Apremilast

Mechanism of Action

Apremilast is a selective inhibitor of the enzyme phosphodiesterase 4 (PDE4), hindering the conversion of cyclic adenosine monophosphate (cAMP) to AMP, further causing an intracellular accumulation of cyclic adenosine monophosphate (cAMP).[1] The inhibition of PDE4 is selective on the innate immune response causing a reduction in the production of inflammatory mediators such as CX-CL9, CX-CL10, IFN-γ, TNF-α, IL-2, IL-8, IL-12, and IL-23 and further decreasing the inflammatory response.[5][2] 

The diminished inflammatory response by PDE4 inhibition is what is reported to confer a therapeutic benefit and clinical improvements in psoriatic arthritis, plaque psoriasis, and Behcet disease, although the specific mechanism of apremilast is not well defined.[6] Apremilast inhibitory effects on other phosphodiesterases, receptors, or enzymes are insignificant.[7]

Administration

Apremilast is available in tablet form for oral consumption in adults in 10 mg, 20 mg, and 30 mg dosage forms. Its use for treatment in children aged 0 to 17 years has not been studied, and no data on safety and efficacy has been reported.[2]

The dosing schedule for treating Psoriasis, Psoriatic arthritis, and Behcet disease is started as a 5-day titration period, gradually increasing the apremilast dose over the first five days until the recommended dose is reached.[2]

• Day 1 - 10 mg in the morning once a day
• Day 2 - 10 mg in the morning and 10 mg in the evening
• Day 3 - 10 mg in the morning and 20 mg in the evening
• Day 4 - 20 mg in the morning and 20 mg in the evening
• Day 5 - 20 mg in the morning and 30 mg in the evening
• Day 6 - 30 mg twice daily moving forward

During the apremilast treatment initiation, patients should be started on a 10 mg dosage, followed by gradual dosage titration by an increase of 10 mg daily for six days, reaching the optimal daily dosage of 30 mg twice daily by day 6. The titration schedule helps prevent unwanted gastrointestinal adverse effects (severe diarrhea, nausea, and vomiting) that may occur with the initial therapy during the first few weeks. If the patient has impaired renal function (CrCl <30 mL/min), the dosing is 10 mg on days 1 to 3 and 20 mg on days 4 and 5 [(titrate using morning doses only (skip evening doses)] with a maintenance dose of 30 mg once daily in the morning after that. If a dose is missed, the patient is advised to talk to the doctor and pharmacist about when to take the next dose. Apremilast may be taken with or without regard. However, it should not be crushed, chewed, or split.[2]

Adverse Effects

Some of the reported adverse effects include:

• Diarrhea (8% to 41%)
• Nausea (9% to 19%)
• Headache (6% to 14%)
• Upper respiratory tract infection (4% to 12%)
• Vomiting (3% to 9%)
• Nasopharyngitis (3%)
• Upper abdominal pain (2% to 9%)
• Fatigue (3%)
• Dyspepsia (3%)
• Decreased appetite (3%)
• Weight loss (13%)
• Insomnia (2%)
• Back pain (2% - 8%)
• Migraine (2%)
• Frequent bowel movements (2%)
• Mood disorders and suicidal ideation (5%)
• Arthralgia (6%)[8][2]

The most frequently reported side effects of apremilast are gastrointestinal (diarrhea, nausea), transpiring during the first fourteen days of initiating therapy and typically resolving within twenty-eight days.[9][10] The onset of depression and suicidal ideations and behaviors were also reported during clinical trials and may occur while on therapy.[11]

Contraindications

Subjects with established hypersensitivity to apremilast or any elements of the agent's formulations are contraindicated to therapy with apremilast. Reproductive studies conducted in animal models during pregnancy demonstrated an increased risk of fetal loss with apremilast therapy. No reproductive studies with apremilast treatment during pregnancy in humans have been reported to date.[12] 

Women of reproductive potential are highly encouraged for pregnancy planning and prevention.[13] Contraception use during therapy with apremilast is recommended in child-bearing women. Women who are breastfeeding are contraindicated to treatment. The administration of live vaccinations while being treated with apremilast is also contraindicated.[2]

Apremilast is a selective immunosuppressant agent and is considered a class of immunomodulatory or immunosuppressive medications. As per rheumatology recommendations and guidelines, apremilast is advised to be held for one to two weeks following the administration of the COVID-19 vaccination, as it may reduce the vaccine's therapeutic efficacy. 

