Otezla

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

May administer with or without food.

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

suicidal ideation / Delayed / 0.1-0.2
angioedema / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known

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

diarrhea / Early / 7.7-41.3
nausea / Early / 7.4-22.0
headache / Early / 4.8-14.4
weight loss / Delayed / 4.9-12.0
infection / Delayed / 0.6-11.5
vomiting / Early / 0.8-8.7
abdominal pain / Early / 0.6-8.7
back pain / Delayed / 2.0-7.7
arthralgia / Delayed / 5.8-5.8
dyspepsia / Early / 3.0-3.0
fatigue / Early / 3.0-3.0
pharyngitis / Delayed / 0.2-2.6
insomnia / Early / 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

Otezla

Rx

Oral phosphodiesterase-4 inhibitor (PDE4) and a targeted synthetic DMARD
Used in adults for the treatment of active psoriatic arthritis, oral ulcers associated with Behcet's Disease, and plaque psoriasis in candidates for systemic or phototherapy
Patients with severe diarrhea, nausea, and vomiting may need dose reduction or drug discontinuation

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.

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.

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.[56870]

No dosage adjustments are needed.

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.

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.
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.
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.
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.

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

60 mg/day PO.

60 mg/day PO.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

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.[56883] The specific mechanism by which apremilast exerts its therapeutic effect is not fully elucidated.[56870]

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.

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.

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.