ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions (incidence >= 1%) in subjects treated with VTAMA cream were folliculitis, nasopharyngitis, contact dermatitis, headache, and pruritus. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Dermavant Sciences, Inc. at 1-8DERMAVANT 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 rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.In two randomized, double-blind, multicenter, vehicle-controlled clinical trials (PSOARING and PSOARING 2), 1025 adults with plaque psoriasis were treated with VTAMA cream or vehicle cream once daily for up to 12 weeks.Subjects ranged in age from 18 to 75 years, with an overall median age of 51 years. The majority of subjects were white (85%) and male (57%); and 85% were non-Hispanic or Latino.Table presents adverse reactions that occurred in at least 1% of subjects treated with VTAMA Cream, and for which the rate exceeded the rate for vehicle.Two (0.3%) subjects using VTAMA cream developed urticaria. Adverse reactions leading to treatment discontinuation in >1% of subjects who received VTAMA cream were contact dermatitis (2.9%) and folliculitis (2.8%).In an open label safety trial (PSOARING 3), 763 subjects were treated for up to an additional 40 weeks after completing PSOARING or PSOARING 2. In addition to the adverse reactions reported in the 12-week PSOARING and PSOARING clinical trials, the following adverse reactions were reported: urticaria (1.0%) and drug eruption (0.7%).. spl-table-1.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term carcinogenicity studies were conducted in mice (daily topical administration at doses of 0.5, 1.5 and 3% tapinarof cream) and in rats (subcutaneous administration at doses of 0.1, 0.3, and mg/kg/day tapinarof). No drug-related neoplasms were noted in mice after 98 (females) to 102 (males) weeks of daily topical administration at doses up to 3% tapinarof cream (44 times the MRHD based on AUC comparisons). No drug-related neoplasms were noted in female rats after 83 weeks of daily subcutaneous administration at doses up to mg/kg/day tapinarof (9 times the MRHD based on AUC comparisons).Tapinarof revealed no evidence of mutagenicity or clastogenicity in an Ames assay, an in vitro mammalian chromosomal aberration assay, an in vitro mouse lymphoma assay and two in vivo micronucleus assays in mice and rats.Tapinarof did not impair female fertility at subcutaneous doses up to 30 mg/kg/day (268 times the MRHD based on AUC comparisons).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term carcinogenicity studies were conducted in mice (daily topical administration at doses of 0.5, 1.5 and 3% tapinarof cream) and in rats (subcutaneous administration at doses of 0.1, 0.3, and mg/kg/day tapinarof). No drug-related neoplasms were noted in mice after 98 (females) to 102 (males) weeks of daily topical administration at doses up to 3% tapinarof cream (44 times the MRHD based on AUC comparisons). No drug-related neoplasms were noted in female rats after 83 weeks of daily subcutaneous administration at doses up to mg/kg/day tapinarof (9 times the MRHD based on AUC comparisons).Tapinarof revealed no evidence of mutagenicity or clastogenicity in an Ames assay, an in vitro mammalian chromosomal aberration assay, an in vitro mouse lymphoma assay and two in vivo micronucleus assays in mice and rats.Tapinarof did not impair female fertility at subcutaneous doses up to 30 mg/kg/day (268 times the MRHD based on AUC comparisons).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Tapinarof is an aryl hydrocarbon receptor (AhR) agonist. The specific mechanisms by which VTAMA cream exerts its therapeutic action in psoriasis patients are unknown.. 12.2 Pharmacodynamics. Pharmacodynamics of VTAMA cream are unknown.Cardiac ElectrophysiologyAt the approved recommended dosage, VTAMA does not prolong the QTc interval to any clinically relevant extent. 