Otezla (Apremilast), an Oral PDE-4 Inhibitor, Receives FDA Approval for the Treatment of Patients with Active Psoriatic Arthritis

May 2015, Vol 3, No 5 - Inside Drug Update
Loretta Fala

Psoriatic arthritis, a progressive, potentially debilitating type of arthritic inflammation, affects approximately 7 million people in the United States.1,2

An Estimated 15% to 30% of patients with psoriasis will develop psoriatic arthritis.1,3 Psoriasis, a chronic, relapsing disease characterized by thick patches of inflamed, scaly skin resulting from excessive proliferation of skin cells, affects up to 2.6% of people in the United States.2

Both psoriatic arthritis and psoriasis are chronic autoimmune diseases.1 The symptoms of psoriatic arthritis, like the symptoms of psoriasis, may flare and subside, varying from person to person.3 In some cases, the arthritis precedes skin disorders. Psoriatic arthritis can affect any joint in the body; it may affect 1 or more joints (eg, 1 or both knees), and it may affect fingers and toes.3 Some patients also develop dactylitis, a condition in which the fingers and toes swell profusely.3 Many patients with psoriatic arthritis are affected by the joint disease and the psoriasis that often accompanies it.4

Psoriatic arthritis affects women and men equally.5 Although it generally develops between the ages of 30 years and 50 years, psoriatic arthritis can also start in childhood.3 An estimated 40% of patients with psoriatic arthritis have a family member with the disease, suggesting that heredity may play a key role. Psoriatic arthritis may also be triggered by an infection, including a streptococcal throat infection.3

The chronic pain, fatigue, limitations in physical function, and work disability associated with psoriatic arthritis can have a profound effect on the patient’s health-related quality of life.6 Furthermore, the risk for cardiovascular disease and other comorbidities is greater in patients with psoriatic arthritis and other inflammatory diseases than in individuals without these diseases.2,4 Psoriatic arthritis can also have a substantial impact on a patient’s psychological well-being, because of the itching, pain, and potential for social rejection encountered by many patients.2,4

Psoriatic arthritis imposes a considerable economic burden on patients and society. Based on a 2010 review of the literature, in the United States, direct annual medical costs associated with psoriatic arthritis total nearly $1.9 billion.4 In this review of 49 studies, patients with psoriatic arthritis had a lower health-related quality of life compared with the general population.4 Moreover, the direct and indirect costs associated with psoriatic arthritis, including lost productivity and disability, increase with worsening disease activity (ie, joint involvement and psoriatic skin lesions) and worsening physical function.4

Evidence shows that persistent inflammation associated with psoriatic arthritis causes joint damage over time. Consequently, early diagnosis of psoriatic arthritis is essential, because early detection and treatment may prevent further damage to the joints.3

The therapeutic goals for patients with psoriatic arthritis are to alleviate symptoms, control inflammation in affected joints, and prevent joint pain and disability.7 Treatment depends on the severity of the disease, the number of joints involved, and the associated skin symptoms.1

During the early stages of psoriatic arthritis, nonsteroidal anti-inflammatory drugs (NSAIDs) and cortisone may be used to manage mild inflammation. For patients with erosive disease or for those in whom NSAIDs fail to work, the disease-modifying antirheumatic drugs (DMARDs), including methotrexate, sulfasalazine, leflunomide, and a number of biologic agents may be used to slow the progression of psoriatic arthritis and spare the joints and other tissues from permanent damage.1,7

Until recently, the US Food and Drug Administration (FDA)-approved treatments for psoriatic arthritis included corticosteroids, several tumor necrosis factor blockers, and an interleukin-12/interleukin-23 inhibitor.8

A Novel Oral Therapeutic Option for Psoriatic Arthritis

On March 21, 2014, the FDA approved apremilast (Otezla; Celgene) for the treatment of adults with active psoriatic arthritis. An oral inhibitor of phosphodiesterase (PDE)-4, apremilast is the first oral therapy to receive FDA approval for the treatment of adult patients with active psoriatic arthritis.8

According to Curtis Rosebraugh, MD, MPH, Director of the Office of Drug Evaluation II at the FDA Center for Drug Evaluation and Research, “Relief of pain and inflammation and improving physical function are important treatment goals for patients with active psoriatic arthritis. Otezla provides a new treatment option for patients suffering from this disease.”8

Mechanism of Action

Apremilast is a small-molecule inhibitor of PDE-4 specific for cyclic aden­osine monophosphate (cAMP). Inhibition of PDE-4 results in increased intracellular cAMP levels. The specific mechanism by which apremilast exerts its therapeutic effect in patients with psoriatic arthritis is not well defined.9

Dosing and Administration

To reduce the risk of gastrointestinal symptoms, it is recommended that apremilast is titrated to the recommended dose of 30 mg twice daily, to be taken orally starting on day 6. The recommended initial dosage titration of apremilast from day 1 to day 5 is shown in Table 1.9 Coadministration of apremilast with food does not alter the extent of absorption of this drug.9

