Apremilast (Otezla)
apremilast — oral phosphodiesterase 4 (PDE4) inhibitor
Approved Indications & Off-Label Uses
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Active psoriatic arthritis | Adults; pediatric ≥6 years (≥20 kg) | Monotherapy or with DMARDs | FDA Approved |
| Plaque psoriasis | Adults (candidates for phototherapy/systemic therapy); pediatric ≥6 years (≥20 kg, moderate-severe) | Monotherapy | FDA Approved |
| Oral ulcers associated with Behçet’s disease | Adults | Monotherapy | FDA Approved (2019) |
Apremilast is the only oral PDE4 inhibitor approved for psoriatic disease and Behçet’s disease. Unlike biologics, it does not require injection, does not require pre-treatment TB screening, and carries no immunosuppression-related infection warnings. It occupies a therapeutic niche between topical agents and biologics for patients who prefer oral therapy or who are not candidates for immunosuppressive biologics. Efficacy is generally lower than TNF, IL-17, and IL-23 inhibitors for moderate-to-severe disease.
Hidradenitis suppurativa: Small case series; Evidence quality: Very low.
Atopic dermatitis: Phase II data available; Evidence quality: Low.
Granuloma annulare: Case reports; Evidence quality: Very low.
Dosing by Clinical Scenario
5-Day Titration Schedule (All Indications, Adults)
| Day | AM Dose | PM Dose | Notes |
|---|---|---|---|
| Day 1 | 10 mg | — | Titration reduces GI symptoms (diarrhoea, nausea, vomiting) associated with initial therapy Do not crush, split, or chew tablets; may take with or without food |
| Day 2 | 10 mg | 10 mg | |
| Day 3 | 10 mg | 20 mg | |
| Day 4 | 20 mg | 20 mg | |
| Day 5 | 20 mg | 30 mg | |
| Day 6+ | 30 mg | 30 mg | Maintenance: 30 mg BID (or Otezla XR 75 mg once daily) |
Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| PsA / PsO / Behçet’s — adults | 5-day titration (see above) | 30 mg BID | 30 mg BID (60 mg/day) | Same titration and maintenance for all 3 indications Or Otezla XR 75 mg QD after titration |
| Severe renal impairment (CrCl <30 mL/min) | Titrate using AM schedule only; skip PM doses | 30 mg once daily | 30 mg QD | 50% dose reduction due to increased systemic exposure |
| Pediatric PsA/PsO (≥6 yrs, ≥50 kg) | 5-day titration | 30 mg BID | 30 mg BID | Same as adult dosing Monitor growth (height and weight) |
| Pediatric PsA/PsO (≥6 yrs, 20–<50 kg) | 5-day titration (reduced) | 20 mg BID | 20 mg BID | Weight-based dosing Monitor growth; interrupt if not growing as expected |
The 5-day titration is critical for patient retention. Diarrhoea and nausea are most pronounced during the first 2 weeks and tend to resolve with continued dosing. Counsel patients to expect transient GI symptoms and that these typically improve. Taking apremilast with food may reduce nausea for some patients, although food does not affect overall bioavailability. Patients who develop severe GI symptoms should have their dose reduced or treatment temporarily suspended.
