Apremilast is an oral phosphodiesterase-4 (PDE4) inhibitor and is considered a targeted synthetic DMARD (tsDMARD). The drug is indicated for use in adults with oral ulcers associated with Behcet's Disease, plaque psoriasis in patients who are candidates for phototherapy or systemic therapy, and for adults with active psoriatic arthritis (PsA). The drug has also been shown to be effective in treating psoriasis of the nails, dactylitis, and enthesitis. Psoriasis treatment guidelines recommend the use of PDE4 inhibitors as an initial treatment option for plaque psoriasis, and also recommend the use of apremilast for adults with plaque psoriasis in whom other standard DMARD treatments have been unsuccessful. Apremilast has been studied in large clinical trials for PsA and reduces the clinical manifestations of PsA, but the drug is not considered as efficacious as biologic therapies. Compared to biologic agents commonly used for PsA (e.g., TNF-blockers, interleukin-targeted treatments), definitive evidence of apremilast efficacy for reducing the progression of radiographic damage is lacking. Most PsA guidelines position apremilast as an alternative limited to patients who failed to reach the treatment target on conventional DMARDs and for whom biologic treatments may be contraindicated or inappropriate. In adult patients with active PsA and predominant enthesitis who are naive to conventional DMARDs and biologics, apremilast may be considered as an option. Compared to traditional DMARDs for PsA, apremilast does not require routine therapeutic drug monitoring. However, the drug is expensive and thus is often considered second line in comparison to conventional DMARD therapies. Apremilast is often used in conjunction with other conventional DMARDs to try to optimize treatment, given its relatively low evidence for efficacy when used alone. Use of the drug has been associated with cases of severe diarrhea, nausea, and vomiting; some requiring hospitalization. If these symptoms develop during treatment, consider reducing the dosage or suspending therapy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-May administer with or without food.
Oral Solid Formulations
-Swallow whole; do not crush, split, or chew tablets.
Gastrointestinal adverse reactions were reported during apremilast clinical trials. Diarrhea was reported in 9.3% of patients during titration (vs. 1.2% placebo) and in 7.7% to 41.3% of patients on maintenance therapy (vs. 1.6% to 20.4% placebo). Nausea was reported in 7.4% of patients during titration and 8.9% to 22% on maintenance (vs. 1.4% and 3.1% to 10.7% placebo, respectively). Nausea and diarrhea were 2 of the most common adverse reactions leading to discontinuation of apremilast therapy. Vomiting also was reported during clinical trials at a rate of 0.8% during titration (vs. 0.4% placebo) and 3.2% to 8.7% with maintenance therapy (vs. 0.4% to 2% placebo). Abdominal pain was reported in 0.6% of patients during titration and 2% to 8.7% during maintenance (vs. 0% and 0.2% to 2% placebo, respectively). Other gastrointestinal events reported with maintenance doses included frequent bowel movements (2% vs. 0% placebo) and dyspepsia (3% vs. 1% placebo) Gastroesophageal reflux disease was reported with an unknown incidence.
Upper respiratory tract infection was reported in 0.6% of patients during titration for both apremilast and placebo with more patients experiencing upper respiratory tract infection during the maintenance phase of clinical trials in the apremilast group, 3.9% to 11.5% vs. 1.8% to 6% placebo. Pharyngitis (i.e., nasopharyngitis) was reported in 0.2% of patients during titration for both apremilast and placebo with more patients also experiencing pharyngitis during the maintenance phase of clinical trials in the apremilast group, 2.6% vs. 1.6% placebo. Bronchitis (1% vs. 0% placebo), folliculitis (1% vs. 0% placebo), and tooth abscess (1% vs. 0% placebo) were reported with maintenance doses of apremilast. Cough was also reported during apremilast clinical trials.
Hypersensitivity reactions including rash have been reported during clinical trials with apremilast. During postmarketing use of the drug, cases of angioedema and anaphylaxis or anaphylactoid reactions have been reported. If signs or symptoms of a serious hypersensitivity reaction develops during treatment, discontinue apremilast and institute appropriate therapy.
Weight loss can occur with apremilast therapy. In plaque psoriasis and psoriatic arthritis clinical trials, weight decreases of 5% to 10% of body weight were reported in 4.9% to 12% of patients treated with apremilast compared to 3.3% to 5% treated with placebo. Weight decreases of at least 10% of body weight occurred in 2% of subjects treated with apremilast in plaque psoriasis studies compared to 1% of subjects treated with placebo. Anorexia was also reported during clinical trials. Weight should be monitored regularly during apremilast therapy. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of apremilast should be considered.
During apremilast clinical trials, headache was reported in 4.8% of patients during the titration phase (vs. 1.8% placebo) and in up to 5.9% to 14.4% of patients during the maintenance phase (vs. 2.2% to 10.7% placebo). Tension headache (8% vs. 4% placebo), sinus headache (1% vs. 0% placebo) and migraine (2% vs. 1% placebo) were also reported with maintenance doses of apremilast during clinical trials. Headache was among the most common reasons leading to discontinuation of therapy.
