Roflumilast

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 15.10.2023

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Synonym(s)

CAS No:162401-32-3; PDE-4 selective phosphodiesterase inhibitor

Definition
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Roflumilast is the first approved drug from the group of phosphodiesterase 4 inhibitors (PDE-4 inhibitors) to be used for the treatment of chronic obstructive pulmonary disease (COPD).

Indication
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Approved for long-term therapy in adult patients with severe COPD and chronic bronchitis and frequent worsening of the clinical picture (so-called exacerbations) in the past in addition to treatment with a bronchodilator drug.

Topical roflumilast for psoriasis and seborrheic dermatitis (not previously approved):

  • Psoriasis: Roflumilast, as a selective, potent inhibitor of phosphodiesterase 4 (PDE4), has been studied in clinical trials for several dermatologic conditions, including psoriasis, atopic dermatitis, and seborrheic dermatitis. In a randomized double-blind study, the efficacy of 0.3% roflumilast cream applied once daily for a period of 8 weeks, in 331 patients with plaque psoriasis (Thurston AW Jr et al 2023). Previously, topically aplicated roflumilast (0.3% cream) was found to be detectable in both skin and plasma, but at higher concentrations in skin than in plasma. In three study arms, subjects applied either a 0.3% roflumilast cream, a 0.15% roflumilast cream, or a cream without active ingredient once daily. After six weeks of local therapy, 28 and 23 percent of patients in the two Roflumilast groups achieved an appearance-free or almost appearance-free skin appearance (placebo group: 8%). The Psoriasis Area and Severity Index (PASI score) to determine the severity of psoriasis was also significantly higher in the Roflumilast groups than in the placebo group. With regard to application site side effects, there was no difference in the three study arms.
  • Seborrheic dermatitis: A randomized, double-blind, vehicle-controlled phase 3 study evaluated the topical application of the PDE4 inhibitor roflumilast in the form of a 0.3% foam in patients with seborrheic dermatitis. With respect to the primary endpoint, there was a highly statistically significant difference (p < 0.0001) between the roflumilast-treated cohort (80.1%) and the vehicle-controlled group (59.2%) after 8 weeks of therapy. Complete disappearance of erythema (57.9%) and scaling (58.2%) was achieved in more than 50%. With regard to tolerability, no local undesirable side effects were observed. The safety profile of Roflumilast foam was comparable to previous studies.

Dosage and method of use
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55ug/day p.o.

Undesirable effects
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The therapeutic range of PDE4 inhibitors is limited for use in respiratory diseases due to dose-limiting side effects such as nausea, diarrhoea and headache.

With low efficacy of the drug against COPD and asthma, these studies showed gastrointestinal side effects. Particularly in underweight patients with COPD, possible further weight loss can be a therapy limiting factor.

Interactions
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CYP1A2 inhibitors enhance the effect, CYP1A2 inducers (e.g. rifampicin) reduce the effect.

Contraindication
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Liver dysfunction

Preparations
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Daxas® 500ug/Tabl

Note(s)
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Topical roflumilast in psoriasis: Roflumilast, as a selective, potent inhibitor of phosphodiesterase 4 (PDE4), has been studied in clinical trials for several dermatological conditions, including psoriasis, atopic dermatitis and seborrheic dermatitis. In a randomized double-blind study, the efficacy of 0.3% roflumilast cream applied once daily for a period of 8 weeks, in 331 patients with plaque psoriasis (Thurston AW Jr et al 2023). Previously, topically aplicated roflumilast (0.3% cream) was found to be detectable in both skin and plasma, but at higher concentrations in skin than in plasma. In three study arms, subjects applied either a 0.3% roflumilast cream, a 0.15% roflumilast cream, or a cream without active ingredient once daily. After six weeks of local therapy, 28 and 23 percent of patients in the two Roflumilast groups achieved an appearance-free or almost appearance-free skin appearance (placebo group: 8%). The Psoriasis Area and Severity Index(PASI score) to determine the severity of psoriasis was also significantly higher in the Roflumilast groups than in the placebo group. With regard to application site side effects, there was no difference in the three study arms.

Topical Roflumilast in Seborrheic Dermatitis: A randomized, double-blind, vehicle-controlled phase 3 study evaluated the topical application of the PDE4 inhibitor roflumilast in the form of a 0.3% foam in patients with seborrheic dermatitis. With respect to the primary endpoint, there was a highly statistically significant difference (p < 0.0001) between the roflumilast-treated cohort (80.1%) and the vehicle-controlled group (59.2%) after 8 weeks of therapy. Complete disappearance of erythema (57.9%) and scaling (58.2%) was achieved in more than 50%. With regard to tolerability, no local undesirable side effects were observed. The safety profile of Roflumilast foam was comparable to previous studies.

Note: When a drug inhibits PDE-4, intracellular cAMP levels increase, reducing the expression of cytokines such as TNF-α, interleukin (IL-)23 and -17, and other inflammatory mediators. In addition, cAMP also affects the concentration of anti-inflammatory cytokines such as IL-10: IL-10 levels increase. Thus, the network of pro- and anti-inflammatory mediators is modulated intracellularly, and downregulation of the inflammatory response occurs. The PDE-4 inhibitor apremilast (Otezla®) is used in moderate to severe chronic plaque psoriasis, but is administered orally.

Literature
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  1. Garnock-Jones KP (2015) Roflumilast: A Review in COPD. Drugs 75:1645-1656.
  2. Jafari Andarian S et al. (2016) The safety and effectiveness of the current treatment regimen with or without roflumilast in advanced COPD patients: A systematic review and meta-analysis of randomized controlled trials. Med J Islam Repub Iran 30:332.
  3. Luo J et al. (2016) Can roflumilast, a phosphodiesterase-4 inhibitor, improve clinical outcomes in patients with moderate-to-severe chronic obstructive pulmonary disease? A meta-analysis. Respir Res 17:18
  4. Papp KA et al (2020) Roflumilast Cream Improves Signs and Symptoms of Plaque Psoriasis: Results from a Phase 1/2a Randomized, Controlled Study. J Drugs Dermatol 19:734-740.
  5. Thurston AW Jr et al (2023) Pharmacokinetics of roflumilast cream in chronic plaque psoriasis: data from phase I to phase III studies. Am J Clin Dermatol 24:315-324.
  6. Wedzicha JA et al (2016) Roflumilast: a review of its use in the treatment of COPD. Int J Chron Obstruct Pulmon Dis 11:81-90.
  7. Yuan L et al. (2016) Potential treatment benefits and safety of roflumilast in COPD: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis 11:1477-1483.

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Last updated on: 15.10.2023