VUSION

6 ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rate 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. A total of 835 infants and young children were evaluated in the clinical development program. Of 418 subjects in the VUSION group, 58 (14%) reported one or more adverse events. Of 417 subjects in the zinc oxide/white petrolatum control group, 85 (20%) reported one or more adverse events. Adverse events that occurred at a rate of ≥ 1% for subjects who were treated with VUSION were approximately the same in type and frequency as for subjects who were treated with zinc oxide/white petrolatum ointment. 6.2 Post-marketing Experience The following adverse reactions have been identified during post approval use of VUSION. 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. Gastrointestinal Disorders: vomiting General Disorders and Administration Site Conditions: burning sensation, condition aggravated, inflammation, pain Injury, Poisoning and Procedural Complications: accidental exposure Skin and Subcutaneous Tissue Disorders: blister, dermatitis contact, diaper dermatitis, dry skin, erythema, pruritus, rash, skin exfoliation

4 CONTRAINDICATIONS None • None

11 DESCRIPTION VUSION contains the synthetic antifungal agent, miconazole nitrate (0.25%) USP, zinc oxide (15%) USP, and white petrolatum (81.35%) USP. The chemical name of miconazole nitrate is 1-[2, 4-dichloro-ß-{(2,4-dichlorobenzyl)oxy} phenethyl] imidazole mononitrate with empirical formula C 18 H 14 Cl 4 N 2 O•HNO 3 and molecular weight of 479.15. The structural formula of miconazole nitrate is as follows: The zinc oxide has an empirical formula of ZnO and a molecular weight of 81.39. The white petrolatum, which is obtained from petroleum and is wholly or nearly decolorized, is a purified mixture of semisolid saturated hydrocarbons having the general chemical formula C n H 2n+2 . The hydrocarbons consist mainly of branched and unbranched chains. White petrolatum contains butylated hydroxytoluene (BHT) as stabilizer. Each gram of VUSION contains 2.5 mg of miconazole nitrate USP, 150 mg of zinc oxide USP, and 813.5 mg of white petrolatum USP containing butylated hydroxytoluene, trihydroxystearin, and Chemoderm 1001/B fragrance. VUSION is a smooth, uniform, white ointment. Miconazole Nitrate Structural Formula

2 DOSAGE AND ADMINISTRATION VUSION is not for oral, ophthalmic, or intravaginal use. Before applying VUSION, gently cleanse the skin with lukewarm water and pat dry with a soft towel. Avoid using any scented soaps, shampoos, or lotions on the diaper area. Gently apply a thin layer of VUSION to the diaper area with each diaper change for 7 days. Do not rub VUSION into the skin as this may cause additional irritation. Thoroughly wash hands after applying VUSION. Continue treatment for the full 7 days, even if there is improvement. Do not use VUSION for longer than 7 days. The safety of VUSION when used for longer than 7 days is not known. If symptoms have not improved by day 7, see your health care provider. • VUSION Ointment is for topical use only. VUSION Ointment is not for oral, ophthalmic, or intravaginal use. ( 2 ) • VUSION Ointment should be applied as a thin layer to the affected area at each diaper change for 7 days. ( 2 ) • VUSION Ointment should be used as part of a treatment regimen that includes gentle cleansing of the diaper area and frequent diaper changes. ( 2 )

