Zoryve - Drug Monograph

Introduction

Zoryve (roflumilast) cream 0.3% is a topical phosphodiesterase-4 (PDE4) inhibitor developed by Arcutis Biotherapeutics. It represents a novel therapeutic approach for inflammatory skin conditions, offering a non-steroidal treatment option with a favorable safety profile. FDA-approved in July 2022, Zoryve is the first and only topical PDE4 inhibitor indicated for plaque psoriasis.

Mechanism of Action

Zoryve contains roflumilast, a highly potent and selective PDE4 inhibitor. PDE4 is an enzyme that degrades cyclic adenosine monophosphate (cAMP), an important intracellular second messenger. By inhibiting PDE4, Zoryve increases intracellular cAMP levels, which subsequently modulates the production of various pro-inflammatory and anti-inflammatory mediators. This mechanism results in reduced production of TNF-α, IFN-γ, IL-12, IL-17, and IL-23 while increasing anti-inflammatory cytokines such as IL-10. The net effect is decreased inflammation in the skin without the risks associated with topical corticosteroids.

Indications

• Treatment of plaque psoriasis in patients 12 years of age and older
• Applied topically to affected areas for intertriginous (skin fold) and non-intertriginous areas

Dosage and Administration

• Standard dosing: Apply a thin layer to affected areas twice daily
• Application: Use enough to cover the affected area lightly; rub in gently and completely
• Duration: Use until cleared; may be used for up to 8 weeks as studied in clinical trials
• Special populations: No dosage adjustment required for renal or hepatic impairment
• Pediatric patients: Safety and efficacy established in patients 12 years and older

Pharmacokinetics

• Absorption: Minimal systemic absorption with mean plasma concentrations below the limit of quantitation (<0.05 ng/mL)
• Distribution: Primarily local effect with negligible systemic distribution
• Metabolism: If absorbed systemically, roflumilast undergoes extensive metabolism via CYP3A4 and CYP1A2
• Elimination: Primarily renal excretion of metabolites; terminal half-life of roflumilast is approximately 17 hours when administered systemically

Contraindications

• Hypersensitivity to roflumilast or any component of the formulation

Warnings and Precautions

• Local reactions: May cause application site reactions including itching, redness, or irritation
• Use on damaged skin: Avoid application to broken or infected skin unless directed by healthcare provider
• Occlusive dressings: Should not be used with occlusive dressings unless medically supervised
• Eye contact: Avoid contact with eyes; if contact occurs, rinse thoroughly with water
• Pregnancy: No adequate human data; use only if potential benefit justifies potential risk
• Lactation: Unknown if excreted in human milk; use caution when administering to nursing women

Drug Interactions

• Minimal systemic absorption results in low potential for drug interactions
• Theoretical interactions with strong CYP3A4 inducers or inhibitors are unlikely due to minimal systemic exposure
• No clinically significant drug interactions identified in clinical studies

Adverse Effects

• Application site reactions (itching, pain, irritation)
• Upper respiratory tract infection
• Headache
• Urinary tract infection
• Diarrhea

• Hypersensitivity reactions (rare)
• No serious treatment-related adverse events reported in clinical trials

Monitoring Parameters

• Clinical response assessment at 2, 4, and 8 weeks of treatment
• Skin irritation or signs of hypersensitivity at application sites
• Patient-reported symptoms and quality of life measures
• No laboratory monitoring required due to minimal systemic exposure

Patient Education

• Apply thinly to affected areas only; do not use more than directed
• Wash hands before and after application unless hands are treatment areas
• Avoid contact with eyes, mouth, and other mucous membranes
• Report any signs of skin irritation, worsening condition, or hypersensitivity reactions
• May be used on face, intertriginous areas, and other sensitive skin areas
• Not for ophthalmic, oral, or intravaginal use
• Store at room temperature (20-25°C/68-77°F); do not freeze
• Continue use as directed even if improvement is noticed; do not stop abruptly

References

1. FDA Approval Letter: Zoryve (roflumilast) cream. July 2022. 2. Lebwohl MG, et al. Roflumilast Cream 0.3% in Plaque Psoriasis: A Randomized, Double-Blind, Vehicle-Controlled Phase 3 Study. J Am Acad Dermatol. 2022;86(4):726-734. 3. Blauvelt A, et al. Efficacy and Safety of Roflumilast Cream 0.3% in Patients With Plaque Psoriasis: Results From 2 Phase 3 Trials. J Am Acad Dermatol. 2022;86(4):735-743. 4. Zoryve [package insert]. Westlake Village, CA: Arcutis Biotherapeutics, Inc.; 2022. 5. Papp K, et al. Roflumilast Cream: A Phosphodiesterase 4 Inhibitor for the Treatment of Plaque Psoriasis. Expert Rev Clin Immunol. 2022;18(6):551-557. 6. ClinicalTrials.gov: DERMIS-1 and DERMIS-2 trials (NCT04211363, NCT04211389).