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  • CLASSES

    Other Systemic Antipsoriatics
    Phosphodiesterase-4 (PDE-4) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Phosphodiesterase-4 inhibitor (PDE4i) and a targeted synthetic DMARD
    Used in adults for the treatment of active psoriatic arthritis (PsA) and moderate to severe plaque psoriasis
    Patients with severe diarrhea, nausea, and vomiting may need dose reduction or drug discontinuation

    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 as follows to a final dose of 30 mg PO twice daily. Day 1: 10 mg PO in the morning. Day 2: 10 mg PO twice daily. Day 3: 10 mg PO in the morning and 20 mg PO in the evening. Day 4: 20 mg PO twice daily. 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 as follows to a final dose of 30 mg PO twice daily. Day 1: 10 mg PO in the morning. Day 2: 10 mg PO twice daily. Day 3: 10 mg PO in the morning and 20 mg PO in the evening. Day 4: 20 mg PO twice daily. 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

    No dosage adjustments are needed.

    Renal Impairment

    CrCl 30 mL/minute or more: No dosage adjustment is required.
     
    CrCl less than 30 mL/minute: Do not exceed 30 mg PO once daily. For initiation of therapy, administer 10 mg PO in the morning for Days 1, 2, and 3. Give 20 mg PO in the morning for Days 4 and 5, and then give 30 mg PO once daily in the morning 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.
     
    Apremilast may cause significant weight loss in some patients. Patients treated with apremilast should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of the drug should be considered.

    Dehydration, diarrhea, geriatric, hypovolemia, vomiting

    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 apremilast dosage reduction or discontinuation of the drug. Hospitalization was required in some cases. Closely monitor patients who are more susceptible to complications of diarrhea or vomiting, including geriatric patients 65 years and older, those with hypovolemia or dehydration, and patients receiving medications that may lead to volume depletion or hypotension. Consider apremilast dose reduction or treatment suspension for any patient who develops severe diarrhea, nausea, or vomiting.

    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. Dosage adjustments are not required in patients with mild or moderate renal impairment.

    Labor, pregnancy

    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 at https://mothertobaby.org/ongoing-study/otezla/ or by calling 1-877-311-8972. In animal embryo-fetal development studies, the administration of apremilast to cynomolgus monkeys during organogenesis resulted in dose-related increases in abortion/embryo-fetal death at dose exposures 2.1-times the maximum recommended human therapeutic dose (MRHD) and no adverse effect at an exposure of 1.4-times the MRHD. In mice, there were no apremilast-induced malformations up to exposures 4-times the MRHD. The effects of the drug on labor and obstetric delivery in pregnant women are unknown. In mice, dystocia was noted at doses corresponding to 4-times the MRHD (on an AUC basis at doses of 80 mg/kg/day or more) of apremilast.

    Breast-feeding

    Apremilast should be used with caution in breast-feeding women until specific data or guideline recommendations are available. There are no data on the presence of apremilast in human milk, the effects on the breast-fed infant, or the effects on milk production. Apremilast was detected in the milk of lactating mice. Due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for apremilast and any potential adverse effects on the nursing infant from the drug or the underlying maternal condition.

    Children

    The safety and effectiveness of apremilast in infants, children, and adolescents less than 18 years of age have not been established.

    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 / 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.
    Apalutamide: (Major) Avoid coadministration of apremilast with apalutamide due to decreased plasma concentrations of apremilast. Apremilast is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the single-dose apremilast AUC and Cmax by 72% and 43%, respectively.
    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.
    Lumacaftor; Ivacaftor: (Major) Coadministration of apremilast and lumacaftor; ivacaftor is not recommended due to the potential for decreased apremilast exposure and reduced efficacy. Lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of another strong CYP450 inducer decreased the apremilast AUC and Cmax by 72% and 43%, respectively.
    Lumacaftor; Ivacaftor: (Major) Coadministration of apremilast and lumacaftor; ivacaftor is not recommended due to the potential for decreased apremilast exposure and reduced efficacy. Lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of another strong CYP450 inducer decreased the apremilast AUC and Cmax by 72% and 43%, respectively.
    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.
    Mitotane: (Major) Avoid coadministration of apremilast with mitotane due to decreased plasma concentrations of apremilast. Apremilast is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the single-dose apremilast AUC and Cmax by 72% and 43%, respectively.
    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 should be used with caution in breast-feeding women until specific data or guideline recommendations are available. There are no data on the presence of apremilast in human milk, the effects on the breast-fed infant, or the effects on milk production. Apremilast was detected in the milk of lactating mice. Due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for apremilast and any potential adverse effects on the nursing infant from the drug or the underlying maternal condition.

    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 a major circulating component (45%) followed by inactive metabolite M12 (39%), a glucuronide conjugate of O-demethylated apremilast. It is extensively metabolized in humans with up to 23 metabolites identified in plasma, urine and feces. Apremilast is metabolized by both cytochrome (CYP) oxidative metabolism with subsequent glucuronidation and non-CYP mediated hydrolysis. In vitro, CYP metabolism of apremilast is primarily mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6. Following oral administration of radio-labeled apremilast, about 58% and 39% of the radioactivity is recovered in urine and feces, respectively, with about 3% and 7% of the radioactive dose recovered as apremilast in urine and feces, respectively. The terminal half-life is approximately 6 to 9 hours.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4, CYP1A2, CYP2A6, P-glycoprotein (P-gp)
    Apremilast is a substrate of CYP3A4, CYP1A2, CYP2A6, and P-glycoprotein (P-gp). Apremilast exposure is decreased when the drug is co-administered with strong CYP450 inducers (e.g., rifampin) and may result in loss of efficacy. Drug interaction studies indicate no significant pharmacokinetic interaction exists with CYP3A4 substrates or with CYP3A4 and P-gp inhibitors.

    Oral Route

    The absolute oral 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.