Apremilast

Introduction Overview

Generic Name

apremilast

Brand Name

Otezla

Dosage Form

Tablets (10 mg, 20 mg, 30 mg)

Drug Class

Antirheumatics

Pharmacokinetics

Absorption:
Apremilast is readily absorbed after oral administration with peak plasma concentrations generally attained within 2.5 hours post-dose. The bioavailability of apremilast is approximately 73%, indicating good oral absorption. Food effects are minimal, allowing administration with or without food, which provides flexibility in dosing. The absorption is not significantly affected by gastric pH or gastrointestinal motility variations, making the drug reliable for systemic delivery across diverse patient populations.

Distribution:
Apremilast exhibits moderate plasma protein binding (~68%), mostly reversible and nonspecific, allowing adequate distribution into tissues. The apparent volume of distribution in healthy adults ranges around 87 L, suggesting distribution beyond the vascular compartment, including the interstitial space but with no significant penetration into the central nervous system as this is not a CNS-acting drug. Distribution is influenced by body weight, but no dosing adjustment is required.

Metabolism:
Apremilast undergoes extensive metabolism primarily via hepatic pathways involving cytochrome P450 enzymes, especially CYP3A4, with minor contributions from CYP1A2 and CYP2A6. The major metabolic pathways include oxidative metabolism and subsequent glucuronidation. The metabolites are inactive. Since CYP3A4 is involved, strong inducers of this enzyme can significantly lower apremilast plasma levels and reduce its efficacy. This has important clinical implications concerning drug-drug interactions and dosage adjustments.

Elimination:
The elimination of apremilast from plasma follows a biphasic decline with an elimination half-life of approximately 6 to 9 hours. Excretion occurs mainly via urine (~58%) and feces (~39%), mostly as metabolites rather than unchanged drug. Renal impairment can reduce clearance of apremilast, necessitating dosage adjustments in patients with moderate to severe renal dysfunction, while mild hepatic impairment does not require dosing changes. The drug does not accumulate substantially with twice-daily dosing due to its moderate half-life and steady state is reached within 3 to 5 days of consistent administration.

Dosage Forms

Available Dosage Forms:
- Oral tablets available in strengths of 10 mg, 20 mg, and 30 mg.

Dosages for Adults and Adolescents:
- For adult patients with psoriatic arthritis, plaque psoriasis, or Behçet's disease oral ulcers, the recommended starting dose involves a titration over 5 days: Day 1 (10 mg once), Day 2 (10 mg twice), Day 3 (10 mg plus 20 mg), Day 4 (20 mg twice), Day 5 (20 mg plus 30 mg), followed by a maintenance dose of 30 mg twice daily orally.
- For pediatric patients (age 6 years and older, weighing at least 20 kg) with moderate to severe plaque psoriasis:
* Patients weighing 20 to less than 50 kg: start with a 4-day titration ending at 20 mg twice daily maintenance.
* Patients weighing 50 kg or more: the 5-day adult titration schedule applies with 30 mg twice daily maintenance dosing.

Specific Patient Populations:
- Patients with moderate or severe renal impairment require dosage adjustment; typically, a reduction in maintenance dose is recommended due to reduced clearance.
- Mild or moderate hepatic impairment does not necessitate dosing adjustments.
- Geriatric and other populations have no specific dose modifications but require monitoring for tolerability.

Otezla Starter Pack:
- Otezla starter packs contain the tablets needed for the initial 5-day titration period, designed to facilitate dose escalation and minimize early gastrointestinal side effects.

Clinical Practice Notes:
- Tablets should be swallowed whole and can be taken with or without food.
- If a dose is missed, it should be taken as soon as possible unless close to the next dose, avoiding double dosing.
- In case of overdose, medical attention should be sought immediately.

Mechanism Of Action

Otezla (apremilast) acts as a selective inhibitor of the intracellular enzyme phosphodiesterase 4 (PDE4), which is a key regulator of cyclic adenosine monophosphate (cAMP) in immune cells. PDE4 normally degrades cAMP, thereby modulating inflammatory cell signaling pathways. By inhibiting PDE4, Otezla elevates intracellular cAMP levels, which leads to a downstream regulation of pro-inflammatory and anti-inflammatory mediators.

Elevated cAMP activates protein kinase A (PKA), which phosphorylates transcription factors that alter gene expression profiles in immune cells such as monocytes, T cells, and dendritic cells. This results in downregulation of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-17 (IL-17), interleukin-23 (IL-23), and interferon-gamma (IFN-γ) — all of which play pivotal roles in the pathogenesis of psoriasis and psoriatic arthritis. Concurrently, Otezla increases the production of anti-inflammatory cytokines like interleukin-10 (IL-10), which contribute to immune modulation and reduction of tissue inflammation.

