ZORYVE® cream, 0.3%, is indicated for topical treatment of plaque psoriasis, including intertriginous areas, in adult and pediatric patients 6 years of age and older.

ZORYVE cream, 0.15%, is indicated for topical treatment of mild to moderate atopic dermatitis in adult and pediatric patients 6 years of age and older.

Use ZORYVE cream, 0.3%, for the treatment of plaque psoriasis.

{ "type": "p", "children": [], "text": "Use ZORYVE cream, 0.3%, for the treatment of plaque psoriasis." }

Use ZORYVE cream, 0.15%, for the treatment of mild to moderate atopic dermatitis.

{ "type": "p", "children": [], "text": "Use ZORYVE cream, 0.15%, for the treatment of mild to moderate atopic dermatitis." }

Apply ZORYVE cream to affected areas once daily and rub in completely. Wash hands after application, unless ZORYVE cream is for treatment of the hands.

{ "type": "p", "children": [], "text": "Apply ZORYVE cream to affected areas once daily and rub in completely. Wash hands after application, unless ZORYVE cream is for treatment of the hands." }

ZORYVE cream is for topical use only and not for ophthalmic, oral, or intravaginal use.

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{ "type": "ul", "children": [ "Cream, 0.3%: 3 mg of roflumilast per gram of white to off-white cream in 60-gram tubes.", "Cream, 0.15%: 1.5 mg of roflumilast per gram of white to off-white cream in 60-gram tubes." ], "text": "" }

ZORYVE cream is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

{ "type": "p", "children": [], "text": "ZORYVE cream is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]." }

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.

Plaque Psoriasis

In two multicenter, randomized, double-blind, vehicle-controlled trials (DERMIS-1 and DERMIS-2), 881 adult and pediatric subjects 6 years of age or older with plaque psoriasis were treated with ZORYVE cream, 0.3%, or vehicle cream once daily for 8 weeks.

The median age was 47 years (range 6 to 88). The majority of the subjects were male (64%) and White (82%). The median body surface area (BSA) affected was 5.5% (range 2% to 20%). The proportion of subjects who discontinued treatment due to an adverse reaction was 1.0% for subjects treated with ZORYVE cream, 0.3%, and 1.3% for subjects treated with vehicle cream. The most common adverse reaction that led to discontinuation of ZORYVE cream, 0.3%, was application site urticaria (0.3%).

Table 1 presents adverse reactions that occurred in at least 1% of subjects treated with ZORYVE cream, 0.3%, and for which the rate exceeded the rate for vehicle cream.

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 1: Adverse Reactions Reported in ≥1% of Subjects with Plaque Psoriasis Treated with ZORYVE Cream, 0.3%, (and More Frequently than Vehicle Cream) for 8 Weeks in Trials DERMIS-1 and DERMIS-2</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Adverse Reaction</th><th align="center" class="Rrule">ZORYVE Cream, 0.3%<br/>(N=576)<br/>n (%)</th><th align="center" class="Rrule">Vehicle Cream<br/>(N=305)<br/>n (%)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Diarrhea</td><td align="center" class="Rrule">18 (3.1)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Headache</td><td align="center" class="Rrule">14 (2.4)</td><td align="center" class="Rrule">3 (1.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Insomnia</td><td align="center" class="Rrule">8 (1.4)</td><td align="center" class="Rrule">2 (0.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Nausea</td><td align="center" class="Rrule">7 (1.2)</td><td align="center" class="Rrule">1 (0.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Application site pain</td><td align="center" class="Rrule">6 (1.0)</td><td align="center" class="Rrule">1 (0.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Upper respiratory tract infection</td><td align="center" class="Rrule">6 (1.0)</td><td align="center" class="Rrule">1 (0.3)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Urinary tract infection</td><td align="center" class="Rrule">6 (1.0)</td><td align="center" class="Rrule">2 (0.7)</td> </tr> </tbody> </table></div>

In 594 subjects with plaque psoriasis who continued treatment with ZORYVE cream, 0.3%, for up to 64 weeks in open-label extension trials, the adverse reaction profile was consistent with that observed in vehicle-controlled trials.

Atopic Dermatitis

In two multicenter, randomized, double-blind, vehicle-controlled trials (INTEGUMENT-1 and INTEGUMENT-2), 1336 adult and pediatric subjects 6 years of age or older with mild to moderate atopic dermatitis were treated with ZORYVE cream, 0.15%, or vehicle cream once daily for 4 weeks.

The median age was 20 years (range 6 to 91). The majority of the subjects were female (57%) and White (60%). The median body surface area (BSA) affected was 10% (range 3% to 88%).

The proportion of subjects who discontinued treatment due to an adverse reaction was 1.6% for subjects treated with ZORYVE cream, 0.15%, and 1.1% for subjects treated with vehicle cream.

Table 2 presents adverse reactions that occurred in at least 1% of subjects treated with ZORYVE cream, 0.15%, and for which the rate exceeded the rate for vehicle cream.

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 2: Adverse Reactions Reported in ≥1% of Subjects with Atopic Dermatitis Treated with ZORYVE Cream, 0.15%, (and More Frequently than Vehicle Cream) for 4 Weeks in Trials INTEGUMENT-1 and INTEGUMENT-2</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Adverse Reaction</th><th align="center" class="Rrule">ZORYVE Cream, 0.15%<br/>(N=885)<br/>n (%)</th><th align="center" class="Rrule">Vehicle Cream<br/>(N=451)<br/>n (%)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Headache</td><td align="center" class="Rrule">26 (2.9)</td><td align="center" class="Rrule">4 (0.9)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Nausea</td><td align="center" class="Rrule">17 (1.9)</td><td align="center" class="Rrule">2 (0.4)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Application site pain</td><td align="center" class="Rrule">13 (1.5)</td><td align="center" class="Rrule">3 (0.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Diarrhea</td><td align="center" class="Rrule">13 (1.5)</td><td align="center" class="Rrule">2 (0.4)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Vomiting</td><td align="center" class="Rrule">13 (1.5)</td><td align="center" class="Rrule">2 (0.4)</td> </tr> </tbody> </table></div>

The adverse reaction of insomnia was reported in fewer than 1% of subjects treated with ZORYVE cream, 0.15%.

The co-administration of roflumilast with systemic CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) may increase roflumilast systemic exposure and may result in increased adverse reactions. If these products are co-administered with ZORYVE cream, weigh the potential for increased adverse reactions against benefit [see Clinical Pharmacology (12.3)].

The co-administration of roflumilast with oral contraceptives containing gestodene and ethinyl estradiol may increase roflumilast systemic exposure and may result in increased adverse reactions. If these products are co-administered with ZORYVE cream, weigh the potential for increased adverse reactions against benefit [see Clinical Pharmacology (12.3)].

Risk Summary

There are insufficient data available on the use of ZORYVE cream 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 36 and 31 times the maximum recommended human dose (MRHD), respectively. Roflumilast induced post-implantation loss in rats at oral doses greater than or equal to 12 times the MRHD. Roflumilast induced stillbirth and decreased pup viability in mice at oral doses 19 and 59 times the MRHD, respectively. Roflumilast has been shown to adversely affect pup post-natal development when dams were treated with an oral dose 59 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. In the U.S. 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 cream during labor and delivery. There are no human studies that have investigated effects of ZORYVE cream 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 (36 times the MRHD on a mg/m2 basis). No evidence of structural abnormalities or effects on survival rates were observed. Roflumilast did not affect embryo-fetal development at a maternal oral dose of 0.2 mg/kg/day (4 times the MRHD on a mg/m2 basis).

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 (12 times the MRHD on a mg/m2 basis). Roflumilast did not cause fetal structural abnormalities at maternal oral doses up to 1.8 mg/kg/day (35 times the MRHD on a mg/m2 basis).

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 (31 times the MRHD on a mg/m2 basis).

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 (19 and 59 times the MRHD on a mg/m2 basis, respectively). Roflumilast induced delivery retardation in pregnant mice at maternal oral doses greater than 2 mg/kg/day (19 times the MRHD on a mg/m2 basis). Roflumilast decreased pup rearing frequencies at a maternal oral dose of 6 mg/kg/day during pregnancy and lactation (59 times the MRHD on a mg/m2 basis). Roflumilast also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at a maternal oral dose of 12 mg/kg/day (116 times the MRHD on a mg/m2 basis).

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). When a 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 mother's clinical need for ZORYVE cream and any potential adverse effects on the breastfed infant from ZORYVE cream or from the underlying maternal condition.

Clinical Considerations

To minimize potential exposure to the breastfed infant via breast milk, use ZORYVE cream 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 cream 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 0.32 and 0.02 mcg/g in the milk and pup liver, respectively.

Plaque Psoriasis

The safety and effectiveness of ZORYVE cream, 0.3%, for the topical treatment of plaque psoriasis, including intertriginous areas, have been established in pediatric patients 6 years of age and older. Use of ZORYVE cream, 0.3%, in pediatric patients 6 years of age and older is supported by data from two 8-week, vehicle-controlled, safety and efficacy trials which included 18 subjects 6 to 17 years of age, of whom 11 received ZORYVE cream, 0.3%. Use of ZORYVE cream, 0.3%, in pediatric patients 12 years of age and older is also supported by data from open-label trials of 2 and 24 weeks duration which included 18 subjects 12 to 17 years of age treated with ZORYVE cream, 0.3%. Use of ZORYVE cream, 0.3%, in pediatric patients 6 to less than 12 years of age is also supported by data from one 4-week, open-label, safety and pharmacokinetic (PK) study which included 20 pediatric subjects 6 to less than 12 years of age [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].

The safety and effectiveness of ZORYVE cream, 0.3%, have not been established in pediatric patients younger than 6 years of age.

Atopic Dermatitis

The safety and effectiveness of ZORYVE cream, 0.15%, for the topical treatment of mild to moderate atopic dermatitis have been established in pediatric patients 6 years of age and older. Use of ZORYVE cream, 0.15%, in this age group is supported by data from two 4-week, vehicle-controlled, safety and efficacy trials which included 615 subjects 6 to 17 years of age, of whom 406 received ZORYVE cream, 0.15%. Use of ZORYVE cream, 0.15%, in pediatric patients 6 years of age and older is also supported by data from 481 pediatric subjects treated with ZORYVE cream, 0.15%, in open-label trials, of which 104 were treated for 52 weeks [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)].

The safety and effectiveness of ZORYVE cream, 0.15%, have not been established in pediatric patients younger than 6 years of age.

There were 184 patients 65 years of age and older in clinical studies for plaque psoriasis and atopic dermatitis [see Clinical Studies (14.1, 14.2)].

Plaque Psoriasis

Of the 576 patients treated with ZORYVE cream, 0.3%, in the 2 controlled clinical studies for plaque psoriasis, 56 (9.7%) were 65 to 74 years of age and 21 (3.7%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Atopic Dermatitis

Of the 885 patients treated with ZORYVE cream, 0.15%, in the 2 controlled clinical studies for atopic dermatitis, 36 (4.1%) were 65 to 74 years of age and 8 (0.9%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the geriatric 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 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 [see Contraindications (4) and Clinical Pharmacology (12.3)].

ZORYVE (roflumilast) cream is a white to off-white cream for topical use. The active ingredient, roflumilast, is a phosphodiesterase 4 (PDE4) inhibitor.

{ "type": "p", "children": [], "text": "ZORYVE (roflumilast) cream is a white to off-white cream for topical use. The active ingredient, roflumilast, is a phosphodiesterase 4 (PDE4) inhibitor." }

Roflumilast is described chemically as 3-cyclopropylmethoxy-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide. The empirical formula is C17H14Cl2F2N2O3, and the molecular weight is 403.21.

{ "type": "p", "children": [], "text": "Roflumilast is described chemically as 3-cyclopropylmethoxy-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide. The empirical formula is C17H14Cl2F2N2O3, and the molecular weight is 403.21." }

The structural formula is represented below:

{ "type": "p", "children": [], "text": "The structural formula is represented below:" }

Roflumilast is practically insoluble in water and hexane, sparingly soluble in ethanol, and freely soluble in acetone.

{ "type": "p", "children": [], "text": "Roflumilast is practically insoluble in water and hexane, sparingly soluble in ethanol, and freely soluble in acetone." }

Each gram of cream, 0.15% or 0.3%, contains 1.5 mg or 3 mg of roflumilast, respectively, in a cream base containing ceteareth-10 phosphate, cetearyl phosphate, cetostearyl alcohol, diethylene glycol monoethyl ether, hexylene glycol, isopropyl palmitate, methylparaben, propylparaben, purified water, sodium hydroxide, and white petrolatum. Hydrochloric acid may have been added to adjust pH.

{ "type": "p", "children": [], "text": "Each gram of cream, 0.15% or 0.3%, contains 1.5 mg or 3 mg of roflumilast, respectively, in a cream base containing ceteareth-10 phosphate, cetearyl phosphate, cetostearyl alcohol, diethylene glycol monoethyl ether, hexylene glycol, isopropyl palmitate, methylparaben, propylparaben, purified water, sodium hydroxide, and white petrolatum. Hydrochloric acid may have been added to adjust pH." }

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

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 investigated 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 (AUC0-24) 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 AUC0-24 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 investigated 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 AUC0-24 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 investigated 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 AUC0-24 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 investigated 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 (AUC0-24) 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 AUC0-24 was 102 ± 96.5 and 743 ± 710 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 9.6 L/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 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.

Specific Populations

Following topical administration, no clinically significant differences in the pharmacokinetics of roflumilast and roflumilast N-oxide were observed based on age, 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 Cmax of 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 [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 (7.1)].

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 Cmax and AUC for roflumilast, respectively, and a 34% decrease and a 4% increase in Cmax and 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 Cmax and AUC for roflumilast, respectively, and a 38% reduction and 3% increase in Cmax and 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 Cmax and AUC along with a 210% decrease and 52% increase in roflumilast N-oxide Cmax and 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 Cmax and AUC of roflumilast by 20% and 56%, respectively. Roflumilast N-oxide Cmax was 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 Cmax and AUC; and a 4% decrease in Cmax and 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 Cmax of roflumilast and roflumilast N-oxide, respectively. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: In vitro studies suggest that the biotransformation of roflumilast to its N-oxide metabolite is mediated by CYP1A2 and 3A4. Based on further in vitro results 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, in vitro studies demonstrated no induction of the CYP1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weak induction of CYP2B6 by roflumilast.

