TERAZOL® 7 VAGINAL CREAM 0.4%

NDA 019579/S-035 NDA 019641/S-028 NDA 019964/S-030 Page 4 TERAZOL ® 7 VAGINAL CREAM 0.4% (terconazole) TERAZOL ® 3 VAGINAL CREAM 0.8% (terconazole) TERAZOL ® 3 VAGINAL SUPPOSITORIES 80mg (terconazole) 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. Reference ID: 3379688 NDA 019579/S-035 NDA 019641/S-028 NDA 019964/S-030 Page 5 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 Following intravaginal administration of terconazole in humans, 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 normal humans, 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 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 women. The absorption characteristics of terconazole 0.8% in pregnant or non-pregnant patients with vulvovaginal candidiasis were also similar to those found in normal volunteers. Following oral (30 mg) administration of 14 C-labelled terconazole, the harmonic 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 harmonic 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. Reference ID: 3379688 NDA 019579/S-035 NDA 019641/S-028 NDA 019964/S-030 Page 6 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: Terconazole exhibits fungicidal activity in vitro against Candida albicans. Antifungal activity has also been demonstrated against other fungi. 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. The exact pharmacologic mode of action of terconazole is uncertain; however, it may exert its antifungal activity by the disruption of normal fungal cell membrane permeability. No resistance to terconazole has developed during successive passages of C. albicans. 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: Discontinue use and do not retreat with terconazole if sensitization, irritation, fever, chills or flu-like symptoms are reported during use. Reference ID: 3379688 NDA 019579/S-035 NDA 019641/S-028 NDA 019964/S-030 Page 7 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 (25x the recommended intravaginal human dose of the suppository formulation, 50x the recommended intravaginal human dose of the 0.8% vaginal cream formulation, and 100x 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. Reference ID: 3379688 NDA 019579/S-035 NDA 019641/S-028 NDA 019964/S-030 Page 8 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. 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. Reference ID: 3379688 NDA 019579/S-035 NDA 019641/S-028 NDA 019964/S-030 Page 9 ADVERSE REACTIONS Clinical Trials 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). Vulvovaginal burning (5.2%), itching (2.3%) or irritation (3.1%) occurred less frequently with terconazole 0.4% vaginal cream than with the vehicle placebo. Fever (1.7% vs. 0.5% with placebo) and chills (0.4% vs. 0.0% with placebo) have also been reported. The therapy-related dropout rate was 1.9%. The adverse drug experience on terconazole most frequently causing discontinuation was vulvovaginal itching (0.6%), which was lower than the incidence for placebo (0.9%). 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). Genital complaints in general, and burning and itching in particular, occurred less frequently in the terconazole 0.8% vaginal cream 3 day regimen (5% vs. 6%-9% 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 therapy-related dropout rate was 2.0% for the terconazole 0.8% vaginal cream. 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 were 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 Reference ID: 3379688 NDA 019579/S-035 NDA 019641/S-028 NDA 019964/S-030 Page 10 placebo) and chills (1.8% vs. 0.7% with placebo) have also been reported. The therapy-related dropout rate was 3.5% and the placebo therapy-related dropout rate was 2.7%. 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 Overdose of terconazole in humans has not been reported to date. 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. 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. Reference ID: 3379688 NDA 019579/S-035 NDA 019641/S-028 NDA 019964/S-030 Page 11 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 45g (NDC 50458-535-01) tubes with an ORTHO* Measured-Dose Applicator. Store at Controlled Room Temperature 15–30°C (59–86°F). TERAZOL ® 3 (terconazole) Vaginal Cream 0.8% is available in 20g (NDC 50458-536-01) tubes with an ORTHO* Measured-Dose Applicator. Store at Controlled Room Temperature 15–30°C (59–86°F). TERAZOL ® 3 (terconazole) Vaginal Suppositories 80 mg are available as 2.5g, 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). *Trademark Manufactured by: Janssen Ortho, LLC, Manati, Puerto Rico 00674 (for the Vaginal Cream) Jubilant HollisterStier General Partnership, Kirkland, Quebec, Canada H9H 4J4 (for the Vaginal Cream and Vaginal Suppositories) Manufactured for: (logo) Janssen Pharmaceuticals, Inc. Titusville, New Jersey 08560 © Janssen Pharmaceuticals, Inc. 1998 Revised MONTH YEAR TERAZOL ® 7 VAGINAL CREAM 0.4% (terconazole) TERAZOL ® 3 VAGINAL CREAM 0.8% (terconazole) PATIENT INSTRUCTIONS Reference ID: 3379688 NDA 019579/S-035 NDA 019641/S-028 NDA 019964/S-030 Page 12 Filling the applicator: Remove the cap from the tube. Use the pointed tip on the top of the cap to puncture the seal on the tube. Screw the applicator onto the tube. Squeeze the tube from the bottom and fill the applicator until the plunger stops. Unscrew the applicator from the tube. Using the applicator: 1. Lie on your back with your knees drawn up toward your chest. Holding the applicator by the ribbed end of the barrel, insert the filled applicator into the vagina as far as it will comfortably go. Slowly press the plunger of the applicator to release the cream into the vagina. Reference ID: 3379688 NDA 019579/S-035 NDA 019641/S-028 NDA 019964/S-030 Page 13 Remove the applicator from the vagina. Apply one applicatorful each night for as many days at bedtime, as directed by your doctor. Cleaning the applicator: (Does not apply to sample applicators, which are for one time use only) After each use, you should thoroughly clean the applicator by following the procedure below: 1. Pull the plunger out of the barrel. Wash the pieces with lukewarm, soapy water, and dry them thoroughly. Put the applicator back together by gently pushing the plunger into the barrel as far as it will go. NOTE: Store the cream at Controlled Room Temperature 15–30°C (59–86°F). See end flap for lot number and expiration date. TERAZOL ® 3 VAGINAL SUPPOSITORIES 80mg (terconazole) Three oval suppositories, for use inside the vagina only. Designed to be inserted into the vagina. Reference ID: 3379688 NDA 019579/S-035 NDA 019641/S-028 NDA 019964/S-030 Page 14 HOW TO USE: Place one suppository into the vagina each night at bedtime, for 3 nights, as directed by your doctor. The TERAZOL Suppository is self-lubricating and may be inserted with or without the applicator. A. Insertion with the applicator 1. Filling the applicator Break off suppository from the plastic strip. Pull the plastic completely apart at the notched end. Place the flat end of the suppository into the open end of the applicator as shown. You are now ready to insert the suppository into the vagina. 2. Using the applicator Lie on your back with your knees drawn up toward your chest. Holding the applicator by the ribbed end of the barrel, gently insert it into the vagina as far as it will comfortably go. Press the plunger to release the suppository into the vagina. Reference ID: 3379688 NDA 019579/S-035 NDA 019641/S-028 NDA 019964/S-030 Page 15 Remove the applicator from the vagina. 3. Cleaning the applicator (Does not apply to sample applicators, which are for one time use only) After each use, you should thoroughly clean the applicator by following the procedure below: Pull the plunger out of the barrel. Wash both pieces with lukewarm, soapy water, and dry them thoroughly. Put the applicator back together by gently pushing the plunger into the barrel as far as it will go. B. Insertion without the applicator Lie on your back with your knees drawn up toward your chest. Place the suppository on the tip of your finger as shown. Insert the suppository gently into the vagina as far as it will