TERAZOL 7- terconazole cream TERAZOL 3- terconazole cream TERAZOL 3- terconazole suppository

Terazol 3 by

Drug Labeling and Warnings

Terazol 3 by is a Prescription medication manufactured, distributed, or labeled by Janssen Pharmaceuticals, Inc., Janssen Cilag Manufacturing, LLC, Noramco, Inc., Janssen Ortho LLC, Janssen Pharmaceuticals, Inc, Jubilant HollisterStier General Partnership. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

DESCRIPTION

TERAZOL® 7 (terconazole) Vaginal Cream 0.4% is a white to off-white, water washable cream for intravaginal administration containing 0.4% 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, compounded in a cream base consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl myristate, polysorbate 60, polysorbate 80, propylene glycol, stearyl alcohol, and purified water.

TERAZOL® 3 (terconazole) Vaginal Cream 0.8% is a white to off-white, water washable cream for intravaginal administration containing 0.8% 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, compounded in a cream base consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl myristate, polysorbate 60, polysorbate 80, propylene glycol, stearyl alcohol, and purified water.

TERAZOL® 3 (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-(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.

The structural formula of terconazole is as follows:

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: 64–76%) of terconazole remains in the vaginal area during the suppository retention period (16 hours); approximately 10% (range: 5–16%) 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 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 2.0% 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 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 in vitro

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

TERAZOL® 7 (terconazole) Vaginal Cream 0.4%, TERAZOL® 3 (terconazole) Vaginal Cream 0.8% and TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg are indicated for the local treatment of vulvovaginal candidiasis (moniliasis). As these products 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 of the components of the cream or suppositories.

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

For vulvovaginal use only. TERAZOL® 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 terconazole is not affected by oral contraceptive usage.

The levels of estradiol 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

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 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 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.

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 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.

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.

TERAZOL® 7 (terconazole) Vaginal Cream 0.4%

During controlled clinical studies conducted in the United States, 521 patients with vulvovaginal candidiasis were treated with terconazole 0.4% vaginal cream. Based on comparative analyses with placebo, the adverse experiences considered most likely related to terconazole 0.4% vaginal cream were headache (26% vs. 17% with placebo) and body pain (2.1% vs. 0% with placebo). Fever (1.7% vs. 0.5% with placebo) and chills (0.4% vs. 0.0% with placebo), vulvovaginal burning, itching and irritation have also been reported. The adverse drug experience on terconazole most frequently causing discontinuation was vulvovaginal itching.

TERAZOL® 3 (terconazole) Vaginal Cream 0.8%

During controlled clinical studies conducted in the United States, patients with vulvovaginal candidiasis were treated with terconazole 0.8% vaginal cream for three days. Based on comparative analyses with placebo and a standard agent, the adverse experiences considered most likely related to terconazole 0.8% vaginal cream were headache (21% vs. 16% with placebo) and dysmenorrhea (6% vs. 2% with placebo). Other adverse experiences reported with terconazole 0.8% vaginal cream were abdominal pain (3.4% vs. 1% with placebo) and fever (1% vs. 0.3% with placebo). The adverse drug experience most frequently causing discontinuation of therapy was vulvovaginal itching, 0.7% with the terconazole 0.8% vaginal cream group and 0.3% with the placebo group.

TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg

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 TERAZOL®. 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 listed 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

OVERDOSAGE

In the rat, the oral LD 50 values were found to be 1741 and 849 mg/kg for the male and female, respectively. The oral LD 50 values for the male and female dog were ≅1280 and ≥640 mg/kg, respectively.

In the event of oral ingestion of suppository or cream, supportive and symptomatic measures should be carried out. If the cream is accidentally applied to the eyes, wash with clean water or saline and seek medical attention if symptoms persist.

DOSAGE AND ADMINISTRATION

TERAZOL® 7 (terconazole) Vaginal Cream 0.4%

One full applicator (5 g) of TERAZOL® 7 Vaginal Cream (20 mg terconazole) should be administered intravaginally once daily at bedtime for seven consecutive days.

TERAZOL® 3 (terconazole) Vaginal Cream 0.8%

One full applicator (5 g) of TERAZOL® 3 Vaginal Cream (40 mg terconazole) should be administered intravaginally once daily at bedtime for three consecutive days.

TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg

One TERAZOL® 3 Vaginal Suppository (80 mg terconazole) should be 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 these products is not affected by menstruation.

HOW SUPPLIED

TERAZOL® 7 (terconazole) Vaginal Cream 0.4% is available in 45 g (NDC: 50458-535-01) tubes with an ORTHO1 Measured-Dose Applicator. Store at Controlled Room Temperature 15–30°C (59–86°F).

TERAZOL® 3 (terconazole) Vaginal Cream 0.8% is available in 20 g (NDC: 50458-536-01) tubes with an ORTHO1 Measured-Dose Applicator. Store at Controlled Room Temperature 15–30°C (59–86°F).

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: 50458-531-01) with a vaginal applicator. Store at Controlled Room Temperature 15–30°C (59–86°F).

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