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 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 (35 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 (12 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 (29 times the MRHD on a mg/m2 basis).

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, and missing in 1.6% of subjects. 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's 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 3). Success was defined as a score of "Clear" (0) or "Almost Clear" (1), plus a 2-grade improvement from baseline.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 3: IGA Treatment Success at Week 8 in Subjects with Mild to Severe Plaque Psoriasis in Trials DERMIS-1 and DERMIS-2</span> </caption> <col align="left" valign="middle" width="30%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="15%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule" rowspan="2"></th><th align="center" class="Rrule" colspan="2">DERMIS-1</th><th align="center" class="Rrule" colspan="2">DERMIS-2</th> </tr> <tr class="Botrule"> <th align="center" class="Rrule">ZORYVE Cream, 0.3%</th><th align="center" class="Rrule">Vehicle Cream</th><th align="center" class="Rrule">ZORYVE Cream, 0.3%</th><th align="center" class="Rrule">Vehicle Cream</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule">Subjects randomized</th><th align="center" class="Rrule">N=286</th><th align="center" class="Rrule">N=153</th><th align="center" class="Rrule">N=290</th><th align="center" class="Rrule">N=152</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">Abbreviations: CI = Confidence Interval</td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>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).</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Treatment difference and 95% CI are based on the CMH method stratified by site, baseline IGA, and baseline intertriginous involvement.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">IGA success<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="center" class="Rrule">41.5%</td><td align="center" class="Rrule">5.8%</td><td align="center" class="Rrule">36.7%</td><td align="center" class="Rrule">7.1%</td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">  Difference from vehicle (95% CI)<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a></td><td align="center" class="Rrule" colspan="2">39.7% (32.4%, 47.0%)</td><td align="center" class="Rrule" colspan="2">29.5% (21.5%, 37.6%)</td> </tr> </tbody> </table></div>

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.

<div class="scrollingtable"><table class="Noautorules" width="85%"> <col align="left" valign="top" width="100%"/> <thead> <tr> <th align="left">Figure 1: WI-NRS Success Over Time in Subjects with Mild to Severe Plaque Psoriasis in Trials DERMIS-1 and DERMIS-2<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></th> </tr> </thead> <tfoot> <tr> <td align="left" valign="top"><span class="Sup">†</span>The treatment difference at Week 2 in DERMIS-1 was not statistically significant.</td> </tr> <tr> <td align="left" colspan="1"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>WI-NRS success is a reduction of at least 4 points in subjects with a WI-NRS score of 4 or higher at baseline.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr> <td align="left"> <p class="First"> <img alt="Figure 1" src="/dailymed/image.cfm?name=roflumilast-02.jpg&amp;setid=ec1bb0d1-f38a-4080-831a-68791d1d1fdb"/></p> </td> </tr> </tbody> </table></div>

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%).

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 age). The trial population was 57% female; 59.5% were White, 20.3% Black or African American, 13.2% Asian, 3.4% Other, 2.8% more than one race, 0.6% American Indian or Alaska Native, and 0.1% Native Hawaiian or Other Pacific Islander. For ethnicity, 82.8% of subjects identified as Not Hispanic or Latino, 16.6% identified as Hispanic or Latino, and 0.6% were unknown. At baseline, subjects had a mean affected BSA of 14% (range of 3% to 88%), and 42% had facial involvement. At baseline, 24% of subjects had a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 2 (mild), and 76% had a vIGA-AD score of 3 (moderate). Eight hundred thirteen (60.8%) subjects 12 years of age and older had a baseline WI-NRS score of 4 or higher on a scale of 0 to 10.

The primary endpoint was the proportion of subjects who achieved vIGA-AD treatment success at Week 4 (Table 4). Success was defined as a score of "Clear" (0) or "Almost Clear" (1), plus a 2-grade improvement from baseline.

Secondary endpoints included the proportion of subjects that achieved vIGA-AD success at Weeks 2 and 1 (Figure 2) and WI-NRS success at Weeks 4, 2, and 1 (Figure 3). WI-NRS success was defined as a reduction of at least 4 points from baseline in subjects 12 years of age or older with a baseline WI-NRS score of at least 4.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 4: Efficacy Results at Week 4 in Subjects with Mild to Moderate Atopic Dermatitis in Trials INTEGUMENT-1 and INTEGUMENT-2</span> </caption> <col align="left" valign="middle" width="30%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="15%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule" rowspan="2"></th><th align="center" class="Rrule" colspan="2">INTEGUMENT-1</th><th align="center" class="Rrule" colspan="2">INTEGUMENT-2</th> </tr> <tr class="Last"> <th align="center" class="Rrule">ZORYVE Cream, 0.15%</th><th align="center" class="Rrule">Vehicle Cream</th><th align="center" class="Rrule">ZORYVE Cream, 0.15%</th><th align="center" class="Rrule">Vehicle Cream</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">Abbreviations: CI = Confidence Interval</td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-4" name="footnote-4">*</a> </dt> <dd>vIGA-AD success was defined as a vIGA-AD score of "Clear" (0) or "Almost Clear" (1), plus a 2-grade vIGA-AD score improvement from baseline at Week 4 (Multiple Imputation).</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">†</a> </dt> <dd>The difference in percent and related 95% CIs are Mantel-Haenszel estimates stratified by pooled study site and vIGA-AD randomization strata.</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">‡</a> </dt> <dd>WI-NRS success was defined as a reduction of at least 4 points from baseline for subjects 12 years of age or older with a baseline score of at least 4.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Subjects randomized</span></td><td align="center" class="Rrule"><span class="Bold">N=433</span></td><td align="center" class="Rrule"><span class="Bold">N=221</span></td><td align="center" class="Rrule"><span class="Bold">N=451</span></td><td align="center" class="Rrule"><span class="Bold">N=232</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">vIGA-AD success<a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a></td><td align="center" class="Rrule">32.0%</td><td align="center" class="Rrule">15.2%</td><td align="center" class="Rrule">28.9%</td><td align="center" class="Rrule">12.0%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Difference from vehicle (95% CI)<a class="Sup" href="#footnote-5" name="footnote-reference-5">†</a></td><td align="center" class="Rrule" colspan="2">17.4% (11.09%, 23.75%)</td><td align="center" class="Rrule" colspan="2">16.5% (10.61%, 22.42%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Subjects ≥12 years randomized with baseline WI-NRS ≥4</span></td><td align="center" class="Rrule"><span class="Bold">N=278</span></td><td align="center" class="Rrule"><span class="Bold">N=135</span></td><td align="center" class="Rrule"><span class="Bold">N=264</span></td><td align="center" class="Rrule"><span class="Bold">N=136</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">WI-NRS success<a class="Sup" href="#footnote-6" name="footnote-reference-6">‡</a></td><td align="center" class="Rrule">33.6%</td><td align="center" class="Rrule">20.7%</td><td align="center" class="Rrule">30.2%</td><td align="center" class="Rrule">12.4%</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Difference from vehicle (95% CI)<a class="Sup" href="#footnote-5">†</a></td><td align="center" class="Rrule" colspan="2">13.3% (4.01%, 22.60%)</td><td align="center" class="Rrule" colspan="2">15.0% (6.52%, 23.54%)</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="85%"> <col align="left" valign="top" width="100%"/> <thead> <tr> <th align="left">Figure 2: vIGA-AD Success Over Time in Subjects with Mild to Moderate Atopic Dermatitis in Trials INTEGUMENT-1 and INTEGUMENT-2<a class="Sup" href="#footnote-7" name="footnote-reference-7">*</a></th> </tr> </thead> <tfoot> <tr> <td align="left" valign="top"><span class="Sup">†</span>The treatment difference at Week 1 in INTEGUMENT-2 was not statistically significant.</td> </tr> <tr> <td align="left" colspan="1"> <dl class="Footnote"> <dt> <a href="#footnote-reference-7" name="footnote-7">*</a> </dt> <dd>vIGA-AD success was defined as a vIGA-AD score of "Clear" (0) or "Almost Clear" (1), plus a 2-grade vIGA-AD score improvement from baseline at Week 4 (Multiple Imputation).</dd> </dl> </td> </tr> </tfoot> <tbody> <tr> <td align="left"> <p class="First"> <img alt="Figure 2" src="/dailymed/image.cfm?name=roflumilast-03.jpg&amp;setid=ec1bb0d1-f38a-4080-831a-68791d1d1fdb"/></p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="85%"> <col align="left" valign="top" width="100%"/> <thead> <tr> <th align="left">Figure 3: WI-NRS Success Over Time in Subjects with Mild to Moderate Atopic Dermatitis in Trials INTEGUMENT-1 and INTEGUMENT-2<a class="Sup" href="#footnote-8" name="footnote-reference-8">*</a></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="1"> <dl class="Footnote"> <dt> <a href="#footnote-reference-8" name="footnote-8">*</a> </dt> <dd>WI-NRS success in subjects 12 years of age or older is a reduction of at least 4 points in subjects with a WI-NRS score of 4 or higher at baseline.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr> <td align="left"> <p class="First"> <img alt="Figure 3" src="/dailymed/image.cfm?name=roflumilast-04.jpg&amp;setid=ec1bb0d1-f38a-4080-831a-68791d1d1fdb"/></p> </td> </tr> </tbody> </table></div>

How Supplied

ZORYVE (roflumilast) cream is a white to off-white cream supplied as follows:

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]

Lactation

Advise patients to use ZORYVE cream on the smallest area of skin and for the shortest duration possible while breastfeeding. Instruct patients who are breastfeeding not to apply ZORYVE cream 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)].

Marketed by: Arcutis Biotherapeutics, Inc.Westlake Village, CA 91361For more information, call 1-805-418-5006 or visit http://www.zoryve.com.

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© 2024 Arcutis Biotherapeutics, Inc. All rights reserved.

{ "type": "p", "children": [], "text": "© 2024 Arcutis Biotherapeutics, Inc. All rights reserved." }