1 INDICATIONS AND USAGE • VUSION Ointment is indicated for adjunctive treatment of diaper dermatitis when complicated by documented candidiasis (microscopic evidence of pseudohyphae and /or budding yeast) in immunocompetent pediatric patients 4 weeks and older. ( 1.1 ) • VUSION Ointment should not be used as a substitute for frequent diaper changes. ( 1.1 ) • VUSION Ointment should not be used to prevent the occurrence of diaper dermatitis, since preventative use may result in the development of drug resistance. ( 1.2 ) 1.1 Indication VUSION Ointment is indicated for the adjunctive treatment of diaper dermatitis only when complicated by documented candidiasis (microscopic evidence of pseudohyphae and/or budding yeast), in immunocompetent pediatric patients 4 weeks and older. A positive fungal culture for Candida albicans is not adequate evidence of candidal infection since colonization with C. albicans can result in a positive culture. The presence of candidal infection should be established by microscopic evaluation prior to initiating treatment. VUSION should be used as part of a treatment regimen that includes measures directed at the underlying diaper dermatitis, including gentle cleansing of the diaper area and frequent diaper changes. VUSION should not be used as a substitute for frequent diaper changes. 1.2 Limitations of Use The safety and efficacy of VUSION have not been demonstrated in immunocompromised patients, or in infants less than 4 weeks of age (premature or term). The safety and efficacy of VUSION have not been evaluated in incontinent adult patients. VUSION should not be used to prevent the occurrence of diaper dermatitis, such as in an adult institutional setting, since preventative use may result in the development of drug resistance.

7 DRUG INTERACTIONS Drug-drug interaction studies were not conducted. Women who take a warfarin anticoagulant and use a miconazole intravaginal cream or suppository may be at risk for developing an increased prothrombin time, international normalized ratio (INR), and bleeding. The potential for this interaction between warfarin and VUSION is unknown.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The miconazole component of VUSION is an antifungal agent [see Clinical Pharmacology (12.4) ]. The mechanism of action of white petrolatum and zinc oxide for the adjunctive treatment of diaper dermatitis is unknown. 12.2 Pharmacodynamics The human pharmacodynamics of Vusion is unknown [see Clinical Pharmacology (12.4) for fungal pharmacodynamics]. 12.3 Pharmacokinetics The topical absorption of miconazole from VUSION was studied in immunocompetent male and female infants and children (n=17) with diaper dermatitis complicated by documented candidiasis (microscopic evidence of pseudohyphae and/or budding yeast) ranging in age from 1 month to 21 months. After multiple daily applications to the affected area at every diaper change (approximately 5-12 times per day) for 7 days, the plasma concentrations of miconazole were below the lower limit of quantitation (LOQ) of 0.5 ng/mL in 15 out of 17 (88%) subjects. In the other 2 remaining subjects, the plasma concentrations of miconazole were 0.57 and 0.58 ng/mL, respectively at a single timepoint (4 hours after the last application) on Day 7. 12.4 Microbiology The miconazole nitrate component in this product has been shown to have in vitro activity against Candida albicans , an organism that is associated with diaper dermatitis. The activity of miconazole nitrate against C. albicans is based on the inhibition of the ergosterol biosynthesis in the cell membrane. The accumulation of ergosterol precursors and toxic peroxides results in cytolysis of the cell. In vitro minimal inhibitory concentration (MIC) test results for C. albicans isolates obtained from treatment failures in Clinical Study 1 [ see Clinical Studies (14) ] does not appear to indicate that resistance to miconazole nitrate was the reason for treatment failure. The clinical significance of the in vitro activity of miconazole nitrate against C. albicans in the setting of diaper dermatitis is unclear.

12.1 Mechanism of Action The miconazole component of VUSION is an antifungal agent [see Clinical Pharmacology (12.4) ]. The mechanism of action of white petrolatum and zinc oxide for the adjunctive treatment of diaper dermatitis is unknown.

12.2 Pharmacodynamics The human pharmacodynamics of Vusion is unknown [see Clinical Pharmacology (12.4) for fungal pharmacodynamics].

12.3 Pharmacokinetics The topical absorption of miconazole from VUSION was studied in immunocompetent male and female infants and children (n=17) with diaper dermatitis complicated by documented candidiasis (microscopic evidence of pseudohyphae and/or budding yeast) ranging in age from 1 month to 21 months. After multiple daily applications to the affected area at every diaper change (approximately 5-12 times per day) for 7 days, the plasma concentrations of miconazole were below the lower limit of quantitation (LOQ) of 0.5 ng/mL in 15 out of 17 (88%) subjects. In the other 2 remaining subjects, the plasma concentrations of miconazole were 0.57 and 0.58 ng/mL, respectively at a single timepoint (4 hours after the last application) on Day 7.

