Apremilast (Tablets, Tablet kit) Instructions for Use

ATC Code

L04AA32 (Apremilast)

Active Substance

Apremilast (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Selective immunosuppressant, PDE4 inhibitor

Pharmacotherapeutic Group

Immunosuppressants, selective immunosuppressants

Pharmacological Action

Apremilast is an inhibitor of phosphodiesterase 4 (PDE4) and acts intracellularly by modulating pro-inflammatory and anti-inflammatory mediators. PDE4 is a specific cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE) and is the dominant PDE in inflammatory cells. Inhibition of PDE4 leads to an increase in intracellular cAMP levels, which in turn suppresses the inflammatory response by modulating the expression of TNFα, interleukin (IL)-23, IL-17, and other inflammatory cytokines. cAMP also modulates the levels of certain anti-inflammatory cytokines, such as IL-10. These pro- and anti-inflammatory mediators are involved in the pathogenesis of psoriasis and psoriatic arthritis.

In patients with psoriatic arthritis, Apremilast significantly modulated, but did not completely inhibit, plasma proteins: IL-1α, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1β (MIP-1β), matrix metalloproteinase-3 (MMP-3), and TNFα. After 40 weeks of treatment with Apremilast, a decrease in plasma concentrations of IL-17 and IL-23 and an increase in IL-10 concentration were observed.

In patients with psoriasis, Apremilast reduced focal epidermal thickening of affected skin areas, infiltration by inflammatory cells, and the expression of pro-inflammatory genes, including genes for inducible nitric oxide synthase (iNOS), IL-12/IL-23p40, IL-17A, IL-22, and IL-8.

The efficacy of Apremilast treatment did not differ between patients with psoriatic arthritis who were concurrently receiving or not receiving disease-modifying antirheumatic drugs (DMARDs), including methotrexate. In patients who had taken DMARDs or biological DMARDs prior to Apremilast therapy, the therapeutic effects of Apremilast were more pronounced than in those who received placebo. During therapy with Apremilast, a significant, statistically significant improvement in functional activity was noted.

During therapy with Apremilast, patients with moderate to severe psoriasis showed significant improvement compared to placebo. The efficacy of Apremilast was manifested in relation to a complex of clinical manifestations of psoriasis, including itching, nail and scalp involvement, as well as quality of life. The positive clinical effect of Apremilast did not depend on previous drug therapy for psoriasis and its outcomes. The response to Apremilast treatment was rapid and was expressed in a significant reduction in psoriasis symptoms as early as the second week of treatment, compared to placebo.

Pharmacokinetics

After oral administration, Apremilast is well absorbed from the gastrointestinal tract, with an absolute bioavailability of approximately 73%. The median T_max is approximately 2.5 hours. The pharmacokinetics of Apremilast are linear, with an increase in exposure proportional to the dose (within 10-100 mg/day). After once-daily administration of Apremilast, accumulation is minimal, and after twice-daily administration, it is approximately 53% in healthy individuals and 68% in patients with psoriasis. The bioavailability of Apremilast is not impaired when taken with food, so it can be taken regardless of meals.

The binding of Apremilast to human plasma proteins is approximately 68%. The mean apparent V_d is 87 L, indicating extravascular distribution.

Apremilast is extensively metabolized, both by CYP450 isoenzymes and by non-CYP pathways, including oxidation, hydrolysis, and conjugation. Therefore, inhibition of any single one of these pathways is not expected to cause significant drug interactions. The oxidative metabolism of Apremilast involves mainly the CYP3A4 isoenzyme and, to a lesser extent, the CYP1A2 and CYP2A6 isoenzymes. After oral administration, the main component in the blood is Apremilast. The compound is extensively metabolized, with only 3% and 7% of the administered dose excreted unchanged in the urine and feces, respectively. The main inactive metabolite in the blood is the O-demethylated Apremilast glucuronide conjugate (M12). Since Apremilast is a substrate for the CYP3A4 isoenzyme, its exposure is reduced when co-administered with rifampicin, a strong inducer of the CYP3A4 isoenzyme.

In vitro, Apremilast is not an inhibitor or inducer of CYP450 isoenzymes; therefore, when used in combination with substrates of CYP450 isoenzymes, Apremilast will not impair the clearance or exposure of active substances that are metabolized by CYP450 isoenzymes.

In vitro, Apremilast is a substrate and a weak inhibitor of P-glycoprotein (IC₅₀ >50 µM).