v5

{ "type": "p", "children": [], "text": "v5 " }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="2%"/> <col align="left" valign="top" width="30%"/> <col align="left" valign="top" width="50%"/> <col align="left" valign="top" width="18%"/> <thead> <tr class="Botrule First Last Toprule"> <th align="center" class="Lrule Rrule" colspan="4">Patient Information<br/>ZORYVE<span class="Sup">®</span> (zor-EEV)<br/>(roflumilast) cream</th> </tr> </thead> <tfoot> <tr class="First"> <td align="left" colspan="3">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align="right">Revised: 7/2024</td> </tr> <tr class="Last"> <td align="left" colspan="4">v3</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Important information: ZORYVE cream is for use on the skin (topical use) only.</span> Do not use ZORYVE cream in or on your eyes, mouth, or vagina.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">What is ZORYVE cream?</span> <ul class="Disc"> <li>ZORYVE cream 0.3% is a prescription medicine used on the skin (topical), including in areas with skin folds, to treat plaque psoriasis in people 6 years of age and older. It is not known if ZORYVE cream 0.3% is safe and effective in children with plaque psoriasis under 6 years of age.</li> <li>ZORYVE cream 0.15% is a prescription medicine used on the skin (topical) to treat mild to moderate eczema (atopic dermatitis) in people 6 years of age and older. It is not known if ZORYVE cream 0.15% is safe and effective in children with mild to moderate eczema (atopic dermatitis) under 6 years of age.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Do not use ZORYVE cream if</span> you have certain liver problems.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Before using ZORYVE cream, tell your healthcare provider about all of your medical conditions, including if you:</span> <ul class="Disc"> <li>have liver problems.</li> <li>are pregnant or plan to become pregnant. It is not known if ZORYVE cream will harm your unborn baby.</li> <li>are breastfeeding or plan to breastfeed. It is not known if ZORYVE cream passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with ZORYVE cream.<br/> Breastfeeding women using ZORYVE cream should use it on the smallest area of the skin and for the shortest time needed. Do not apply ZORYVE cream directly to the nipple or areola to avoid contact with your baby.</li> </ul> <span class="Bold">Tell your healthcare provider about the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">How should I use ZORYVE cream?</span> <ul class="Disc"> <li>Use ZORYVE cream exactly as your healthcare provider tells you to use it.</li> <li>Apply ZORYVE cream to the affected areas 1 time a day. Rub the cream in completely until you no longer see it on your skin.</li> <li>Wash your hands after applying ZORYVE cream, unless your hands are being treated. If someone else applies ZORYVE cream for you, they should wash their hands after applying it.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">What are the possible side effects of ZORYVE cream?<br/>The most common side effects of ZORYVE cream 0.3% in people treated for plaque psoriasis include:</span></td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left"> <ul class="Disc"> <li>diarrhea</li> <li>headache</li> <li>trouble sleeping</li> <li>nausea</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul class="Disc"> <li>application site pain</li> <li>upper respiratory tract infections</li> <li>urinary tract infections (UTIs)</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">The most common side effects of ZORYVE cream 0.15% in people treated for atopic dermatitis include:</span></td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left"> <ul class="Disc"> <li>headache</li> <li>nausea</li> <li>application site pain</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul class="Disc"> <li>diarrhea</li> <li>vomiting</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4">These are not all of the possible side effects of ZORYVE cream.<br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.<br/>You may also report side effects to Arcutis Biotherapeutics, Inc. by calling 1-844-692-6729.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">How should I store ZORYVE cream?</span> <ul class="Disc"> <li>Store ZORYVE cream at room temperature from 68°F to 77°F (20°C to 25°C).</li> </ul> <span class="Bold">Keep ZORYVE cream and all medicines out of the reach of children.</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">General information about the safe and effective use of ZORYVE cream.</span> <br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ZORYVE cream for a condition for which it was not prescribed. Do not give ZORYVE cream to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about ZORYVE cream that is written for health professionals. </td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">What are the ingredients in ZORYVE cream?</span> <br/> <span class="Bold">Active ingredient:</span> roflumilast<br/> <span class="Bold">Inactive ingredients:</span> ceteareth-10 phosphate, cetearyl phosphate, cetostearyl alcohol, diethylene glycol monoethyl ether, hexylene glycol, isopropyl palmitate, methylparaben, propylparaben, purified water, sodium hydroxide, and white petrolatum. Hydrochloric acid may have been added to adjust pH.<br/> <span class="Bold">Marketed by:</span> Arcutis Biotherapeutics, Inc.<br/> Westlake Village, CA 91361<br/> For more information, call 1-844-692-6729 or visit http://www.zoryve.com. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"2%\"/>\n<col align=\"left\" valign=\"top\" width=\"30%\"/>\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<col align=\"left\" valign=\"top\" width=\"18%\"/>\n<thead>\n<tr class=\"Botrule First Last Toprule\">\n<th align=\"center\" class=\"Lrule Rrule\" colspan=\"4\">Patient Information<br/>ZORYVE<span class=\"Sup\">®</span> (zor-EEV)<br/>(roflumilast) cream</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First\">\n<td align=\"left\" colspan=\"3\">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\">Revised: 7/2024</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" colspan=\"4\">v3</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Important information: ZORYVE cream is for use on the skin (topical use) only.</span> Do not use ZORYVE cream in or on your eyes, mouth, or vagina.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">What is ZORYVE cream?</span>\n<ul class=\"Disc\">\n<li>ZORYVE cream 0.3% is a prescription medicine used on the skin (topical), including in areas with skin folds, to treat plaque psoriasis in people 6 years of age and older. It is not known if ZORYVE cream 0.3% is safe and effective in children with plaque psoriasis under 6 years of age.</li>\n<li>ZORYVE cream 0.15% is a prescription medicine used on the skin (topical) to treat mild to moderate eczema (atopic dermatitis) in people 6 years of age and older. It is not known if ZORYVE cream 0.15% is safe and effective in children with mild to moderate eczema (atopic dermatitis) under 6 years of age.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Do not use ZORYVE cream if</span> you have certain liver problems.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Before using ZORYVE cream, tell your healthcare provider about all of your medical conditions, including if you:</span>\n<ul class=\"Disc\">\n<li>have liver problems.</li>\n<li>are pregnant or plan to become pregnant. It is not known if ZORYVE cream will harm your unborn baby.</li>\n<li>are breastfeeding or plan to breastfeed. It is not known if ZORYVE cream passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with ZORYVE cream.<br/> Breastfeeding women using ZORYVE cream should use it on the smallest area of the skin and for the shortest time needed. Do not apply ZORYVE cream directly to the nipple or areola to avoid contact with your baby.</li>\n</ul>\n<span class=\"Bold\">Tell your healthcare provider about the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements. \t\t\t\t\t\t\t\t\t</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">How should I use ZORYVE cream?</span>\n<ul class=\"Disc\">\n<li>Use ZORYVE cream exactly as your healthcare provider tells you to use it.</li>\n<li>Apply ZORYVE cream to the affected areas 1 time a day. Rub the cream in completely until you no longer see it on your skin.</li>\n<li>Wash your hands after applying ZORYVE cream, unless your hands are being treated. If someone else applies ZORYVE cream for you, they should wash their hands after applying it.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">What are the possible side effects of ZORYVE cream?<br/>The most common side effects of ZORYVE cream 0.3% in people treated for plaque psoriasis include:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\">\n<ul class=\"Disc\">\n<li>diarrhea</li>\n<li>headache</li>\n<li>trouble sleeping</li>\n<li>nausea</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>application site pain</li>\n<li>upper respiratory tract infections</li>\n<li>urinary tract infections (UTIs)</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">The most common side effects of ZORYVE cream 0.15% in people treated for atopic dermatitis include:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\">\n<ul class=\"Disc\">\n<li>headache</li>\n<li>nausea</li>\n<li>application site pain</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>diarrhea</li>\n<li>vomiting</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\">These are not all of the possible side effects of ZORYVE cream.<br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.<br/>You may also report side effects to Arcutis Biotherapeutics, Inc. by calling 1-844-692-6729.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">How should I store ZORYVE cream?</span>\n<ul class=\"Disc\">\n<li>Store ZORYVE cream at room temperature from 68°F to 77°F (20°C to 25°C).</li>\n</ul>\n<span class=\"Bold\">Keep ZORYVE cream and all medicines out of the reach of children.</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">General information about the safe and effective use of ZORYVE cream.</span>\n<br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ZORYVE cream for a condition for which it was not prescribed. Do not give ZORYVE cream to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about ZORYVE cream that is written for health professionals. \t\t\t\t\t\t\t\t\t</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">What are the ingredients in ZORYVE cream?</span>\n<br/>\n<span class=\"Bold\">Active ingredient:</span> roflumilast<br/>\n<span class=\"Bold\">Inactive ingredients:</span> ceteareth-10 phosphate, cetearyl phosphate, cetostearyl alcohol, diethylene glycol monoethyl ether, hexylene glycol, isopropyl palmitate, methylparaben, propylparaben, purified water, sodium hydroxide, and white petrolatum. Hydrochloric acid may have been added to adjust pH.<br/>\n<span class=\"Bold\">Marketed by:</span> Arcutis Biotherapeutics, Inc.<br/> Westlake Village, CA 91361<br/> For more information, call 1-844-692-6729 or visit http://www.zoryve.com. \t\t\t\t\t\t\t\t\t</td>\n</tr>\n</tbody>\n</table></div>" }

NDC 80610-130-60

{ "type": "p", "children": [], "text": "NDC 80610-130-60" }

ZORYVE® (roflumilast) cream 0.3%

{ "type": "p", "children": [], "text": "ZORYVE®\n (roflumilast) cream 0.3%" }

For Topical Use Only Not for oral, ophthalmic, or intravaginal use

{ "type": "p", "children": [], "text": "For Topical Use Only Not for oral, ophthalmic, or intravaginal use" }

Rx Only Net Wt. 60 g

{ "type": "p", "children": [], "text": "Rx Only Net Wt. 60 g" }

ARCUTIS®

{ "type": "p", "children": [], "text": "ARCUTIS®\n" }

NDC 80610-115-60

{ "type": "p", "children": [], "text": "NDC 80610-115-60" }

ZORYVE® (roflumilast) cream 0.15%

{ "type": "p", "children": [], "text": "ZORYVE®\n (roflumilast) cream 0.15%" }

For Topical Use Only Not for oral, ophthalmic, or intravaginal use

{ "type": "p", "children": [], "text": "For Topical Use Only Not for oral, ophthalmic, or intravaginal use" }

Rx Only Net Wt. 60 g

{ "type": "p", "children": [], "text": "Rx Only Net Wt. 60 g" }

ARCUTIS®

{ "type": "p", "children": [], "text": "ARCUTIS®\n" }

Roflumilast Tablets are indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.

{ "type": "p", "children": [], "text": "Roflumilast Tablets are indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations." }

Limitations of Use 

{ "type": "p", "children": [], "text": "\nLimitations of Use \n" }

Roflumilast Tablets are not a bronchodilator and is not indicated for the relief of acute bronchospasm. Roflumilast Tablets 250 mcg is a starting dose, for the first 4 weeks of treatment only and is not the effective (therapeutic) dose.

{ "type": "p", "children": [], "text": "Roflumilast Tablets are not a bronchodilator and is not indicated for the relief of acute bronchospasm. Roflumilast Tablets 250 mcg is a starting dose, for the first 4 weeks of treatment only and is not the effective (therapeutic) dose." }

The maintenance dose of Roflumilast Tablet is one 500 micrograms (mcg) tablet per day, with or without food.

{ "type": "p", "children": [], "text": "The maintenance dose of Roflumilast Tablet is one 500 micrograms (mcg) tablet per day, with or without food." }

Starting treatment with a dose of Roflumilast Tablet 250 mcg once daily for 4 weeks and increasing to Roflumilast Tablet 500 mcg once daily thereaftermay reduce the rate of treatment discontinuation in some patients [see Clinical Studies (14.1)]. However, 250 mcg per day is not the effective (therapeutic) dose.

{ "type": "p", "children": [], "text": "Starting treatment with a dose of Roflumilast Tablet 250 mcg once daily for 4 weeks and increasing to Roflumilast Tablet 500 mcg once daily thereaftermay reduce the rate of treatment discontinuation in some patients [see Clinical Studies (14.1)]. However, 250 mcg per day is not the effective (therapeutic) dose." }

{ "type": "", "children": [], "text": "" }

The use of Roflumilast Tablets are contraindicated in the following condition: Moderate to severe liver impairment (Child-Pugh B or C) [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6)].

{ "type": "p", "children": [], "text": "The use of Roflumilast Tablets are contraindicated in the following condition: Moderate to severe liver impairment (Child-Pugh B or C) [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6)].\n\n" }

Roflumilast Tablets are not a bronchodilator and should not be used for the relief of acute bronchospasm.

Treatment with Roflumilast Tablets are associated with an increase in psychiatric adverse reactions. In 8 controlled clinical trials 5.9% (263) of patients treated with Roflumilast Tablets 500 mcg daily reported psychiatric adverse reactions compared to 3.3% (137) treated with placebo. The most commonly reported psychiatric adverse reactions were insomnia, anxiety, and depression which were reported at higher rates in those treated with Roflumilast Tablets 500 mcg daily (2.4%, 1.4%, and 1.2% for Roflumilast Tablets versus 1.0%, 0.9%, and 0.9% for placebo, respectively) [see Adverse Reactions (6.1)]. Instances of suicidal ideation and behavior, including completed suicide, have been observed in clinical trials. Three patients experienced suicide-related adverse reactions (one completed suicide and two suicide attempts) while receiving Roflumilast Tablets compared to one patient (suicidal ideation) who received placebo. One patient completed suicide while receiving Roflumilast Tablets in Trial 9 [see Clinical Studies (14.1)], which assessed the effect of adding roflumilast to a fixed-dose combination (FDC) of ICS/LABA on rates of exacerbations in COPD patients over 1 year of treatment. Cases of suicidal ideation and behavior, including completed suicide, have been observed in the post-marketing setting in patients with or without a history of depression. Before using Roflumilast Tablets in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with Roflumilast Tablets in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with Roflumilast Tablets if such events occur.

Weight loss was a common adverse reaction in Roflumilast Tablets clinical trials and was reported in 7.5% (331) of patients treated with Roflumilast Tablets 500 mcg once daily compared to 2.1% (89) treated with placebo [see Adverse Reactions (6.1)]. In addition to being reported as adverse reactions, weight was prospectively assessed in two placebo-controlled clinical trials of one year duration. In these studies, 20% of patients receiving roflumilast experienced moderate weight loss (defined as between 5-10% of body weight) compared to 7% of patients who received placebo. In addition, 7% of patients who received roflumilast compared to 2% of patients receiving placebo experienced severe (>10% body weight) weight loss. During follow-up after treatment discontinuation, the majority of patients with weight loss regained some of the weight they had lost while receiving Roflumilast Tablets. Patients treated with Roflumilast Tablets should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of Roflumilast Tablets should be considered.

A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. The administration of the cytochrome P450 enzyme inducer rifampicin resulted in a reduction in exposure, which may result in a decrease in the therapeutic effectiveness of Roflumilast Tablets. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin) with Roflumilast Tablets are not recommended [see Drug interactions (7.1)and Clinical Pharmacology (12.3)].

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.

The safety data described below reflect exposure of 4438 patients to Roflumilast Tablets 500 mcg once daily in four 1- year placebo-controlled trials, two 6-month placebo-controlled trials, and two 6-month drug add-on trials [see Clinical Studies (14.1)]. In these trials, 3136 and 1232 COPD patients were exposed to Roflumilast Tablets 500 mcg once daily for 6 months and 1 year, respectively.

The population had a median age of 64 years (range 40-91), 73% were male, 92.9% were Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) of 8.9 to 89.1% predicted. In these trials, 68.5% of the patients treated with Roflumilast Tablets reported an adverse reaction compared with 65.3% treated with placebo.

The proportion of patients who discontinued treatment due to adverse reaction was 14.8% for Roflumilast Tablets-treated patients and 9.9% for placebo-treated patients. The most common adverse reactions that led to discontinuation of Roflumilast Tablets were diarrhea (2.4%) and nausea (1.6%).

Serious adverse reactions, whether considered drug-related or not by the investigators, which occurred more frequently in Roflumilast Tablets -treated patients include diarrhea, atrial fibrillation, lung cancer, prostate cancer, acute pancreatitis, and acute renal failure.

Table 1 summarizes the adverse reactions reported by ≥ 2% of patients in the Roflumilast Tablets group in 8 controlled COPD clinical trials.

Table 1:           Adverse Reactions Reported by ≥ 2% of Patients Treated with Roflumilast Tablets 500 mcg daily and Greater Than Placebo

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="33%"/> <col width="34%"/> <col width="33%"/> <tbody class="Headless"> <tr class="First"> <td align="justify" class="Botrule Lrule Rrule Toprule" rowspan="4" valign="top"> <p class="First"> <span class="Bold">Adverse Reactions </span> <br/> (Preferred Term)<br/> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Treatment</span> <br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Roflumilast Tablets</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Placebo</span> <br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">(<span class="Bold">N=</span>4438)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">(N=</span>4192)<br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">n (%)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">n (%)<br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Diarrhea<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">420 (9.5)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">113 (2.7)<br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Weight decreased<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">331 (7.5)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">89 (2.1)<br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Nausea<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">209 (4.7)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">60 (1.4)<br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Headache<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">195 (4.4)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">87 (2.1)<br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Back pain<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">142 (3.2)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">92 (2.2)<br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Influenza<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">124 (2.8)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">112 (2.7)<br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Insomnia<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">105 (2.4)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">41 (1.0)<br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Dizziness<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">92 (2.1)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">45 (1.1)<br/> </p> </td> </tr> <tr class="Last"> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Decreased appetite<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">91 (2.1)<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">15 (0.4)<br/> </p> </td> </tr> </tbody> </table></div>

Adverse reactions that occurred in the Roflumilast Tablets group at a frequency of 1 to 2% where rates exceeded that in the placebo group include:

Gastrointestinal disorders - abdominal pain, dyspepsia, gastritis, vomiting

Infections and infestations - rhinitis, sinusitis, urinary tract infection,

Musculoskeletal and connective tissue disorders - muscle spasms

Nervous system disorders - tremor

Psychiatric disorders - anxiety, depression The safety profile of roflumilast reported during Trial 9 was consistent with the key pivotal studies.