20180815

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3 DOSAGE FORMS AND STRENGTHS VUSION (miconazole nitrate, zinc oxide and white petrolatum) contains 2.5 mg of miconazole nitrate USP, 150 mg of zinc oxide USP and 813.5 mg of white petrolatum USP per gram. • Ointment with 0.25% miconazole nitrate, 15% zinc oxide, and 81.35% white petrolatum. ( 3 )

VUSION miconazole nitrate, zinc oxide, white petrolatum MICONAZOLE NITRATE MICONAZOLE ZINC OXIDE ZINC OXIDE PETROLATUM PETROLATUM BUTYLATED HYDROXYTOLUENE TRIHYDROXYSTEARIN

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of VUSION in animals has not been evaluated. Miconazole nitrate was negative in a bacterial reverse mutation test, a chromosome aberration test in mice, and micronucleus assays in mice and rats. Miconazole nitrate had no adverse effect on fertility in a study in rats at oral doses of up to 320 mg/kg/day.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of VUSION in animals has not been evaluated. Miconazole nitrate was negative in a bacterial reverse mutation test, a chromosome aberration test in mice, and micronucleus assays in mice and rats. Miconazole nitrate had no adverse effect on fertility in a study in rats at oral doses of up to 320 mg/kg/day.

NDA021026

VUSION

miconazole nitrate, zinc oxide, white petrolatum

0378-9730

HUMAN PRESCRIPTION DRUG

TOPICAL

PRINCIPAL DISPLAY PANEL – 50 grams NDC 0378-9730-50 Rx only Vusion ® (miconazole nitrate USP, 0.25%; zinc oxide USP, 15%; white petrolatum USP, 81.35%) Ointment For Topical Use Only 50 grams Usual Dosage: See package insert. Caution: Not for oral, ophthalmic, or intravaginal use. Keep out of reach of children. If seal is damaged or punctured, do not use, and return product to place of purchase. Description: Each gram of VUSION ® Ointment contains 2.5 mg miconazole nitrate USP, 150 mg zinc oxide USP, and 813.5 mg white petrolatum USP containing butylated hydroxytoluene, trihyforxystearin, and Chemoderm 1001/B fragrance. Store at 20º to 25ºC (68º to 77ºF). [See USP Controlled Room Temperature.] See flap for lot number and expiration date. For additional information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). Serious side effects associated with the use of this product may be reported to this number. VUSION is a registered trademark of Stiefel Laboratories, Inc., a GSK Company, exclusively licensed to the Mylan Companies. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Made in Canada Mylan.com CON:9730:50:1C:R2 Vusion Ointment 50 grams Carton Label

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling Patients using VUSION should be informed about the following information: • VUSION should be used only as directed by the health care provider. • VUSION should not be used as a substitute for frequent diaper changes. • VUSION should not be used to prevent diaper dermatitis. • VUSION is for external use only. It is not for oral, ophthalmic, or intravaginal use. • Gently cleanse the diaper area with lukewarm water or a very mild soap and pat the area dry with a soft towel before applying VUSION. • Gently apply VUSION to the diaper area with the fingertips after each diaper change. Do not rub VUSION into the skin as this may cause additional irritation. • Thoroughly wash hands after applying VUSION. • Treatment should be continued for 7 days, even if there is improvement. Do not use VUSION for longer than 7 days. If symptoms have not improved by day 7, see your health care provider. • VUSION should not be used on children for whom it is not prescribed.