By modulating this balance of cytokines and cellular response, Otezla effectively reduces the inflammatory cascade responsible for the characteristic epidermal hyperproliferation, scaling, joint inflammation, and ulceration observed in target diseases such as plaque psoriasis, psoriatic arthritis, and Behçet’s disease.

Compared to biologics that directly target cytokines (e.g., TNF inhibitors or IL-17 inhibitors), Otezla provides an oral, non-biologic approach with immunomodulatory effects that indirectly suppress multiple inflammatory pathways. Clinical studies have demonstrated its efficacy and safety profile with favorable impacts on skin and joint symptoms, offering an alternative especially for patients preferring oral therapy or those who are contraindicated or intolerant to biologics.

Pharmacological Actions

Selective inhibition of phosphodiesterase 4 (PDE4) enzyme.
Increase of intracellular cyclic adenosine monophosphate (cAMP) levels.
Downregulation of pro-inflammatory cytokines including TNF-α, IL-17, IL-23, and IFN-γ.
Upregulation of anti-inflammatory cytokines such as IL-10.
Immunomodulatory action reducing skin inflammation and joint swelling.
Non-biologic oral immunosuppressive agent.
Reduction of epidermal hyperplasia and scaling in psoriasis.
Decreased inflammation and pain in psoriatic arthritis.
Improvement of oral ulcers in Behçet’s disease by reducing mucosal inflammation.
Minimal direct immunosuppression compared to biologics, lowering infection risk.
Lack of corticosteroid-related adverse effects due to distinct mechanism.
Potential weight loss effect mediated possibly by appetite modulation or systemic inflammation reduction.

Therapeutic Or Clinical Uses

Treatment of adult patients with active psoriatic arthritis to improve joint symptoms and inflammation.
Management of moderate to severe plaque psoriasis in adult patients requiring systemic therapy or phototherapy.
Treatment of moderate to severe plaque psoriasis in pediatric patients aged 6 years and older weighing at least 20 kg.
Reduction of oral ulcers associated with Behçet’s disease in adult patients.
Therapeutic alternative for patients who prefer oral medication instead of biologics or immunosuppressive injections.
Use in patients who have contraindications or intolerance to biologic therapies or systemic corticosteroids.
Adjunct therapy in patients requiring multidrug approaches for psoriatic disease.
Long-term management of chronic inflammatory skin and joint disorders to improve quality of life.
Reducing symptoms like scaling, redness, itching in psoriasis, and joint pain and swelling in psoriatic arthritis.
Applicable in patients with comorbidities where steroids or biologics may pose higher risks.

Side Or Adverse Effects

Nausea, especially during the first weeks of treatment due to gastrointestinal irritation.
Diarrhea, which is generally mild to moderate and transient but can be severe in rare cases.
Headache, commonly reported but typically mild.
Vomiting occurring infrequently and mostly during initial dose titration.
Upper respiratory tract infections manifesting as common cold symptoms such as stuffy nose and sore throat.
Upper abdominal pain and discomfort.
Weight loss, observed in clinical trials, sometimes significant (>5% body weight), necessitating monitoring.
Mood changes including depression and suicidal thoughts, requiring close observation in at-risk patients.
Rare hypersensitivity reactions including angioedema and anaphylaxis.
Fatigue and insomnia reported in some patients.
Potential for worsening or new onset of depression requiring medical attention.
Gastrointestinal symptoms tend to decrease after continued use beyond the titration phase.
Rash or skin irritation has been rarely reported.
Possible increased risk of infections secondary to immunomodulation.
No significant hepatotoxicity or nephrotoxicity identified in clinical studies.

Precautions

Monitor patients for signs of depression or mood changes, especially in those with a history of psychiatric illness.
Start dosing with gradual upward titration over 5 days to minimize gastrointestinal side effects.
Monitor body weight regularly due to risk of weight loss; evaluate and consider discontinuation if clinically significant.
Use caution in patients with moderate to severe renal impairment and adjust dose accordingly.
Assess for hypersensitivity reactions before and during treatment; discontinue immediately if angioedema or anaphylaxis occurs.
Patient counseling on the possibility of nausea, diarrhea, and headache at therapy initiation.
Evaluate risk-benefit ratio in patients with pre-existing severe gastrointestinal disease.
Careful use in pregnant women; advise effective contraception as Otezla may harm an unborn baby.
Uncertain safety in breastfeeding; consult healthcare provider prior to use.
Avoid concomitant use with strong CYP3A4 inducers that can significantly reduce apremilast levels and efficacy.
Monitor renal function periodically during long-term use.
Assess mental health frequently and instruct patients to report suicidal ideations promptly.
Regularly review concomitant medications to minimize drug interactions.
Educate patients about signs of severe diarrhea, dehydration, or weight loss and the importance of immediate reporting.
Do not abruptly discontinue without physician advice; consider dose tapering to prevent GI symptoms.

