Zoryve Cream

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 cream 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

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Following application of ZORYVE cream, the plasma concentration versus time profile was relatively flat, generally with a peak-to-trough ratio less than 2.

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

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_0-24was 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 less than 12 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_0-24was 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 less than 6 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_0-24was 51.6 ± 29.9 and 539 ± 372 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively.

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_0-24was 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.

Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively.

The plasma clearance after short-term intravenous infusion of roflumilast is on average about 9.6 L/h. Following topical administration, the half-lives of roflumilast and the N-oxide metabolite were 4.0 and 4.6 days, respectively.

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

, 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 ratio was observed following intravenous administration, whereas following oral administration the N-oxide metabolite circulated on average about 10-fold higher than the parent drug.

Following topical administration, no clinically significant differences in the pharmacokinetics of roflumilast and roflumilast N-oxide were observed based on sex, race, or ethnicity.

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_maxof roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively, in Child-Pugh A subjects and by 26% and 40%, respectively, in Child-Pugh B subjects, as compared to healthy subjects

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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.

No formal drug-drug interaction studies were conducted with roflumilast cream.

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

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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_maxand AUC for roflumilast, respectively, and a 34% decrease and a 4% increase in C_maxand AUC for roflumilast N-oxide, respectively.

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_maxand AUC for roflumilast, respectively, and a 38% reduction and 3% increase in C_maxand AUC for roflumilast N-oxide, respectively.

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_maxand AUC along with a 210% decrease and 52% increase in roflumilast N-oxide C_maxand AUC, respectively.

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_maxand AUC of roflumilast by 20% and 56%, respectively. Roflumilast N-oxide C_maxwas decreased by 14% while roflumilast N-oxide AUC was increased by 23%.

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_maxand AUC; and a 4% decrease in C_maxand 27% increase in AUC for roflumilast N-oxide, respectively.

Oral Contraceptives Containing Gestodene and Ethinyl Estradiol: In an open-label crossover study in 20 healthy adult volunteers, co-administration of a single oral dose of roflumilast with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state caused a 38% increase and 12% decrease in C_maxof roflumilast and roflumilast N-oxide, respectively. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively.

Cytochrome P450 (CYP) Enzymes:

studies suggest that the biotransformation of roflumilast to its N-oxide metabolite is mediated by CYP1A2 and 3A4. Based on furtherresults in human liver microsomes, roflumilast and roflumilast N-oxide in therapeutic plasma concentrations do not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11; therefore, there is a low probability of relevant interactions with substances metabolized by these P450 enzymes. In addition,studies demonstrated no induction of the CYP1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weak induction of CYP2B6 by roflumilast.