Apremilast (Monograph)

Brand name: Otezla
Drug class: Disease-modifying Antirheumatic Drugs

Medically reviewed by Drugs.com on Sep 27, 2023. Written by ASHP.

Introduction

Disease-modifying antirheumatic drug (DMARD); a selective phosphodiesterase type 4 (PDE4) inhibitor.

Uses for Apremilast

Psoriatic Arthritis

Management of active psoriatic arthritis in adults.

Various drugs and drug classes are used to treat psoriatic arthritis. Apremilast is considered an oral small molecule (OSM), which is one of several classes of disease-modifying treatments for this condition.

The American College of Rheumatology (ACR)/National Psoriasis Foundation guideline conditionally recommends the use of TNF blocking agents over OSMs in treatment-naive patients with active psoriatic arthritis; however, an OSM such as apremilast may be considered in treatment-naive patients without severe psoriasis or psoriatic arthritis, in those who prefer oral over parenteral therapy, and those with contraindications to TNF blocking therapy (e.g., CHF, previous serious infection, recurrent infections, demyelinating disease).

In patients not responding to treatment with an OSM, switching to another OSM is generally recommended over adding another OSM to the current regimen except in the case of apremilast since evidence of benefit with this drug is mostly with combination therapy. Switching to apremilast monotherapy may be considered instead of apremilast combination therapy if the patient has intolerable adverse events with the current OSM.

Recommendations for use and selection of disease-modifying therapies in psoriatic arthritis vary based on the presence of certain disease characteristics (e.g., psoriatic spondylitis/axial disease, enthesitis) and comorbidities (e.g., inflammatory bowel disease, diabetes).

Plaque Psoriasis

Management of plaque psoriasis in adults who are candidates for phototherapy or systemic therapy.

Various drugs and drug classes are used to treat psoriasis including systemic biologic and nonbiologic therapies; apremilast is a nonbiologic option for treatment of this condition.

Guidelines generally recommend apremilast for treatment of adults with moderate to severe psoriasis; also may be used to augment efficacy of certain biologic agents (e.g., adalimumab, etanercept, infliximab, ustekinumab).

Recommendations for use and selection of psoriasis therapies vary based on patient age, disease characteristics (e.g., severity, location, presence of psoriatic arthritis), and comorbidities (e.g., inflammatory bowel disease).

Oral Ulcers Associated with Behçet Disease

Management of oral ulcers associated with Behçet disease in adults.

Treatment of Behçet disease is determined by involved organs, severity and duration of disease, age, gender, frequency of attacks, and patient preferences. The European Alliance of Associations for Rheumatology (EULAR) guidelines recommend topical treatments (such as steroids) and colchicine for mucocutaneous lesions. Apremilast can be considered as an alternative to colchicine in selected patients who have recurrent lesions despite colchicine use.

Apremilast Dosage and Administration

General

Pretreatment Screening

• Evaluate renal function prior to starting apremilast; dosage reductions are recommended for severe renal impairment.

• Weigh the risks and benefits of apremilast therapy in patients with a history of depression and/or suicidal thoughts or behaviors.

Patient Monitoring

• Monitor patients for the potential development of serious hypersensitivity reactions including anaphylaxis and angioedema.

• Monitor patients for diarrhea, nausea, and vomiting.

• Monitor for emergence or worsening of depression, suicidal thoughts or other mood changes.

• Monitor weight regularly; consider discontinuing apremilast if unexplained or clinically significant weight loss occurs.

Administration

Oral Administration

Administer orally without regard to meals.

Swallow tablets intact. Do not crush, split, or chew.

Dosage

Adults

Psoriatic Arthritis

Oral

Initiate at a dosage of 10 mg daily and titrate as follows (over 5 days in increments of 10 mg daily) to reduce the risk of GI symptoms:

• 10 mg in the morning on day 1

• 10 mg in the morning and 10 mg in the evening on day 2

• 10 mg in the morning and 20 mg in the evening on day 3

• 20 mg in the morning and 20 mg in the evening on day 4

• 20 mg in the morning and 30 mg in the evening on day 5, and 30 mg twice daily thereafter

Maintenance dosage: 30 mg twice daily.