Table 1

The recommended dose for patients with severe renal impairment is 30 mg once daily. For initial dose titration in these patients, titration should follow the morning schedule in Table 1; the afternoon doses should be skipped.9

Apremilast is available in 10-mg, 20-mg, and 30-mg tablets.9

Clinical Trials

The safety and efficacy of apremilast were demonstrated in 3 multicenter, randomized, double-blind, placebo-controlled trials of similar design.9 In these studies (ie, PsA-1, PsA-2, PsA-3), a total of 1493 adult patients with active psoriatic arthritis (≥3 swollen joints and ≥3 tender joints) despite previous or current treatment with DMARD therapy were randomized to receive placebo, apremilast 20 mg twice daily, or apremilast 30 mg twice daily.9

Enrolled patients had a diagnosis of psoriatic arthritis for at least 6 months. The primary end point was the percentage of patients who achieved American College of Rheumatology (ACR)20 response at week 16.9 An ACR20 is defined as a 20% improvement in tender and swollen joint counts and a 20% improvement in 3 of the 5 remaining

ACR core set mea­sures (ie, patient and physician global assessments, pain, disability, others.)10 An ACR50 represents a 50% improvement in both measures; an ACR70, a 70% improvement in both measures.10

In these studies, placebo-controlled efficacy data were also collected and analyzed through week 24. If patients’ tender and swollen joint counts had not improved by at least 20%, they were considered nonresponders at week 16. Placebo nonresponders were rerandomized 1:1 in a blind fashion to either apremilast 20 mg twice daily or 30 mg twice daily, after titration. Patients receiving apremilast continued their initial treatment. At week 24, all remaining patients receiving placebo were rerandomized to either 20 mg twice daily or to 30 mg twice daily.9

Patients enrolled across the 3 clinical studies had a median duration of psoriatic arthritis disease of 5 years, with a variety of psoriatic arthritis subtypes, including symmetric polyarthritis (62%), asymmetric oligoarthritis (27%), distal interphalangeal joint arthritis (6%), arthritis mutilans (3%), and predominant spondylitis (2.1%).

Patients received concomitant therapy with at least 1 DMARD (65%), methotrexate (55%), sulfasalazine (9%), leflunomide (7%), low-dose oral corticosteroids (14%), and NSAIDs (71%). Previous treatment with small-molecule DMARDs was reported in only 76% of patients, and previous treatment with biologic DMARDs was reported in 22% of patients, including 9% who failed previous biologic DMARD treatment.9

The proportion of patients who achieved a clinical response (ie, ACR20, ACR50, or ACR70 responses) in studies PsA-1, PsA-2, and PsA-3 are shown in Table 2. Patients receiving apremilast ± DMARDs showed greater reductions in signs and symptoms of psoriatic arthritis compared with placebo ± DMARDs as demonstrated by the proportion of patients who achieved an ACR20 response at week 16.9

Table 2

Apremilast 30 mg twice daily also demonstrated improvement for each ACR component versus placebo at week 16 in study PsA-1, as shown in Table 3. These results from study PsA-1 were consistent with those observed in studies PsA-2 and PsA-3.

Table 3

In study PsA-1, apremilast 30 mg twice daily also showed a greater improvement in mean change from baseline for the health assessment questionnaire disability index (HAQ-DI) score at week 16 compared with the placebo group. The proportions of HAQ-DI responders (≥0.3 improvement from baseline) at week 16 were 38% for the apremilast (30 mg twice daily) group compared with 27% for the placebo group. Consistent results were observed in studies PsA-2 and PsA-3.9


The most common adverse reactions associated with apremilast occurring in ≥5% of patients were nausea (8.3%), diarrhea (7.7%), and headache (5.9%). In addition, upper respiratory tract infections were reported in 3.9% of patients and vomiting in 3.2%.9

Similarly, the most common reasons leading to treatment discontinuation with apremilast were diarrhea (1.8%), nausea (1.8%), and headache (1.2%).

In clinical trials, the proportion of pa­tients with psoriatic arthritis who discontinued treatment because of any adverse reaction was 4.6% for patients taking apremilast 30 mg twice daily and 1.2% for patients receiving placebo.9

Warnings and Precautions

Apre­milast is contraindicated in patients with a known hypersensitivity to apremilast or any of the excipients in the formulation.9

Drug interactions
Use of apremilast with strong cytochrome P450 enzyme inducers (eg, rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended, because it may result in a loss of efficacy of apremilast.9

Patients should be advised of the potential emergence or worsening of depression, suicidal thoughts, or other mood changes. The risks and benefits of treatment with apremilast should be weighed carefully in patients with a history of depression and/or suicidal thoughts or behavior.9

Weight decrease
The patient’s weight should be monitored regularly. If unexplained or clinically significant weight loss occurs, discontinuation of apremilast should be considered.9

Use in Specific Populations

Adequate and well-controlled studies with apremilast have not been conducted in pregnant women. Apremilast should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.9

Nursing mothers
It is not known whether apremilast or its metabolites are present in human milk. However, because many drugs are present in human milk, caution should be exercised when apremilast is administered to a nursing woman.9

Severe renal impairment
Increased systemic exposure of apremilast has been observed in patients with severe renal impairment; a reduction in dose to 30 mg once daily is recommended.9


The FDA approval of apremilast marks the availability of the first oral treatment option for patients with active psoriatic arthritis. Having an oral option can be important for patients who are unable or unwilling to use other therapeutic options.

