Apremilast

Uses

Apremilast is used for the treatment of adult patients with active psoriatic arthritis and moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Apremilast is also used to associated treatment for these conditions: Psoriatic arthritis aggravated, Severe Plaque psoriasis, Moderate Plaque psoriasis, Ulceration of the mouth

How Apremilast works

The full mechanism of action of this drug is not fully established, however, it is known that apremilast is an inhibitor of phosphodiesterase 4 (PDE4), which mediates the activity of cyclic adenosine monophosphate (cAMP), a second messenger. The inhibition of PDE4 by apremilast leads to increased intracellular cAMP levels. An increase in cAMP results in the suppression of inflammation by decreasing the expression of TNF-α, IL-17, IL-23, and other inflammatory mediators. The above inflammatory mediators have been implicated in various psoriatic conditions as well as Behcet's disease, leading to their undesirable inflammatory symptoms such as mouth ulcers, skin lesions, and arthritis. Apremilast administration leads to a cascade which eventually decreases the levels of the above mediators, relieving inflammatory symptoms.

Dosage

Apremilast dosage

The recommended initial dosage titration of Apremilast from Day 1 to Day 5 is shown below. Following the 5-day titration, the recommended maintenance dosage is 30 mg twice daily taken orally starting on Day 6. This titration is intended to reduce the gastrointestinal symptoms associated with initial therapy. Apremilast can be administered without regard to meals.

Day 1: 10 mg in morning

Day 2: 10 mg in morning and 10 mg in evening

Day 3: 10 mg in morning and 20 mg in evening

Day 4: 20 mg in morning and 20 mg in evening

Day 5: 20 mg in morning and 30 mg in evening

Day 6 and thereafter: 30 mg twice daily

Dosage adjustment in patients with severe renal impairment

Apremilast dosage should be reduced to 30 mg once daily in patients with severe renal impairment. For initial dosage titration, it is recommended that Apremilast be titrated using only the morning schedule and the evening doses be skipped.

Side Effects

The most frequently occurring side effects of Apremilast are nausea, diarrhea, and headache.

Other less frequent side effects are upper respiratory tract infection, vomiting, nasopharyngitis, abdominal pain, hypersensitivity, gastroesophageal reflux disease, dyspepsia, fatigue, decrease appetite, cough, rash, insomnia.

Toxicity

The oral LD50 in mice was greater than 2000 mg/kg in mice. In rats, oral LD50 was 2000 mg/kg males and 300 mg/kg in females.

Overdose information

In healthy subjects receiving a maximum dose of 100 mg (given as 50 mg twice daily) for about 5 days, no significant toxicity was observed. In cases of an overdose, supportive and symptomatic treatment should be administered. Contact the local poison control center for the most recent overdose management for apremilast.

Precaution

Treatment with Apremilast is associated with an increase in adverse reactions of 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. Prescribers should carefully evaluate the risks and benefits of continuing treatment with Apremilast if such events occur.

During the controlled period of the studies in psoriatic arthritis, weight decrease between 5%-10% of body weight was reported in 10% of subjects treated with Apremilast 30 mg twice daily compared to 3.3% treated with placebo.

Interaction

Co-administration of strong cytochrome P450 enzyme inducer Rifampin resulted in a reduction of systemic exposure of Apremilast.Therefore.the use of cytochrome P450 enzyme inducers (e.g. Rifampin, Phenobarbital,Carbamazepine, Phenytoin) with Apremilast is not recommended.

Food Interaction

• Avoid St. John's Wort. Apremilast is a CYP3A substrate; therefore, co-administration with St. John's wort, a CYP3A inducer, may reduce the serum level of apremilast.
• Take with or without food.

Apremilast Drug Interaction

Unknown: charcoal, fluticasone / salmeterol, contained in alcoholic beverages , aspirin, sulfamethoxazole / trimethoprim, calcium / vitamin d, ubiquinone, duloxetine, cholecalciferol, omega-3 polyunsaturated fatty acids, sodium iodide, pregabalin, metoprolol, naproxen, acetaminophen, sars-cov-2 mrna , alirocumab, multivitamin with minerals, ocular lubricant ophthalmic, cholecalciferol

Apremilast Disease Interaction

Moderate: depression, renal dysfunction, weight loss

Volume of Distribution

The average apparent volume of distribution (Vd) is about 87 L, suggesting that apremilast is distributed in the extravascular compartment.

Elimination Route

An oral dose of apremilast is well-absorbed and the absolute bioavailability is approximately 73%. Tmax is approximately 2.5 hours and Cmax has been reported to be approximately 584 ng/mL in one pharmacokinetic study. Food intake does not appear to affect apremilast absorption.

Half Life

The average elimination half-life of this drug ranges from 6-9 hours.

Clearance

In healthy patients, the plasma clearance of apremilast is about 10 L/hour.

Elimination Route

Only 3% and 7% of an apremilast dose are detected in the urine and feces as unchanged drug, respectively, indicating extensive metabolism and high absorption.

Pregnancy & Breastfeeding use

Pregnancy: Pregnancy Category C.

Nursing mothers: It is not known whether Apremilast or its metabolites are present in human milk; however Apremilast was detected in milk of lactating mice. Caution should be exercised when Apremilast is administered to a nursing woman.

Usage in Pediatric Patients

The safety and effectiveness of Apremilast in pediatric patients less than18 years of age have not been established.

Contraindication

Apremilast is contraindicated in patients with a known hypersensitivity to Apremilast or to any of the excipients in the formulation.

Special Warning

Use in Paediatric patient: The safety and effectiveness of Apremilast in paediatric patients less than 18 years of age have not been established.

Interaction with other Medicine

Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of Apremilast. Therefore, the use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with Apremilast is not recommended.

Storage Condition

Store at cool & dry place, protected from light & moisture. Keep the medicine out of the reach of children.

Innovators Monograph

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