Usage
Apremilast is prescribed for the treatment of:
- Psoriatic arthritis: A chronic inflammatory disease affecting joints and skin.
- Plaque psoriasis: A chronic skin condition characterized by red, raised, scaly patches.
- Behçet’s disease (oral ulcers): A rare disorder causing inflammation in blood vessels throughout the body. It frequently manifests with painful mouth sores.
Pharmacological Classification: Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4). Specifically, it targets the PDE4 subtype prevalent in inflammatory cells.
Mechanism of Action: Apremilast works by inhibiting PDE4, an enzyme that breaks down cyclic adenosine monophosphate (cAMP). By blocking PDE4, apremilast increases intracellular cAMP levels, which in turn modulates the inflammatory response by reducing the production of pro-inflammatory cytokines (like TNF-α, IL-17, IL-23, and IFN-γ) and increasing the production of anti-inflammatory cytokines (like IL-10).
Alternate Names
Apremilast is the generic name.
Brand Name: Otezla
How It Works
Pharmacodynamics: Apremilast’s primary effect is the suppression of inflammation through the mechanism described above. Increased intracellular cAMP levels downstream of PDE4 inhibition modulate the inflammatory response by altering the balance of pro-inflammatory and anti-inflammatory cytokine production. This leads to a reduction in the inflammatory manifestations of psoriatic arthritis, plaque psoriasis, and oral ulcers in Behçet’s disease.
Pharmacokinetics:
- Absorption: Apremilast is well absorbed orally, reaching peak plasma concentration approximately 2.5 hours after administration. Food does not significantly affect absorption.
- Metabolism: Primarily metabolized via CYP3A4 (a liver enzyme), with minor contributions from CYP1A2 and CYP2C9.
- Elimination: Approximately 68% of the dose is excreted in urine and 21% in feces. The terminal half-life is about 6 to 9 hours.
Mode of Action: Apremilast selectively inhibits PDE4. This leads to increased intracellular cAMP, which downregulates pro-inflammatory mediators and upregulates anti-inflammatory mediators.
Receptor Binding/Enzyme Inhibition: Apremilast specifically inhibits PDE4. It does not bind to or inhibit other PDE subtypes.
Elimination Pathways: Primarily hepatic metabolism via CYP3A4, with renal excretion of metabolites.
Dosage
Standard Dosage
Adults:
- Psoriatic Arthritis/Behçet’s Disease: Titrate to 30 mg twice daily (morning and evening).
- Plaque Psoriasis: Titrate to 30 mg twice daily (morning and evening).
Titration schedule (for all adult indications):
- Day 1: 10 mg in the morning.
- Day 2: 10 mg AM and 10 mg PM.
- Day 3: 10 mg AM and 20 mg PM.
- Day 4: 20 mg AM and 20 mg PM.
- Day 5: 20 mg AM and 30 mg PM.
- Day 6 onwards: 30 mg twice daily (morning and evening).
Children (Plaque Psoriasis only, 6 years and older):
- 20 kg to <50 kg: Titrate to 20 mg twice daily.
- ≥50 kg: Titrate to 30 mg twice daily.
The titration schedule follows the same pattern as adults, reaching the maintenance dose on Day 6.
Special Cases:
- Elderly Patients: No dose adjustment is typically required, but monitor for gastrointestinal side effects.
- Patients with Renal Impairment:
- Mild/Moderate: No dose adjustment.
- Severe (CrCl <30 mL/min): 30 mg once daily.
- Patients with Hepatic Dysfunction: No dose adjustment.
- Patients with Comorbid Conditions: Exercise caution in patients with a history of depression or suicidal ideation.
Clinical Use Cases Apremilast’s use is limited to the specific conditions mentioned above. There’s no defined dosage recommendations for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Adjustments are primarily made for severe renal impairment.
