Zoryve roflumilast .5 mg/g Cream — NDC 80610-105-60 (Billing 80610-0105-60)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics Pharmacodynamics of ZORYVE cream in the treatment of plaque psoriasis and atopic dermatitis are unknown.

12.3Pharmacokinetics Absorption Following application of ZORYVE cream, the plasma concentration versus time profile was relatively flat, generally with a peak-to-trough ratio less than 2. Plaque Psoriasis The PK of ZORYVE cream, 0.3%, was assessed in 18 adult and 6 pediatric subjects 13 to 16 years of age with plaque psoriasis and a mean ± SD body surface area (BSA) involvement of 26.8 ± 6.80% and 13.0 ± 3.58% in adult and pediatric subjects, respectively. In this study, on average, subjects applied 3 to 6.5 g of ZORYVE cream, 0.3%, once daily for 15 days.

Plasma concentrations of roflumilast and roflumilast N-oxide (see Metabolism ) were quantifiable in all but two subjects at Day 15. In adults, the mean ± SD systemic exposure (AUC 0-24 ) was 72.7 ± 53.1 and 628 ± 648 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. In pediatric subjects (13 to 16 years of age), the mean ± SD AUC 0-24 was 25.1 ± 24.0 and 140 ± 179 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively.

The PK of ZORYVE cream, 0.3%, was assessed in 10 pediatric subjects (6 to 11 years of age) with at least mild plaque psoriasis and a mean ± SD BSA involvement of 10.9 ± 6.56%. The 14-day mean ± SD extrapolated AUC 0-24 was 75.6 ± 87.3 and 693 ± 986 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. In another study, the PK of ZORYVE cream, 0.3%, was assessed in 9 pediatric subjects (2 to 5 years of age) with at least mild plaque psoriasis and a mean ± SD BSA involvement of 9.44 ± 5.57%.

The 14-day mean ± SD extrapolated AUC 0-24 was 51.6 ± 29.9 and 539 ± 372 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. Atopic Dermatitis The PK of ZORYVE cream, 0.15%, was assessed in 12 pediatric subjects 12 to 16 years of age and 13 pediatric subjects 6 to 11 years of age with atopic dermatitis and a mean ± SD BSA involvement of 33.7 ± 14.8% and 43.5 ± 10.5%, respectively. On average, subjects applied 8.2 to 10.5 g of ZORYVE cream, 0.15%, once daily.

In pediatric subjects 12 to 16 years of age, the Day 14 mean ± SD systemic exposure (AUC 0-24 ) was 62.9 ± 53.0 and 336 ± 310 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. In pediatric subjects 6 to 11 years of age, the Day 14 mean ± SD AUC 0-24 was 102 ± 96.5 and 743 ± 710 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. The PK of ZORYVE cream, 0.05%, was assessed in 9 pediatric subjects 2 to 5 years of age with atopic dermatitis and a mean ± SD BSA involvement of 42.4 ± 6.21%.

On average, subjects applied 5.2 g of ZORYVE cream, 0.05%, once daily. In pediatric subjects 2 to 5 years of age, the Day 14 mean ± SD systemic exposure (AUC 0-24 ) was 47.2 ± 27.4 and 338 ± 280 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. 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

9.6L/h. Following topical administration, the half-lives of roflumilast and the N-oxide metabolite were 4.0 and 4.6 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%… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics Absorption Following application of ZORYVE cream, the plasma concentration versus time profile was relatively flat, generally with a peak-to-trough ratio less than 2. Plaque Psoriasis The PK of ZORYVE cream, 0.3%, was assessed in 18 adult and 6 pediatric subjects 13 to 16 years of age with plaque psoriasis and a mean ± SD body surface area (BSA) involvement of 26.8 ± 6.80% and 13.0 ± 3.58% in adult and pediatric subjects, respectively. In this study, on average, subjects applied 3 to 6.5 g of ZORYVE cream, 0.3%, once daily for 15 days.

Plasma concentrations of roflumilast and roflumilast N-oxide (see Metabolism ) were quantifiable in all but two subjects at Day 15. In adults, the mean ± SD systemic exposure (AUC 0-24 ) was 72.7 ± 53.1 and 628 ± 648 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. In pediatric subjects (13 to 16 years of age), the mean ± SD AUC 0-24 was 25.1 ± 24.0 and 140 ± 179 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively.

The PK of ZORYVE cream, 0.3%, was assessed in 10 pediatric subjects (6 to 11 years of age) with at least mild plaque psoriasis and a mean ± SD BSA involvement of 10.9 ± 6.56%. The 14-day mean ± SD extrapolated AUC 0-24 was 75.6 ± 87.3 and 693 ± 986 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. In another study, the PK of ZORYVE cream, 0.3%, was assessed in 9 pediatric subjects (2 to 5 years of age) with at least mild plaque psoriasis and a mean ± SD BSA involvement of 9.44 ± 5.57%.

The 14-day mean ± SD extrapolated AUC 0-24 was 51.6 ± 29.9 and 539 ± 372 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. Atopic Dermatitis The PK of ZORYVE cream, 0.15%, was assessed in 12 pediatric subjects 12 to 16 years of age and 13 pediatric subjects 6 to 11 years of age with atopic dermatitis and a mean ± SD BSA involvement of 33.7 ± 14.8% and 43.5 ± 10.5%, respectively. On average, subjects applied 8.2 to 10.5 g of ZORYVE cream, 0.15%, once daily.

