ZORYVE- roflumilast_aerosol, foam

Roflumilast and its active metabolite (roflumilast N-oxide) are inhibitors of PDE4. Roflumilast and roflumilast N-oxide inhibition of PDE4 (a major cyclic 3',5'-adenosine monophosphate (cyclic AMP) metabolizing enzyme) activity leads to accumulation of intracellular cyclic AMP. The specific mechanism(s) by which roflumilast exerts its therapeutic action is not well defined. Pharmacodynamics of ZORYVE foam, 0. 3%, in the treatment of seborrheic dermatitis is unknown. Absorption The pharmacokinetics of ZORYVE foam, 0. 3%, was investigated in 10 adult and 10 pediatric (11 to 16 years of age) subjects with seborrheic dermatitis. In this study, a mean dose of approximately 4. 1 g of ZORYVE foam, 0. 3%, was applied once daily for 15 days to a mean +/- SD body surface area (BSA) involvement of 6. 27% in adult and pediatric subjects, respectively. Plasma concentrations of roflumilast were quantifiable in all but two subjects at Day 15. Plasma concentrations of roflumilast N-oxide were quantifiable in all subjects at Day 15. Following application of ZORYVE foam, 0. 3%, the plasma concentration versus time profile was relatively flat, with mean peak-to-trough ratios of 1. 62 for roflumilast and roflumilast N-oxide, respectively. In adults, the mean +/- SD maximum concentration (C max 0-24 0-24 Distribution Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively. Elimination The plasma clearance after short-term intravenous infusion of roflumilast is on average about 9. Following topical administration, the half-lives of roflumilast and the N-oxide metabolite were 3. 4 days, respectively. Metabolism Roflumilast is extensively metabolized via Phase I (cytochrome P450) and Phase II (conjugation) reactions. The N-oxide metabolite is the only major metabolite observed in the plasma of humans. Following oral administration, roflumilast and roflumilast N-oxide account for the majority (87. 5%) of total dose administered in plasma. Roflumilast was not detectable in urine, while roflumilast N-oxide was only a trace metabolite (less than 1%). Other conjugated metabolites such as roflumilast N-oxide glucuronide and 4-amino-3,5-dichloropyridine N-oxide were detected in urine. While roflumilast is 3 times more potent than roflumilast N-oxide at inhibition of the PDE4 enzyme in vitro Specific Populations Following topical administration, no clinically significant differences in the pharmacokinetics of roflumilast and roflumilast N-oxide were observed based on age (9 to 87 years), sex, race, or ethnicity. Patients with Hepatic Impairment No studies were conducted with topical roflumilast in subjects with hepatic impairment; however, oral roflumilast 250 mcg once daily for 14 days was studied in subjects with mild to moderate hepatic impairment classified as Child-Pugh A and B (8 subjects in each group). The AUC of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively, in Child-Pugh A subjects and by 92% and 41%, respectively, in Child-Pugh B subjects, as compared to age-, weight-, and gender-matched healthy subjects. The C max [see Contraindications (4) Patients with Renal Impairment No studies were conducted with topical roflumilast in subjects with renal impairment. Following oral administration in 12 subjects with severe renal impairment, no clinically significant differences in the pharmacokinetics of roflumilast and roflumilast N-oxide were observed. Drug Interaction Studies Clinical Studies Since a major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2, drug interaction studies were performed with oral roflumilast and systemic inhibitors of CYP3A4 and CYP1A2 [see Drug Interactions (7) Erythromycin: In an open-label crossover study in 16 healthy volunteers, the co-administration of CYP3A4 inhibitor erythromycin (500 mg 3 times daily for 13 days) with a single oral dose of 500 mcg roflumilast resulted in 40% and 70% increase in C max max Ketoconazole: In an open-label crossover study in 16 healthy volunteers, the co-administration of a strong CYP3A4 inhibitor ketoconazole (200 mg twice daily for 13 days) with a single oral dose of 500 mcg roflumilast resulted in 23% and 99% increase in C max max Fluvoxamine: In an open-label crossover study in 16 healthy volunteers, the co-administration of dual CYP 3A4/1A2 inhibitor fluvoxamine (50 mg daily for 14 days) with a single oral dose of 500 mcg roflumilast showed a 12% and 156% increase in roflumilast C max max Enoxacin: In an open-label crossover study in 16 healthy volunteers, the co-administration of dual CYP 3A4/1A2 inhibitor enoxacin (400 mg twice daily for 12 days) with a single oral dose of 500 mcg roflumilast resulted in an increased C max max Cimetidine: In an open-label crossover study in 16 healthy volunteers, the co-administration of a dual CYP 3A4/1A2 inhibitor cimetidine (400 mg twice daily for 7 days) with a single oral dose of 500 mcg roflumilast resulted in a 46% and 85% increase in roflumilast C max max In Vitro Studies Cytochrome P450 (CYP) Enzymes: In vitro in vitro in vitro.

