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Roflumilast (Topical)

Brand name: Zoryve
Drug class: Skin and Mucous Membrane Agents, Miscellaneous
Chemical name: 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide
Molecular formula: C17H14Cl2F2N2O3
CAS number: 1189992-00-4

Medically reviewed by Drugs.com on Aug 24, 2022. Written by ASHP.

Introduction

Roflumilast is a phosphodiesterase (PDE) type 4 inhibitor.

Uses for Roflumilast (Topical)

Roflumilast has the following uses:

Roflumilast is indicated for topical treatment of plaque psoriasis, including intertriginous areas, in patients 12 years of age and older.

Roflumilast (Topical) Dosage and Administration

General

Roflumilast is available in the following dosage form(s) and strength(s):

Cream, 0.3%: 3 mg of roflumilast per gram in 60-gram tubes.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

For topical use only. Not for ophthalmic, oral, or intravaginal use.

Pediatric Patients

Dosage and Administration
  • Pediatric patients ≥12 years of age: Apply once daily to affected areas.

Adults

Dosage and Administration
  • Apply once daily to affected areas.

Cautions for Roflumilast (Topical)

Contraindications

  • Moderate to severe liver impairment (Child-Pugh B or C).

Warnings/Precautions

Specific Populations

Pregnancy

There are no randomized clinical trials of oral or topical roflumilast in pregnant women. 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 9 and 8 times the maximum recommended human dose (MRHD), respectively. Roflumilast induced post-implantation loss in rats at oral doses greater than or equal to 3 times the MRHD. Roflumilast induced stillbirth and decreased pup viability in mice at oral doses 5 and 15 times the MRHD, respectively. Roflumilast has been shown to adversely affect pup post-natal development when dams were treated with an oral dose 15 times the MRHD during pregnancy and lactation periods in mice.

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.

Roflumilast should not be used during labor and delivery. There are no human studies that have investigated effects of roflumilast on preterm labor or labor at term; however, animal studies showed that oral roflumilast disrupted the labor and delivery process in mice.

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 (9 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 (equivalent to 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 (3 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 (9 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 (8 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 (5 and 15 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 (5 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 (15 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 (29 times the MRHD on a mg/m2 basis).

Lactation

There is no information regarding the presence of roflumilast 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. When a drug is present in animal milk, it is likely that the drug will present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for roflumilast and any potential adverse effects on the breastfed infant from roflumilast or from the underlying maternal condition.

To minimize potential exposure to the breastfed infant via breast milk, use roflumilast on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply roflumilast directly to the nipple and areola to avoid direct infant exposure.

Pediatric Use

The safety and effectiveness of roflumilast have been established in pediatric patients ages 12 years and older for the treatment of plaque psoriasis. Use of roflumilast in this age group is supported by data from two 8-week vehicle-controlled safety and efficacy trials which included 14 adolescent patients aged 12 to 17 years, of whom 8 received roflumilast. Eighteen adolescent patients were treated with roflumilast in open-label trials of 2- and 24-weeks duration. The adverse reaction profile was similar to that observed in adults.

The safety and effectiveness of roflumilast in pediatric patients below the age of 12 years have not been established.

Geriatric Use

Of the 881 subjects with psoriasis exposed to roflumilast or vehicle for up to 8 weeks in 2 controlled clinical trials, 106 were 65 years of age or 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 geriatric 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.

Hepatic Impairment

Oral roflumilast 250 mcg once daily for 14 days was studied in subjects with hepatic impairment. The AUC and CmaxValues of roflumilast and roflumilast N-oxide were increased in subjects with moderate (Child-Pugh B) hepatic impairment. Roflumilast is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C).

Common Adverse Effects

The most common adverse reactions (reported in ≥1% of patients) are diarrhea, headache, insomnia, application site pain, upper respiratory tract infections, and urinary tract infections.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Coadministration 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. The risk of such concurrent use should be weighed carefully against benefit.

  • Coadministration of roflumilast 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.

Actions

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.

Advice to Patients

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

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Roflumilast

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Cream

0.3%

Zoryve

Arcutis Biotherapeutics Inc.

AHFS Drug Information. © Copyright 2023, Selected Revisions August 24, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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