The safety and efficacy of apremilast, a novel PDE-4 inhibitor, were demonstrated in 3 randomized, double-blind, placebo-controlled trials that involved 1493 patients. In all 3 studies, a statistically significant proportion of patients receiving apremilast achieved an ACR20 response at week 16 compared with placebo. Treatment with apremilast 30 mg twice daily also resulted in improvement for each ACR component, including tender joints, swollen joints, and physical function.


  1. Cleveland Clinic Foundation. Psoriatic arthritis. http://my.cleveland clinic.org/orthopaedics-rheumatology/diseases-conditions/hic-psoriatic-arthritis.aspx. Accessed May 1, 2014.
  2. National Institutes of Health. Psoriasis. Fact sheet. Updated October 2010. http://report.nih.gov/NIHfactsheets/Pdfs/Psoriasis%28NIAMS%29.pdf. Accessed April 28, 2014.
  3. Emery P, Ash Z. American College of Rheumatology. Psoriatic arthritis. Updated September 2012. www.rheumatology.org/Practice/Clinical/Patients/Diseases_And_Conditions/Psoriatic_Arthritis/. Accessed May 1, 2014.
  4. Lee S, Mendelsohn A, Sarnes E. The burden of psoriatic arthritis: a literature review from a global health systems perspective. P T. 2010;35:680-689.
  5. Gelfand JM, Gladman DD, Mease PJ, et al. Epidemiology of psoriatic arthritis in the population of the United States. J Am Acad Dermatol. 2005;53:573-577.
  6. Armstrong AW, Schupp C, Wu J, Bebo B. Quality of life and work productivity impairment among psoriasis patients: findings from the National Psoriasis Foundation survey data 2003-2011. PLoS One. 2012;7:e52935.
  7. Mayo Clinic staff. Psoriatic arthritis: treatment and drugs. January 29, 2014. Accessed May 1, 2014.
  8. US Food and Drug Administration. FDA approves Otezla to treat psoriatic arthritis. Press release. March 21, 2014. www.fda.gov/newsevents/newsroom/pressannouncements/ucm390091.htm. Accessed April 23, 2014.
  9. Otezla (apremilast) tablets [prescribing information]. Summit, NJ: Celgene Corporation; March 2014.
  10. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;38:727-735.
Related Items
Products and Services - April 2016
April 2016, Vol 4, No 4 published on April 24, 2016 in Inside Drug Update
Products and Services - March 2016
March 2016, Vol 4, No 3 published on March 25, 2016 in Inside Drug Update
Products and Services - February 2016
February 2016, Vol 4, No 2 published on March 8, 2016 in Inside Drug Update
New Perspectives in the Treatment of Opioid-Induced Respiratory Depression
Loretta Fala, John A. Welz, MPH
New Perspectives in the Treatment of Opioid-Induced Respiratory Depression published on February 2, 2016
Finacea (Azelaic Acid) Foam the Newest Topical Treatment FDA Approved for the Treatment of Inflammatory Lesions of Rosacea
Loretta Fala
January 2016, Vol 4, No 1 published on January 28, 2016 in Inside Drug Update
Products and Services - January 2016
January 2016, Vol 4, No 1 published on January 28, 2016 in Inside Drug Update
Cosentyx (Secukinumab): First IL-17A Antagonist Receives FDA Approval for Moderate-to-Severe Plaque Psoriasis
Loretta Fala
December 2015, Vol 3, No 12 published on December 18, 2015 in Inside Drug Update
Products and Services - December 2015
December 2015, Vol 3, No 12 published on December 18, 2015 in Inside Drug Update
ProAir RespiClick (Albuterol Sulfate): First Breath-Actuated Inhaler Approved for the Treatment or Prevention of Bronchospasm
Lisa A. Raedler, PhD, RPh
November 2015, Vol 3, No 11 published on December 10, 2015 in Inside Drug Update
Inside Products and Services - November 2015
November 2015, Vol 3, No 11 published on December 10, 2015 in Inside Drug Update
Last modified: May 27, 2015
  • American Health & Drug Benefits
  • The Journal of Hematology Oncology Pharmacy
  • Lynx CME
  • The Oncology Pharmacist