml following daily intravaginal administration of 5 g of terconazole 0.8% cream (40 mg of terconazole) for 7 days. Distribution of terconazole into body tissues and fluids following intravaginal administration has not been determined. Systemically absorbed terconazole appears to be extensively metabolized, primarily by oxidative N- and O-dealkylation, dioxolane ring cleavage, and conjugation pathways. Following oral administration of a single 30 mg dose of radiolabelled terconazole, the elimination half-life of the parent drug was 6.9 hours (range: 4�11.3 hours); the half-life of total radioactivity was roughly 52 hours. Excretion of radioactivity following a single 30 mg radiolabelled dose was by both renal (32�56%) and fecal (47�52%) routes.

Indications...Dosage The following organisms are generally considered susceptible to terconazole in vitro: Candida albicans; Trichophyton mentagrophytes�; Trichophyton rubrum�; Trichophyton tonsurans�; Trichophyton verrucosum�; and Epidermophyton floccosum�. Most susceptible strains of these dermatophytes are inhibited in vitro by terconazole concentrations of 10 �g/ml or less. Higher concentrations of 100 �g/ml are usually required for in vitro inhibition of Microsporum audouinii and M. canis. In vitro, concentrations of 10�100 �g/ml inhibit Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida pseudotropicalis, Candida stellatoidea, and Candida tropicalis. For the treatment of vulvovaginal candidiasis due to Candida sp.: Intravaginal dosage (Terazol� 7 -- 0.4% vaginal cream): Adults and adolescents: Insert 1 applicatorful (5 g) intravaginally once daily at bedtime for 7 consecutive days. Intravaginal dosage (Terazol� 3 -- 0.8% vaginal cream): Adults and adolescents: Insert 1 applicatorful (5 g) intravaginally once daily at bedtime for 3 consecutive days. Intravaginal dosage (Terazol� 3 vaginal suppositories): Adults and adolescents: Insert one 80 mg suppository intravaginally once daily at bedtime for 3 consecutive days. Patients with renal impairment: No dosage adjustment needed.

Administration �Terconazole is administered intravaginally as a cream or suppository. �Therapy with terconazole should be continued during menstruation. �If an adequate response is not achieved, the diagnosis should be reconfirmed by smears and/or cultures and other pathogens commonly associated with vulvovaginitis ruled out.

Contraindications The hydrogenated vegetable oil base contained in the suppository formulation of terconazole may interact with certain rubber or latex products, such as latex condoms, vaginal contraceptive diaphragms, or cervical caps. Therefore, concurrent use of these contraceptive devices with the suppository formulation is not recommended. Use of terconazole vaginal cream should be considered as an alternative to the suppositories in patients planning on using latex condoms, contraceptive diaphragms, or cervical caps. Terconazole is classified as pregnancy category C. There are no adequate and controlled studies using intravaginal terconazole in women during the first trimester of pregnancy. The drug has been used intravaginally during the second and third trimesters in at least 100 women without adverse effects. There was no evidence of teratogenicity when terconazole was administered to pregnant rats or rabbits at dosages of up to 100 times the recommended intravaginal human dose; however, there was some evidence of embryotoxicity in rats and rabbits that received the drug prior to mating and throughout gestation (see Adverse Reactions). The doses used in these studies produced plasma concentrations which exceeded by 30�44 times the levels seen in healthy adults after intravaginal administration of terconazole. However, because terconazole is absorbed from the human vagina and exposure to the fetus could occur through direct transfer of terconazole from the irritated vagina to the fetus by diffusion across amniotic membranes, it is recommended that terconazole not be used during the first trimester of pregnancy unless the potential benefits justify the possible risks to the fetus. It is not known if terconazole is excreted in human milk; however, the drug is distributed into milk in rats. In a study in lactating rats receiving oral terconazole, there was a decrease in offspring survival during the first few post-partum days. Because of the potential for adverse effects of terconazole in nursing infants, a decision should be made whether to discontinue breast-feeding or discontinue the drug, taking into account the importance of the drug to the mother. Safety and efficacy of terconazole have not been established in children younger than 18 years of age.

Interactions The efficacy of terconazole is not affected by oral contraceptive use. The spermicides nonoxynol-9 and octoxynol should not be administered concurrently with butoconazole, clotrimazole, econazole, miconazole, terconazole, or tioconazole intravaginal preparations. These intravaginal azole antifungals may inactivate the spermicides, leading to contraceptive failure. Also, the base ingredients of some of these azole intravaginal creams and suppositories may interact with the latex of contraceptive devices used concurrently with the spermicides, leading to breakdown of the physical barrier. Conversely, it is possible that spermicides may cause decreased effectiveness of these azole antifungals.

Adverse Reactions During controlled clinical trials, headache was the most common adverse reaction reported in patients treated with terconazole vaginal cream or suppositories. Headache occurred in 21�30% of patients treated with intravaginal terconazole and in 17�20% of patients treated with placebo vehicle. Dysmenorrhea was reported in 6% of patients treated with terconazole 0.8% vaginal cream and in 2% of placebo-treated patients. Other adverse events reported more often in patients treated with intravaginal terconazole than in those treated with placebo include vaginal pain (4.2% vs. 0.7%), abdominal pain (3.4% vs. 1%), body pain (2.1�3.9% vs 0�1.7%), fever (1�2.8% vs. 0.3�1.4%), and chills (0.4�1.8% vs. 0�0.7%). Vulvovaginal burning (5.2%), pruritus (2.3%) or irritation (3.1%) occurred less frequently with terconazole 0.4% vaginal cream than with placebo vehicle. Genital complaints, especially burning and itching, also occurred less frequently with terconazole 0.8% vaginal cream than with placebo vehicle (5% vs. 6�9%). Although vulvovaginal burning occurred more often in patients treated with terconazole vaginal suppositories than in patients given placebo (15.2% vs. 11.2%), the difference was not statistically significant. The therapy-related dropout rate was 1.9% for the 0.4% vaginal cream, 2% for the 0.8% vaginal cream, and 3.5% for the vaginal suppositories. The adverse reaction most frequently causing discontinuation of therapy was vulvovaginal burning or pruritus. Photosensitivity reactions have been observed in volunteers following repeated application of terconazole 2% and 0.8% topical creams under conditions of filtered UV light. However, photosensitivity reactions have not been observed in patients who were treated with terconazole suppositories or intravaginal cream. Terconazole has been used intravaginally during the second and third trimesters of pregnancy in at least 100 women without adverse effects. There was no evidence of teratogenicity when terconazole was administered to pregnant rats or rabbits at dosages of up to 100 times the recommended intravaginal human dose; however, there was some evidence of embryotoxicity in rats and rabbits that received the drug prior to mating and throughout gestation. Embryotoxicity was manifested as a decrease in litter size, reduced fetal weight, delayed ossification, and an increased incidence of skeletal variants. Although the doses used in these studies produced plasma concentrations which exceeded by 30�44 times the levels seen in healthy adults after intravaginal administration of terconazole, it is recommended that terconazole not be used during the first trimester of pregnancy (pregnancy category C). Studies to determine the carcinogenic potential of terconazole have not been performed. 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 or dominant lethal mutations in mouse germ cells. No impairment of fertility occurred when female rats were administered terconazole orally up to 40 mg/kg/day.

Terconazole Terazol