Depression and suicidal ideation and behavior have been reported in patients receiving apremilast therapy. During clinical trials, depression or depressed mood was reported in 1% to 1.3% of patients treated with apremilast compared to 0.4% to 1% for placebo. Depression was reported as serious in up to 0.2% of patients in the apremilast group. Depression was reported as the reason for study discontinuation in up to 0.3% treated with apremilast. Serious depression was not reported in patients receiving placebo. Suicidal ideation and behavior were reported in up to 0.2% of patients in the apremilast group. In clinical trials of both plaque psoriasis and psoriatic arthritis, 1 patient treated with apremilast attempted suicide while 3 patients in the placebo groups committed suicide. If these reactions occur, prescribers should carefully evaluate the risks and benefits of continuing treatment.
Fatigue (3% vs. 2% placebo) and insomnia (2% vs. 1% placebo) were reported with maintenance doses of apremilast in clinical trials.
During clinical trials, back pain was noted in 2% to 7.7% of patients receiving maintenance doses of apremilast and in 1% to 5.8% of patients in the placebo group. In addition, arthralgia was reported by 5.8% of apremilast recipients compared 2.9% of patients who received placebo.
Apremilast is contraindicated in patients with a known hypersensitivity to apremilast or any excipients in the formulation. Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported during postmarketing use. If signs or symptoms of a serious hypersensitivity reaction develops during treatment, discontinue use of the drug and institute appropriate therapy.
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. The American Academy of Dermatology and National Psoriasis Foundation recommend considering treatment discontinuation for any individual experiencing a more than 5% weight loss from baseline.
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.
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.
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.
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. The drug has been found to cross the placenta in both mice and monkeys. 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. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to apremilast; information about the registry can be obtained at mothertobaby.org/ongoing-study/otezla or by calling 1-877-311-8972.
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.
The safety and effectiveness of apremilast in infants, children, and adolescents less than 18 years of age have not been established.
For the treatment of active psoriatic arthritis:
Oral dosage:
Adults: 10 mg PO once daily on day 1, then 10 mg PO twice daily on day 2, then 10 mg PO in the morning and 20 mg PO in the evening on day 3, then 20 mg PO twice daily on day 4, then 20 mg PO in the morning and 30 mg PO in the evening on day 5, and then 30 mg PO twice daily.
For the treatment of plaque psoriasis in persons who are candidates for systemic therapy or phototherapy:
Oral dosage:
Adults: 10 mg PO once daily on day 1, then 10 mg PO twice daily on day 2, then 10 mg PO in the morning and 20 mg PO in the evening on day 3, then 20 mg PO twice daily on day 4, then 20 mg PO in the morning and 30 mg PO in the evening on day 5, and then 30 mg PO twice daily.
For the treatment of oral ulcers (aphthous ulcer, canker sores) associated with Behcet's syndrome:
Oral dosage:
Adults: Titrate as follows to the target dose to reduce risk of GI symptoms. 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. Max: 60 mg/day.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
No dosage adjustments are needed.
Patients with Renal Impairment Dosing
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.
*non-FDA-approved indication
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.
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.
Butalbital; Acetaminophen: (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.
Butalbital; Acetaminophen; 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.
Butalbital; Acetaminophen; 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.
Butalbital; Aspirin; 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.
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.
Encorafenib: (Major) Coadministration of apremilast with encorafenib is not recommended due to decreased plasma concentrations of apremilast. Apremilast is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the single-dose apremilast AUC and Cmax by 72% and 43%, respectively.
Enzalutamide: (Major) Coadministration of apremilast with enzalutamide is not recommended due to decreased plasma concentrations of apremilast. Apremilast is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the single-dose apremilast AUC and Cmax by 72% and 43%, respectively.
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.
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.
Phenobarbital; Hyoscyamine; Atropine; 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.
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.
Rifapentine: (Major) Coadministration of apremilast with rifapentine is not recommended due to decreased plasma concentrations of apremilast. Apremilast is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the single-dose apremilast AUC and Cmax by 72% and 43%, respectively.
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.
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 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 is not fully elucidated.
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.
-Route-Specific Pharmacokinetics
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.
-Special Populations
Hepatic Impairment
Moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment does not affect the pharmacokinetics of apremilast.
Renal Impairment
The pharmacokinetics of apremilast were studied in patients with mild, moderate, and severe renal impairment defined by a creatinine clearance of 60 to 89 mL/minute, 30 to 59 mL/minute, and less than 30 mL/minute, respectively. Pharmacokinetics are not affected by mild or moderate renal impairment. In a single-dose pharmacokinetic analysis (n = 8), the AUC and Cmax of apremilast were increased by 88% and 42%, respectively, in patients with severe renal impairment. Therefore, the dose of the drug should be reduced in patients with severe renal impairment.
Geriatric
In a single-dose pharmacokinetic analysis, the AUC and Cmax were higher in geriatric subjects compared to younger subjects (13% and 6%, respectively).
Gender Differences
The extent of apremilast exposure is about 31% higher in females compared to males; however, dosage adjustments are not recommended based on gender.
Ethnic Differences
No differences were seen in the pharmacokinetics of apremilast in terms of race and ethnicity.