Warnings

Risk of depression and suicidal thoughts; patients should be closely monitored for mood changes.
Severe gastrointestinal adverse effects including diarrhea, nausea, and vomiting may require treatment interruption.
Anaphylaxis and angioedema have been reported; use is contraindicated in patients with known hypersensitivity to apremilast or any excipients.
Potential for clinically significant weight loss; patient weight should be regularly monitored during treatment.
Loss of efficacy may occur if used concomitantly with strong CYP450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin).
Not recommended to use during pregnancy unless the potential benefit justifies the potential risk to the fetus.
Limited data on breastfeeding safety; caution is advised.
May cause immunosuppression; risk of infection should be considered although less than biologics.
Patients should avoid sudden discontinuation of therapy to prevent potential rebound or gastrointestinal symptoms.
Monitor renal function and adjust dose accordingly in renal impairment.
Patients should be advised to report any severe diarrhea, unexplained weight loss, new or worsening depression, or suicidal ideation immediately.
Not approved for patients under 6 years or weighing less than 20 kg.
Careful assessment needed before prescribing to patients with a history of severe psychiatric conditions.
Potential drug interactions should be carefully evaluated and managed.
Long-term safety data in certain populations is limited; ongoing monitoring recommended.

Contraindication

Known hypersensitivity to apremilast or any of the inactive ingredients in the formulation.
History of anaphylaxis or severe allergic reactions to Otezla.
Not indicated for use in children under 6 years of age or under 20 kg body weight.
Concomitant use with strong cytochrome P450 enzyme inducers is contraindicated due to decreased efficacy.
Patients with severe gastrointestinal diseases that may exacerbate symptoms during treatment should avoid use unless benefits outweigh risks.
Use in pregnant women unless benefits justify the potential risk; contraindicated if effective contraception cannot be assured.
Patients with known severe depression or suicidal ideation who cannot be closely monitored.
Known hypersensitivity to any excipients such as lactose monohydrate, microcrystalline cellulose, or colorants in tablet formulations.
Severe renal impairment without appropriate dose adjustment.
Use with caution in patients with multiple co-morbidities that predispose to infection.

Drug Interactions

Strong cytochrome P450 3A4 (CYP3A4) enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) significantly reduce apremilast plasma concentrations, potentially leading to loss of efficacy.
Enzalutamide, a CYP3A4 inducer, may decrease the effectiveness of Otezla.
Fosphenytoin, a prodrug of phenytoin, can induce CYP enzymes and lower apremilast levels.
Mitotane induces CYP3A4 and may reduce apremilast exposure.
Primidone has CYP3A4 inducing properties that may alter apremilast pharmacokinetics.
Rifabutin and rifapentine, related to rifampin, can also induce metabolism reducing plasma levels of apremilast.
St John's Wort, a herbal supplement, is a known strong CYP3A4 inducer and can reduce plasma concentration of apremilast.
Tofacitinib may have pharmacodynamic interactions; caution advised when co-administering other immunomodulators.
No significant interactions with common CYP450 substrates, inhibitors, or inducers besides those listed have been identified.
Use with caution when combined with other immunosuppressants, as additive immunomodulatory effects may occur.
No known interactions with food or antacids; Otezla can be administered regardless of meals.
Monitoring is recommended when starting or stopping any CYP3A4-modulating agent during Otezla therapy.
No dose adjustment necessary for minor CYP inhibitors or inducers.
No significant interaction with commonly used cardiovascular or diabetic medications documented.
Patients should inform healthcare providers of all prescription, over-the-counter, and herbal supplements to avoid potential interactions.

Preparations Of The Drug

Tablet formulations available in three dosages: 10 mg, 20 mg, and 30 mg.
Each tablet contains apremilast as the active ingredient with specific inactive components including lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide colorants specific to strength.
10 mg tablets contain ferric oxide red as coloring agent.
20 mg tablets contain ferric oxide red and ferric oxide yellow for color differentiation.
30 mg tablets contain ferric oxide red, yellow, and ferrosoferric oxide for distinct appearance.
Tablets are film-coated to mask taste and improve swallowability.
Packaged in starter kits containing a 5-day titration schedule to mitigate gastrointestinal side effects and ease initiation.
Available in bottles or blister packaging depending on market and pharmacy.
No parenteral or liquid formulations currently available; oral route exclusively utilized.
Manufactured and distributed by Amgen Inc., with strict quality controls ensuring batch consistency and stability.
Storage conditions typically recommend keeping tablets at room temperature away from moisture and light.
No generic formulations widely available as of current approval stage, though apremilast generics have been FDA-approved recently but may not yet be commercially available.
Each tablet is designed for precise dosing corresponding to the titration and maintenance regimens.