The following adverse reactions have been identified from spontaneous reports of Roflumilast Tablets received worldwide and have not been listed elsewhere. These adversereactions have been chosen for inclusion due to a combination of seriousness,frequency of reporting or potential causal connection to Roflumilast Tablets.Because these adverse reactions were reported voluntarily from a population ofuncertain size, it is not possible to estimate their frequency or establish a causal relationship to Roflumilast Tablets exposure: hypersensitivity reactions (including angioedema, urticaria, and rash), gynecomastia.

Strong cytochrome P450 enzyme inducers decrease systemic exposure to roflumilast and may reduce the therapeutic effectiveness of Roflumilast Tablets. Therefore the use of strong cytochrome P450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, and phenytoin) with Roflumilast Tablets is not recommended [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

The co-administration of Roflumilast Tablets (500 mcg) with CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) may increase roflumilast systemic exposure and may result in increased adverse reactions. The risk of such concurrent use should be weighed carefully against benefit [see Clinical Pharmacology (12.3)].

The co-administration of Roflumilast Tablets (500 mcg) with oral contraceptives containing gestodene and ethinyl estradiol may increase roflumilast systemic exposure and may result in increased side effects. The risk of such concurrent use should be weighed carefully against benefit [see Clinical Pharmacology (12.3)].

Risk summary There are no randomized clinical studies of Roflumilast Tablets in pregnant women. In animal reproductive toxicity studies, Roflumilast Tablets administered to pregnant rats and rabbits during the period of organogenesis produced no fetal structural abnormalities. The highest Roflumilast Tablets dose in these studies was approximately 30 and 26 times, respectively, the maximum recommended human dose (MRHD). Roflumilast Tablets induced post-implantation loss in rats at doses greater than or equal to approximately 10 times the MRHD. Roflumilast Tablets induced stillbirth and decreased pup viability in mice at doses corresponding to approximately 16 and 49 times, respectively, the MRHD. Roflumilast Tablets has been shown to adversely affect pup post-natal development when dams were treated with the drug during pregnancy and lactation periods in mice at doses corresponding to 49 times the MRHD (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. 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 Roflumilast Tablets should not be used during labor and delivery. There are no human studies that have investigated effects of Roflumilast Tablets on preterm labor or labor at term; however, animal studies showed that Roflumilast Tablets 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 Tablets (approximately 30 times the MRHD on an AUC basis). No evidence of structural abnormalities or effects on survival rates were observed. Roflumilast Tablets did not affect embryo-fetal development at approximately 3 times the MRHD (on a mg/m2 basis at a maternal oral dose of 0.2 mg/kg/day). In a fertility and embryo-fetal development study, male rats were dosed orally with up to 1.8 mg/kg/day Roflumilast Tablets for 10 weeks and females for two weeks prior to pairing and throughout the organogenesis period. Roflumilast Tablets induced pre- and post-implantation loss at doses greater than or equal to approximately 10 times the MRHD (on a mg/m2 basis at maternal oral doses greater than or equal to 0.6 mg/kg/day). Roflumilast Tablets did not cause fetal structural abnormalities at exposures up to approximately 29 times the MRHD (on an AUC basis at maternal oral doses up to 1.8 mg/kg/day). In an embryo-fetal development study in rabbits, pregnant does were dosed orally with 0.8 mg/kg/day Roflumilast Tablets during the period of organogenesis. Roflumilast Tablets did not cause fetal structural abnormalities at exposures approximately 26 times the MRHD (on a mg/m2 basis at maternal oral doses of 0.8 mg/kg/day). In pre- and post-natal developmental studies in mice, dams were dosed orally with up to 12 mg/kg/day Roflumilast Tablets during the period of organogenesis and lactation. Roflumilast Tablets induced stillbirth and decreased pup viability at doses corresponding to approximately 16 and 49 times, respectively, the MRHD (on a mg/m2 basis at maternal doses >2 mg/kg/day and 6 mg/kg/day, respectively). Roflumilast Tablets induced delivery retardation in pregnant mice at doses greater or equal to approximately 16 times the MRHD (on a mg/m2 basis at maternal doses  >2 mg/kg/day). Roflumilast Tablets decreased pup rearing frequencies at approximately 49 times the MRHD (on a mg/m2 basis at a maternal dose of 6 mg/kg/day) during pregnancy and lactation. Roflumilast Tablets also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at approximately 97 times the MRHD (on a mg/m2 basis at a maternal dose of 12 mg/kg/day).

Risk Summary There is no information regarding the presence of Roflumilast Tablets 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. Excretion of roflumilast and/or its metabolites into human milk is probable. Roflumilast Tablets should not be used by women who are nursing. 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 0.32 and 0.02 mcg/g in the milk and pup liver, respectively.

COPD does not normally occur in children. The safety and effectiveness of RoflumilastTablets in pediatric patients have not been established.

Of the 4438 COPD subjects exposed to Roflumilast Tablets for up to 12 months in 8 controlled clinical trials, 2022 were > 65 years of age and 471 were > 75 years of age. 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. Based on available data for roflumilast, no adjustment of dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3)].

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 AUCs 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 Cmax of 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. Roflumilast Tablets 500 mcg has not been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering Roflumilast Tablets to patients who have mild liver impairment (Child-Pugh A). Roflumilast Tablets are not recommended for use in patients with moderate or severe liver impairment (Child-Pugh B or C) [see Contraindications (4) and Clinical Pharmacology (12.3)].

In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, the AUCs of roflumilast and roflumilast N-oxide were decreased by 21% and 7%, respectively and Cmax were reduced by 16% and 12%, respectively. No dosage adjustment is necessary for patients with renal impairment [see ClinicalPharmacology (12.3)].

No case of overdose has been reported in clinical studies with Roflumilast Tablets.During the Phase I studies of Roflumilast Tablets, the following symptoms were observed at an increased rate after a single oral dose of 2,500 mcg and a singledose of 5,000 mcg: headache, gastrointestinal disorders, dizziness,palpitations, lightheadedness, clamminess and arterial hypotension.

In case of overdose, patients should seek immediate medical help. Appropriate supportive medical care should be provided. Since roflumilast is highly protein bound, hemodialysis is not likely to be an efficient method of drug removal. It is not known whether roflumilast is dialyzable by peritoneal dialysis.

The active ingredient in Roflumilast Tablets is roflumilast. Roflumilast and its active metabolite (roflumilast N-oxide) are selective phosphodiesterase 4 (PDE4) inhibitors. The chemical name of roflumilast is N-(3,5- dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide. Its molecular formula is C17H14Cl2F2N2O3 and the molecular weight is 403.22.

{ "type": "p", "children": [], "text": "The active ingredient in Roflumilast Tablets is roflumilast. Roflumilast and its active metabolite (roflumilast N-oxide) are selective phosphodiesterase 4 (PDE4) inhibitors. The chemical name of roflumilast is N-(3,5- dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide. Its molecular formula is C17H14Cl2F2N2O3 and the molecular weight is 403.22." }

The chemical structure is:

{ "type": "p", "children": [], "text": "The chemical structure is:\n" }

The drug substance is a white to off-white non-hygroscopic powder with a melting point of 160°C. It is practically insoluble in water and hexane, sparingly soluble in ethanol and methanol, and soluble in N,N-Dimethyl formamide.

{ "type": "p", "children": [], "text": "The drug substance is a white to off-white non-hygroscopic powder with a melting point of 160°C. It is practically insoluble in water and hexane, sparingly soluble in ethanol and methanol, and soluble in N,N-Dimethyl formamide. " }

Roflumilast Tablets are supplied as white to off-white, round, flat face bevel edged, uncoated tablets, debossed with “R” on one side and “0.25” or “0.5” on the other side. Each tablet contains 250 mcg or 500 mcg of roflumilast.

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Each tablet of Roflumilast Tablets for oral administration contains the following inactive ingredients: lactose monohydrate, magnesium stearate, polysorbate 80 and pregelatinised starch.

{ "type": "p", "children": [], "text": "Each tablet of Roflumilast Tablets for oral administration contains the following inactive ingredients: lactose monohydrate, magnesium stearate, polysorbate 80 and pregelatinised starch." }

Roflumilast and its active metabolite (roflumilast N-oxide) are selective inhibitors of phosphodiesterase 4 (PDE4). Roflumilast and roflumilast N-oxide inhibition of PDE4 (a major cyclic-3′,5′-adenosinemonophosphate (cyclic AMP)-metabolizing enzyme in lung tissue) activity leads to accumulation of intracellular cyclic AMP. While the specific mechanism(s) bywhich Roflumilast Tablets exerts its therapeutic action in COPD patients is not well defined, it is thought to be related to the effects of increased intracellular cyclic AMP in lung cells.

In COPD patients, 4-week treatment with Roflumilast Tablets 500 mcg oral once daily reduced sputum neutrophils and eosinophils by 31%, and 42%, respectively. In a pharmacodynamic study in healthy volunteers, Roflumilast Tablets 500 mcg once daily reduced the number of total cells, neutrophils and eosinophils found in bronchoalveolar lavage fluid following segmental pulmonary lipopolysaccharide (LPS) challenge by 35%, 38% and 73%, respectively. The clinical significance of these findings is unknown.

Absorption

The absolute bioavailability of roflumilast following a 500 mcg oral dose is approximately 80%. Maximum plasma concentrations (Cmax) of roflumilast typically occur approximately one hour after dosing (ranging from 0.5 to 2 hours) in the fasted state while plateau-like maximum concentrations of the N-oxide metabolite are reached in approximately eight hours (ranging from 4 to 13 hours). Food has no effect on total drug absorption, but delays time to maximum concentration (Tmax) of roflumilast by one hour and reduces Cmax by approximately 40%, however, Cmax and Tmax of roflumilast N-oxide are unaffected. An in vitro study showed that roflumilast and roflumilast N-oxide did not inhibit P-gp transporter.

Distribution

Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively. Volume of distribution for single-dose 500 mcg roflumilast is about 2.9 L/kg. Studies in rats with radiolabeled roflumilast indicate low penetration across the blood-brain barrier.

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. Together, roflumilast and roflumilast N-oxide account for the majority (87.5%) of total dose administered in plasma. In urine, roflumilast was not detectable 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 three 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 about 10-fold greater than the plasma AUC of roflumilast.

In vitro studies and clinical drug-drug interaction studies suggest that the biotransformation of roflumilast to its N-oxide metabolite is mediated by CYP1A2 and 3A4. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of roflumilast and roflumilast N-oxide 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, in vitro studies demonstrated no induction of the CYP1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weak induction of CYP2B6 by roflumilast.

Elimination

The plasma clearance after short-term intravenous infusion of roflumilast is on average about 9.6 L/h. Following an oral dose, the median plasma effective half-life of roflumilast and its N-oxide metabolite are approximately 17 and 30 hours, respectively. Steady state plasma concentrations of roflumilast and its N-oxide metabolite are reached after approximately 4 days for roflumilast and 6 days for roflumilast N-oxide following once-daily dosing. Following intravenous or oral administration of radiolabeled roflumilast, about 70% of the radioactivity was recovered in the urine.

Special Populations

Hepatic Impairment

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 Cmax of 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. Roflumilast Tablets 500 mcg has not been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering Roflumilast Tablets to patients who have mild liver impairment (Child-Pugh A). Roflumilast Tablets is not recommended for use in patients with moderate or severe liver impairment (Child-Pugh B or C) [see Contraindications (4) and Use in Specific Populations (8.6)].

Renal Impairment

In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, roflumilast and roflumilast N-oxide AUCs were decreased by 21% and 7%, respectively and Cmax were reduced by 16% and 12%, respectively. No dosage adjustment is necessary for patients with renal impairment [see Use in Specific Populations (8.7)].

Age

Roflumilast 500 mcg once daily for 15 days was studied in young, middle aged, and elderly healthy subjects.The exposure in elderly (> 65 years of age) were 27% higher in AUC and 16% higher in Cmax for roflumilast and 19% higher in AUC and 13% higher in Cmax for roflumilast-N-oxide than that in young volunteers (18-45 years old). No dosage adjustment is necessary for elderly patients [see Use in Specific Populations (8.5)].

Gender

In a Phase I study evaluating the effect of age and gender on the pharmacokinetics of roflumilast and roflumilast N-oxide, a 39% and 33% increase in roflumilast and roflumilast N-oxide AUC were noted in healthy female subjects as compared to healthy male subjects. No dosage adjustment is necessary based on gender.

Smoking

The pharmacokinetics of roflumilast and roflumilast N-oxide were comparable in smokers as compared to non-smokers. There was no difference in Cmax between smokers and non-smokers when roflumilast 500 mcg was administered as a single dose to 12 smokers and 12 non-smokers. The AUC of roflumilast in smokers was 13% less than that in non-smokers while the AUC of roflumilast N-oxide in smokers was 17% more than that in non-smokers.

Race

As compared to Caucasians, African Americans, Hispanics, and Japanese showed 16%, 41%, and 15% higher AUC, respectively, for roflumilast and 43%, 27%, and 16% higher AUC, respectively, for roflumilast N-oxide. As compared to Caucasians, African Americans, Hispanics, and Japanese showed 8%, 21%, and 5% higher Cmax, respectively, for roflumilast and 43%, 27%, and 17% higher Cmax, respectively, for roflumilast N-oxide. No dosage adjustment is necessary for race.

Drug Interactions

Drug interaction studies were performed with roflumilast and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction [see Drug Interactions ( 7 )]. No significant drug interactions were observed when 500 mcg oral roflumilast was administered with inhaled salbutamol, formoterol, budesonide and oral montelukast, digoxin, theophylline, warfarin, sildenafil, midazolam, or antacids.

The effect of concomitant drugs on the exposure of roflumilast and roflumilast N-oxide is shown in the Figure 1 below.

