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  • CLASSES

    Other Systemic Antipsoriatics
    Selective Immunosuppressants

    DEA CLASS

    Rx

    DESCRIPTION

    Phosphodiesterase-4 inhibitor
    Used for the treatment of active psoriatic arthritis and moderate to severe plaque psoriasis
    Possible loss of efficacy with concomitant strong cytochrome P450 inducers

    COMMON BRAND NAMES

    Otezla

    HOW SUPPLIED

    Otezla Oral Tab: 30mg, 10-20-30mg

    DOSAGE & INDICATIONS

    For the treatment of active psoriatic arthritis.
    Oral dosage
    Adults

    To reduce the risk of gastrointestinal symptoms, titrate to a final dose of 30 mg PO twice daily.
    Day 1: 10 mg PO in the morning.
    Day 2: 10 mg PO in the morning and 10 mg PO in the evening.
    Day 3: 10 mg PO in the morning and 20 mg PO in the evening.
    Day 4: 20 mg PO in the morning and 20 mg PO in the evening.
    Day 5: 20 mg PO in the morning and 30 mg PO in the evening.
    Day 6 and thereafter: 30 mg PO twice daily.

    For the treatment of moderate to severe plaque psoriasis in patients who are candidates for phototherapy or systemic therapy.
    Oral dosage
    Adults

    To reduce the risk of gastrointestinal symptoms, titrate to a final dose of 30 mg PO twice daily.
    Day 1: 10 mg PO in the morning.
    Day 2: 10 mg PO in the morning and 10 mg PO in the evening.
    Day 3: 10 mg PO in the morning and 20 mg PO in the evening.
    Day 4: 20 mg PO in the morning and 20 mg PO in the evening.
    Day 5: 20 mg PO in the morning and 30 mg PO in the evening.
    Day 6 and thereafter: 30 mg PO twice daily.

    MAXIMUM DOSAGE

    Adults

    60 mg/day PO.

    Geriatric

    60 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    CrCl >= 30 mL/min: No dosage adjustment required.
    CrCl < 30 mL/min: 30 mg PO once daily. For initiation of therapy, administer 10 mg PO in the morning for Days 1—3, 20 mg PO in the morning for Days 4 and 5 and 30 mg PO once daily on Day 6 and thereafter.

    ADMINISTRATION

    Oral Administration

    May administer with or without food.

    Oral Solid Formulations

    Swallow whole; do not crush, split, or chew tablets.

    STORAGE

    Otezla:
    - Store below 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Apremilast is contraindicated in patients with a known hypersensitivity to apremilast or any excipients in the formulation.

    Pregnancy

    Apremilast is classified as FDA pregnancy category C. Apremilast should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Adequate and well-controlled studies with apremilast have not been conducted in pregnant women. There is a pregnancy exposure registry that monitors outcomes in pregnant women exposed to apremilast; information about the registry can be obtained by calling 1-877-311-8972.

    Breast-feeding

    According to the manufacturer, apremilast should be used with caution in breast-feeding women. It is not known if apremilast is excreted into human breast milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Depression, suicidal ideation

    Use caution when prescribing apremilast to patients with a history of depression or suicidal ideation. Apremilast treatment is associated with an increased risk of depression. Patients, as well as families and caregivers, should be advised to be alert for signs of depression, worsening of depression, suicidal thoughts, or other mood changes. If such events occur, patients or caregivers should contact their healthcare provider. If these reactions occur, prescribers should carefully evaluate the risks and benefits of continuing treatment.

    Renal failure, renal impairment

    The exposure to apremilast is increased in patients with renal failure or severe renal impairment (CrCl less than 30 mL/minute), and dosage reduction is required. Pharmacokinetics were not characterized in subjects with mild or moderate renal impairment.

    Dehydration, geriatric

    Severe diarrhea, nausea, and vomiting have been associated with apremilast therapy. In most cases, these gastrointestinal adverse reactions developed within the first few weeks of treatment; symptoms quickly resolved after dosage reduction or treatment discontinuation. Hospitalization was required in some cases. Closely monitor patients who are more susceptible to complications of diarrhea or vomiting, including geriatric patients and patients receiving medications that may lead to dehydration or hypotension. Consider apremilast dose reduction or treatment suspension for any patient who develops severe diarrhea, nausea, or vomiting.