Pharmacology & Mechanism of Action
Mechanism of Action
Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4), the dominant PDE isoform in inflammatory cells. PDE4 inhibition raises intracellular cyclic adenosine monophosphate (cAMP) levels, which in turn modulates a network of pro-inflammatory and anti-inflammatory mediators. Increased cAMP downregulates pro-inflammatory cytokines (TNF-α, IL-23, IL-17, IFN-γ) and upregulates anti-inflammatory mediators (IL-10). Unlike biologics that target a single cytokine, apremilast broadly modulates the inflammatory response at the intracellular signalling level. The specific mechanism by which apremilast exerts its therapeutic effect in psoriatic disease and Behçet’s disease is not fully defined, but clinical data show reductions in circulating IL-17, IL-22, and TNF-α levels.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral: bioavailability ~73%; Tmax ~2.5 hours; food does not alter extent of absorption; linear PK (10–100 mg) | Rapid oral absorption; can be taken with or without food; BID dosing achieves ~53–68% accumulation |
| Distribution | Vd 87 L (extravascular distribution); protein binding ~68% | Distributes well beyond plasma compartment; moderate protein binding unlikely to cause displacement interactions |
| Metabolism | Extensively metabolised (>23 metabolites); CYP3A4 (major), CYP1A2, CYP2A6 (minor); also non-CYP hydrolysis and glucuronidation; parent drug = 45% of circulating radioactivity; major metabolite M12 (inactive) = 39% | Susceptible to strong CYP3A4 inducers (rifampin reduces exposure); NOT an inhibitor or inducer of CYP enzymes — low risk of affecting other drugs |
| Elimination | CL ~10 L/hr; t½ ~6–9 hours; 58% urine, 39% faeces (mostly as metabolites; <3% unchanged in urine) | Short half-life necessitates BID dosing; primarily renal excretion of metabolites; dose reduce for severe renal impairment |
Side Effects & Adverse Reactions
Data below are from pooled Phase III PsA trials (PALACE 1–3; OTEZLA 30 mg BID N=497 vs placebo N=495) through Week 16, supplemented by PsO trials (ESTEEM 1–2) and long-term extension data (FDA PI, revised 07/2023). GI adverse effects are characteristically most pronounced during the first 2 weeks and diminish over time.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Diarrhoea | Day 1–5: 9.3%; Day 6–112: 7.7% | PDE4 class effect; most events first 2 weeks; usually self-limiting (vs 1.2%/1.6% placebo) |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nausea | Day 1–5: 7.4%; Day 6–112: 8.9% | Second most common GI AE; improves with continued dosing (vs 1.4%/3.1% placebo) |
| Headache | Day 1–5: 4.8%; Day 6–112: 5.9% | Including tension headache; dose-related (vs 1.8%/2.2% placebo) |
| Upper respiratory tract infection | 3.9% | Day 6–112 data; not a class effect (vs 1.8% placebo) |
| Vomiting | 3.2% | Usually early onset; can be severe in some patients (vs 0.4% placebo) |
| Nasopharyngitis | 2.6% | Mild (vs 1.6% placebo) |
| Upper abdominal pain | 2.0% | GI-related; may accompany diarrhoea (vs 0.2% placebo) |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Depression / depressed mood | PsA: 1.0% vs 0.8% placebo; PsO: 1.3% vs 0.4% | Variable; monitor throughout treatment | Weigh risks/benefits before use in patients with depression history; d/c due to depression: 0.3% (PsA); advise patients/caregivers to report mood changes |
| Suicidal ideation/behaviour | PsA: 0.2% vs 0% placebo; PsO: 0.1% vs 0.2% | Variable | Carefully evaluate risk-benefit; consider discontinuation if suicidal thoughts emerge |
| Weight decrease (5–10% body weight) | PsA: 10% vs 3.3% placebo; PsO: 12% vs 5% | Gradual over weeks to months | Monitor weight regularly; evaluate unexplained weight loss; consider discontinuation if clinically significant |
| Weight decrease (≥10% body weight) | PsO: 2% vs 1% placebo | Gradual | Discontinuation should be strongly considered |
| Severe diarrhoea/nausea/vomiting | Uncommon but reported; some hospitalisations (postmarketing) | Usually first few weeks | Dose reduction or suspension; higher risk in patients ≥65 years or on volume-depleting medications |
| Hypersensitivity (angioedema/anaphylaxis) | Rare (postmarketing) | Any time | Discontinue permanently; initiate emergency therapy |
Diarrhoea, nausea, and vomiting are the most clinically impactful side effects of apremilast and the leading causes of early discontinuation. The 5-day titration markedly reduces their severity. Most GI symptoms are self-limiting and resolve within the first 2–4 weeks. Patients who experience severe symptoms should have their dose reduced or treatment temporarily suspended — improvement is typically rapid after dose reduction. Elderly patients (≥65) and those on diuretics or antihypertensives should be monitored more closely due to dehydration risk.