In vitro, Apremilast slightly inhibits or has no effect (IC₅₀ >10 µM) on the organic anion transporters OAT1 and OAT3, the organic cation transporter OCT2, the organic anion transporting polypeptide (OATP) 1B1 and OATP1B3, or the breast cancer resistance protein (BCRP) and is not a substrate for these transporters.

In healthy individuals, the clearance of Apremilast averages about 10 L/h and the terminal T_1/2 is approximately 9 hours. After oral administration of a labeled compound, approximately 58% and 39% of the radioactivity is excreted by the kidneys and intestines, respectively, with approximately 3% and 7% of the dose as radiolabeled Apremilast.

The exposure of Apremilast in elderly individuals (65-85 years) is approximately 13% higher in terms of area under the concentration/time curve (AUC) and 6% higher in C_max compared to volunteers aged 18-55 years.
In severe renal impairment, after a single 30 mg dose of Apremilast, AUC and C_max values increased by approximately 89% and 42%, respectively.

Indications

Treatment of active psoriatic arthritis (PsA) in adults as monotherapy or in combination with disease-modifying antirheumatic drugs (DMARDs) in case of insufficient response or intolerance to prior DMARD therapy.

Treatment of moderate to severe plaque psoriasis in adults in case of insufficient response, contraindications, or intolerance to other basic anti-inflammatory therapy, including cyclosporine, methotrexate, or drugs used in combination with PUVA therapy.

ICD codes

Dosage Regimen

Initiate treatment with a titration schedule to improve gastrointestinal tolerability. Administer the initial dose of 10 mg orally in the morning on Day 1.

On Day 2, administer 10 mg orally in the morning and 10 mg orally in the evening. On Day 3, administer 10 mg orally in the morning and 20 mg orally in the evening.

On Day 4, administer 20 mg orally in the morning and 20 mg orally in the evening. On Day 5, administer 20 mg orally in the morning and 30 mg orally in the evening.

From Day 6 onward, administer the maintenance dose of 30 mg orally twice daily. Take tablets with or without food.

For patients with severe renal impairment (creatinine clearance less than 30 mL/min), reduce the maintenance dose to 30 mg once daily. No dose adjustment is required for patients with hepatic impairment.

Monitor patient body weight regularly. Evaluate unexplained or clinically significant weight loss and consider treatment discontinuation.

Avoid concomitant use with potent CYP450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin, St. John’s wort) as this may reduce Apremilast efficacy.

Adverse Reactions

Immune system disorders Uncommon – hypersensitivity reactions.

Metabolism and nutrition disorders Common – decreased appetite; Uncommon – weight decreased.

Nervous system disorders: Common – migraine, tension headache, headache, insomnia.

Respiratory, thoracic and mediastinal disorders: Common – cough, bronchitis, upper respiratory tract infections, nasopharyngitis.

Gastrointestinal disorders Very common – diarrhea, nausea; Common – vomiting, dyspepsia, frequent bowel movements, upper abdominal pain, gastroesophageal reflux disease.

Skin and subcutaneous tissue disorders Uncommon – rash.

Musculoskeletal and connective tissue disorders Common – back pain.

General disorders and administration site conditions Common – fatigue.

Contraindications

Hypersensitivity to Apremilast, pregnancy; children under 18 years of age.

Use with caution in patients with severe renal impairment, in patients with low body weight.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy.

Apremilast was detected in the milk of mice. It is not known whether Apremilast or its metabolites are excreted in human breast milk. Since the risk of adverse effects on the infant during breastfeeding cannot be excluded, Apremilast should not be used during breastfeeding.

Use in Hepatic Impairment

The drug is approved for use in patients with hepatic impairment.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

The drug is approved for use in elderly patients.

Special Precautions

In patients with severe renal impairment, the dose of Apremilast should be reduced to 30 mg once daily.

In patients with low body weight at the start of the course of therapy, body weight should be regularly monitored during treatment. In case of unexplained or clinically significant weight loss, a thorough medical examination of the patient should be performed and discontinuation of treatment should be considered.

Drug Interactions

Concomitant use with the potent CYP3A4 isoenzyme inducer rifampicin leads to a decrease in the systemic exposure of Apremilast and a reduction in its efficacy. Therefore, the combined use of potent CYP3A4 inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort preparations) with Apremilast is not recommended. With simultaneous repeated administration of Apremilast and rifampicin, the AUC and C_max of Apremilast decrease by 72% and 43%, respectively. Under conditions of combined use of Apremilast with potent CYP3A4 inducers (e.g., rifampicin), the clinical response may be reduced.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.