12.3 Pharmacokinetics. AbsorptionNo accumulation was observed with repeat topical application. Plasma concentration of tapinarof was below the quantifiable limits (BQL) of the assay (lower limit of quantification was 50 pg/mL) in 68% of the pharmacokinetic samples. On Day 1, mean +- SD values of max and AUC 0-last were 0.90 +- 1.4 ng/mL and 4.1 +- 6.3 ng.h/mL, respectively, following mean daily dose of 5.23 applied to mean body surface area involvement of 27.2% (range 21 to 46%) in 21 subjects with moderate to severe plaque psoriasis. On Day 29, the mean +- SD max and AUC 0-last were 0.12 +- 0.15 ng/mL and 0.61 +- 0.65 ng.h/mL, respectively. DistributionHuman plasma protein binding of tapinarof is approximately 99% in vitro. EliminationMetabolismTapinarof is metabolized in the liver by multiple pathways including oxidation, glucuronidation, and sulfation in vitro. Drug Interaction StudiesIn Vitro StudiesCytochrome P450 (CYP) Enzymes: Tapinarof is not an inhibitor of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CRP2D6 or CYP3A4/5. Tapinarof is not an inducer of CYP1A2, CYP2B6 or CYP3A4. Transporter Systems: Tapinarof is not an inhibitor of BCRP, MATE1, MATE-2K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, or P-gp. Tapinarof is not substrate for BCRP, OATP1B1, OATP1B3, or P-gp.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Two multicenter, randomized, double-blind, vehicle-controlled trials were conducted to evaluate the safety and efficacy of VTAMA cream for the treatment of adults with plaque psoriasis (PSOARING [NCT03956355] and PSOARING [NCT03983980]). These trials were conducted in total of 1025 subjects randomized 2:1 to VTAMA cream or vehicle cream applied once daily for 12 weeks to any lesion regardless of anatomic location.Baseline disease severity was graded using the 5-point Physicians Global Assessment (PGA). The majority of subjects had Moderate disease (82%), while 10% had Mild disease, and 8% had Severe disease at baseline. The extent of disease involvement assessed by mean body surface area (BSA), excluding the scalp, palms, and soles, was 8% (range to 20%). Subjects ranged in age from 18 to 75 years, with median age of 51 years. Overall, 57% of the subjects were male and 85% were White.The primary efficacy endpoint in both studies was the proportion of subjects who achieved treatment success, defined as PGA score of Clear (0) or Almost Clear (1) and at least 2-grade improvement from baseline. Efficacy results from the two trials are summarized in Table 2.Following 12 weeks of treatment, 73 subjects randomized to VTAMA achieved complete disease clearance (PGA 0) and had VTAMA withdrawn. These subjects were followed for up to 40 additional weeks with median time to first worsening (PGA >= [Mild]) of 114 days (95% CI: 85, 142).. table-2.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.In two randomized, double-blind, multicenter, vehicle-controlled clinical trials (PSOARING and PSOARING 2), 1025 adults with plaque psoriasis were treated with VTAMA cream or vehicle cream once daily for up to 12 weeks.Subjects ranged in age from 18 to 75 years, with an overall median age of 51 years. The majority of subjects were white (85%) and male (57%); and 85% were non-Hispanic or Latino.Table presents adverse reactions that occurred in at least 1% of subjects treated with VTAMA Cream, and for which the rate exceeded the rate for vehicle.Two (0.3%) subjects using VTAMA cream developed urticaria. Adverse reactions leading to treatment discontinuation in >1% of subjects who received VTAMA cream were contact dermatitis (2.9%) and folliculitis (2.8%).In an open label safety trial (PSOARING 3), 763 subjects were treated for up to an additional 40 weeks after completing PSOARING or PSOARING 2. In addition to the adverse reactions reported in the 12-week PSOARING and PSOARING clinical trials, the following adverse reactions were reported: urticaria (1.0%) and drug eruption (0.7%).. spl-table-1.

NURSING MOTHERS SECTION.