Drug Interactions
Apremilast is metabolised primarily by CYP3A4 but is NOT an inhibitor or inducer of CYP enzymes, P-glycoprotein, or major transporters. Its interaction profile is therefore mainly one-directional: strong CYP3A4 inducers significantly reduce apremilast exposure, while CYP3A4 inhibitors cause only modest increases that are not clinically meaningful.
Monitoring Parameters
- Body WeightBaseline, then regularly
RoutineWeight decrease of 5–10% occurred in 10–12% of patients vs 3–5% placebo. Monitor weight at each visit. If unexplained or clinically significant weight loss occurs, evaluate and consider discontinuation. - Depression / MoodBaseline screening; ongoing
RoutineDepression reported in 1.0–1.3% vs 0.4–0.8% placebo. Suicidal ideation/behaviour observed in 0.1–0.2%. Assess depression history before starting. Advise patients and caregivers to report mood changes promptly. - GI TolerabilityFirst 2–4 weeks
Trigger-basedDiarrhoea, nausea, and vomiting are most pronounced during the first 2 weeks. Severe GI symptoms have led to hospitalisation, particularly in elderly patients or those on volume-depleting agents. Dose reduce or suspend if severe. - Renal FunctionBaseline
RoutineAssess CrCl before initiation. Patients with severe renal impairment (CrCl <30 mL/min) require dose reduction to 30 mg once daily. No adjustment needed for mild-moderate impairment. - Growth (Pediatric)Regular intervals
RoutinePer 2025 label: closely monitor height and weight in pediatric patients. Interrupt treatment if growth is not proceeding as expected.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to apremilast or any excipient — angioedema and anaphylaxis reported postmarketing
Relative Contraindications (Specialist Input Recommended)
- Active depression or suicidal ideation — carefully weigh risks/benefits; treatment associated with increased depression incidence
- Pregnancy — animal studies showed dose-related fetal loss in monkeys at ≥2× MRHD; advise pregnancy planning/prevention; pregnancy registry available (1-877-311-8972)
Use with Caution
- Underweight or malnourished patients — weight loss of 5–10% in up to 12% of patients; monitor closely
- Elderly patients (≥65 years) — higher risk of complications from severe GI symptoms (dehydration, hypotension)
- Patients on volume-depleting medications (diuretics) — monitor hydration during initial treatment
- Concomitant strong CYP3A4 inducers — loss of efficacy; avoid rifampin, phenytoin, carbamazepine, phenobarbital
- Severe renal impairment — reduce dose to 30 mg QD
- Lactation — unknown if apremilast or metabolites present in human milk; detected in mouse milk
Treatment with apremilast is associated with an increased incidence of depression (PsA: 1.0% vs 0.8% placebo; PsO: 1.3% vs 0.4%). Suicidal ideation and behaviour have been observed in 0.1–0.2% of treated patients. Before prescribing to patients with a history of depression or suicidal thoughts, carefully weigh risks and benefits. Instruct patients, caregivers, and families to be alert for emergence or worsening of depression, suicidal thoughts, or mood changes, and to contact their healthcare provider promptly if such changes occur.
Patient Counselling
Purpose of Therapy
Apremilast is an oral tablet that works by reducing inflammation from the inside out. It targets an enzyme called PDE4 that plays a role in inflammation. By blocking this enzyme, apremilast helps reduce skin plaques, joint pain, and mouth ulcers associated with psoriatic disease or Behçet’s disease.
How to Take
Treatment starts with a gradual dose increase over 5 days (using a starter pack) to reduce stomach and bowel side effects. After the first 5 days, the regular dose is one 30 mg tablet in the morning and one in the evening, every day. The tablet can be taken with or without food. Do not crush, split, or chew the tablet. An extended-release option (Otezla XR 75 mg) is available as a single daily tablet.
Sources
- OTEZLA (apremilast) [prescribing information]. Thousand Oaks, CA: Amgen Inc.; Revised 07/2023. FDA Label (PDF)Primary regulatory source for dosing, titration schedule, adverse reactions (Tables 2–4), weight loss data, depression warnings, and PK parameters.