Figure 1. Effect of concomitant drugs on the exposure of roflumilast and roflumilast N-oxide. Note that the dashed lines indicate the lower and higher bounds (0.8-1.25) of the 90% confidence interval of the geometric mean ratio of Cmax or AUC for roflumilast or roflumilast N-oxide for Treatment (Roflumilast Tablets + Coadministered Drug) vs. Reference (Roflumilast Tablets). The dosing regimens of coadministered drugs was: Midazolam: 2 mg po SD; Erythromycin: 500 mg po TID; Ketoconazole: 200 mg po BID; Rifampicin: 600 mg po QD; Fluvoxamine: 50 mg po QD; Digoxin: 250 mcg po SD; Maalox: 30 mL po SD; Salbutamol: 0.2 mg po TID; Cimetidine: 400 mg po BID; Formoterol: 40 mcg po BID; Budesonide: 400 mcg po BID; Theophylline:375 mg po BID; Warfarin: 250 mg po SD; Enoxacin: 400 mg po BID; Sildenafil:100 mg SD; Minulet (combination oral contraceptive): 0.075 mg gestodene/0.03 mg ethinylestradiol po QD; Montelukast:10 mg po QD

Drug interactions considered to be significant are described in more detail below [see Warnings and Precautions (5.4) and Drug Interactions (7)]. Inhibitors of CYP3A4 and CYP1A2:

Erythromycin: In an open-label crossover study in 16 healthy volunteers, the coadministration of CYP3A4 inhibitor erythromycin (500 mg three times daily for 13 days) with a single oral dose of 500 mcg Roflumilast Tablets resulted in 40% and 70% increase in Cmax and AUC for roflumilast, respectively, and a 34% decrease and a 4% increase in Cmax and AUC for roflumilast N-oxide, respectively.

Ketoconazole: In an open-label crossover study in 16 healthy volunteers, the coadministration of a strong CYP3A4 inhibitor ketoconazole (200 mg twice daily for 13 days) with a single oral dose of 500 mcg Roflumilast Tablets resulted in 23% and 99% increase in Cmax and AUC for roflumilast, respectively, and a 38% reduction and 3% increase in Cmax and AUC for roflumilast N-oxide, respectively.

Fluvoxamine: In an open-label crossover study in 16 healthy volunteers, the coadministration of dual CYP3A4/1A2 inhibitor fluvoxamine (50 mg daily for 14 days) with a single oral dose of 500 mcg Roflumilast Tablets showed a 12% and 156% increase in roflumilast Cmax and AUC along with a 210% decrease and 52% increase in roflumilast N-oxide Cmax and AUC, respectively.

Enoxacin: In an open-label crossover study in 16 healthy volunteers, the coadministration of dual CYP3A4/1A2 inhibitor enoxacin (400 mg twice daily for 12 days) with a single oral dose of 500 mcg Roflumilast Tablets resulted in an increased Cmax and AUC of roflumilast by 20% and 56%, respectively. Roflumilast N-oxide Cmax was decreased by 14% while roflumilast N-oxide AUC was increased by 23%.

Cimetidine: In an open-label crossover study in 16 healthy volunteers, the coadministration of a dual CYP3A4/1A2 inhibitor cimetidine (400 mg twice daily for 7 days) with a single dose of 500 mcg oral Roflumilast Tablets resulted in a 46% and 85% increase in roflumilast Cmax and AUC; and a 4% decrease in Cmax and 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, coadministration of a single oral dose of 500 mcg Roflumilast Tablets 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 Cmax of roflumilast and roflumilast N-oxide, respectively. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively.

Inducers of CYP enzymes: Rifampicin: In an open-label, three-period, fixed-sequence study in 15 healthy volunteers, coadministration of the strong CYP3A4 inducer rifampicin (600 mg once daily for 11 days) with a single oral dose of 500 mcg Roflumilast Tablets resulted in reduction of roflumilast Cmax and AUC by 68% and 79%, respectively; and an increase of roflumilast N-oxide Cmax by 30% and reduced roflumilast N-oxide AUC by 56%.

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 ≥ 8 mg/kg/day (approximately 11 times the MRHD based on summed AUCs of roflumilast and its metabolites).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 (approximately 10 and 15 times the MRHD, respectively, based on summed AUCs of roflumilast and its metabolites).

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

In a human spermatogenesis study, 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, roflumilast decreased fertility rates in male rats at 1.8 mg/kg/day (approximately 29 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 (approximately 10 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 (approximately 24 times the MRHD on a mg/m2 basis).

The efficacy and safety of Roflumilast Tablets in COPD was evaluated in 8 randomized, double-blind, controlled, parallel-group clinical trials in 9394 adult patients (4425 receiving Roflumilast Tablets 500 mcg) 40 years of age and older with COPD. Of the 8 trials, two were placebo-controlled dose selection trials (Trials 1 and 2) of 6 months' duration that evaluated the efficacy of Roflumilast Tablets 250 mcg and 500 mcg once daily, four were placebo-controlled 1-year trials (Trials 3, 4, 5, and 6) primarily designed to evaluate the efficacy of Roflumilast Tablets on COPD exacerbations, and two were 6-month efficacy trials (Trials 7 and 8) which assessed the effect of Roflumilast Tablets as add-on therapy to a long-acting beta agonist or long-acting anti-muscarinic. The 8 trials enrolled patients with nonreversible obstructive lung disease (FEV1/FVC ≤ 70% and ≤ 12% or 200 mL improvement in FEV1 in response to 4 puffs of albuterol/salbutamol) but the severity of airflow obstruction at baseline was different among the trials. Patients enrolled in the dose selection trials had the full range of COPD severity (FEV1 30-80% predicted); median age of 63 years, 73% male, and 99% Caucasian. Patients enrolled in the four exacerbation trials had severe COPD (FEV1≤ 50% predicted); median age of 64 years, 74% male, and 90% Caucasian. Patients enrolled in the two 6-month efficacy trials had moderate to severe COPD (FEV1 40-70% predicted); median age of 65 years, 68% male, and 97% Caucasian. COPD exacerbations and lung function (FEV1) were co-primary efficacy outcome measures in the four 1-year trials. In the two 6-month supportive efficacy trials, lung function (FEV1) alone was the primary efficacy outcome measure.

The two 6-month dose-selection efficacy trials (Trials 1 and 2) explored doses of 250 mcg and 500 mcg once daily in a total of 1929 patients (751 and 724 on Roflumilast Tablets 250 and 500 mcg, respectively). The selection of the 500 mcg dose was primarily based on nominal improvements in lung function (FEV1) over the 250 mcg dose. The once-daily dosing regimen was primarily based on the determination of a plasma half-life of 17 hours for roflumilast and 30 hours for its active metabolite roflumilast N-oxide [see Clinical Pharmacology (12.3)]. An additional placebo-controlled 1-year trial (Trial 9) evaluated the effect of Roflumilast Tablets 500 mcg on COPD exacerbations when added to a fixed-dose combination (FDC) product containing an inhaled corticosteroid and long-acting beta agonist (ICS/LABA). At screening, patients were required to have two or more exacerbations in the previous year. This trial randomized a total of 2354 patients (1178 randomized to Roflumilast Tablets, 1176 to placebo). Approximately 60% of the patients enrolled had severe COPD (postbronchodilator FEV1 30%-50% of predicted) associated with chronic bronchitis and 39% had very severe COPD (postbronchodilator FEV1 ≤ 30% of predicted) associated with chronic bronchitis; mean age of 64 years, 69% male, and 80% Caucasian. The use of long-acting muscarinic antagonists was allowed. Effect on Exacerbations

The effect of Roflumilast Tablets 500 mcg once daily on COPD exacerbations was evaluated in five 1-year trials (Trials 3, 4, 5, 6 and 9). Two of the trials (Trials 3 and 4) conducted initially enrolled a population of patients with severe COPD (FEV1≤ 50% of predicted) inclusive of those with chronic bronchitis and/or emphysema who had a history of smoking of at least 10 pack years. Inhaled corticosteroids were allowed as concomitant medications and used in 61% of both Roflumilast Tablets and placebo-treated patients and short-acting beta agonists were allowed as rescue therapy. The use of long-acting beta agonists, long-acting anti-muscarinics, and theophylline were prohibited. The rate of moderate or severe COPD exacerbations was a co-primary endpoint in both trials. There was not a symptomatic definition of exacerbation in these 2 trials. Exacerbations were defined in terms of severity requiring treatment with a moderate exacerbation defined as treatment with systemic glucocorticosteroids in Trial 3 or systemic glucocorticosteroids and/or antibiotics in Trial 4 and a severe exacerbation defined as requiring hospitalizations and/or leading to death in Trial 3 or requiring hospitalization in Trial 4. The trials randomized 1176 patients (567 on Roflumilast Tablets) in Trial 3 and 1514 patients (760 on Roflumilast Tablets) in Trial 4. Both trials failed to demonstrate a significant reduction in the rate of COPD exacerbations.

Exploratory analyses of the results of Trials 3 and 4 identified a subpopulation of patients with severe COPD associated with chronic bronchitis and COPD exacerbations within the previous year that appeared to demonstrate a better response in the reduction of the rate of COPD exacerbations compared to the overall population. As a result, two subsequent trials (Trial 5 and Trial 6) were conducted that enrolled patients with severe COPD but associated with chronic bronchitis, at least one COPD exacerbation in the previous year, and at least a 20 pack-year smoking history. In these trials, long-acting beta agonists and short-acting anti-muscarinics were allowed and were used by 44% and 35% of patients treated with Roflumilast Tablets and 45% and 37% of patients treated with placebo, respectively. The use of inhaled corticosteroids was prohibited. As in Trials 3 and 4, the rate of moderate exacerbations (defined as requiring intervention with systemic glucocorticosteroids) or severe exacerbations (defined as leading to hospitalization and/or to death) was a co-primary endpoint.

Trial 5 randomized a total of 1525 patients (765 on Roflumilast Tablets) and Trial 6 randomized a total of 1571 patients (772 on Roflumilast Tablets). In both trials, Roflumilast Tablets 500 mcg once daily demonstrated a significant reduction in the rate of moderate or severe exacerbations compared to placebo (Table 2). These two trials provide the evidence to support the use of Roflumilast Tablets for the reduction of COPD exacerbations.

Table 2: Effect of Roflumilast Tablets on Rate of Moderate or Severe Exacerbations

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="33%"/> <col width="12%"/> <col width="11%"/> <col width="12%"/> <col width="10%"/> <col width="10%"/> <col width="12%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Study</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="6" valign="top"> <p class="First"> <span class="Bold">Exacerbations Per Patient-Year</span> <br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Roflumilast Tablets</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Placebo</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Absolute</span> <br/> <span class="Bold">Reduction</span><span class="Sup">1</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">RR</span><span class="Sup">2</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">95% CI</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Percent Reduction</span><span class="Sup">3</span> <br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Trial 5<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1.1<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1.3<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.2<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.85<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.74, 0.98<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">15<br/> </p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Trial 6<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1.2<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1.5<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.3<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.82<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.71, 0.94<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">18<br/> </p> </td> </tr> </tbody> </table></div>

1 Absolute reduction measured as difference between placebo and roflumilast-treated patients.

2 RR is Rate Ratio.

3 Percent reduction is defined as 100 (1-RR).

For patients in Trials 5 and 6 who received concomitant long-acting beta agonists or short-acting anti-muscarinics, reduction of moderate or severe exacerbations with Roflumilast Tablets was similar to that observed for the overall populations of the two trials. In Trial 9, when added to background therapy of FDC ICS/LABA, the rate ratio for COPD exacerbations among patients administered Roflumilast Tablets vs. placebo was 0.92 (95% CI 0.81, 1.04). Effect on Lung Function

While Roflumilast Tablets is not a bronchodilator, all 1-year trials (Trials 3, 4, 5, and 6) evaluated the effect of Roflumilast Tablets on lung function as determined by the difference in FEV1 between Roflumilast Tablets and placebo-treated patients (pre-bronchodilator FEV1 measured prior to study drug administration in three of the trials and post- bronchodilator FEV1 measured 30 minutes after administration of 4 puffs of albuterol/salbutamol in one trial) as a co-primary endpoint. In each of these trials Roflumilast Tablets 500 mcg once daily demonstrated a statistically significant improvement in FEV1 which averaged approximately 50 mL across the four trials. Table 3 shows FEV1 results from Trials 5 and 6 which had demonstrated a significant reduction in COPD exacerbations.

Table 3: Effect of Roflumilast Tablets on FEV1

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="37%"/> <col width="16%"/> <col width="16%"/> <col width="16%"/> <col width="15%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Study</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Change in FEV<span class="Sub">1</span> from Baseline, mL</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Roflumilast Tablets</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Placebo</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Effect</span><span class="Sup">1</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">95% CI</span> <br/> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Trial 5<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">46<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">39<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">18, 60<br/> </p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Trial 6<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">33<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-25<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">58<br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">41, 75<br/> </p> </td> </tr> </tbody> </table></div>

1.Effect measured as difference between Roflumilast Tablets and placebo-treated patients.

Lung function was also evaluated in two 6-month trials (Trials 7 and 8) to assess the effect of Roflumilast Tablets when administered as add-on therapy to treatment with a long-acting beta agonist or a long-acting anti-muscarinic. These trials were conducted in a different population of COPD patients [moderate to severe COPD (FEV1 40 to 70% of predicted) without a requirement for chronic bronchitis or frequent history of exacerbations] from that for which efficacy in reduction of exacerbations has been demonstrated and provide safety support to the Roflumilast Tablets COPD program. Starting dose titration trial The tolerability of Roflumilast Tablets was evaluated in a 12-week randomized, double-blind, parallel group trial in patients with severe COPD associated with chronic bronchitis (Trial 10). At screening, patients were required to have had at least one exacerbation in the previous year. A total of 1323 patients were randomized to receive Roflumilast Tablets 500 mcg once a day for 12 weeks (n=443), Roflumilast Tablets 500 mcg every other day for 4 weeks followed by Roflumilast Tablets 500 mcg once a day for 8 weeks (n=439), or Roflumilast Tablets 250 mcg once a day for 4 weeks followed by Roflumilast Tablets 500 mcg once a day for 8 weeks (n=441). Over the 12 week study period, the percentage of patients discontinuing treatment was 6.2% lower in patients initially receiving Roflumilast Tablets 250 mcg daily for 4 weeks followed by Roflumilast Tablets 500 mcg daily for 8 weeks (18.4%) compared to those receiving Roflumilast Tablets 500 mcg daily for 12 weeks (24.6%) (Odds Ratio = 0.66; 95% CI: 0.47 to 0.93; p=0.017). Because this trial was limited to 12 weeks in duration, whether initiation of dosing with Roflumilast Tablets 250 mcg improves the long term tolerability of Roflumilast Tablets 500 mcg has not been determined.