Plaque Psoriasis

Oral

Initiate at a dosage of 10 mg daily and titrate as follows (over 5 days in increments of 10 mg daily) to reduce the risk of GI symptoms:

• 10 mg in the morning on day 1

• 10 mg in the morning and 10 mg in the evening on day 2

• 10 mg in the morning and 20 mg in the evening on day 3

• 20 mg in the morning and 20 mg in the evening on day 4

• 20 mg in the morning and 30 mg in the evening on day 5, and 30 mg twice daily thereafter

Maintenance dosage: 30 mg twice daily.

Oral Ulcers Associated with Behçet Disease

Oral

Initiate at a dosage of 10 mg daily and titrate as follows (over 5 days in increments of 10 mg daily) to reduce the risk of GI symptoms.

• 10 mg in the morning on day 1

• 10 mg in the morning and 10 mg in the evening on day 2

• 10 mg in the morning and 20 mg in the evening on day 3

• 20 mg in the morning and 20 mg in the evening on day 4

• 20 mg in the morning and 30 mg in the evening on day 5, and 30 mg twice daily thereafter

Maintenance dosage: 30 mg twice daily.

Special Populations

Hepatic Impairment

No dosage adjustment required.

Renal Impairment

Severe renal impairment (Cl_cr <30 mL/minute): Maintenance dosage of 30 mg once daily. Initiate at a dosage of 10 mg daily and titrate as follows to reduce the risk of GI symptoms:

• 10 mg in the morning for 3 days (days 1, 2, and 3)

• 20 mg in the morning for 2 days (days 4 and 5)

• 30 mg once daily thereafter

Geriatric Patients

Manufacturer makes no specific dosage recommendations.

Cautions for Apremilast

Contraindications

• Known hypersensitivity to apremilast or any ingredient in the formulation.

Warnings/Precautions

Hypersensitivity

Hypersensitivity reactions including cases of angioedema and anaphylaxis reported. Avoid use in patients with a known hypersensivity to the drug of any of its excipients.

Discontinue if signs or symptoms of serious hypersensitivity reactions occur and initiate appropriate therapy.

GI Effects

Severe diarrhea, nausea, and vomiting reported.

Monitor patients who are more susceptible to complications, such as patients ≥65 years of age and those taking drugs that can lead to volume depletion or hypotension.

Reduce apremilast dosage or suspend therapy if patients develop severe diarrhea, nausea, or vomiting.

Depression and Suicidality

Depression, depressed mood, and suicidal ideation/behaviors reported.

Carefully weigh risks and benefits prior to using apremilast in patients with a history of depression and/or suicidal thoughts or behavior. Carefully evaluate the risks and benefits of continuing therapy if such effects occur.

Weight Loss

Weight loss of ≥5–10% of body weight reported.

Regularly monitor patient’s weight. If unexplained or clinically important weight loss occurs, evaluate weight loss and consider discontinuing apremilast.

Interactions

Concomitant use of potent CYP inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin) not recommended.

Specific Populations

Pregnancy

Pregnancy registry at [Web]877-311-8972 or .

Increases in spontaneous abortion and embryofetal death reported in animal reproduction studies.

Lactation

Distributed into milk in mice; not known whether distributed into human milk.

Consider the benefits of breast-feeding and the importance of apremilast to the patient along with potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.

Geriatric Use

No overall differences in safety observed between geriatric and younger adults with psoriatic arthritis.

No overall differences in efficacy and safety observed between geriatric and younger adults with plaque psoriasis.

Monitor patients ≥65 years of age closely for volume depletion or hypotension resulting from treatment-related severe diarrhea, nausea, or vomiting.

Hepatic Impairment

Moderate or severe hepatic impairment (Child-Pugh class B or C) does not alter pharmacokinetics of apremilast. No dosage adjustment necessary.

Renal Impairment

Systemic exposure increased in patients with severe renal impairment (Cl_cr <30 mL/minute). Reduced dosage recommended.

