Roflumilast

What is roflumilast?

Roflumilast is a phosphodiesterase-4 (PDE4) inhibitor used for the treatment of chronic obstructive pulmonary disease (COPD) and plaque psoriasis. 

What is roflumilast used for?

Oral roflumilast (Daliresp®) was approved by the US Food and Drug Administration (FDA) in 2011 for patients with severe COPD and a history of recurrent exacerbations. 

Topical roflumilast 0.3% cream (Zorvye™) was approved by the FDA in 2022 for the treatment of plaque psoriasis in patients aged 12 years and older. This is the first topical PDE4 inhibitor approved for use in psoriasis. 

Another PDE4 inhibitor, apremilast, is available for use in psoriasis, in oral tablet form; and crisaborole ointment is a topical PDE4 inhibitor approved for use in atopic dermatitis, with trials underway to evaluate its efficacy for psoriasis as well.

How does roflumilast work?

• Roflumilast selectively inhibits the enzyme phosphodiesterase-4 (PDE4).
  • PDE4 regulates intracellular cyclic adenosine monophosphate (cAMP) hydrolysis and is involved in immune responses to extracellular stimuli.
• PDE4 activity has been found to be higher in psoriatic skin.
• By inhibiting PDE4, roflumilast increases intracellular cAMP levels and downregulates inflammatory modulators that contribute to psoriatic skin changes, such as interleukin-17 (IL-17), interleukin-23 (IL-23), interferon-γ, and tumour necrosis factor alpha (TNF-α).
  • This suppresses epidermal inflammation and keratinocyte proliferation, which reduces skin redness, itching, thickening, and plaque formation.

Dosing and administration of topical roflumilast

• Apply topical roflumilast 0.3% cream once daily to affected areas of plaque psoriasis; rub in completely.
• Can be used in intertriginous areas (for plaque psoriasis between skin folds).
• Not for oral, ophthalmic, or intravaginal use.
• Wash hands after application, unless treating psoriasis on the hands.
• Store at room temperature. 

Pharmacokinetics

• Plasma concentrations of roflumilast and its active metabolite roflumilast N-oxide were quantifiable after 15 days of applying 3–6.5g of 0.3% topical roflumilast cream daily in 22/24 patients.
• Plasma protein binding ~99% for roflumilast; and 97% for roflumilast N-oxide.
• Metabolised by phase I (cytochrome P450) and phase II (conjugation) reactions.
• Following topical application, the mean half-life of roflumilast was 4 days, and 4.6 days for roflumilast N-oxide.

What are the benefits of topical roflumilast?

Topical roflumilast has been found to improve symptoms of psoriasis after ≥2 weeks of use. 

Phase III clinical trial data involving 881 patients found that use of 0.3% roflumilast cream daily was associated with improvement in psoriatic symptoms compared to vehicle cream (Lebwohl et al, 2022).

Specifically, a difference after 8 weeks was found in:

• ≥2 (out of 4) point improvement of the Investigator Global Assessment (IGA) score: 37.5–42.4% for roflumilast vs 6.1–6.9% for vehicle cream
• 75% reduction in Psoriasis Assessment and Severity Index (PASI) score: 39.0–41.6% for roflumilast vs 5.3–7.6% for vehicle cream
• 4 point reduction in Worst Itch Numeric Rating Scale (WI-NRS) score: approx 67.5–69.4% for roflumilast vs 26.8–35.6% for vehicle cream. 

A 52-week multi-centre open label study found that efficacy and tolerability was maintained over one year of daily use, with no new safety concerns, and low rates of discontinuation due to lack of efficacy or adverse effects (Stein Gold et al, 2021).

To date there are no comparative studies with other established topical psoriasis therapies (such as calcipotriol, topical steroids, coal tar, or dithranol).

What are the side effects and risks of roflumilast?

Topical roflumilast is generally well-tolerated.

Rates of reported side-effects are low, and include:

• Application site reactions (eg, burning, stinging)
• Gastrointestinal side-effects (eg, nausea, diarrhoea)
• Nasopharyngitis
• Headaches
• Insomnia
• High blood pressure
• Urinary tract infection. 

Use in pregnancy and lactation

Safety in pregnancy and breastfeeding is unknown. As at 2022, there have been no clinical trials of oral or topical roflumilast in people who are pregnant or breastfeeding. 

Pregnancy

• Animal study data — exposure to oral roflumilast up to 3 times the maximum recommended human dose (MRHD) during the organogenesis period was not associated with increased rates of foetal structural abnormalities in pregnant rats and rabbits; although higher rates of post-implantation loss and stillbirth were observed following exposure to 3–5 times the MRHD.
• Use during labour and delivery is not advised by the manufacturer.

Breastfeeding

• Roflumilast and/or its metabolites have been found to be passed into the milk of lactating rats in animal studies, so some is likely to pass into human breast milk.
• Direct application to the nipple and direct infant exposure following application should be avoided. 

Geriatric use

• No dose adjustment required for geriatric patients based on current data.
• In clinical trials, no overall differences in efficacy or safety in subjects aged 65 years and older have been observed.

Drug interactions

Concomitant use of the following agents may increase systemic exposure to roflumilast and therefore increase the risk of adverse effects — consider the risks and benefits of concurrent use:

• Strong CYP3A4 inhibitors or dual CYP3A4 / CYP1A2 inhibitors (such as erythromycin, ketoconazole, and rifampicin)
• Oral contraceptive pills containing gestodene or ethinyl oestradiol. 

No formal drug-to-drug interaction studies have yet been conducted.

What are the contraindications to roflumilast?

• Hypersensitivity to roflumilast or its constituents.
• Moderate to severe liver impairment (Child-Pugh B or C).