Roflumilast Tablets 500 mcg are supplied as white to off-white, round, flat face bevel edged, uncoated tablets, debossed with “R” on one side and “0.5” on the other side Roflumilast 500 mcg Tablets are available:

Bottles of 30 tablets, NDC 0904-7483-03

Bottles of 90 tablets, NDC 0904-7483-89

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

 Advise the patient to read the FDA-approved patient labeling (Medication Guide). • Bronchospasm Roflumilast Tablets are not a bronchodilator and should not be used for immediate relief of breathing problems (i.e., as a rescue medication). • Psychiatric Events including Suicidality Treatment with Roflumilast Tablets is associated with an increase in psychiatric adverse reactions. Cases of suicidal ideation and behavior, including completed suicide, have been observed in the post-marketing setting in patients with or without a history of depression. The risks and benefits of treatment with Roflumilast Tablets in patients with a history of depression and/or suicidal thoughts or behavior should be carefully considered. Advise patients, caregivers, and families to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider so that the risks and benefits of continuing treatment with Roflumilast Tablets may be considered [see Warnings and Precautions (5.2)]. • Weight Decrease Weight loss was a common adverse reaction in Roflumilast Tablets clinical trials. During follow-up after treatment discontinuation, the majority of patients with weight loss regained some of the weight they had lost while receiving Roflumilast Tablets. Advise patients treated with Roflumilast Tablets to have their weight monitored regularly. If unexplained weight loss occurs, patients should inform their healthcare provider so that the weight loss can be evaluated, as discontinuation of Roflumilast Tablets may need to be considered [see Warnings and Precautions (5.3)]. • Drug Interactions The use of cytochrome P450 enzyme inducers resulted in a reduction in exposure which may result in decreased therapeutic effectiveness of Roflumilast Tablets. The use of strong cytochrome P450 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin) with Roflumilast Tablets is not recommended [see Drugs that Induce Cytochrome P450 (CYP) Enzymes (7.1) and Clinical Pharmacology (12.3)].

{ "type": "p", "children": [], "text": " Advise the patient to read the FDA-approved patient labeling (Medication Guide).\n • Bronchospasm\n Roflumilast Tablets are not a bronchodilator and should not be used for immediate relief of breathing problems (i.e., as a rescue medication). • Psychiatric Events including Suicidality\n Treatment with Roflumilast Tablets is associated with an increase in psychiatric adverse reactions. Cases of suicidal ideation and behavior, including completed suicide, have been observed in the post-marketing setting in patients with or without a history of depression. The risks and benefits of treatment with Roflumilast Tablets in patients with a history of depression and/or suicidal thoughts or behavior should be carefully considered. Advise patients, caregivers, and families to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider so that the risks and benefits of continuing treatment with Roflumilast Tablets may be considered [see Warnings and Precautions (5.2)].\n • Weight Decrease\n Weight loss was a common adverse reaction in Roflumilast Tablets clinical trials. During follow-up after treatment discontinuation, the majority of patients with weight loss regained some of the weight they had lost while receiving Roflumilast Tablets. Advise patients treated with Roflumilast Tablets to have their weight monitored regularly. If unexplained weight loss occurs, patients should inform their healthcare provider so that the weight loss can be evaluated, as discontinuation of Roflumilast Tablets may need to be considered [see Warnings and Precautions (5.3)].\n • Drug Interactions\n The use of cytochrome P450 enzyme inducers resulted in a reduction in exposure which may result in decreased therapeutic effectiveness of Roflumilast Tablets. The use of strong cytochrome P450 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin) with Roflumilast Tablets is not recommended [see Drugs that Induce Cytochrome P450 (CYP) Enzymes (7.1) and Clinical Pharmacology (12.3)].\n" }

Manufactured by: MSN Pharmaceuticals Inc. Piscataway, NJ 08854-3714 Distributed by:  MAJOR® PHARMACEUTICALS Indianapolis, IN 46268 USA

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Packaged and Distributed by:

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MAJOR® PHARMACEUTICALS

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Indianapolis, IN 46268 USA

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Refer to package label for Distributor's NDC Number

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Issued on: November 2023

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ROFLUMILAST (roe-FLUE-mi-last) Tablets

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Read this Medication Guide before you start taking Roflumilast Tablets 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.

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What is the most important information I should know about Roflumilast Tablets? Roflumilast Tablets can cause serious side effects. Tell your healthcare provider right away if you have any of the symptoms listed below while taking Roflumilast Tablets.

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Roflumilast Tablets may affect the way other medicines work, and other medicines may affect how Roflumilast Tablets works. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. What are Roflumilast Tablets? Roflumilast Tablets are a prescription medicine used in adults with severe Chronic Obstructive Pulmonary Disease (COPD) to decrease the number of flare-ups or the worsening of COPD symptoms (exacerbations).

{ "type": "p", "children": [], "text": "\nRoflumilast Tablets may affect the way other medicines work, and other medicines may affect how Roflumilast Tablets works. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.\nWhat are Roflumilast Tablets?\n Roflumilast Tablets are a prescription medicine used in adults with severe Chronic Obstructive Pulmonary Disease (COPD) to decrease the number of flare-ups or the worsening of COPD symptoms (exacerbations)." }

Roflumilast Tablets are not a bronchodilator and should not be used for treating sudden breathing problems. Your healthcare provider may give you other medicine to use for sudden breathing problems. It is not known if Roflumilast Tablets is safe and effective in children. Who should not take Roflumilast Tablets? Do not take Roflumilast Tablets if you: • have certain liver problems. Talk with your healthcare provider before you take Roflumilast Tablets if you have liver problems. What should I tell my healthcare provider before taking Roflumilast Tablets? Before you take Roflumilast Tablets, tell your healthcare provider if you:

{ "type": "p", "children": [], "text": "\nRoflumilast Tablets are not a bronchodilator and should not be used for treating sudden breathing problems. Your healthcare provider may give you other medicine to use for sudden breathing problems. It is not known if Roflumilast Tablets is safe and effective in children.\nWho should not take Roflumilast Tablets?\n\nDo not take Roflumilast Tablets if you:\n • have certain liver problems. Talk with your healthcare provider before you take Roflumilast Tablets if you have liver problems.\nWhat should I tell my healthcare provider before taking Roflumilast Tablets?\n Before you take Roflumilast Tablets, tell your healthcare provider if you:" }

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How should I take Roflumilast Tablets?

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What are the possible side effects of Roflumilast Tablets? Roflumilast Tablets can cause serious side effects, including: See “What is the most important information I should know about Roflumilast Tablets?” The most common side effects of Roflumilast Tablets include:

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of Roflumilast Tablets?\n\nRoflumilast Tablets can cause serious side effects, including:\n See “What is the most important information I should know about Roflumilast Tablets?”\n\nThe most common side effects of Roflumilast Tablets include:\n" }

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Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Roflumilast Tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How do I store Roflumilast Tablets?

{ "type": "p", "children": [], "text": "Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Roflumilast Tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\nHow do I store Roflumilast Tablets?\n" }

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Keep Roflumilast Tablets and all medicines out of the reach of children. General information about Roflumilast Tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Roflumilast Tablets for a condition for which it was not prescribed. Do not give Roflumilast Tablets to other people, even if they have the same symptoms that you have. It may harm them.

{ "type": "p", "children": [], "text": "\nKeep Roflumilast Tablets and all medicines out of the reach of children.\n\nGeneral information about Roflumilast Tablets\n Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Roflumilast Tablets for a condition for which it was not prescribed. Do not give Roflumilast Tablets to other people, even if they have the same symptoms that you have. It may harm them." }

This Medication Guide summarizes the most important information about Roflumilast Tablets. For more information about Roflumilast Tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Roflumilast Tablets that is written for health professionals.

{ "type": "p", "children": [], "text": "This Medication Guide summarizes the most important information about Roflumilast Tablets. For more information about Roflumilast Tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Roflumilast Tablets that is written for health professionals." }

For more information about Roflumilast Tablets call Novadoz Pharmaceuticals LLC at 1-855-668-2369. What are the ingredients in Roflumilast Tablets? Active ingredient: roflumilast Inactive ingredients: lactose monohydrate, magnesium stearate, polysorbate 80 and pregelatinised starch, . This Medication Guide has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "For more information about Roflumilast Tablets call Novadoz Pharmaceuticals LLC at 1-855-668-2369.\nWhat are the ingredients in Roflumilast Tablets?\n\nActive ingredient: roflumilast\nInactive ingredients: lactose monohydrate, magnesium stearate, polysorbate 80 and pregelatinised starch, .\nThis Medication Guide has been approved by the U.S. Food and Drug Administration.\n\n" }

Manufactured by: MSN Pharmaceuticals Inc. Piscataway, NJ 08854-3714 Distributed by:  MAJOR® PHARMACEUTICALS Indianapolis, IN 46268 USA

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Packaged and Distributed by:

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MAJOR® PHARMACEUTICALS

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Indianapolis, IN 46268 USA

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Refer to package label for Distributor's NDC Number

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Issued on: November 2023

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MAJOR®

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NDC 0904-7483-89

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Roflumilast

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Tablets

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500 mcg

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Pharmacist: Dispense

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with Medication Guide

{ "type": "p", "children": [], "text": "with Medication Guide" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

90 Tablets

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

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.

Shake can prior to each use. Apply a thin layer of ZORYVE foam, 0.3%, once daily to affected areas of body and/or scalp when they are not wet. Rub in completely.

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Wash hands after application.

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Avoid fire, flame, and smoking during and immediately following application [see Warnings and Precautions (5.1)].

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ZORYVE foam, 0.3%, is for topical use only and not for ophthalmic, oral, or intravaginal use.

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Topical foam, 0.3%: 3 mg of roflumilast per gram of white to off-white foam in 60-gram pressurized cans.

{ "type": "p", "children": [], "text": "Topical foam, 0.3%: 3 mg of roflumilast per gram of white to off-white foam in 60-gram pressurized cans." }

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)].

{ "type": "p", "children": [], "text": "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)]." }

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

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.

Seborrheic Dermatitis

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 [see Clinical Studies (14.1)].

Table 1 presents adverse reactions that occurred in at least 1% of subjects treated with ZORYVE foam, 0.3%.

<div class="scrollingtable"><table width="50%"> <caption> <span>Table 1: Adverse Reactions Reported in ≥1% of Adult and Pediatric Subjects 9 Years of Age and Older with Seborrheic Dermatitis Treated with ZORYVE Foam, 0.3%, for 8 Weeks in Trial 203 and Trial STRATUM</span> </caption> <col align="left" valign="middle" width="35%"/> <col align="center" valign="middle" width="35%"/> <col align="center" valign="middle" width="30%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Adverse Reaction </th><th align="center" class="Rrule">ZORYVE foam, 0.3%<br/>(N=458)<br/>n (%)</th><th align="center" class="Rrule">Vehicle foam<br/>(N=225)<br/>n (%)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Nasopharyngitis</td><td align="center" class="Rrule">7 (1.5)</td><td align="center" class="Rrule">1 (0.4)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Nausea</td><td align="center" class="Rrule"> 6 (1.3)</td><td align="center" class="Rrule">0 (0)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Headache</td><td align="center" class="Rrule">5 (1.1)</td><td align="center" class="Rrule">0 (0)</td> </tr> </tbody> </table></div>

The following additional adverse reactions were reported in fewer than 1% of subjects treated with ZORYVE foam, 0.3%: diarrhea and insomnia.

The adverse reaction profile in pediatric subjects was consistent with that observed in adults [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3)].

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.

Plaque Psoriasis

In two multicenter, randomized, double-blind, vehicle-controlled trials (Trial 204 and ARRECTOR), 734 adult and pediatric subjects 12 years of age and older with plaque psoriasis of the scalp and body were treated with ZORYVE foam, 0.3%, or vehicle foam once daily for 8 weeks [see Clinical Studies (14.2)].

Table 2 presents adverse reactions that occurred in at least 1% of subjects treated with ZORYVE foam, 0.3%.

<div class="scrollingtable"><table width="50%"> <caption> <span>Table 2: Adverse Reactions Reported in ≥1% of Adult and Pediatric Subjects 12 Years of Age and Older with Plaque Psoriasis of the Scalp and Body Treated with ZORYVE Foam, 0.3%, for 8 Weeks in Trial 204 and Trial ARRECTOR</span> </caption> <col align="left" valign="middle" width="35%"/> <col align="center" valign="middle" width="35%"/> <col align="center" valign="middle" width="30%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Adverse Reaction</th><th align="center" class="Rrule">ZORYVE foam, 0.3%<br/>(N=479)<br/>n (%)</th><th align="center" class="Rrule">Vehicle foam<br/>(N=255)<br/>n (%)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Headache</td><td align="center" class="Rrule">15 (3.1)</td><td align="center" class="Rrule">3 (1.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Diarrhea</td><td align="center" class="Rrule">12 (2.5)</td><td align="center" class="Rrule">4 (1.6)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Nausea</td><td align="center" class="Rrule">8 (1.7)</td><td align="center" class="Rrule">0 (0)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Nasopharyngitis</td><td align="center" class="Rrule">6 (1.3)</td><td align="center" class="Rrule">2 (0.8)</td> </tr> </tbody> </table></div>

The following additional adverse reaction was reported in fewer than 1% of subjects treated with ZORYVE foam, 0.3%: insomnia.

The adverse reaction profile in pediatric subjects was consistent with that observed in adults [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3)].

Drugs that Inhibit Cytochrome P450 (CYP) Enzymes

No formal drug-drug interaction studies were conducted with ZORYVE foam, 0.3%; however, the co-administration of oral 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 [see Clinical Pharmacology (12.3)].

Oral Contraceptives Containing Gestodene and Ethinyl Estradiol

The co-administration of roflumilast with oral contraceptives containing gestodene and ethinyl estradiol 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 [see Clinical Pharmacology (12.3)].

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 21 and 18 times the maximum recommended human dose (MRHD), respectively. Roflumilast induced post-implantation loss in rats at oral doses greater than or equal to 7 times the MRHD. Roflumilast induced stillbirth and decreased pup viability in mice at oral doses 11 and 34 times the MRHD, respectively. Roflumilast has been shown to adversely affect pup post-natal development when dams were treated with an oral dose 34 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. In the U.S. 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 (21 times the MRHD on a mg/m2 basis). No evidence of structural abnormalities or effects on survival rates were observed. Roflumilast did not affect embryo-fetal development at a maternal oral dose of 0.2 mg/kg/day (2 times the MRHD on a mg/m2 basis).

