Zoryve Cream
(roflumilast)Dosage & Administration
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Zoryve Cream Prescribing Information
Plaque Psoriasis
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.
Atopic Dermatitis
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.
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.
ZORYVE cream is for topical use only and not for ophthalmic, oral, or intravaginal use.
- 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.
Pregnancy
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).
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 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.
Pediatric Use
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.
Geriatric Use
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.
Hepatic Impairment
Oral roflumilast 250 mcg once daily for 14 days was studied in subjects with hepatic impairment. The systemic exposure of roflumilast and roflumilast N-oxide were increased in subjects with moderate (Child-Pugh B) hepatic impairment. ZORYVE 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 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)].
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.
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.
| Adverse Reaction | ZORYVE Cream, 0.3% (N=576) n (%) | Vehicle Cream (N=305) n (%) |
|---|---|---|
| Diarrhea | 18 (3.1) | 0 (0.0) |
| Headache | 14 (2.4) | 3 (1.0) |
| Insomnia | 8 (1.4) | 2 (0.7) |
| Nausea | 7 (1.2) | 1 (0.3) |
| Application site pain | 6 (1.0) | 1 (0.3) |
| Upper respiratory tract infection | 6 (1.0) | 1 (0.3) |
| Urinary tract infection | 6 (1.0) | 2 (0.7) |
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.
| Adverse Reaction | ZORYVE Cream, 0.15% (N=885) n (%) | Vehicle Cream (N=451) n (%) |
|---|---|---|
| Headache | 26 (2.9) | 4 (0.9) |
| Nausea | 17 (1.9) | 2 (0.4) |
| Application site pain | 13 (1.5) | 3 (0.7) |
| Diarrhea | 13 (1.5) | 2 (0.4) |
| Vomiting | 13 (1.5) | 2 (0.4) |
The adverse reaction of insomnia was reported in fewer than 1% of subjects treated with ZORYVE cream, 0.15%.