ZORYVE registered ZORYVE foam, 0. 3%, is a phosphodiesterase 4 inhibitor indicated for the treatment of seborrheic dermatitis in adult and pediatric patients 9 years of age and older.

DOSAGE AND ADMINISTRATION
Shake can prior to each use. Apply a thin layer of ZORYVE foam, 0. 3%, once daily to affected areas on skin and/or scalp when they are not wet. Rub in completely. Wash hands after application. Avoid fire, flame, and smoking during and immediately following application [see Warnings and Precautions (5. 1) ZORYVE foam, 0. 3%, is for topical use only and not for ophthalmic, oral, or intravaginal use. Apply once daily to affected areas. ( 2 For topical use only. Not for ophthalmic, oral, or intravaginal use.
INSTRUCTIONS FOR USE
This Instructions for Use contains information on how to apply ZORYVE foam. Read this Instructions for Use before you start using ZORYVE foam and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. Use ZORYVE foam exactly as your healthcare provider tells you. Important information you need to know before applying ORYVE foam: ZORYVE foam is for use on skin only (topical use). ZORYVE foam is flammable. Before Applying ZORYVE foam for the first time: Applying ZORYVE foam: Apply a thin layer of ZORYVE foam 1 time a day Step 1: Shake. Shake the can well before each use. Step 2: Dispense. Turn the can upside down and press the nozzle. Dispense a small amount into your hand. Step 3: Apply. Use enough ZORYVE foam to cover all affected areas with a thin layer. Rub the foam in completely. If you are treating your scalp, part the hair so that ZORYVE foam can be applied directly to the affected area on the skin. Wash your hands after applying. Storing ZORYVE foam Store ZORYVE foam at room temperature between 68°F to 77°F (20°C to 25°C). Keep away from heat and flame. The contents in ZORYVE foam are under pressure. Do not Do not Do not Store the can upright. Keep ZORYVE foam and all medicines out of the reach of children. Marketed by: For more information, call 1-844-692-6729 or visit http://www. This Instructions for Use has been approved by the U. Food and Drug Administration. v1 Image Image Image Image Image.

The most common adverse reactions (reported in >=1% of patients) are nasopharyngitis, nausea, and headache. 1 To report SUSPECTED ADVERSE REACTIONS, contact Arcutis Biotherapeutics, Inc. at 1-844-692-6729 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 practice. In two multicenter, randomized, double-blind, vehicle-controlled trials (Trial 203 and STRATUM), 683 adult and pediatric subjects 9 years of age or older with seborrheic dermatitis were treated with ZORYVE foam, 0. 3%, or vehicle foam once daily for 8 weeks. The combined trial population was 79% White, 11% Black, and 5% Asian; for ethnicity, 79% identified as non-Hispanic/Latino and 21% identified as Hispanic/Latino. Fifty percent (50%) were male and 50% were female. The median age was 41 years (range 9 to 87 years). The median body surface area (BSA) affected was 2. Table 1 presents adverse reactions that occurred in at least 1% of subjects treated with ZORYVE foam, 0. Table 1: Adverse Reactions Reported in >=1% of Subjects with Seborrheic Dermatitis Treated with ZORYVE Foam, 0. 3%, for 8 Weeks in Trial 203 and Trial STRATUM Adverse Reaction ZORYVE foam, 0. 3% Vehicle foam Nasopharyngitis 7 (1. 4) Nausea 6 (1. 3) 0 (0) Headache 5 (1. 1) 0 (0) The following additional adverse reactions were reported in fewer than 1% of subjects treated with ZORYVE foam, 0. 3%: diarrhea and insomnia. In 408 subjects who continued treatment with ZORYVE foam, 0. 3%, for up to 24 to 52 weeks in an open-label, long-term trial, the adverse reaction profile was consistent with that observed in vehicle-controlled trials.

ZORYVE foam, 0. 3%, is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C) [see Use in Specific Populations (8. 6) Clinical Pharmacology (12. 3) Moderate to severe liver impairment (Child-Pugh B or C).

