Otezla Xr (apremilast)

No dosing information is available for this tab.

Apremilast is available as an immediate- and extended-release tablet.

Administer apremilast orally without regard to meals. Do not crush, split, or chew tablets; swallow whole.

Apremilast tablets should be stored below 30degreesC. Apremilast extended-release tablets should be stored between 20-25degreesC with excursions permitted between 15-30degreesC.

No dosing information is available for this tab.

Concomitant use of cytochrome P-450 (CYP) enzyme inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin) with apremilast is not recommended because loss of apremilast efficacy may occur.

Apremilast undergoes cytochrome P-450 (CYP)-mediated oxidative metabolism, with subsequent glucuronidation, and non-CYP-mediated hydrolysis. In vitro, oxidative metabolism is mediated principally by CYP3A4, with minor contributions from CYP1A2 and CYP2A6.

In vitro, apremilast does not inhibit CYP isoenzyme 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, nor does apremilast induce CYP isoenzyme 1A2, 2B6, 2C9, 2C19, or 3A4.

In vitro data indicate that apremilast is a substrate but not an inhibitor of P-glycoprotein (P-gp) and that the drug is neither a substrate nor an 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).

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Apremilast; Roflumilast/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of apremilast(1) and roflumilast(2,3) by CYP3A4.

CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may reduce the clinical effectiveness of apremilast(1) and roflumilast.(2,3)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Monitor patients receiving concurrent CYP3A4 inducers for decreased apremilast(1) and roflumilast(2,3) efficacy. Concurrent use is not recommended.(1,2) The dosage of roflumilast may need to be adjusted or additional COPD therapy may need to be adjusted during and for up to two weeks after therapy with a CYP3A4 inducer has been completed.

DISCUSSION: Pretreatment with rifampin (600 mg daily for 15 days) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of apremilast by 43% and 72%, respectively.(1) In an open-label study in 16 healthy males, rifampin (600 mg daily) decreased AUC and Cmax of a single dose of roflumilast (500 mcg) by 80% and 68%, respectively. The AUC and Cmax of roflumilast N-oxide decreased by 56% and 30%, respectively.(2) The total PDE4 inhibitory activity of roflumilast decreased by 60%.(2-4) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St. John's wort.

There are no moderate interactions for this drug.

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

There are no contraindication contraindications for this drug.

• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Depression

• Weight loss

Adverse effects reported in >=5% of patients receiving apremilast for active psoriatic arthritis include diarrhea, nausea, and headache.

Adverse effects reported in >=5% of patients receiving apremilast for plaque psoriasis include diarrhea, nausea, upper respiratory tract infection, and headache, including tension headache.

Adverse effects reported in >=10% of patients receiving apremilast for Behcet disease include diarrhea, nausea, headache, and upper respiratory tract infection.

Rare or Very Rare

• Anaphylaxis
• Angioedema
• Hypersensitivity drug reaction
• Suicidal
• Suicidal ideation

More Frequent

• Diarrhea
• Headache disorder
• Nausea
• Upper respiratory infection
• Weight loss

Less Frequent

• Arthralgia
• Back pain
• Depression
• Fatigue
• Insomnia
• Pharyngitis
• Upper abdominal pain
• Vomiting

Rare or Very Rare

• Anorexia
• Bronchitis
• Cough
• Dental abscess
• Dyspepsia
• Folliculitis
• Gastroesophageal reflux disease
• Migraine
• Skin rash

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The efficacy and safety of apremilast have been established in pediatric patients >=6 years of age weighing >=20 kg with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. This indication for use is supported by results from a 52-week, well-controlled trial involving 245 pediatric patients (6-17 years of age). Safety and efficacy of apremilast have not been established in pediatric patients <6 years of age or weighing <20 kg with moderate to severe plaque psoriasis.

The efficacy and safety of apremilast have been established in pediatric patients >=6 years of age weighing >=20 kg with psoriatic arthritis. This indication for use is supported by results from trials in adults with psoriatic arthritis, pharmacokinetic data in adults with psoriatic arthritis, adults with psoriasis, and pediatric patients with psoriasis, and safety data from a trial involving 245 pediatric patients (6-17 years of age) with psoriasis. Safety and efficacy of apremilast have not been established in pediatric patients <6 years of age or weighing <20 kg with psoriatic arthritis.

The efficacy and safety of apremilast extended-release have been established in pediatric patients >=6 years of age weighing >=50 kg with moderate to severe plaque psoriasis and psoriatic arthritis. This indication for use is supported by pharmacokinetic data from healthy adults demonstrating comparable pharmacokinetic exposure between apremilast extended-release 75 mg once daily and apremilast 30 mg twice daily.

Safety and efficacy of apremilast extended-release have not been established in pediatric patients <6 years of age or weighing <50 kg with moderate to severe plaque psoriasis or psoriatic arthritis.

Safety and efficacy of apremilast and apremilast extended-release have not been established in pediatric patients with oral ulcers associated with Behcet disease.

Growth (height and weight) should be closely monitored in pediatric patients receiving apremilast. Treatment may need to be interrupted if pediatric patients are not growing or gaining weight as expected.

Available data with apremilast use in pregnant women have not identified a drug-associated risk of major birth defects or adverse maternal or fetal outcomes. Data from a pregnancy registry that compared pregnant women treated with apremilast (n=15) to disease-matched pregnant women not administered apremilast (n=106) revealed a single stillbirth and no reports of liveborn infants with major birth defects nor miscarriages in the apremilast-exposed cohort. The data are limited by the small number of apremilast-exposed pregnancies in the registry.

In animal reproduction studies, administration of apremilast to cynomolgus monkeys during organogenesis resulted in dose-related increases in spontaneous abortion and embryofetal death at doses approximately 2 times the maximum recommended human dose. Based on these animal findings, apremilast may increase fetal risk and women should be advised of this potential risk.

Apremilast is distributed into milk in mice; it is not known whether the drug is 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 from the underlying maternal condition.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In controlled clinical trials evaluating apremilast for the management of psoriatic arthritis, about 10% of patients were >=65 years of age, and about 1% were >=75 years of age. No overall differences in safety were observed between geriatric and younger adults.

Similarly, no overall differences in efficacy and safety were observed between geriatric and younger adults in two placebo-controlled plaque psoriasis trials.

Following oral administration of a single 30-mg dose of apremilast, AUC and peak plasma concentrations of the drug were approximately 13 and 6% higher, respectively, in patients 65-85 years of age compared with those 18-55 years of age.

Patients >=65 years of age should be monitored closely for volume depletion or hypotension resulting from treatment-related severe diarrhea, nausea, or vomiting.