Monitoring

Once apremilast treatment is initiated, patients should be monitored for the development of adverse gastrointestinal manifestations (severe diarrhea, nausea, or vomiting). Dose reduction or treatment interruption should be prompted in the event of severe diarrhea, nausea, or vomiting. Patients with an underlying psychiatric history managed with apremilast should be monitored closely and routinely, as treatment may increase the risk of depression and suicidal behaviors. Patients receiving apremilast treatment should also routinely have their weight monitored, as significant weight reductions may occur and require dose reduction or treatment interruption.[2] 

Toxicity

Once consumed, the agent is metabolized hepatically by the cytochrome P450 (CYP) system, specifically the CYP3A4 enzyme, and possesses a terminal half-life of 6 to 9 hours. Although moderate to severe hepatic impairment do not require dosing adjustments, patients with underlying severe renal impairments characterized as CrCl less than 30 mL/min requires dosage adjustment. The agent is eliminated primarily by the kidneys and excreted in urine (58%) and feces (39%). Subjects with a CrCl greater than or equal to 30 mL/minute do not require dosing adjustments.

The use of apremilast in sequence with potent CYP450 inducers (rifampin, phenytoin, phenobarbital) is not recommended as drug-drug reactions may occur further, causing alterations in drug plasma concentration. No clinically significant drug interactions were reported with CYP450 inhibitors (ketoconazole, methotrexate)e).[13]

Enhancing Healthcare Team Outcomes

Apremilast is classified as a small-molecule phosphodiesterase 4 (PDE4) inhibitor. It is indicated for psoriatic arthritis in adult patients with moderately to severely active disease, plaque psoriasis in adult patients that are candidates for phototherapy or systemic therapy, and adults with oral ulcers associated with Behcet's disease. Managing patients with such ailments necessitates interprofessional communication and continuity of care from the healthcare team. The interprofessional healthcare team should include a primary care physician (PCP), a rheumatologist, a dermatologist, a physical therapist (PT), nursing staff, and a pharmacist. Open-ended communication among patients and providers and thorough clinical analysis by the healthcare team can lead to more precise and practical treatment strategies leading to improved patient outcomes. [Level 5]

Patients being initiated on therapy with apremilast should be counseled thoroughly on the 5-day titration regime and the potential risk of gastrointestinal adverse effects. Patients experiencing these effects should also be counseled that the effects can occur within the first 14 days of initiating therapy and typically resolve within 28 days. Patients who experience severe diarrhea, nausea, or vomiting should have dosing adjustments or discontinue their treatment. Patients who develop severe diarrhea should be assessed for complications such as volume depletion and hypotension and corrected promptly, particularly in elderly patients receiving apremilast.

Patients should also be advised of potential neuropsychiatric adverse effects such as depression and suicidal ideation or behavior while receiving therapy. Patients with an underlying psychiatric history considering apremilast should be consulted with their psychiatrist to determine the patient's baseline psychiatric health and with the specialist to determine the benefits of therapy. Routine psychiatric assessments should be done before and after initiating treatment in such patient demographics. Patients should also be monitored by their prescribing clinician for regular weight checks and advised to report any significant weight decreases. In such an occurrence, dosing adjustments or treatment termination by the healthcare team should be prompted.

The interprofessional team should also regularly review the latest guidelines on psoriatic arthritis, plaque psoriasis, and oral ulcers associated with Behcet disease. Patients with any known hypersensitivity to apremilast and its constituents are contraindicated for treatment. Apremilast is labeled as pregnancy category C. Women of reproductive potential should be advised about the potential risk of pregnancy loss with apremilast. They should be informed of pregnancy planning and prevention. Contraception should be considered prior to initiate apremilast treatment in childbearing females. Lactating and breastfeeding women should also be advised not to receive apremilast. The primary care physician should be aware of the patient's vaccination status, and all immunizations should be up to date before starting treatment. The patient should also be advised that receiving live vaccinations during treatment with apremilast is not recommended.

The interprofessional healthcare team should carefully monitor and routinely follow up with patients with severe renal impairment receiving apremilast. Patients with creatinine clearance of less than 30 mL/min should be thoroughly counseled and educated on dosing modifications and the risk of adverse events. In such patients, during the initial 5-day titration of therapy, subjects should be advised to miss their evening dosages and have their daily dosages decreased to 30mg once daily after that. The healthcare team should reconsider subjects who have not shown clinical improvements or therapeutic benefits over the 16-week period for discontinuation of apremilast. Continuous intercommunication between the PCP and specialists and their patients can help establish a therapeutic alliance when managed with apremilast promoting medication compliance, reducing adverse effects from apremilast, and improving disease outcomes.[2]