Introduction
Otezla (apremilast) is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) approved by the FDA for the treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, and oral ulcers associated with Behçet's disease. Developed by Celgene (now Bristol Myers Squibb), it represents a novel therapeutic approach that modulates intracellular inflammatory pathways without the immunosuppressive effects associated with biologic agents.
Mechanism of Action
Apremilast specifically inhibits phosphodiesterase 4 (PDE4), resulting in increased intracellular cyclic adenosine monophosphate (cAMP) levels. Elevated cAMP modulates the expression of pro-inflammatory and anti-inflammatory mediators through downstream effects on various transcription factors. This mechanism leads to:
- Decreased production of inflammatory cytokines (TNF-α, IL-17, IL-23)
- Increased production of anti-inflammatory cytokines (IL-10)
- Modulation of neutrophil and T-cell function
Unlike biologic agents, apremilast does not target specific extracellular cytokines or immune cells directly, providing a different mechanism of action for immune-mediated inflammatory conditions.
Indications
FDA-approved indications: 1. Moderate to severe plaque psoriasis in adults who are candidates for phototherapy or systemic therapy 2. Active psoriatic arthritis in adults 3. Oral ulcers associated with Behçet's disease in adults
Dosage and Administration
Titration Schedule (to reduce gastrointestinal symptoms):- Day 1: 10 mg AM
- Day 2: 10 mg AM and PM
- Day 3: 10 mg AM and 20 mg PM
- Day 4: 20 mg AM and PM
- Day 5: 20 mg AM and 30 mg PM
- Day 6 and thereafter: 30 mg twice daily
- Renal impairment (CrCl <30 mL/min): Maximum dose 30 mg once daily
- Hepatic impairment: No dosage adjustment necessary
- Elderly: No dosage adjustment necessary
- Pediatrics: Safety and effectiveness not established
Pharmacokinetics
Absorption: Rapidly absorbed with peak plasma concentrations occurring at approximately 2.5 hours. Absolute bioavailability is ~73%. Food does not significantly affect absorption. Distribution: Mean apparent volume of distribution is 87 L. Protein binding is approximately 68%. Metabolism: Extensive hepatic metabolism primarily via CYP3A4 with minor contributions from CYP1A2 and CYP2A6. Not a significant inhibitor or inducer of CYP enzymes. Elimination: Mean half-life is approximately 6-9 hours. Excretion is primarily renal (58%) and fecal (39%).Contraindications
1. Hypersensitivity to apremilast or any component of the formulation 2. No other absolute contraindications identified
Warnings and Precautions
Depression: Weight loss of 5-10% of body weight occurred in approximately 12% of patients. Monitor weight regularly; consider discontinuation if unexplained or clinically significant weight loss occurs. Psychiatric Symptoms: Depression (1.3%), insomnia, anxiety, and mood changes reported. Patients with history of depression or suicidal thoughts should be monitored closely. Diarrhea and Nausea: Most common adverse reactions. Usually occur during initial titration and often resolve with continued treatment. Drug Interactions with CYP450 Inducers: Strong CYP450 inducers (rifampin, phenobarbital, carbamazepine, phenytoin) may reduce apremilast exposure. Consider alternative treatments. Pregnancy: Limited human data. Use during pregnancy only if potential benefit justifies potential risk.Drug Interactions
Clinically Significant Interactions:- Strong CYP450 inducers: Decreased apremilast exposure (AUC decreased by 72%)
- Strong CYP450 inhibitors: May increase apremilast exposure (clinical significance unknown)
- No clinically significant interactions with methotrexate or oral contraceptives
Adverse Effects
Most Common (≥5%):- Diarrhea (17%)
- Nausea (17%)
- Headache (14%)
- Upper respiratory tract infection (9%)
- Vomiting (7%)
- Nasopharyngitis (6%)
- Abdominal pain (6%)
- Depression (1.3%)
- Suicidal ideation and behavior (<1%)
- Severe diarrhea leading to dehydration
- Significant weight loss
Monitoring Parameters
1. Weight at baseline and regularly during treatment 2. Psychiatric symptoms (depression, suicidal ideation) 3. Gastrointestinal symptoms, especially during titration 4. Clinical response assessment at 16-24 weeks 5. Renal function in patients with pre-existing renal impairment
Patient Education
1. Take exactly as prescribed; do not change dosage without medical advice 2. Report any thoughts of self-harm or mood changes immediately 3. Monitor weight regularly and report significant weight loss 4. Gastrointestinal symptoms often improve after the first few weeks 5. Inform all healthcare providers about Otezla use 6. Report severe or persistent diarrhea 7. Do not stop medication abruptly without consulting your physician 8. Use effective contraception during treatment
References
1. Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) 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.
2. 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.
3. 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.
4. Otezla® (apremilast) [package insert]. Summit, NJ: Celgene Corporation; 2021.
5. Schafer PH, Parton A, Gandhi AK, et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol. 2010;159(4):842-855.
6. Menter A, Strober BE, Kaplan DH, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. J Am Acad Dermatol. 2019;80(4):1029-1072.