Common Adverse Effects

Adverse events reported in ≥5% of patients with psoriatic arthritis: Diarrhea, nausea, and headache.

Adverse events reported in ≥5% of patients with psoriasis: Diarrhea, nausea, upper respiratory tract infection, and headache (including tension headache).

Adverse effects reported in ≥10% of patients with Behçet disease: Diarrhea, nausea, headache, and upper respiratory tract infection.

Drug Interactions

Undergoes oxidative metabolism (mediated mainly by CYP3A4, with minor contributions from CYP1A2 and CYP2A6) with subsequent glucuronidation; also undergoes non-CYP-mediated hydrolysis.

Does not inhibit CYP isoenzyme 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro; does not induce CYP isoenzyme 1A2, 2B6, 2C9, 2C19, or 3A4 in vitro.

A substrate but not an inhibitor of P-glycoprotein (P-gp) in vitro; neither a substrate nor inhibitor of organic anion transporters (OAT) 1 and 3, organic anion transporting polypeptides (OATP) 1B1 and 1B3, organic cation transporter (OCT) 2, or breast cancer resistance protein (BCRP) in vitro.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP inducers: Reduced systemic exposure and possible loss of efficacy of apremilast; concomitant use not recommended.

Specific Drugs

Apremilast Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability of about 73%. Peak plasma concentrations achieved about 2.5 hours after oral administration.

Food

Food does not alter extent of absorption.

Special Populations

Moderate or severe hepatic impairment does not alter apremilast pharmacokinetics.

In patients with severe renal impairment, AUC and peak plasma concentrations increased by approximately 88 and 42%, respectively. Mild to moderate renal impairment did not affect apremilast pharmacokinetics.

In healthy geriatric individuals (65–85 years of age), AUC and peak plasma concentrations increased by about 13 and 6%, respectively, compared with younger adults (18–55 years of age).

In healthy women, extent of exposure and peak plasma concentrations increased by about 31 and 8%, respectively, compared with men.

Apremilast exposure is similar among Hispanic white, non-Hispanic white, and African Americans; pharmacokinetics in healthy Chinese and Japanese men similar to that in healthy white men.

Distribution

Extent

Not known whether apremilast distributes into milk.

Plasma Protein Binding

Approximately 68%.

Elimination

Metabolism

Undergoes oxidative metabolism (mediated mainly by CYP3A4, with minor contributions from CYP1A2 and CYP2A6) with subsequent glucuronidation; also undergoes non-CYP-mediated hydrolysis.

Elimination Route

Following oral administration of radiolabeled apremilast, radioactivity recovered in urine (58%) and feces (39%), with about 3 or 7% of dose recovered as unchanged drug in urine or feces, respectively.

Half-life

Approximately 6–9 hours.

Stability

Storage

Oral

Tablets

Store at <30°C.

Actions

• Selectively inhibits PDE4, the dominant phosphodiesterase expressed in immune cells and a major enzyme involved in metabolism of cyclic adenosine-3',5'-monophosphate (cAMP).

• Selective inhibition of PDE4 results in accumulation of intracellular cAMP, a modulator of inflammatory responses, which can down-regulate inflammatory responses by increasing expression of anti-inflammatory mediators and partially inhibiting expression of inflammatory cytokines that are thought to play a role in the pathogenesis of psoriasis and active psoriatic arthritis.

Advice to Patients

• Importance of taking apremilast only as prescribed.

• Advise patients to not crush, split, or chew apremilast tablets.

• Inform patients that apremilast may be taken without regard to meals.

• Advise patients of the potential for serious allergic reactions following administration and to contact a clinician if symptoms of an allergic reaction occur.

• Advise patients to contact a clinician if they experience severe diarrhea, nausea, or vomiting.

• Risk of emergence or worsening of depression. Instruct patients and their caregivers or families to be alert for the emergence or worsening of depression, suicidal thoughts, or other mood changes and to contact a clinician if such changes occur.

• Risk of weight loss. Importance of regularly monitoring for weight loss; advise patients to inform clinician if substantial or unexplained weight loss occurs.

• Risk of interactions with potent CYP inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin). Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• Advise patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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