In pediatric subjects 12 to 16 years of age, the Day 14 mean ± SD systemic exposure (AUC 0-24 ) was 62.9 ± 53.0 and 336 ± 310 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. In pediatric subjects 6 to 11 years of age, the Day 14 mean ± SD AUC 0-24 was 102 ± 96.5 and 743 ± 710 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. The PK of ZORYVE cream, 0.05%, was assessed in 9 pediatric subjects 2 to 5 years of age with atopic dermatitis and a mean ± SD BSA involvement of 42.4 ± 6.21%.

On average, subjects applied 5.2 g of ZORYVE cream, 0.05%, once daily. In pediatric subjects 2 to 5 years of age, the Day 14 mean ± SD systemic exposure (AUC 0-24 ) was 47.2 ± 27.4 and 338 ± 280 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. 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

9.6L/h. Following topical administration, the half-lives of roflumilast and the N-oxide metabolite were 4.0 and 4.6 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 , the plasma AUC of roflumilast N-oxide on average is approximately 8-fold greater than the plasma AUC of roflumilast following topical administration. A similar… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Pharmacodynamics of ZORYVE cream in the treatment of plaque psoriasis and atopic dermatitis are unknown.

14 CLINICAL STUDIES

14.1Plaque Psoriasis Adult and Pediatric Subjects 6 Years of Age and Older Two multicenter, randomized, double-blind, vehicle-controlled trials (DERMIS-1 [NCT04211363] and DERMIS-2 [NCT04211389]) enrolled a total of 881 adult and pediatric subjects 6 years of age or older with mild to severe plaque psoriasis. Subjects were randomized 2:1 to receive ZORYVE cream, 0.3%, or vehicle cream applied topically once daily for 8 weeks. The median age of the trial population was 47 years (range 6 to 88 years of age).

The trial population was 64% male and 36% female; 82.3% were White, 7.1% Asian, 3.6% Black or African American, 0.9% Native Hawaiian or Other Pacific Islander, 0.7% American Indian or Alaska Native, 0.5% more than one race, 3.3% other races, and 1.6% with missing racial information. For ethnicity, 75.7% of subjects identified as Not Hispanic or Latino, 24.1% identified as Hispanic or Latino, and 0.2% were unknown. The median body surface area (BSA) affected of the trial population was 5.5% (range 2% to 20%).

At baseline, 16% of subjects had an Investigator Global Assessment (IGA) score of 2 (mild), 76% had an IGA score of 3 (moderate), and 8% had an IGA score of 4 (severe). One hundred seventy-nine (20%) subjects had a baseline intertriginous IGA (I-IGA) score of 2 or higher (mild), and 678 (77%) subjects had a baseline 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 4).

Success was defined as a score of "Clear" (0) or "Almost Clear" (1), plus a 2-grade improvement from baseline. Table 4: IGA Treatment 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). at Week 8 in Adult and Pediatric Subjects 6 Years of Age and Older with Mild to Severe Plaque Psoriasis in Trials DERMIS-1 and DERMIS-2 DERMIS-1 DERMIS-2 ZORYVE Cream, 0.3% Vehicle Cream ZORYVE Cream, 0.3% Vehicle Cream Subjects randomized N=286 N=153 N=290 N=152 Abbreviations: CI = Confidence Interval IGA success 41.5% 5.8% 36.7% 7.1% Difference from vehicle (95% CI) Treatment difference and 95% CI are based on the CMH method stratified by site, baseline IGA, and baseline intertriginous involvement.

39.7% (32.4%, 47.0%) 29.5% (21.5%, 37.6%) Secondary endpoints included the proportion of subjects that achieved I-IGA success at Week 8 and WI-NRS success sequentially at Weeks 8, 4, and 2 (see Figure 1 ). WI-NRS success was defined as a reduction of at least 4 points from baseline in subjects with a baseline WI-NRS score of at least 4. Figure 1: WI-NRS Success WI-NRS success is a reduction of at least 4 points in subjects with a WI-NRS score of 4 or higher at baseline.

Over Time in Adult and Pediatric Subjects 12 Years of Age and Older with Mild to Severe Plaque Psoriasis in Trials DERMIS-1 and DERMIS-2 † The treatment difference at Week 2 in DERMIS-1 was not statistically significant. Among subjects with an I-IGA score of at least 2 (mild) at baseline (approximately 22% of subjects in DERMIS-1 and 19% in DERMIS-2), there was a higher percentage of subjects who achieved I-IGA success at Week 8 in the group who received ZORYVE cream, 0.3%, compared to the group who received vehicle cream (DERMIS-1: 71.5% vs.

13.8%; DERMIS-2: 67.5% vs. 17.4%). Figure 1

14.2Atopic Dermatitis Adult and Pediatric Subjects 6 Years of Age and Older Two multicenter, randomized, double-blind, vehicle-controlled trials (INTEGUMENT-1 [NCT04773587] and INTEGUMENT-2 [NCT04773600]) enrolled a total of 1337 adult and pediatric subjects 6 years of age and older (615 subjects were 6 to 17 years of age) with mild to moderate atopic dermatitis. Subjects were randomized 2:1 to receive ZORYVE cream, 0.15%, or vehicle cream applied once daily for 4 weeks. The median age of the trial population was 20 years (range 6 to 91 years of a… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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 (12 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 (11 and 17 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 (35 times the MRHD on a mg/m 2 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 (12 times the MRHD on a mg/m 2 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 (29 times the MRHD on a mg/m 2 basis).