apremilast (Rx)

>10% (Psoriasis and Psoriatic Arthritis)

Diarrhea (7.7-17%)

Nausea (7.4-17%)

>10% (Behςet Disease)

Diarrhea (41.3%)

Nausea (19.2%)

Headache (14.4%)

Upper respiratory tract infection (11.5%)

1-10% (Behςet Disease)

Upper abdominal pain (8.7%)

Vomiting (8.7%)

Back pain (7.7%)

Viral upper respiratory tract infection (6.7%)

Arthralgia (5.8%)

1-10% (Psoriasis and Psoriatic Arthritis)

Upper respiratory tract infection (0.6-9%)

Tension headache (8%)

Headache (4.8-6%)

Vomiting (0.8-4%)

Fatigue (3%)

Dyspepsia (3%)

Decreased appetite (3%)

Insomnia (2%)

Back pain (2%)

Migraine (2%)

Frequent bowel movements (2%)

Depression (1%)

Bronchitis (1%)

Tooth abscess (1%)

Folliculitis (1%)

Frequency Not Defined (Psoriasis and Psoriatic Arthritis)

Immune system disorders: Hypersensitivity

Investigations: Weight decrease

Gastrointestinal disorders: Frequent bowel movement, gastroesophageal reflux disease, dyspepsia

Metabolism and nutrition disorders: Decreased appetite

Nervous system disorders: Migraine

Respiratory, thoracic, and mediastinal disorders: Cough

Skin and SC tissue disorders: Rash

Contraindications

Hypersensitivity to apremilast or to any of the excipients in the formulation

Cautions

Associated with an increase in adverse reactions of depression; before using, evaluate patient for history of depression and/or suicidal thoughts or behavior

Weight decrease of 5-10% of body weight reported in 10-12% of patients

Severe GI adverse effects

• Severe diarrhea, nausea, and vomiting reported; mostly occurred within the first few weeks of treatment
• In some cases, patients were hospitalized
• Patients aged ≥65 yr and patients taking medications that cause volume depletion or hypotension may be at a higher risk of these complications; monitor those who are more susceptible to complications of diarrhea or vomiting
• Quick improvement observed with dosage reduction or discontinuation; consider dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting

Drug interaction overview

• Coadministration with strong CYP inducers (eg, rifampin, carbamazepine, phenobarbital phenytoin) may occur and result in a loss of efficacy of apremilast; therefore, coadministration is not recommended

Pregnancy

Available pharmacovigilance data use in pregnant women have not established a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes, but data are extremely limited

Based on findings from animal reproduction studies, may increase the risk for fetal loss

Pregnancy exposure registry

• Registry monitors pregnancy outcomes in women exposed to apremilast during pregnancyRegistry information can be obtained by calling 1-877-311-8972 or visiting https://mothertobaby.org/ongoing-study/otezla

Animal data

• In a pre- and postnatal study in mice, apremilast was administered to pregnant female mice at doses of 10, 80, or 300 mg/kg/day from Day 6 of gestation through Day 20 of lactation, with weaning on Day 21
• Dystocia, reduced viability, and reduced birth weights occurred at doses corresponding to ≥4-times the MRHD (on an AUC basis at doses ≥80 mg/kg/day)
• No adverse effects occurred at a dose 1.3- times the MRHD (10 mg/kg/day)No evidence for functional impairment of physical development, behavior, learning ability, immune competence, or fertility in the offspring at doses up to 7.5-times the MRHD (on an AUC basis at a dose of 300 mg/kg/day)
• Apremilast distributed across the placenta into the fetal compartment in mice and monkeys
• Advise pregnant women of the potential risk of fetal lossConsider pregnancy planning and prevention for females of reproductive potential

Lactation

There are no data on the presence of apremilast in human milk, the effects on the breastfed infant, or the effects on milk production

Detected in the milk of lactating mice

Consider developmental and health benefits of breastfeeding along with the mother’s clinical need and any potential adverse effects on the breastfed infant or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Oral small molecule inhibitor of phosphodiesterase-4 specific for cAMP, resulting in increased intracellular cAMP levels

The specific mechanism by which apremilast exerts it therapeutic action in psoriatic arthritis is not well defined

Absorption

Absolute bioavailability: 73%

Peak plasma time: 2.5 hr

Coadministration with food does not alter absorption

Distribution

Protein bound: 68%

Vd: 87 L

Metabolism

Apremilast is a major circulating component (45%) followed by inactive metabolite M12 (39%), a glucuronide conjugate of O-demethylated apremilast

Metabolized by both CYP oxidative metabolism with subsequent glucuronidation and non-CYP mediated hydrolysis

In vitro CYP metabolism primarily by CYP3A4, with minor contribution from CYP1A2 and CYP2A6

Elimination

Half-life: 6-9 hr

Clearance: 10 L/hr

Excretion: 58% urine; 39% feces

Oral Administration

To reduce risk of GI symptoms associated with initial therapy, titrate to recommended dose (30 mg PO BID) according to the dosage schedules listed above

Can be administered without regard to meals

Swallow tablet whole; do not crush, split, or chew

Storage

Store below 30ºC (86ºF)