Apremilast (Otezla®, Celgene) is an oral small-molecule inhibitor of the enzyme phosphodiesterase 4, which plays an important role in chronic inflammation associated with psoriasis.
In July 2019, apremilast was also approved by the FDA for treatment of mouth ulcers associated with Behçet disease.
What is apremilast used for?
In September 2014, the US Food and Drug Administration (FDA) approved the use of apremilast in patients with plaque psoriasis. It was approved for use in the European Union in January 2015, and New Zealand in psoriasis in November 2016.
Apremilast was approved for the treatment of plaque psoriasis in patients:
- Who failed to respond to or were intolerant to treatment with etanercept and adalimumab
- Those with a history of hepatitis B, hepatitis C, demyelinating disease, malignancy, chronic infection (eg HIV) or congestive heart failure
- Patients on long-term systemic corticosteroid therapy.
The European Medicines Agency's (EMA) granted marketing authorisation throughout the European Union in January 2015 for:
- Treatment of moderate-to-severe chronic plaque psoriasis in adult patients who failed to respond to or, who have a contraindication to, or are intolerant to other systemic therapy including ciclosporin, methotrexate or psoralen and ultraviolet-A light (PUVA)
- alone or in combination with DMARDs, for the treatment of active psoriatic arthritis in adult patients who have had an inadequate response, or who have been intolerant to a prior DMARD therapy.
Apremilast was also shown to be effective for the treatment of oral ulceration in Behçet disease.
There are off-label studies demonstrating efficacy in palmoplantar psoriasis, scalp psoriasis, atopic dermatitis, alopecia areata and hidradenitis suppurativa. There have been mixed reports regarding efficacy in sarcoidosis, lichen planus and discoid lupus erythematosus.
How does apremilast work in psoriasis?
- Psoriasis plaque formation is thought to be caused by dysregulated immune activity within the skin.
- This dysregulation can lead to an increase in production of proinflammatory cytokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-17, and IL-23 which promote chronic inflammation of the epidermis and proliferation of keratinocytes.
- These changes result in redness, itching, epidermal thickening and scaly plaques.
- PDE4 is the predominant intracellular cyclic adenosine monophosphate (cAMP)-degrading enzyme within a variety of inflammatory cells, including eosinophils, neutrophils, macrophages, T cells, and monocytes.
- PDE4 degrades cAMP into its inactive form AMP, thus allowing these immune cells to produce elevated levels of proinflammatory cytokines and decreased levels of anti-inflammatory cytokines.
- Apremilast is an inhibitor of PDE4 and prevents the degradation of cAMP to AMP, suppressing the production of proinflammatory cytokines including tumour necrosis factor TNF-α, IL-17, and interferon (IFN)-γ and promoting the production of anti-inflammatory mediators such as IL-10.
How is apremilast administered?
The recommended maintenance dose of apremilast is 30 mg twice daily. To reduce the risk of gastrointestinal symptoms, the recommended dose is initially titrated according to the following schedule:
Day 1: 10 mg in the morning
Day 2: 10 mg in the morning and 10 mg in the evening
Day 3: 10 mg in the morning and 20 mg in the evening
Day 4: 20 mg in the morning and 20 mg in the evening
Day 5: 20 mg in the morning and 30 mg in the evening
Day 6 and thereafter: 30 mg twice daily
For patients with severe renal impairment, the recommended maintenance dose is 30 mg once daily, titrated using the morning schedule only, as listed above.
- Apremilast can be taken with or without food.
- Tablets should not be crushed, split, or chewed.
Link to key clinical-trial evidence about apremilast
Potential drug interactions with apremilast
- Apremilast should not be administered together with drugs that increase the activity of hepatic cytochrome P450 enzymes, eg, rifampicin, phenobarbital, carbamazepine, phenytoin.
- Co-administration with rifampicin has resulted in a reduction of circulating apremilast with a loss of efficacy.
- No significant pharmacokinetic interactions were observed when 30 mg of oral apremilast was administered with oral contraceptives, ketoconazole, or methotrexate.
What are the adverse effects of apremilast?
Apremilast is well tolerated. No monitoring or testing is required.
- Diarrhoea (17%), nausea (17%), and upper respiratory tract infection (9%) were the most commonly reported adverse reactions in clinical trials in 1426 adult patients with moderate to severe plaque psoriasis treated with apremilast compared with placebo.
- The most common adverse reactions leading to discontinuation of apremilast were nausea (1.6%), diarrhoea (1.0%), and headache (0.8%).
Use in pregnancy
- The incidences of malformations and pregnancy loss in human pregnancies have not been established for apremilast.
- Apremilast should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In animal embryo-fetal development studies, the administration of apremilast to cynomolgus monkeys during organogenesis resulted in dose-related increases in abortion/embryo-fetal death at dose exposures 2.1-times the maximum recommended human therapeutic dose.
Use in nursing mothers
It is not known whether apremilast or its metabolites are present in human milk.
The safety and effectiveness of apremilast have not been established in patients less than 18 years of age.
No overall differences were observed in the efficacy and safety of apremilast in elderly subjects ≥65 years of age compared with those <65 years of age in clinical trials involving 1257 plaque psoriasis patients.
The maintenance dose of apremilast should be reduced to 30 mg once daily in patients with severe renal impairment (CrCl < 30 mL/min).
No dose adjustments of apremilast are necessary for patients with moderate and severe hepatic impairment.
Apremilast is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation.
Treatment with apremilast is associated with an increase in depression. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider.
Patients treated with apremilast should have their body weight monitored regularly. In clinical trials in psoriasis, weight decrease between 5%-10% of body weight occurred in 12% (96/784) of subjects treated with apremilast compared to 5% (19/382) treated with placebo.
If unexplained or clinically significant weight loss occurs, discontinuation of apremilast should be considered.
Apremilast may reduce alcohol consumption in those with alcohol use disorders.
We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA), UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).