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 (7 times the MRHD on a mg/m2 basis). Roflumilast did not cause fetal structural abnormalities at maternal oral doses up to 1.8 mg/kg/day (20 times the MRHD on a mg/m2 basis).

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 (18 times the MRHD on a mg/m2 basis).

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 (11 and 34 times the MRHD on a mg/m2 basis, respectively). Roflumilast induced delivery retardation in pregnant mice at maternal oral doses greater than 2 mg/kg/day (11 times the MRHD on a mg/m2 basis). Roflumilast decreased pup rearing frequencies at a maternal oral dose of 6 mg/kg/day during pregnancy and lactation (34 times the MRHD on a mg/m2 basis). Roflumilast also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at a maternal oral dose of 12 mg/kg/day (68 times the MRHD on a mg/m2 basis).

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). When a 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 mother's clinical need for ZORYVE foam, 0.3%, and any potential adverse effects on the breastfed infant from ZORYVE foam, 0.3%, or from the underlying maternal condition.

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 0.32 and 0.02 mcg/g in the milk and pup liver, respectively. The concentration of roflumilast in animal milk does not necessarily predict the concentration of drug in human milk.

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.

Seborrheic Dermatitis

The safety and effectiveness of ZORYVE topical 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 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, 0.3% [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.

Plaque Psoriasis

The safety and effectiveness of ZORYVE topical foam, 0.3%, for the treatment of plaque psoriasis of the scalp and body have been established in pediatric patients 12 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 12 subjects 12 to 17 years of age, of whom 8 received ZORYVE foam, 0.3%. Use of ZORYVE foam, 0.3%, in pediatric patients 12 years of age and older is also supported by data from an open-label trial of 8 weeks duration which included 7 subjects 12 to 17 years of age treated with ZORYVE foam, 0.3%.

The safety and effectiveness of ZORYVE foam, 0.3%, in pediatric patients below the age of 12 years with plaque psoriasis have not been established.

Seborrheic Dermatitis

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.

Plaque Psoriasis

Of the 734 subjects with plaque psoriasis of the scalp and body exposed to ZORYVE foam, 0.3%, or vehicle for up to 8 weeks in the controlled clinical trials, 82 (11%) were 65 years of age or older, and 21 (3%) 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 (12.3)].

ZORYVE (roflumilast) topical foam, 0.3%, is a white to off-white foam for topical use. The active ingredient, roflumilast, is a phosphodiesterase 4 (PDE4) inhibitor.

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The chemical name of roflumilast is 3-cyclopropylmethoxy-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide with a molecular formula of C17H14Cl2F2N2O3 and the molecular weight of 403.21.

{ "type": "p", "children": [], "text": "The chemical name of roflumilast is 3-cyclopropylmethoxy-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide with a molecular formula of C17H14Cl2F2N2O3 and the molecular weight of 403.21." }

The structural formula of roflumilast is:

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Roflumilast is practically insoluble in water and hexane, sparingly soluble in ethanol, and freely soluble in acetone.

{ "type": "p", "children": [], "text": "Roflumilast is practically insoluble in water and hexane, sparingly soluble in ethanol, and freely soluble in acetone." }

Each gram of ZORYVE topical foam, 0.3%, contains 3 mg of roflumilast in a foam base containing ceteareth-10 phosphate, cetearyl phosphate, cetostearyl alcohol, diethylene glycol monoethyl ether, hexylene glycol, isopropyl palmitate, methylparaben, propylparaben, purified water, sodium hydroxide, and white petrolatum. Hydrochloric acid may have been added to adjust pH. ZORYVE topical foam, 0.3%, is dispensed from an aluminum can pressurized with propellant (butane, isobutane, and propane).

{ "type": "p", "children": [], "text": "Each gram of ZORYVE topical foam, 0.3%, contains 3 mg of roflumilast in a foam base containing ceteareth-10 phosphate, cetearyl phosphate, cetostearyl alcohol, diethylene glycol monoethyl ether, hexylene glycol, isopropyl palmitate, methylparaben, propylparaben, purified water, sodium hydroxide, and white petrolatum. Hydrochloric acid may have been added to adjust pH. ZORYVE topical foam, 0.3%, is dispensed from an aluminum can pressurized with propellant (butane, isobutane, and propane)." }

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 and plaque psoriasis is unknown.

Absorption

Seborrheic Dermatitis

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 6.5 ± 1.08% and 5.5 ± 1.27% 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 1.68 and 1.62 for roflumilast and roflumilast N-oxide, respectively.

In adults, the mean ± SD maximum concentration (Cmax) was 2.2 ± 1.6 and 13.8 ± 9.0 ng/mL for roflumilast and the N-oxide metabolite, respectively. The mean ± SD systemic exposure (AUC0-24) was 36.6 ± 23.7 and 261 ± 190 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. In pediatric subjects, the extrapolated mean ± SD AUC0-24 (based on pre-dose concentration) was 25.1 ± 30.2 and 253 ± 404 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively.

Plaque Psoriasis

The pharmacokinetics of ZORYVE foam, 0.3%, was investigated in 19 adults and 7 pediatric subjects 12 to 16 years of age with plaque psoriasis of the scalp and body. The entire scalp (BSA of approximately 4.5%) was treated in addition to the mean ± SD BSA involvement on the body of 25.0 ± 7.88% and 10.4 ± 0.54% in adults and pediatric subjects, respectively. In this study, the mean daily dose administered in adults was 10.3 g and in pediatric subjects from 12 to 16 years of age was 5.3 g of ZORYVE foam, 0.3%, once daily for 15 days. Following application of ZORYVE foam, 0.3%, the plasma concentration versus time profile was flat, with mean peak-to-trough ratios of approximately 1.2 for both roflumilast and roflumilast N-oxide.

In adults, the mean ± SD Cmax was 4.48 ± 2.28 and 29.9 ± 17.5 ng/mL for roflumilast and the N-oxide metabolite, respectively, on Day 15. The mean ± SD AUC0-24 was 90 ± 58.7 and 567 ± 436 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively, on Day 15. In pediatric subjects, the extrapolated mean ± SD AUC0-24 (based on pre-dose concentration) was 35.5 ± 41.4 and 270 ± 293 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively, on Day 15.

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 9.6 L/h. Following topical administration, the mean half-lives of both roflumilast and the N-oxide metabolite were in the range of 3.6 to 5 days.

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 7-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.

Specific Populations

Following topical administration, no clinically significant differences in the pharmacokinetics of roflumilast and roflumilast N-oxide were observed based on age, 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 Cmax of 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 [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

No formal drug-drug interaction studies were conducted with roflumilast topical foam, 0.3%.

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 Cmax and AUC for roflumilast, respectively, and a 34% decrease and a 4% increase in Cmax and 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 Cmax and AUC for roflumilast, respectively, and a 38% reduction and 3% increase in Cmax and 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 Cmax and AUC along with a 210% decrease and 52% increase in roflumilast N-oxide Cmax and 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 Cmax and AUC of roflumilast by 20% and 56%, respectively. Roflumilast N-oxide Cmax was 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 Cmax and AUC; and a 4% decrease in Cmax and 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 Cmax of roflumilast and roflumilast N-oxide, respectively. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: In vitro studies suggest that the biotransformation of roflumilast to its N-oxide metabolite is mediated by CYP1A2 and 3A4. Based on further in vitro results in human liver microsomes, roflumilast and roflumilast N-oxide 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, in vitro studies demonstrated no induction of the CYP1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weak induction of CYP2B6 by roflumilast.

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).

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.

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 3: IGA Treatment Success at Week 8 in Adult and Pediatric Subjects 9 Years of Age and Older with Moderate to Severe Seborrheic Dermatitis in Trial STRATUM and Trial 203</span> </caption> <col align="left" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule" colspan="2">STRATUM</th><th align="center" class="Rrule" colspan="2">Trial 203</th> </tr> <tr class="Botrule"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">ZORYVE foam, 0.3%</th><th align="center" class="Rrule">Vehicle foam</th><th align="center" class="Rrule">ZORYVE foam, 0.3%</th><th align="center" class="Rrule">Vehicle foam</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule">Number of subjects randomized</th><th align="center" class="Rrule">N=304</th><th align="center" class="Rrule">N=153</th><th align="center" class="Rrule">N=154</th><th align="center" class="Rrule">N=72</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">Abbreviations: CI = Confidence Interval</td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>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).</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Treatment difference and 95% CI are based on the CMH method stratified by pooled site and baseline IGA strata.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">IGA success<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="center" class="Rrule">79.5%</td><td align="center" class="Rrule">58.0%</td><td align="center" class="Rrule">73.1%</td><td align="center" class="Rrule">40.8%</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Difference from Vehicle (95% CI)<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a></td><td align="center" class="Rrule" colspan="2">20.6% (11.2%, 30.0%)</td><td align="center" class="Rrule" colspan="2">33.8% (20.3%, 47.4%)</td> </tr> </tbody> </table></div>

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)).

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.

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 4: S-IGA and B-IGA Treatment Success at Week 8 in Adult and Pediatric Subjects 12 Years of Age and Older with Plaque Psoriasis of the Scalp and Body in Trial ARRECTOR and Trial 204</span> </caption> <col align="left" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule" colspan="2">Trial ARRECTOR</th><th align="center" class="Rrule" colspan="2">Trial 204</th> </tr> <tr class="Botrule"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">ZORYVE foam, 0.3%</th><th align="center" class="Rrule">Vehicle foam</th><th align="center" class="Rrule">ZORYVE foam, 0.3%</th><th align="center" class="Rrule">Vehicle foam</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule">Number of subjects randomized</th><th align="center" class="Rrule">N=281</th><th align="center" class="Rrule">N=151</th><th align="center" class="Rrule">N=200</th><th align="center" class="Rrule">N=104</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">Abbreviations: CI = Confidence Interval</td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>S-IGA treatment success and B-IGA treatment success were defined as a score of "Clear" (0) or "Almost Clear" (1), plus a 2-grade score improvement from baseline at Week 8 (Multiple Imputation).</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>Treatment difference and 95% CI are based on the CMH method stratified by pooled site and baseline IGA strata.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">S-IGA success<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></td><td align="center" class="Rrule">66.4%</td><td align="center" class="Rrule">27.8%</td><td align="center" class="Rrule">56.7%</td><td align="center" class="Rrule">11.0%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Difference from Vehicle (95% CI)<a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a></td><td align="center" class="Rrule" colspan="2">37.1% (27.1%, 47.1%)</td><td align="center" class="Rrule" colspan="2">47.7% (37.9%, 57.5%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">B-IGA success<a class="Sup" href="#footnote-3">*</a></td><td align="center" class="Rrule">45.5%</td><td align="center" class="Rrule">20.1%</td><td align="center" class="Rrule">39.0%</td><td align="center" class="Rrule">7.4%</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Difference from Vehicle (95% CI)<a class="Sup" href="#footnote-4">†</a></td><td align="center" class="Rrule" colspan="2">24.8% (15.0%, 34.6%)</td><td align="center" class="Rrule" colspan="2">32.4% (23.3%, 41.6%)</td> </tr> </tbody> </table></div>

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)].

Marketed by: Arcutis Biotherapeutics, Inc.Westlake Village, CA 91361

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For more information on ZORYVE foam, call 1-805-418-5006 or visit http://www.zoryve.com.

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© 2025 Arcutis Biotherapeutics, Inc. All rights reserved.