Risk Summary There are insufficient data available on the use of ZORYVE foam, 0. 3%, in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, roflumilast administered orally to pregnant rats and rabbits during the period of organogenesis produced no fetal structural abnormalities at doses up to 30 and 26 times the maximum recommended human dose (MRHD), respectively. Roflumilast induced post-implantation loss in rats at oral doses greater than or equal to 10 times the MRHD. Roflumilast induced stillbirth and decreased pup viability in mice at oral doses 16 and 49 times the MRHD, respectively. Roflumilast has been shown to adversely affect pup post-natal development when dams were treated with an oral dose 49 times the MRHD during pregnancy and lactation periods in mice (see Data The background risk of major birth defects and miscarriage for the indicated population is unknown. 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. Clinical Considerations Labor and delivery Avoid using ZORYVE foam, 0. 3%, during labor and delivery. There are no human studies that have investigated effects of ZORYVE foam, 0. 3%, on preterm labor or labor at term; however, animal studies showed that oral roflumilast disrupted the labor and delivery process in mice. Data Animal data In an embryo-fetal development study, pregnant rats were dosed orally during the period of organogenesis with up to 1. 8 mg/kg/day roflumilast (30 times the MRHD on a mg/m 2 2 In a fertility and embryo-fetal development study, male rats were dosed orally with up to 1. 8 mg/kg/day roflumilast for 10 weeks and females for 2 weeks prior to pairing and throughout the organogenesis period. Roflumilast induced pre- and post-implantation loss at maternal oral doses greater than or equal to 0. 6 mg/kg/day (10 times the MRHD on a mg/m 2 2 In an embryo-fetal development study in rabbits, pregnant does were dosed orally with 0. 8 mg/kg/day roflumilast during the period of organogenesis. Roflumilast did not cause fetal structural abnormalities at the maternal oral doses of 0. 8 mg/kg/day (26 times the MRHD on a mg/m 2 In pre- and post-natal developmental studies in mice, dams were dosed orally with up to 12 mg/kg/day roflumilast during the period of organogenesis and lactation. Roflumilast induced stillbirth and decreased pup viability at maternal oral doses greater than 2 mg/kg/day and 6 mg/kg/day, respectively (16 and 49 times the MRHD on a mg/m 2 2 2 2 Risk Summary There are no data on the presence of roflumilast or its metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. Roflumilast and/or its metabolites are excreted into the milk of lactating rats (see Data Clinical Considerations To minimize potential exposure to the breastfed infant via breast milk, use ZORYVE foam, 0. 3%, on the smallest area of skin and for the shortest duration possible while breastfeeding. To avoid direct infant exposure, advise breastfeeding women not to apply ZORYVE foam, 0. 3%, directly to the nipple or areola. If applied to the patient's chest, avoid exposure via direct contact with the infant's skin. Data Animal data Roflumilast and/or its metabolite concentrations measured 8 hours after an oral dose of 1 mg/kg given to lactating rats were 0. 02 mcg/g in the milk and pup liver, respectively. The safety and effectiveness of ZORYVE foam, 0. 3%, for the treatment of seborrheic dermatitis have been established in pediatric patients 9 years of age and older. Use of ZORYVE foam, 0. 3%, in this age group is supported by data from two 8-week, vehicle-controlled trials which included 32 pediatric subjects 9 to 17 years of age, of whom 17 received ZORYVE foam, 0. 3%, and from open-label trials of up to 52 weeks which included 23 pediatric subjects treated with ZORYVE foam, 0. The adverse reaction profile was consistent with that observed in adults [see Adverse Reactions (6. 1) Clinical Pharmacology (12. 3) Clinical Studies (14) The safety and effectiveness of ZORYVE foam, 0. 3%, in pediatric patients below the age of 9 years have not been established. Of the 683 subjects with seborrheic dermatitis exposed to ZORYVE foam, 0. 3%, or vehicle for up to 8 weeks in the controlled clinical trials, 98 (14%) were 65 years of age or older, and 33 (5%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Oral roflumilast 250 mcg once daily for 14 days was studied in subjects with hepatic impairment. The systemic exposure of roflumilast and roflumilast N-oxide were increased in subjects with moderate (Child-Pugh B) hepatic impairment. ZORYVE foam, 0. 3%, is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C). No dosage adjustment is needed in patients with mild (Child-Pugh A) hepatic impairment [see Contraindications (4) Clinical Pharmacology (12.

No formal drug-drug interaction studies were conducted with ZORYVE foam, 0. Co-administration of roflumilast with systemic CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously may increase roflumilast systemic exposure and may result in increased adverse reactions. If these products are co-administered with ZORYVE foam, 0. 3%, weigh the potential for increased adverse reactions against benefit. ( 7 Drugs that Inhibit Cytochrome P450 (CYP) Enzymes The co-administration of roflumilast with systemic CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously (e. , erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) may increase roflumilast systemic exposure and may result in increased adverse reactions. 3%, weigh the potential for increased adverse reactions against benefit [see Clinical Pharmacology (12.