    ADVERSE REACTIONS

    Severe

    suicidal ideation / Delayed / 0.1-0.2

    Moderate

    migraine / Early / 2.0-2.0
    depression / Delayed / 1.0-1.3

    Mild

    diarrhea / Early / 7.7-17.0
    nausea / Early / 7.4-17.0
    weight loss / Delayed / 0-12.0
    infection / Delayed / 0.6-9.0
    headache / Early / 4.8-5.9
    vomiting / Early / 0.8-4.0
    abdominal pain / Early / 0.6-4.0
    dyspepsia / Early / 3.0-3.0
    fatigue / Early / 3.0-3.0
    pharyngitis / Delayed / 0.2-2.6
    insomnia / Early / 2.0-2.0
    back pain / Delayed / 2.0-2.0
    folliculitis / Delayed / 1.0-1.0
    gastroesophageal reflux / Delayed / Incidence not known
    cough / Delayed / Incidence not known
    rash (unspecified) / Early / Incidence not known
    anorexia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
    Acetaminophen; Butalbital; Caffeine: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
    Amobarbital: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
    Aspirin, ASA; Butalbital; Caffeine: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
    Barbiturates: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
    Butabarbital: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
    Carbamazepine: (Major) The coadministration of apremilast and carbamazepine is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2. Carbamazepine is a strong CYP3A4 inducer and also induces CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and carbamazepine which may result in a loss of efficacy of apremilast.
    Enzalutamide: (Major) The coadministration of apremilast and enzalutamide is not recommended. Apremilast is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of apremilast by 72%.
    Fosphenytoin: (Major) The coadministration of apremilast and phenytoin or fosphenytoin is not recommended. Apremilast is metabolized primarily by CYP3A4; phenytoin is a strong CYP3A4 inducer. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and phenytoin which may result in a loss of efficacy of apremilast.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) The coadministration of apremilast and rifampin is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2 and CYP2D6. Rifampin is a strong CYP3A4 inducer and also induces CYP1A2 and CYP2D6. Coadministration of rifampin (600 mg daily for 15 days) with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. This reduction in systemic exposure may result in a loss of efficacy of apremilast.
    Isoniazid, INH; Rifampin: (Major) The coadministration of apremilast and rifampin is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2 and CYP2D6. Rifampin is a strong CYP3A4 inducer and also induces CYP1A2 and CYP2D6. Coadministration of rifampin (600 mg daily for 15 days) with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. This reduction in systemic exposure may result in a loss of efficacy of apremilast.
    Mephobarbital: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
    Methohexital: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
    Pentobarbital: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
    Phenobarbital: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
    Phenytoin: (Major) The coadministration of apremilast and phenytoin is not recommended. Apremilast is metabolized primarily by CYP3A4; phenytoin is a strong CYP3A4 inducer. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and phenytoin which may result in a loss of efficacy of apremilast.
    Primidone: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
    Rifampin: (Major) The coadministration of apremilast and rifampin is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2 and CYP2D6. Rifampin is a strong CYP3A4 inducer and also induces CYP1A2 and CYP2D6. Coadministration of rifampin (600 mg daily for 15 days) with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. This reduction in systemic exposure may result in a loss of efficacy of apremilast.
    Secobarbital: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.
    St. John's Wort, Hypericum perforatum: (Major) The coadministration of apremilast and St. John's Wort is not recommended. Apremilast is a substrate of CYP3A4; St. John's Wort is a strong CYP3A4 inducer. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A reduction in systemic exposure of apremilast may be seen with coadministration of apremilast and St. John's Wort which may result in a loss of efficacy of apremilast.
    Thiopental: (Major) The coadministration of apremilast and barbiturates is not recommended. Apremilast is metabolized primarily by CYP3A4, with minor metabolism by CYP1A2; barbiturates are strong CYP3A4 inducers and also induce CYP1A2. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and barbiturates which may result in a loss of efficacy of apremilast.

    PREGNANCY AND LACTATION

    Pregnancy

    Apremilast is classified as FDA pregnancy category C. Apremilast should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Adequate and well-controlled studies with apremilast have not been conducted in pregnant women. There is a pregnancy exposure registry that monitors outcomes in pregnant women exposed to apremilast; information about the registry can be obtained by calling 1-877-311-8972.

    According to the manufacturer, apremilast should be used with caution in breast-feeding women. It is not known if apremilast is excreted into human breast milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Apremilast is a phosphodiesterase-4 (PDE4) inhibitor specific for cyclic adenosine monophosphate (cAMP). Inhibition of PDE4 results in an increase in the intracellular concentration of cAMP, resulting in a partial inhibition of the production of many pro-inflammatory mediators and an increase in the production of some anti-inflammatory mediators. The specific mechanism by which apremilast exerts its therapeutic effect in patients with psoriatic arthritis and plaque psoriasis is not fully elucidated.

    PHARMACOKINETICS

    Apremilast is administered orally. Apremilast is 68% bound to plasma proteins and has a mean volume of distribution of 87 L. Apremilast is primarily metabolized by cytochrome (CYP) 3A4, with some minor metabolism by CYP1A2 and CYP2A6. There are 23 known metabolites that have been identified in plasma, urine, and feces. The terminal half-life is approximately 6—9 hours. The major route elimination for apremilast is via the urine (58%), followed by feces (39%).
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP1A2, CYP2A6, P-gp
    Apremilast is a substrate of CYP3A4, CYP1A2, CYP2A6, and P-glycoprotein (P-gp). Drug interaction studies indicate no significant pharmacokinetic interaction exists between apremilast and CYP3A4 substrates (oral contraceptive containing ethinyl estradiol and norgestimate) or a CYP3A4 and P-gp inhibitor (ketoconazole).

    Oral Route

    The absolute bioavailability of apremilast is 73%, with a median peak plasma concentration of approximately 2.5 hours. Food does not alter the extent of apremilast absorption.