8.2 Lactation. Risk SummaryNo data are available regarding the presence of tapinarof in human milk or the effects of tapinarof on the breastfed infant, or on milk production. Tapinarof was detected in rat offspring following subcutaneous administration to pregnant female rats which suggests that tapinarof was transferred into the milk of lactating rats see Data). When drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for VTAMA cream and any potential adverse effects on the breastfed infant from VTAMA cream or from the underlying maternal condition. DataIn prenatal and postnatal development study, tapinarof was administered by subcutaneous injection to pregnant rats at doses of 1, 6, and 30 mg/kg/day from gestation day through lactation day 20. Tapinarof was quantifiable in offspring plasma samples on postnatal day 10 at doses of and 30 mg/kg/day, suggesting that tapinarof is present in animal milk.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionNo accumulation was observed with repeat topical application. Plasma concentration of tapinarof was below the quantifiable limits (BQL) of the assay (lower limit of quantification was 50 pg/mL) in 68% of the pharmacokinetic samples. On Day 1, mean +- SD values of max and AUC 0-last were 0.90 +- 1.4 ng/mL and 4.1 +- 6.3 ng.h/mL, respectively, following mean daily dose of 5.23 applied to mean body surface area involvement of 27.2% (range 21 to 46%) in 21 subjects with moderate to severe plaque psoriasis. On Day 29, the mean +- SD max and AUC 0-last were 0.12 +- 0.15 ng/mL and 0.61 +- 0.65 ng.h/mL, respectively. DistributionHuman plasma protein binding of tapinarof is approximately 99% in vitro. EliminationMetabolismTapinarof is metabolized in the liver by multiple pathways including oxidation, glucuronidation, and sulfation in vitro. Drug Interaction StudiesIn Vitro StudiesCytochrome P450 (CYP) Enzymes: Tapinarof is not an inhibitor of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CRP2D6 or CYP3A4/5. Tapinarof is not an inducer of CYP1A2, CYP2B6 or CYP3A4. Transporter Systems: Tapinarof is not an inhibitor of BCRP, MATE1, MATE-2K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, or P-gp. Tapinarof is not substrate for BCRP, OATP1B1, OATP1B3, or P-gp.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThe available data on VTAMA cream use in pregnant women are insufficient to evaluate for drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, subcutaneous administration of tapinarof to pregnant rats and rabbits during the period of organogenesis resulted in no significant adverse effects at doses 268 and 16 times, respectively, the maximum recommended human dose (MRHD) see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of major birth defects, loss, and other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.DataAnimal DataIn an embryofetal development study in rats, tapinarof was administered by subcutaneous injection to pregnant animals at doses of 1.2, 6.9 and 34 mg/kg/day during the period of organogenesis. Tapinarof was not associated with embryofetal lethality or fetal malformations. Tapinarof increased the incidence of skeletal variations (incomplete ossification of nasal bones) at the dose of 34 mg/kg/day (268 times the MRHD based on AUC comparisons).In an embryofetal development study in rabbits, tapinarof was administered by subcutaneous injection to pregnant animals twice daily at doses of 0.3, 1, and mg/kg/day during the period of organogenesis. Maternal toxicity as evidenced by decreased maternal body weight gain and associated increased post-implantation loss (embryolethality) was observed at mg/kg/day. In addition, fetal skeletal variations were observed at mg/kg/day. Tapinarof was not associated with embryofetal lethality or fetal malformations at doses up to mg/kg/day (16 times the MRHD based on AUC comparison) or fetal malformations at doses up to mg/kg/day (30 times the MRHD based on AUC comparison).In second embryofetal development study in rabbits, tapinarof was administered by continuous subcutaneous infusion to pregnant animals at doses of 1, and mg/kg/day during the period of organogenesis. Tapinarof was not associated with embryofetal lethality or fetal malformations at doses up to mg/kg/day (20 times the MRHD based on AUC comparison).In prenatal and postnatal development study, tapinarof was administered by subcutaneous injection to pregnant rats at doses of 1, and 30 mg/kg/day beginning on gestation day through lactation day 20. Maternal toxicity associated with decreases in body weight gain and food consumption was noted at 30 mg/kg/day (268 times the MRHD based on AUC comparisons). Tapinarof decreased fetal survival and viability that resulted in reduced litter sizes and decreased fetal weights at doses greater than or equal to mg/kg/day (45 times the MRHD based on AUC comparisons). No tapinarof-related effects on fetal survival and viability were noted at dose of mg/kg/day (6 times the MRHD based on AUC comparisons). No tapinarof-related effects on postnatal development, neurobehavioral or reproductive performance of offspring were noted at doses up to 30 mg/kg/day (268 times the MRHD based on AUC comparison).

