Zoryve (roflumilast): Uses, Dosage, Side Effects & Warnings

Uses

1 INDICATIONS AND USAGE ZORYVE topical foam, 0.3%, is a phosphodiesterase 4 inhibitor indicated for the treatment of seborrheic dermatitis in adult and pediatric patients 9 years of age and older. ( 1.1 ) plaque psoriasis of the scalp and body in adult and pediatric patients 12 years of age and older. ( 1.2 ) 1.1 Seborrheic Dermatitis ZORYVE ® topical foam, 0.3%, is indicated for the treatment of seborrheic dermatitis in adult and pediatric patients 9 years of age and older. 1.2 Plaque Psoriasis ZORYVE topical foam, 0.3%, is indicated for the treatment of plaque psoriasis of the scalp and body in adult and pediatric patients 12 years of age and older.

Dosage and administration

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. Wash hands after application. Avoid fire, flame, and smoking during and immediately following application [see Warnings and Precautions (5.1) ] . ZORYVE foam, 0.3%, is for topical use only and not for ophthalmic, oral, or intravaginal use. Apply once daily to affected areas. ( 2 ) For topical use only. Not for ophthalmic, oral, or intravaginal use. ( 2 )

Dosage forms and strengths

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

Contraindications

4 CONTRAINDICATIONS ZORYVE foam, 0.3%, is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C) [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] . Moderate to severe liver impairment (Child-Pugh B or C). ( 4 )

Warnings and precautions

Flammability : The propellants in ZORYVE foam, 0.3%, are flammable. Avoid fire, flame, and smoking during and immediately following application. ( 5.1 ) 5.1 Flammability The propellants in ZORYVE foam, 0.3%, are flammable. Avoid fire, flame, and smoking during and immediately following application.

Side effects

The most common adverse reactions (reported in ≥ 1% of patients) are: Seborrheic dermatitis : nasopharyngitis, nausea, and headache. ( 6.1 ) Plaque psoriasis of the scalp and body : headache, diarrhea, nausea, and nasopharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Arcutis Biotherapeutics, Inc. at 1-844-692-6729 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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%. 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 Adverse Reaction ZORYVE foam, 0.3% (N=458) n (%) Vehicle foam (N=225) n (%) Nasopharyngitis 7 (1.5) 1 (0.4) Nausea 6 (1.3) 0 (0) Headache 5 (1.1) 0 (0) The following additional adverse reactions were reported in fewer than 1% of subjects treated with ZORYVE foam, 0.3%: diarrhea and insomnia. 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%. 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 Adverse Reaction ZORYVE foam, 0.3% (N=479) n (%) Vehicle foam (N=255) n (%) Headache 15 (3.1) 3 (1.2) Diarrhea 12 (2.5) 4 (1.6) Nausea 8 (1.7) 0 (0) Nasopharyngitis 6 (1.3) 2 (0.8) 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) ] .

Drug interactions

Co-administration of roflumilast with systemic CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously may increase roflumilast systemic exposure and may result in increased adverse reactions. If these products are co-administered with ZORYVE foam, 0.3%, weigh the potential for increased adverse reactions against benefit. ( 7.1 ) 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. ( 7.1 ) 7.1 Effects of Other Drugs on ZORYVE Foam, 0.3% 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) ] .

Use in specific populations

8.1 Pregnancy 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 basis). 8.2 Lactation 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. 8.3 Fertility In a human spermatogenesis study, oral roflumilast 500 mcg had no effects on semen parameters or reproductive hormones during the 3-month treatment period and the following 3-month off-treatment period. 8.4 Pediatric Use 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.

Pregnancy

8.1 Pregnancy 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 basis).

Pediatric use

8.4 Pediatric Use 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.

Geriatric use

8.5 Geriatric Use 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.

Description

(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. The chemical name of roflumilast is 3-cyclopropylmethoxy- N -(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide with a molecular formula of C 17 H 14 Cl 2 F 2 N 2 O 3 and the molecular weight of 403.21. The structural formula of roflumilast is: 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). Chemical Structure

Mechanism of action

12.1 Mechanism of Action Roflumilast and its active metabolite (roflumilast N-oxide) are inhibitors of PDE4. Roflumilast and roflumilast N-oxide inhibition of PDE4 (a major cyclic 3′,5′-adenosine monophosphate (cyclic AMP) metabolizing enzyme) activity leads to accumulation of intracellular cyclic AMP. The specific mechanism(s) by which roflumilast exerts its therapeutic action is not well defined.

How supplied

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) ] .

Storage

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) ] .

Patient information

Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information). 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) ] .

Active ingredients

Roflumilast in 4 products

Zoryve NDC products (4)

NDC	Strength & form	Labeler	Type
80610-105	Roflumilast .5 mg/g Cream	Arcutis Biotherapeutics, Inc.	NDA
80610-115	Roflumilast 1.5 mg/g Cream	Arcutis Biotherapeutics, Inc.	NDA
80610-130	Roflumilast 3 mg/g Cream	Arcutis Biotherapeutics, Inc.	NDA
80610-430	Roflumilast 3 mg/g Aerosol, Foam	Arcutis Biotherapeutics, Inc.	NDA

Frequently asked questions

What is Zoryve used for?

1 INDICATIONS AND USAGE ZORYVE topical foam, 0.3%, is a phosphodiesterase 4 inhibitor indicated for the treatment of seborrheic dermatitis in adult and pediatric patients 9 years of age and older. ( 1.1 ) plaque psoriasis of the scalp and body in adult and pediatric patients 12 years of age and older. ( 1.2 ) 1.1 Seborrheic Dermatitis ZORYVE ® topical foam, 0.3%, is indicated for the treatment of…

What are the side effects of Zoryve?

The most common adverse reactions (reported in ≥ 1% of patients) are: Seborrheic dermatitis : nasopharyngitis, nausea, and headache. ( 6.1 ) Plaque psoriasis of the scalp and body : headache, diarrhea, nausea, and nasopharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Arcutis Biotherapeutics, Inc. at 1-844-692-6729 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical… See the full label for the complete list.

Who makes Zoryve?

Zoryve is listed by 1 labeler in the FDA NDC directory, including Arcutis Biotherapeutics, Inc..