- OTEZLA/OTEZLA XR (apremilast) [prescribing information]. Thousand Oaks, CA: Amgen Inc.; Revised 01/2025. DailyMed (Current Label)Updated label with pediatric PsA/PsO dosing, Otezla XR (75 mg QD) formulation, and growth monitoring requirement.
- Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014;73(6):1020-1026. doi:10.1136/annrheumdis-2013-205056PALACE 1 pivotal trial; apremilast 30 mg BID improved ACR20 (38.1% vs 19.0% placebo at week 16) and was well tolerated in active PsA.
- Cutolo M, Myerson GE, Fleischmann RM, et al. A phase III, randomized, controlled trial of apremilast in patients with psoriatic arthritis: results of the PALACE 2 trial. J Rheumatol. 2016;43(9):1724-1734. doi:10.3899/jrheum.151376PALACE 2 trial confirming PsA efficacy; sustained ACR20 improvements through 52 weeks with acceptable safety.
- Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol. 2015;73(1):37-49. doi:10.1016/j.jaad.2015.03.049ESTEEM 1 pivotal PsO trial; PASI 75 at week 16: 33.1% vs 5.3% placebo; significant improvements in scalp psoriasis and nail disease.
- Paul C, Cather J, Gooderham M, et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2). Br J Dermatol. 2015;173(6):1387-1399. doi:10.1111/bjd.14164ESTEEM 2 confirmed PsO efficacy; PASI 75 28.8% vs 5.8% placebo at week 16; long-term response maintained through 52 weeks.
- Hatemi G, Mahr A, Ishigatsubo Y, et al. Trial of apremilast for oral ulcers in Behçet’s syndrome. N Engl J Med. 2019;381(20):1918-1928. doi:10.1056/NEJMoa1816594Phase III trial supporting the 2019 Behçet’s approval; significant reduction in oral ulcers vs placebo at week 12.
- Menter A, Gelfand JM, Connor C, et al. Joint American Academy of Dermatology–National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies. J Am Acad Dermatol. 2020;82(6):1445-1486. doi:10.1016/j.jaad.2020.02.044AAD-NPF guidelines positioning apremilast as a systemic nonbiologic option for psoriasis management.
- Gossec L, Kerschbaumer A, Ferreira RJO, et al. EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update. Ann Rheum Dis. 2024;83(6):706-719. doi:10.1136/ard-2024-225531EULAR 2023 PsA update; positions PDE4 inhibitors for patients who prefer oral therapy or have mild/moderate disease.
- Schafer PH, Parton A, Capone L, et al. Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity. Cell Signal. 2014;26(9):2016-2029. doi:10.1016/j.cellsig.2014.05.014Mechanistic study showing apremilast reduces TNF-α, IL-23, IL-17, and raises IL-10 via PDE4 inhibition in human cells.
- Hoffmann M, Kumar G, Schafer PH, et al. Disposition, metabolism and mass balance of [14C]apremilast following oral administration. Xenobiotica. 2012;42(3):263-275. doi:10.3109/00498254.2011.615407Definitive radiolabel ADME study; confirms CYP3A4 as primary metabolic pathway, 58% renal/39% faecal excretion, and M12 as major inactive metabolite.
- Kavanaugh A, Gladman DD, Edwards CJ, et al. Long-term experience with apremilast in patients with psoriatic arthritis: 5-year results from a PALACE 1-3 pooled analysis. Arthritis Res Ther. 2019;21(1):118. doi:10.1186/s13075-019-1901-35-year pooled PsA safety and efficacy analysis from PALACE 1–3; sustained ACR responses with stable safety profile.
- Man HW, Schafer PH, Wong LM, et al. Discovery of (S)-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide (apremilast), a potent and orally active phosphodiesterase 4 and tumor necrosis factor-alpha inhibitor. J Med Chem. 2009;52(6):1522-1524. doi:10.1021/jm900210dDiscovery paper describing the medicinal chemistry and initial characterisation of apremilast as a PDE4 inhibitor.