14 CLINICAL STUDIES Study 1 was a double-blind, multicenter study in which VUSION was compared to the zinc oxide and white petrolatum combination treatment and included 236 infants and toddlers with diaper dermatitis, complicated by candidiasis as documented by KOH tests that demonstrated pseudohyphae and/or budding yeasts. Study medication was applied at every diaper change for 7 days. The primary endpoint was “Overall Cure” and required that subjects be both clinically cured (total resolution of all signs and symptoms of infection) and microbiologically cured (eradication of candidiasis). Primary efficacy was assessed 1 week following the end of treatment, at Day 14. Study results are shown in the following table. Overall Cure at Day 14 VUSION n=112 Zinc Oxide/White Petrolatum n=124 26 (23%) 12 (10%) Two additional studies provided supportive evidence of the clinical efficacy of VUSION in infants and toddlers with diaper dermatitis, some of whom cultured positive for C. albicans . However, candidal infection was not documented in the culture-positive subjects, as microscopic testing (e.g. KOH) was not done. Therefore, the positive culture results may have reflected colonization rather than infection.

8.5 Geriatric Use Safety and efficacy in a geriatric population have not been evaluated.

8.4 Pediatric Use Efficacy was not demonstrated in infants less than 4 weeks of age. Safety and efficacy have not been established in very-low-birth-weight infants (less than 1500 g). VUSION should not be used to prevent diaper dermatitis. The safety of VUSION when used for longer than 7 days is not known. Do not use more than 7 days.

8.1 Pregnancy Risk Summary There are no available data on VUSION Ointment use in pregnant women to inform a drug‑associated risk for adverse developmental outcomes. In animal reproduction studies, prolonged gestation, increased number of resorptions, and decreased numbers of live young were observed after oral administration of miconazole nitrate during organogenesis to pregnant rats and rabbits. No comparisons of animal exposure with human exposure may be calculated due to minimal systemic exposure in humans after topical administration of VUSION [see Clinical Pharmacology (12.3) ]. 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 Miconazole nitrate administration has been shown to result in prolonged gestation and decreased numbers of live young in rats and in increased number of resorptions and decreased number of live young in rabbits at oral doses of 100 mg/kg/day and 80 mg/kg/day.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on VUSION Ointment use in pregnant women to inform a drug‑associated risk for adverse developmental outcomes. In animal reproduction studies, prolonged gestation, increased number of resorptions, and decreased numbers of live young were observed after oral administration of miconazole nitrate during organogenesis to pregnant rats and rabbits. No comparisons of animal exposure with human exposure may be calculated due to minimal systemic exposure in humans after topical administration of VUSION [see Clinical Pharmacology (12.3) ]. 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 Miconazole nitrate administration has been shown to result in prolonged gestation and decreased numbers of live young in rats and in increased number of resorptions and decreased number of live young in rabbits at oral doses of 100 mg/kg/day and 80 mg/kg/day. 8.2 Lactation Risk Summary There is no available information on the presence of miconazole in human milk, or the effects on the breastfed child, or the effects on milk production following use of VUSION. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VUSION and any potential adverse effects on the breastfed infant from VUSION or from the underlying maternal condition. 8.4 Pediatric Use Efficacy was not demonstrated in infants less than 4 weeks of age. Safety and efficacy have not been established in very-low-birth-weight infants (less than 1500 g). VUSION should not be used to prevent diaper dermatitis. The safety of VUSION when used for longer than 7 days is not known. Do not use more than 7 days. 8.5 Geriatric Use Safety and efficacy in a geriatric population have not been evaluated.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied VUSION (miconazole nitrate, zinc oxide and white petrolatum) contains 2.5 mg of miconazole nitrate USP, 150 mg of zinc oxide USP and 813.5 mg of white petrolatum USP per gram. The smooth, uniform, white ointment supplied in an aluminum tube is available as follows: NDC 0378-9730-50 carton containing one 50 gram tube 16.2 Storage Conditions Store at 20 ° to 25 ° C (68 ° to 77 ° F). [See USP Controlled Room Temperature.] Keep out of reach of children.