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONVTAMA(R) (Vee-TAM-uh)(tapinarof)cream, for topical useImportant information: VTAMA cream is for use on the skin (topical use) only. Do not use VTAMA cream in your eyes, mouth, or vagina. What is VTAMA creamVTAMA cream is prescription medicine used on the skin (topical) to treat plaque psoriasis in adults.It is not known if VTAMA cream is safe and effective in children with psoriasis under 18 years of age.Before using VTAMA cream, tell your healthcare provider about all of your medical conditions, including if you:are pregnant or plan to become pregnant. It is not known if VTAMA cream will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if VTAMA cream passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with VTAMA cream.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should use VTAMA creamUse VTAMA cream exactly as your healthcare provider tells you to use it.Apply thin layer of VTAMA cream only to your psoriasis skin lesions time day. Avoid applying VTAMA cream to unaffected areas of your skin.Wash your hands after applying VTAMA cream unless you are using it to treat your hands.If someone else applies VTAMA cream for you, they should wash their hands after application.What are the possible side effects of VTAMA creamThe most common side effects of VTAMA cream include:red raised bumps around the hair pores (folliculitis)pain or swelling in the nose and throat (nasopharyngitis)skin rash or irritation including itching and redness, peeling, burning, or stingingheadacheitchingfluThese are not all the possible side effects of VTAMA cream.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store VTAMA creamStore VTAMA cream at room temperature between 68F to 77F (20C to 25C).Do not freeze VTAMA cream.Protect VTAMA cream from exposure to excessive heat.Keep VTAMA cream and all medicines out of the reach of children.General information about the safe and effective use of VTAMA cream.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use VTAMA cream for condition for which it was not prescribed. Do not give VTAMA cream to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VTAMA cream that is written for health professionals.What are the ingredients in VTAMA creamActive ingredient: tapinarof Inactive ingredients: benzoic acid, butylated hydroxytoluene, citric acid monohydrate, diethylene glycol monoethyl ether, edetate disodium, emulsifying wax, medium-chain triglycerides, polyoxyl stearyl ether, polyoxyl 20 stearyl ether, polysorbate 80, propylene glycol, purified water, and sodium citrate dihydrate. Marketed by: Dermavant Sciences Inc., 3780 Kilroy Airport Way, Long Beach, CA 90806For more information, go to www.VTAMA.com or call 1-8DERMAVANTU.S. Patents: www.dermavant.com/patentsVTAMA is registered trademark of Dermavant Sciences, GmbH or its affiliatesThis Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 05/2022. are pregnant or plan to become pregnant. It is not known if VTAMA cream will harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if VTAMA cream passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with VTAMA cream.. Use VTAMA cream exactly as your healthcare provider tells you to use it.. Apply thin layer of VTAMA cream only to your psoriasis skin lesions time day. Avoid applying VTAMA cream to unaffected areas of your skin.. Wash your hands after applying VTAMA cream unless you are using it to treat your hands.. If someone else applies VTAMA cream for you, they should wash their hands after application.. red raised bumps around the hair pores (folliculitis). pain or swelling in the nose and throat (nasopharyngitis). skin rash or irritation including itching and redness, peeling, burning, or stinging. headache. itching. flu. Store VTAMA cream at room temperature between 68F to 77F (20C to 25C).. Do not freeze VTAMA cream.. Protect VTAMA cream from exposure to excessive heat.. Keep VTAMA cream and all medicines out of the reach of children.