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v2

{ "type": "p", "children": [], "text": "v2" }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="80%"/> <col align="right" valign="top" width="20%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" colspan="2">Patient Information<br/>ZORYVE<span class="Sup">®</span> (zor-EEV)<br/>(roflumilast) topical foam, 0.3%</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="1">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align="right" colspan="1">Revised: 5/2025</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Important information: ZORYVE foam is for use on the skin (topical use) only.</span> Do not use ZORYVE foam in or on your eyes, mouth, or vagina.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">What is ZORYVE foam?</span> <br/>ZORYVE foam is a prescription medicine used on the skin (topical) to treat: <ul class="Disc"> <li>seborrheic dermatitis in adults and children 9 years of age and older.<br/>It is not known if ZORYVE foam is safe and effective in children with seborrheic dermatitis under 9 years of age.</li> <li>plaque psoriasis of the scalp and body in adults and children 12 years of age and older.<br/>It is not known if ZORYVE foam is safe and effective in children with plaque psoriasis of the scalp and body under 12 years of age.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Do not use ZORYVE foam if</span> you have certain liver problems.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Before using ZORYVE foam, tell your healthcare provider about all of your medical conditions, including if you:</span> <ul class="Disc"> <li>have liver problems.</li> <li>are pregnant or plan to become pregnant. It is not known if ZORYVE foam will harm your unborn baby.</li> <li>are breastfeeding or plan to breastfeed. It is not known if ZORYVE foam passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with ZORYVE foam.<br/>Breastfeeding women using ZORYVE foam should use it on the smallest area of the skin and for the shortest time needed. Do not apply ZORYVE foam directly to the nipple or areola to avoid contact with your baby. Avoid direct skin contact of treated areas with your baby if ZORYVE foam is applied to your chest.</li> </ul> <span class="Bold">Tell your healthcare provider about the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">How should I use ZORYVE foam?</span> <ul class="Disc"> <li>Use ZORYVE foam exactly as your healthcare provider tells you to use it. See the "<a href="#IFU">Instructions for Use</a>" provided with this leaflet for directions about how to apply ZORYVE foam.</li> <li>Shake the can of ZORYVE foam before each use.</li> <li>Apply a thin layer of ZORYVE foam 1 time a day to the affected areas of your body and scalp when they are not wet. Rub the foam in completely.</li> <li>Wash your hands after applying ZORYVE foam. If someone else applies ZORYVE foam for you, they should wash their hands after applying it.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">What should I avoid while using ZORYVE foam?<br/>ZORYVE foam is flammable.</span> Avoid fire, flame, and smoking during and right after you apply ZORYVE foam.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">What are the possible side effects of ZORYVE foam?<br/>The most common side effects of ZORYVE foam in people treated for seborrheic dermatitis include:</span> <ul class="Disc"> <li>common cold</li> <li>nausea</li> <li>headache</li> </ul> <span class="Bold">The most common side effects of ZORYVE foam in people treated for plaque psoriasis include:</span> <ul class="Disc"> <li>headache</li> <li>diarrhea</li> <li>nausea</li> <li>common cold</li> </ul>These are not all of the possible side effects of ZORYVE foam.<br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.<br/>You may also report side effects to Arcutis Biotherapeutics, Inc. by calling 1-844-692-6729.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">How should I store ZORYVE foam?</span> <ul class="Disc"> <li>Store ZORYVE foam at room temperature between 68°F to 77°F (20°C to 25°C).</li> <li>ZORYVE foam is flammable. Keep away from heat and flame.</li> <li>The contents in ZORYVE foam are under pressure. <span class="Bold">Do not</span> puncture or burn the can. <span class="Bold">Do not</span> expose the can to heat or store at temperatures above 120°F (49°C).</li> <li> <span class="Bold">Do not</span> freeze.</li> <li>Store the can upright.</li> </ul> <span class="Bold">Keep ZORYVE foam and all medicines out of the reach of children.</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">General Information about the safe and effective use of ZORYVE foam.</span> <br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ZORYVE foam for a condition for which it was not prescribed. Do not give it 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 ZORYVE foam that is written for health professionals.</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">What are the ingredients in ZORYVE foam?</span> <br/> <span class="Bold">Active ingredient:</span> roflumilast<br/> <span class="Bold">Inactive ingredients:</span> ceteareth-10 phosphate, cetearyl phosphate, cetostearyl alcohol, diethylene glycol monoethyl ether, hexylene glycol, isopropyl palmitate, methylparaben, propylparaben, purified water, sodium hydroxide, and white petrolatum. Hydrochloric acid may have been added to adjust pH.<br/> <span class="Bold">Propellants:</span> butane, isobutane, and propane.<br/> <span class="Bold">Marketed by:</span> <br/>Arcutis Biotherapeutics, Inc.<br/>Westlake Village, CA 91361<br/>For more information on ZORYVE topical foam, call 1-844-692-6729 or visit http://www.zoryve.com.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"80%\"/>\n<col align=\"right\" valign=\"top\" width=\"20%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"center\" class=\"Lrule Rrule\" colspan=\"2\">Patient Information<br/>ZORYVE<span class=\"Sup\">®</span> (zor-EEV)<br/>(roflumilast) topical foam, 0.3%</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"1\">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\" colspan=\"1\">Revised: 5/2025</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Important information: ZORYVE foam is for use on the skin (topical use) only.</span> Do not use ZORYVE foam in or on your eyes, mouth, or vagina.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What is ZORYVE foam?</span>\n<br/>ZORYVE foam is a prescription medicine used on the skin (topical) to treat: \t\t\t\t\t\t\t\t\t<ul class=\"Disc\">\n<li>seborrheic dermatitis in adults and children 9 years of age and older.<br/>It is not known if ZORYVE foam is safe and effective in children with seborrheic dermatitis under 9 years of age.</li>\n<li>plaque psoriasis of the scalp and body in adults and children 12 years of age and older.<br/>It is not known if ZORYVE foam is safe and effective in children with plaque psoriasis of the scalp and body under 12 years of age.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Do not use ZORYVE foam if</span> you have certain liver problems.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Before using ZORYVE foam, tell your healthcare provider about all of your medical conditions, including if you:</span>\n<ul class=\"Disc\">\n<li>have liver problems.</li>\n<li>are pregnant or plan to become pregnant. It is not known if ZORYVE foam will harm your unborn baby.</li>\n<li>are breastfeeding or plan to breastfeed. It is not known if ZORYVE foam passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with ZORYVE foam.<br/>Breastfeeding women using ZORYVE foam should use it on the smallest area of the skin and for the shortest time needed. Do not apply ZORYVE foam directly to the nipple or areola to avoid contact with your baby. Avoid direct skin contact of treated areas with your baby if ZORYVE foam is applied to your chest.</li>\n</ul>\n<span class=\"Bold\">Tell your healthcare provider about the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">How should I use ZORYVE foam?</span>\n<ul class=\"Disc\">\n<li>Use ZORYVE foam exactly as your healthcare provider tells you to use it. See the \"<a href=\"#IFU\">Instructions for Use</a>\" provided with this leaflet for directions about how to apply ZORYVE foam.</li>\n<li>Shake the can of ZORYVE foam before each use.</li>\n<li>Apply a thin layer of ZORYVE foam 1 time a day to the affected areas of your body and scalp when they are not wet. Rub the foam in completely.</li>\n<li>Wash your hands after applying ZORYVE foam. If someone else applies ZORYVE foam for you, they should wash their hands after applying it.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What should I avoid while using ZORYVE foam?<br/>ZORYVE foam is flammable.</span> Avoid fire, flame, and smoking during and right after you apply ZORYVE foam.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What are the possible side effects of ZORYVE foam?<br/>The most common side effects of ZORYVE foam in people treated for seborrheic dermatitis include:</span>\n<ul class=\"Disc\">\n<li>common cold</li>\n<li>nausea</li>\n<li>headache</li>\n</ul>\n<span class=\"Bold\">The most common side effects of ZORYVE foam in people treated for plaque psoriasis include:</span>\n<ul class=\"Disc\">\n<li>headache</li>\n<li>diarrhea</li>\n<li>nausea</li>\n<li>common cold</li>\n</ul>These are not all of the possible side effects of ZORYVE foam.<br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.<br/>You may also report side effects to Arcutis Biotherapeutics, Inc. by calling 1-844-692-6729.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">How should I store ZORYVE foam?</span>\n<ul class=\"Disc\">\n<li>Store ZORYVE foam at room temperature between 68°F to 77°F (20°C to 25°C).</li>\n<li>ZORYVE foam is flammable. Keep away from heat and flame.</li>\n<li>The contents in ZORYVE foam are under pressure. <span class=\"Bold\">Do not</span> puncture or burn the can. <span class=\"Bold\">Do not</span> expose the can to heat or store at temperatures above 120°F (49°C).</li>\n<li>\n<span class=\"Bold\">Do not</span> freeze.</li>\n<li>Store the can upright.</li>\n</ul>\n<span class=\"Bold\">Keep ZORYVE foam and all medicines out of the reach of children.</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">General Information about the safe and effective use of ZORYVE foam.</span>\n<br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ZORYVE foam for a condition for which it was not prescribed. Do not give it 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 ZORYVE foam that is written for health professionals.</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What are the ingredients in ZORYVE foam?</span>\n<br/>\n<span class=\"Bold\">Active ingredient:</span> roflumilast<br/>\n<span class=\"Bold\">Inactive ingredients:</span> ceteareth-10 phosphate, cetearyl phosphate, cetostearyl alcohol, diethylene glycol monoethyl ether, hexylene glycol, isopropyl palmitate, methylparaben, propylparaben, purified water, sodium hydroxide, and white petrolatum. Hydrochloric acid may have been added to adjust pH.<br/>\n<span class=\"Bold\">Propellants:</span> butane, isobutane, and propane.<br/>\n<span class=\"Bold\">Marketed by:</span>\n<br/>Arcutis Biotherapeutics, Inc.<br/>Westlake Village, CA 91361<br/>For more information on ZORYVE topical foam, call 1-844-692-6729 or visit http://www.zoryve.com.</td>\n</tr>\n</tbody>\n</table></div>" }

v2

{ "type": "p", "children": [], "text": "v2" }

This Instructions for Use contains information on how to apply ZORYVE foam.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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 ZORYVE foam:

{ "type": "p", "children": [], "text": "\nImportant information you need to know before applying ZORYVE foam:\n" }

{ "type": "ul", "children": [ "\nZORYVE foam is for use on skin only (topical use). ZORYVE foam is not for use in your eyes, mouth, or vagina.", "\nZORYVE foam is flammable. Avoid fire, flame, and smoking during and right after you apply ZORYVE foam." ], "text": "" }

Before applying ZORYVE foam for the first time:

{ "type": "p", "children": [], "text": "\nBefore applying ZORYVE foam for the first time:\n" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" valign="bottom" width="20%"/> <col align="left" valign="bottom" width="80%"/> <tbody class="Headless"> <tr> <td align="left"><img alt="Image" src="/dailymed/image.cfm?name=zoryve-02.jpg&amp;setid=f9e0b4a9-a227-4947-b00c-41fb18d16589"/></td><td align="left">Gently pull back on the nozzle to break the plastic piece at the base.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col align=\"left\" valign=\"bottom\" width=\"20%\"/>\n<col align=\"left\" valign=\"bottom\" width=\"80%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\"><img alt=\"Image\" src=\"/dailymed/image.cfm?name=zoryve-02.jpg&amp;setid=f9e0b4a9-a227-4947-b00c-41fb18d16589\"/></td><td align=\"left\">Gently pull back on the nozzle to break the plastic piece at the base.</td>\n</tr>\n</tbody>\n</table></div>" }

Applying ZORYVE foam:

{ "type": "p", "children": [], "text": "\nApplying ZORYVE foam:\n" }

Apply a thin layer of ZORYVE foam 1 time a day to the affected areas of your body and scalp when they are not wet.

{ "type": "p", "children": [], "text": "Apply a thin layer of ZORYVE foam 1 time a day to the affected areas of your body and scalp when they are not wet." }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="50%"/> <col align="center" valign="top" width="50%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Step 1: Shake.</span> <ul class="Disc"> <li>Shake the can well before each use.</li> </ul> </td><td align="center" class="Rrule"><img alt="Image" src="/dailymed/image.cfm?name=zoryve-03.jpg&amp;setid=f9e0b4a9-a227-4947-b00c-41fb18d16589"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Step 2: Dispense.</span> <ul class="Disc"> <li>Turn the can upside down and press the nozzle.</li> <li>Dispense a small amount into your hand.</li> </ul> </td><td align="center" class="Rrule"><img alt="Image" src="/dailymed/image.cfm?name=zoryve-04.jpg&amp;setid=f9e0b4a9-a227-4947-b00c-41fb18d16589"/></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"><span class="Bold">Step 3: Apply.</span> <ul class="Disc"> <li>Use enough ZORYVE foam to cover all affected areas with a thin layer. Rub the foam in completely.</li> <li>If you are treating your scalp, part the hair so that ZORYVE foam can be applied directly to the affected area on the skin.</li> <li>Wash your hands after applying the medicine. If someone else applies ZORYVE foam for you, they should wash their hands after applying it.</li> </ul> </td><td align="center" class="Rrule"><img alt="Image" src="/dailymed/image.cfm?name=zoryve-05.jpg&amp;setid=f9e0b4a9-a227-4947-b00c-41fb18d16589"/><br/> <img alt="Image" src="/dailymed/image.cfm?name=zoryve-06.jpg&amp;setid=f9e0b4a9-a227-4947-b00c-41fb18d16589"/></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<col align=\"center\" valign=\"top\" width=\"50%\"/>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\"><span class=\"Bold\">Step 1: Shake.</span>\n<ul class=\"Disc\">\n<li>Shake the can well before each use.</li>\n</ul>\n</td><td align=\"center\" class=\"Rrule\"><img alt=\"Image\" src=\"/dailymed/image.cfm?name=zoryve-03.jpg&amp;setid=f9e0b4a9-a227-4947-b00c-41fb18d16589\"/></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\"><span class=\"Bold\">Step 2: Dispense.</span>\n<ul class=\"Disc\">\n<li>Turn the can upside down and press the nozzle.</li>\n<li>Dispense a small amount into your hand.</li>\n</ul>\n</td><td align=\"center\" class=\"Rrule\"><img alt=\"Image\" src=\"/dailymed/image.cfm?name=zoryve-04.jpg&amp;setid=f9e0b4a9-a227-4947-b00c-41fb18d16589\"/></td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\"><span class=\"Bold\">Step 3: Apply.</span>\n<ul class=\"Disc\">\n<li>Use enough ZORYVE foam to cover all affected areas with a thin layer. Rub the foam in completely.</li>\n<li>If you are treating your scalp, part the hair so that ZORYVE foam can be applied directly to the affected area on the skin.</li>\n<li>Wash your hands after applying the medicine. If someone else applies ZORYVE foam for you, they should wash their hands after applying it.</li>\n</ul>\n</td><td align=\"center\" class=\"Rrule\"><img alt=\"Image\" src=\"/dailymed/image.cfm?name=zoryve-05.jpg&amp;setid=f9e0b4a9-a227-4947-b00c-41fb18d16589\"/><br/>\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=zoryve-06.jpg&amp;setid=f9e0b4a9-a227-4947-b00c-41fb18d16589\"/></td>\n</tr>\n</tbody>\n</table></div>" }

Storing ZORYVE foam

{ "type": "p", "children": [], "text": "\nStoring ZORYVE foam\n" }

{ "type": "ul", "children": [ "Store ZORYVE foam at room temperature between 68°F to 77°F (20°C to 25°C).", "ZORYVE foam is flammable. Keep away from heat and flame.", "The contents in ZORYVE foam are under pressure. Do not puncture or burn the can. Do not expose the can to heat or store at temperatures above 120°F (49°C).", "\nDo not freeze.", "Store the can upright." ], "text": "" }

Keep ZORYVE foam and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep ZORYVE foam and all medicines out of the reach of children.\n" }

Marketed by: Arcutis Biotherapeutics, Inc.Westlake Village, CA 91361

{ "type": "p", "children": [], "text": "\nMarketed by:\nArcutis Biotherapeutics, Inc.Westlake Village, CA 91361" }

For more information on ZORYVE foam, call 1-844-692-6729 or visit http://www.zoryve.com.

{ "type": "p", "children": [], "text": "For more information on ZORYVE foam, call 1-844-692-6729 or visit http://www.zoryve.com." }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration." }

Revised: 5/2025

{ "type": "p", "children": [], "text": "Revised: 5/2025" }

v2

{ "type": "p", "children": [], "text": "v2" }

NDC 80610-430-60

{ "type": "p", "children": [], "text": "NDC 80610-430-60" }

ZORYVE® (roflumilast) topical foam, 0.3%

{ "type": "p", "children": [], "text": "ZORYVE®\n (roflumilast) topical foam, 0.3%" }

Rx Only 60 grams

{ "type": "p", "children": [], "text": "Rx Only 60 grams" }

For Topical Use Only

{ "type": "p", "children": [], "text": "For Topical Use Only" }