Introduction

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

Uses for Apremilast (Systemic)

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 (Systemic) 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.

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.

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.

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