Apremilast

Introduction

Apremilast (Otezla®; Celgene, NJ, USA) is a small oral medicationmolecule inhibitor 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 the treatment of the mouth. ulcers associated with Behçet's disease.

What is apremilast used for?

In September 2014, the United States Food and Drug Administration (FDA) approved the use of apremilast in patients with license plate psoriasis. It was approved for use in New Zealand in psoriasis in November 2016.

Apremilast is approved for the treatment of plaque psoriasis in patients:

• who did not respond or were intolerant to treatment with etanercept (Enbrel®) and adalimumab (Humira®)
• those with a history of hepatitis B, hepatitis C, demyelinating disease, malignancy, chronic infection (e.g HIV) or congestive heart failure
• long-term patients systemic corticosteroid therapy.

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion for apremilast for:

• treatment of moderate to severe chronic plaque psoriasis in adult patients who have not responded or who have contraindication a, or are intolerant of other systemic therapy including cyclosporine, methotrexate or psoralen and ultraviolet-A light (PUVA).

It has been reported to be particularly effective in palmoplantar psoriasis.

Apremilast also proved to be effective for the treatment of oral administration. ulceration in Behçet's disease.

How does apremilast work in psoriasis?

• The plaque formation of psoriasis is believed to be caused by deregulated immune activity within the skin.
• Is deregulation can lead to an increase in the production of proinflammatory cytokines how tumor necrosis factor (TNF) -α, interleukin (IL) -17 and IL-23 that promote chronic inflammation of the epidermis and proliferation of keratinocytes.
• These changes cause redness, itching, epidermal thickening and scaly plates.
• PDE4 is the predominant intracellular enzyme that degrades cyclic adenosine monophosphate (cAMP) within a variety of inflammatory cells, including eosinophils, neutrophils, macrophages, T cellsand monocytes.
• PDE4 degrades cAMP in its inactive AMP form, thus allowing these immune cells to produce elevated levels of pro-inflammatory 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 pro-inflammatory cytokines including tumor necrosis factor TNF-α, IL-17 and interferon (IFN) -γ and promoting the production of antiinflammatory mediators like IL-10.

How is apremilast given?

The recommended dose of apremilast is 30 mg twice a day. To reduce the risk of gastrointestinal symptoms, the recommended dose is adjusted according to the following schedule:

Day 1: 10 mg in the morning
Day 2: 10 mg in the morning and 10 mg in the afternoon.
Day 3: 10 mg in the morning and 20 mg in the afternoon.
Day 4: 20 mg in the morning and 20 mg in the afternoon.
Day 5: 20 mg in the morning and 30 mg in the afternoon.
Day 6 and following: 30 mg twice a day.

For patients with severe renal Deterioration, the recommended dose is 30 mg once a day, adjusted using only the morning schedule, as above.

• Apremilast can be taken with or without food.
• The tablets should not be crushed, split or chewed.

Link to key evidence from clinical trials on apremilast

Possible drug interactions with apremilast

• Apremilast must not be administered together with medicines that increase the activity of hepatic cytochrome P450 enzymeseg rifampicin, phenobarbital, carbamazepine, phenytoin.
• Co-administration with rifampicin has resulted in a reduction in circulating apremilast with a loss of effectiveness.
• Not significant pharmacokinetics Interactions were observed when 30 mg 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.

• Diarrhea (17%), nausea (17%), and upper respiratory tract infection (9%) were the most commonly reported. Adverse reactions in clinical trials in 1,426 adult patients with moderate to severe plaque psoriasis treated with apremilast compared to placebo.
• The most common adverse reactions leading to discontinuation of apremilast were nausea (1.6%), diarrhea (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 embryo-fetal development studies in animals, administration of apremilast to cynomolgus monkeys during organogenesis resulted in dose-related increases in abortion / embryo-fetal death with exposures at dose 2.1 times the recommended human maximum therapeutic dose.

Use in nursing mothers

It is not known whether apremilast or its metabolites are present in human milk.

Pediatric use

The safety and efficacy of apremilast in patients younger than 18 years have not been established.

Geriatric use

No overall differences in the efficacy and safety of apremilast were observed in elderly subjects ≥65 years compared to those <65 años de edad en ensayos clínicos con 1257 pacientes con psoriasis en placas.

Renal insufficiency

The apremilast dose should be reduced to 30 mg once a day in patients with severe renal impairment (creatinine clearance less than 30 ml per minute).

Hepatic impairment

No dose adjustment of apremilast is necessary in patients with moderate and severe hepatic impairment.

Allergic reactions

Apremilast is contraindicated in patients with an acquaintance hypersensitivity apremilast or any of the excipients in the formulation

Depression

Treatment with apremilast is associated with an increase in depression. Patients, their caregivers and their families should be informed of the need to be alert to the onset or worsening of depression, suicidal thoughts, or other mood swings, and if such changes occur, contact their healthcare provider .

Weightloss

Patients treated with apremilast should monitor their body weight regularly. In psoriasis clinical trials, weight loss between 5% and 10% in body weight occurred in 12% (96/784) of apremilast-treated subjects compared to 5% (19/382) treated with placebo.

If clinically significant or unexplained weight loss occurs, discontinuation of apremilast should be considered.