Apremilast Tablets (Otezla)
By William T. Elliott, MD, FACP, and
James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor
of Medicine, University of California, San Francisco.
Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field
The first oral drug for the treatment of psoriatic arthritis has been approved by the FDA. Apremilast is a selective phosphodiesterase 4 (PDE4) inhibitor. It is marketed by the Celgene Corporation as Otezla.
Apremilast is indicated for the treatment of adults with active psoriatic arthritis.1
Due to gastrointestinal symptoms, titration to the recommended dose of 30 mg twice daily is recommended.1 The titration schedule is as follows: 10 mg in the morning on day 1, 10 mg in the morning and in the evening on day 2, 10 mg in the morning and 20 mg in the evening on day 3, 20 mg in the morning and evening on day 4, 20 mg in the morning and 30 mg in the evening on day 5, and 30 mg twice daily thereafter. Apremilast is available as 10 mg, 20 mg, and 30 mg tablets.
Apremilast provides an orally active drug with a different mechanism of action.
The most common side effects are diarrhea, nausea, and headache (frequency of 5-9% in the first 5 days and 7-9% after day 6 to day 112).1 Between 5-10% loss of body weight has been reported in 10% of patients. Patients should have their weight monitored during therapy. A numerically higher frequency of depression has been reported compared to placebo (1% vs 0.8%).1 Risk vs benefit should be weighed before initiating treatment in patients with a history of depression or suicidal thoughts or behavior. If treatment is started, patients and family should be alerted to emergence or worsening of depression or development of mood changes or suicidal thoughts.1
PDE4, a dominant phosphodiesterase expressed in immune cells, is an enzyme responsible for the hydrolysis of cyclic adenosine monophosphate (cAMP).2 This is an important messenger that controls a network of pro-inflammatory and anti-inflammatory mediators. Apremilast affects the synthesis of various pro-inflammatory cytokines and chemokines.3 The safety and efficacy of apremilast were evaluated in three randomized, double-blind, placebo-controlled trials.1,4 Subjects were adults with active disease (≥ 3 swollen joints and ≥ 3 tender joints) despite prior treatment with a disease-modifying antirheumatic drug therapy (DMARD; e.g., methotrexate, leflunomide, sulfasalazine) and/or biologic treatment or current DMARDs. Subjects were allowed to be on a stable dose of DMARD, low-dose oral steroid, and/or an NSAID during the trial. Subjects who failed more than three agents or more than one biologic were excluded. Subjects were randomized to apremilast 30 mg twice daily, 20 mg twice daily, or placebo. The primary endpoint was ACR20 response at week 16. This represents a 20% improvement in swollen and tender joint counts as well as other improvements such as in pain, disease activity, and disability index. The 30 mg dose (recommended dose) showed higher and more consistent response than the 20 mg dose.4 ACR20 were 38%, 32%, and 41% for the 30 mg dose for the three studies compared to 19%, 19%, and 18% for placebo, respectively. Subjects who were biologic-naïve generally had a better response than biologic-experienced and biologic failures.4
Psoriatic arthritis is a chronic systemic inflammatory disease characterized by joint pain, swelling, and stiffness. Psoriatic arthritis is associated with psoriasis, with 14-30% of patients with psoriasis eventually developing psoriatic arthritis. The diagnosis is based on clinical and radiological findings as the vast majority of patients are sero-negative. Currently approved treatment includes corticosteroids, tumor necrosis factor blockers (e.g., etanercept), and interleukin12/interleukin-23 inhibitors (e.g., ustekinumab).5 There are currently no studies directly comparing apremilast to other agents. The results from placebo-controlled studies with etanercept (25 mg subcutaneously twice a week) showed ACR20 of 50% compared to 13% for placebo. This is an absolute percent difference of 37% for etanercept compared to 19% for apremilast suggesting a potential advantage for etanercept. The latter, however, does provide an orally effective treatment with a different adverse reaction profile. The wholesale cost for a 30-day supply of apremilast (30 mg twice daily) is $1875.
- Otezla Prescribing Information. Summit, NJ: Celgene Corporation; March 2014.
- Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol 2012;83:1583-1590.
- Schett G, et al. Apremilast: A novel PDE4 inhibitor in the treatment of autoimmune and inflammatory diseases. Ther Adv Musculoskelet Dis 2010;2:271-278.
- Kavanagh A, 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; Mar 4. doi:10.1136/annrheumdis-2013-205056. [Epub ahead of print].
- http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm390091.htm. Accessed April 6, 2014.