NONCLINICAL TOXICOLOGY
Long-term studies were conducted in hamsters and mice with roflumilast to evaluate its carcinogenic potential. In 2-year oral gavage carcinogenicity studies, roflumilast treatment resulted in dose-related, statistically significant increases in the incidence of undifferentiated carcinomas of nasal epithelium in hamsters at doses greater than or equal to 8 mg/kg/day (20 times the MRHD on an AUC basis). The tumorigenicity of roflumilast appears to be attributed to a reactive metabolite of 4-amino-3,5-dichloropyridine N-oxide (ADCP N-oxide). No evidence of tumorigenicity was observed in mice at roflumilast oral doses up to 12 and 18 mg/kg/day in females and males, respectively (18 and 27 times the MRHD, respectively, on an AUC basis). In a 2-year dermal mouse carcinogenicity study, no evidence of carcinogenicity was observed at topical doses of roflumilast cream up to 1% applied at 2 mL/kg/day (7 times the MRHD on an AUC basis). Roflumilast tested positive in an in vivo in vitro in vitro in vitro in vivo in vitro In a human spermatogenesis study, oral roflumilast 500 mcg had no effects on semen parameters or reproductive hormones during the 3-month treatment period and the following 3-month off-treatment period. In a fertility study, oral roflumilast decreased fertility rates in male rats at 1.8 mg/kg/day (29 times the MRHD on a mg/m 2 2 2
CLINICAL STUDIES
Two randomized, double-blind, vehicle-controlled trials (STRATUM [NCT04973228] and Trial 203 [NCT04091646]) enrolled a total of 683 adult and pediatric subjects with seborrheic dermatitis involving the scalp, face, and/or body with an Investigator Global Assessment (IGA) of moderate or severe (IGA of 3 or 4 on a 5-point scale from 0 to 4). In each trial, subjects were randomized 2:1 to receive ZORYVE foam, 0.3%, or vehicle foam applied once daily for 8 weeks. The combined trial population included 79% White, 11% Black, and 5% Asian; for ethnicity, 79% identified as non-Hispanic/Latino and 21% identified as Hispanic/Latino. Fifty percent (50%) were male and 50% were female. In Trial STRATUM, the trial population ranged in age from 9 to 87 years, including 7% of subjects who were 9 to 17 years of age and 12% of subjects who were 65 years of age or older. At baseline, 94% of subjects had an IGA score of 3 (moderate), and 6% had an IGA score of 4 (severe). At baseline, 67% of subjects had a Worst Itch-Numeric Rating Scale (WI-NRS) score of 4 or higher on a scale of 0 to 10. In Trial 203, the trial population ranged in age from 18 to 85 years, including 18% who were 65 years of age or older. At baseline, 93% of subjects had an IGA score of 3 (moderate), and 7% had an IGA score of 4 (severe). At baseline, 81% of subjects had a Worst Itch-Numeric Rating Scale (WI-NRS) score of 4 or higher on a scale of 0 to 10. The primary endpoint was the proportion of subjects who achieved IGA treatment success at Week 8 (Table 2). Success was defined as a score of "Clear" (0) or "Almost Clear" (1), plus a 2-grade improvement from baseline. Table 2: IGA Treatment Success at Week 8 in Subjects with Moderate to Severe Seborrheic Dermatitis in Trial STRATUM and Trial 203 STRATUM Trial 203 ZORYVE foam, 0.3% Vehicle foam ZORYVE foam, 0.3% Vehicle foam Number of subjects randomized N=304 N=153 N=154 N=72 Abbreviations: CI = Confidence Interval IGA success IGA treatment success was defined as an IGA score of "Clear" (0) or "Almost Clear" (1), plus a 2-grade IGA score improvement from baseline at Week 8 (Multiple Imputation). 79.5% 58.0% 73.1% 40.8% Difference from Vehicle (95% CI) Treatment difference and 95% CI are based on the CMH method stratified by pooled site and baseline IGA strata. 20.6% (11.2%, 30.0%) 33.8% (20.3%, 47.4%) In Trial STRATUM, among subjects with a baseline WI-NRS score of at least 4 (67% of subjects), there was a higher percentage of subjects who achieved a reduction of at least 4 points from baseline at Week 8 in the group who received ZORYVE foam, 0.3%, compared to the group who received vehicle foam (62.8% vs. 40.6% for a treatment difference of 25.7% and 95% CI of (13.4, 38.1)).

Arcutis Biotherapeutics, Inc.

ZORYVE- roflumilast_aerosol, foam Product manual source documgent