1.1 Seborrheic Dermatitis

ZORYVE® topical foam, 0.3%, is indicated for the treatment of seborrheic dermatitis in adult and pediatric patients 9 years of age and older.

1.2 Plaque Psoriasis

ZORYVE topical foam, 0.3%, is indicated for the treatment of plaque psoriasis of the scalp and body in adult and pediatric patients 12 years of age and older.

5.1 Flammability

The propellants in ZORYVE foam, 0.3%, are flammable. Avoid fire, flame, and smoking during and immediately following application.

6.1 Clinical Trials Experience

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.

7.1 Effects of Other Drugs on ZORYVE Foam, 0.3%

8.1 Pregnancy

8.2 Lactation

8.3 Fertility

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.

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

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 (12.3)].

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

Pharmacodynamics of ZORYVE foam, 0.3%, in the treatment of seborrheic dermatitis and plaque psoriasis is unknown.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 (11 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 (10 and 15 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 (4 times the MRHD on an AUC basis).

Roflumilast tested positive in an in vivo mouse micronucleus test, but negative in the following assays: the Ames test, an in vitro chromosome aberration assay in human lymphocytes, an in vitro HPRT assay with V79 cells, an in vitro micronucleus test with V79 cells, a DNA adduct formation assay in rat nasal mucosa, liver, and testes, and an in vivo mouse bone marrow chromosome aberration assay. Roflumilast N-oxide was negative in the Ames test and an in vitro micronucleus test with V79 cells.

In a fertility study, oral roflumilast decreased fertility rates in male rats at 1.8 mg/kg/day (20 times the MRHD on a mg/m2 basis). The male rats also showed increases in the incidence of tubular atrophy, degeneration in the testis, and spermiogenic granuloma in the epididymides. No effect on rat fertility rate or male reproductive organ morphology was observed at 0.6 mg/kg/day (7 times the MRHD on a mg/m2 basis). In a female fertility study, no effect on fertility was observed up to the highest roflumilast dose of 1.5 mg/kg/day in rats (17 times the MRHD on a mg/m2 basis).

14.1 Seborrheic Dermatitis

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 was 50% male, 79% White, 11% Black, 5% Asian, and 5% other races; for ethnicity, 79% identified as non-Hispanic/Latino and 21% identified as Hispanic/Latino. 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 3). Success was defined as a score of "Clear" (0) or "Almost Clear" (1), plus a 2-grade improvement from baseline.

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)).

14.2 Plaque Psoriasis

Two randomized, double-blind, vehicle-controlled trials (ARRECTOR [NCT05028582] and Trial 204 [NCT04128007]) enrolled a total of 736 adult and pediatric subjects 12 years of age and older with mild to severe plaque psoriasis of the scalp and body. 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 was 55% female, 85% White, 5% Black, 6% Asian, and 4% other races; for ethnicity, 79% identified as non-Hispanic/Latino and 19% identified as Hispanic/Latino. The median age was 47 years (range 12 to 87 years).

In Trial ARRECTOR, the trial population ranged in age from 12 to 87 years, including 2% of subjects who were 12 to 17 years of age and 13% of subjects who were 65 years of age or older. At baseline, 86% of subjects had a Scalp Investigator Global Assessment (S-IGA) score of 3 (moderate) on a 5-point scale of 0 to 4, and 14% had an S-IGA score of 4 (severe); 28% of subjects had a Body Investigator Global Assessment (B-IGA) score of 2 (mild), 67% of subjects had a B-IGA score of 3 (moderate), and 5% had a B-IGA score of 4 (severe). At baseline, 76% of subjects had a Scalp Itch-Numeric Rating Scale (SI-NRS) score of 4 or higher on a scale of 0 to 10 and 73% had a Worst Itch-Numeric Rating Scale (WI-NRS) score of 4 or higher.

In Trial 204, the trial population ranged in age from 12 to 87 years, including 1% of subjects who were 12 to 17 years of age, and 9% who were 65 years of age or older. At baseline, 11% of subjects had an S-IGA score of 2 (mild), 76% of subjects had an S-IGA score of 3 (moderate), and 13% had an S-IGA score of 4 (severe); 36% of subjects had a B-IGA score of 2 (mild), 59% of subjects had a B-IGA score of 3 (moderate), and 5% had a B-IGA score of 4 (severe). At baseline, 89% of subjects had an SI-NRS score of 4 or higher on a scale of 0 to 10.

In both trials, S-IGA treatment success, a primary endpoint in ARRECTOR and Trial 204, and B-IGA treatment success, a primary endpoint in ARRECTOR, were defined as a score of "Clear" (0) or "Almost Clear" (1), plus a 2-grade improvement from baseline.

SI-NRS success and WI-NRS success were defined as a reduction of at least 4 points from baseline with a baseline score of at least 4. In Trial ARRECTOR, among subjects with a baseline SI-NRS score of at least 4 (75% of subjects), a higher percentage of subjects achieved SI-NRS success at Week 8 in the group who received ZORYVE foam, 0.3%, compared to the group who received vehicle foam (65.3% vs. 30.3% for a treatment difference of 35.4% and 95% CI of (23.9, 47.0)). In Trial ARRECTOR, among subjects with a baseline WI-NRS score of at least 4 (72% of subjects), a higher percentage of subjects achieved WI-NRS success at Week 8 in the group who received ZORYVE foam, 0.3%, compared to the group who received vehicle foam (63.1% vs. 30.1% for a treatment difference of 32.8% and 95% CI of (20.3, 45.2)).

How Supplied

ZORYVE (roflumilast) topical foam, 0.3%, is a white to off-white foam. It is supplied in a 60-gram pressurized aluminum can (NDC 80610-430-60).

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature].

Do not freeze.

Store upright.

Flammable. Contents under pressure. Do not puncture or incinerate. Do not expose to heat or store at temperatures above 49°C (120°F) [see Warnings and Precautions (5.1)].

Administration Instructions

Advise patients or caregivers that ZORYVE foam, 0.3%, is for topical use only and is not for ophthalmic, oral, or intravaginal use [see Dosage and Administration (2)].

Instruct patients or caregivers to shake the can of ZORYVE foam, 0.3%, prior to each use [see Dosage and Administration (2)].

Instruct patients or caregivers to wash hands after applying ZORYVE foam, 0.3% [see Dosage and Administration (2)].

Flammability

Because the propellants in ZORYVE foam, 0.3%, are flammable, instruct the patient to avoid fire, flame, and smoking during and immediately following application [see Dosage and Administration (2), Warnings and Precautions (5.1)].

Lactation

Advise patients to use ZORYVE foam, 0.3%, on the smallest area of skin and for the shortest duration possible while breastfeeding. Instruct patients who are breastfeeding not to apply ZORYVE foam, 0.3%, directly to the nipple or areola to avoid direct infant exposure. Instruct patients to avoid inadvertent contact of treated areas with infant skin [see Use in Specific Populations (8.2)].