Side Effects
Common Side Effects:
- Diarrhea
- Nausea
- Upper respiratory tract infections
- Headache
- Vomiting
Rare but Serious Side Effects:
- Depression and suicidal ideation
- Severe diarrhea, nausea, and vomiting (especially in elderly patients or those with low blood pressure/volume)
- Allergic reactions (including hives, difficulty breathing, swelling)
- Significant weight loss
Long-Term Effects:
- Potential for depression and weight change with extended use.
Adverse Drug Reactions (ADR): Severe allergic reactions, significant weight loss, worsening depression, and suicidal ideation.
Contraindications
- Hypersensitivity to apremilast
- Pregnancy
Drug Interactions
- CYP450 Inducers (e.g., rifampicin): Reduce apremilast levels and efficacy. Avoid concomitant use.
- Other Interactions: No clinically significant interactions with oral contraceptives, ketoconazole, or methotrexate have been observed. However, be aware of potential interactions with numerous medications, including abatacept, abemaciclib, and others. Always consult a drug interaction checker.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Contraindicated in pregnancy due to the risk of fetal loss.
- Breastfeeding: Not recommended due to limited data on infant safety. Apremilast is present in animal milk.
Drug Profile Summary
- Mechanism of Action: PDE4 inhibitor, increases cAMP, modulates inflammatory response.
- Side Effects: Diarrhea, nausea, upper respiratory tract infection, headache, vomiting, depression, weight loss.
- Contraindications: Hypersensitivity, pregnancy.
- Drug Interactions: CYP450 inducers (e.g., rifampicin) decrease efficacy; consult a comprehensive drug interaction checker for others.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; not recommended while breastfeeding.
- Dosage: Adults: 30 mg BID (after titration). Pediatric (Plaque Psoriasis): 20 mg BID (20 kg to <50 kg) or 30 mg BID (≥50 kg) (after titration). Renal impairment (severe): 30 mg daily.
- Monitoring Parameters: Monitor for gastrointestinal side effects, weight loss, and mood changes (especially depression and suicidal ideation).
Popular Combinations
Apremilast is often used as monotherapy or in combination with other medications for psoriasis or psoriatic arthritis, such as methotrexate or biologics.
Precautions
- General Precautions: Screen for depression, suicidal ideation, and renal function. Monitor weight.
- Pregnant Women: Contraindicated.
- Breastfeeding Mothers: Not recommended.
- Children & Elderly: Monitor for gastrointestinal effects.
- Lifestyle Considerations: No specific restrictions related to alcohol, smoking, or diet. No restrictions on driving unless side effects impair function.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Apremilast?
A: Adults: 30 mg twice daily after initial titration. Pediatrics (6 years and older with plaque psoriasis): 20 mg BID (20- <50 kg) or 30 mg BID (≥50 kg) after titration. Adjust for severe renal impairment (30 mg once daily).
Q2: What are the most common side effects of Apremilast?
A: Diarrhea, nausea, upper respiratory tract infections, headache, and vomiting.
Q3: Is Apremilast safe to use during pregnancy?
A: No, apremilast is contraindicated during pregnancy due to the risk of fetal loss.
Q4: Can I breastfeed while taking Apremilast?
A: It is not recommended to breastfeed while taking apremilast.
Q5: How does Apremilast work?
A: Apremilast inhibits PDE4, leading to increased intracellular cAMP levels and modulation of the inflammatory response.
Q6: What should I monitor in patients taking Apremilast?
A: Monitor for gastrointestinal side effects, weight changes, mood changes (especially depression and suicidal ideation), and renal function.
Q7: Are there any major drug interactions with Apremilast?
A: CYP450 inducers like rifampicin significantly reduce apremilast’s effectiveness. Check for other drug interactions as many exist.
Q8: What are the indications for using Apremilast?
A: Psoriatic arthritis, plaque psoriasis, and oral ulcers associated with Behçet’s disease.
Q9: What should I advise patients with a history of depression before starting Apremilast?
A: Discuss the potential risk of worsening depression and suicidal ideation. Carefully weigh the risks and benefits of treatment and monitor closely for mood changes.