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThe available data on VTAMA cream use in pregnant women are insufficient to evaluate for drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, subcutaneous administration of tapinarof to pregnant rats and rabbits during the period of organogenesis resulted in no significant adverse effects at doses 268 and 16 times, respectively, the maximum recommended human dose (MRHD) see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of major birth defects, loss, and other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.DataAnimal DataIn an embryofetal development study in rats, tapinarof was administered by subcutaneous injection to pregnant animals at doses of 1.2, 6.9 and 34 mg/kg/day during the period of organogenesis. Tapinarof was not associated with embryofetal lethality or fetal malformations. Tapinarof increased the incidence of skeletal variations (incomplete ossification of nasal bones) at the dose of 34 mg/kg/day (268 times the MRHD based on AUC comparisons).In an embryofetal development study in rabbits, tapinarof was administered by subcutaneous injection to pregnant animals twice daily at doses of 0.3, 1, and mg/kg/day during the period of organogenesis. Maternal toxicity as evidenced by decreased maternal body weight gain and associated increased post-implantation loss (embryolethality) was observed at mg/kg/day. In addition, fetal skeletal variations were observed at mg/kg/day. Tapinarof was not associated with embryofetal lethality or fetal malformations at doses up to mg/kg/day (16 times the MRHD based on AUC comparison) or fetal malformations at doses up to mg/kg/day (30 times the MRHD based on AUC comparison).In second embryofetal development study in rabbits, tapinarof was administered by continuous subcutaneous infusion to pregnant animals at doses of 1, and mg/kg/day during the period of organogenesis. Tapinarof was not associated with embryofetal lethality or fetal malformations at doses up to mg/kg/day (20 times the MRHD based on AUC comparison).In prenatal and postnatal development study, tapinarof was administered by subcutaneous injection to pregnant rats at doses of 1, and 30 mg/kg/day beginning on gestation day through lactation day 20. Maternal toxicity associated with decreases in body weight gain and food consumption was noted at 30 mg/kg/day (268 times the MRHD based on AUC comparisons). Tapinarof decreased fetal survival and viability that resulted in reduced litter sizes and decreased fetal weights at doses greater than or equal to mg/kg/day (45 times the MRHD based on AUC comparisons). No tapinarof-related effects on fetal survival and viability were noted at dose of mg/kg/day (6 times the MRHD based on AUC comparisons). No tapinarof-related effects on postnatal development, neurobehavioral or reproductive performance of offspring were noted at doses up to 30 mg/kg/day (268 times the MRHD based on AUC comparison).. 8.2 Lactation. Risk SummaryNo data are available regarding the presence of tapinarof in human milk or the effects of tapinarof on the breastfed infant, or on milk production. Tapinarof was detected in rat offspring following subcutaneous administration to pregnant female rats which suggests that tapinarof was transferred into the milk of lactating rats see Data). When drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for VTAMA cream and any potential adverse effects on the breastfed infant from VTAMA cream or from the underlying maternal condition. DataIn prenatal and postnatal development study, tapinarof was administered by subcutaneous injection to pregnant rats at doses of 1, 6, and 30 mg/kg/day from gestation day through lactation day 20. Tapinarof was quantifiable in offspring plasma samples on postnatal day 10 at doses of and 30 mg/kg/day, suggesting that tapinarof is present in animal milk.. 8.4 Pediatric Use. Safety and efficacy of VTAMA cream have not been established in pediatric subjects with psoriasis under 18 years of age.Juvenile Animal Toxicity DataIn juvenile animal toxicity study, tapinarof was administered by subcutaneous injection to juvenile rats at doses of 1, 10 and 20 mg/kg/day from postnatal day (PND) to 21 and at doses of 1.5, 15, and 30 mg/kg/day from PND 22 to 77. The dose escalation conducted at PND 22 was implemented to maintain consistent systemic exposure across the duration of the dosing period. Renal pelvic dilatation was observed at doses greater than or equal to 15 mg/kg/day (165 times the MRHD based on AUC comparisons). No adverse effects in juvenile animals were noted at 1.5 mg/kg/day (11 times the MRHD based on AUC comparisons).. 8.5 Geriatric Use. Of the 683 subjects exposed to VTAMA cream in the PSOARING or PSOARING clinical trials, 99 (14.5%) were 65 years of age and older, including (1.2%) subjects who were 75 years of age and older. No overall differences in efficacy, safety, or tolerability were observed between elderly subjects and younger adult subjects in clinical trials.