Recommended Topic Related To:

Otezla

"The U.S. Food and Drug Administration today approved Otezla (apremilast) to treat adults with active psoriatic arthritis (PsA).

PsA is a form of arthritis that affects some people with psoriasis. Most people develop psoriasis first and are "...

Otezla

CLINICAL PHARMACOLOGY

Mechanism Of Action

Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels. The specific mechanism(s) by which apremilast exerts its therapeutic action in psoriatic arthritis patients and psoriasis patients is not well defined.

Pharmacokinetics

Absorption

Apremilast when taken orally is absorbed with an absolute bioavailability of ~73%, with peak plasma concentrations (Cmax) occurring at a median time (tmax) of ~2.5 hours. Co-administration with food does not alter the extent of absorption of apremilast.

Distribution

Human plasma protein binding of apremilast is approximately 68%. Mean apparent volume of distribution (Vd) is 87 L.

Metabolism

Following oral administration in humans, apremilast is a major circulating component (45%) followed by inactive metabolite M12 (39%), a glucuronide conjugate of O-demethylated apremilast. It is extensively metabolized in humans with up to 23 metabolites identified in plasma, urine and feces. Apremilast is metabolized by both cytochrome (CYP) oxidative metabolism with subsequent glucuronidation and non-CYP mediated hydrolysis. In vitro, CYP metabolism of apremilast is primarily mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6.

Elimination

The plasma clearance of apremilast is about 10 L/hr in healthy subjects, with a terminal elimination half-life of approximately 6-9 hours. Following oral administration of radio-labeled apremilast, about 58% and 39% of the radioactivity is recovered in urine and feces, respectively, with about 3% and 7% of the radioactive dose recovered as apremilast in urine and feces, respectively.

Specific Populations

Hepatic Impairment: The pharmacokinetics of apremilast is not affected by moderate or severe hepatic impairment.

Renal Impairment: In 8 subjects with severe renal impairment administered a single dose of 30 mg apremilast, the AUC and Cmax of apremilast increased by approximately 88% and 42%, respectively. [See Use in Specific Populations and DOSAGE AND ADMINISTRATION].

Age: A single oral dose of 30-mg apremilast was studied in young adults and elderly healthy subjects. The apremilast exposure in elderly subjects (65 to 85 years of age) was about 13% higher in AUC and about 6% higher in Cmax than in young subjects (18 to 55 years of age). [See Use in Specific Populations].

Gender: In pharmacokinetic studies in healthy volunteers, the extent of exposure in females was about 31% higher and Cmax was about 8% higher than that in male subjects.

Race and Ethnicity: The pharmacokinetics of apremilast in Chinese and Japanese healthy male subjects is comparable to that in Caucasian healthy male subjects. In addition, apremilast exposure is similar among Hispanic Caucasians, non-Hispanic Caucasians, and African Americans.

Drug Interactions

In vitro data: Apremilast is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 and not an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP3A4. Apremilast is a substrate, but not an inhibitor of Pglycoprotein (P-gp) and is not a substrate or an inhibitor of organic anion transporter (OAT)1 and OAT3, organic cation transporter (OCT)2, organic anion transporting polypeptide (OATP)1B1 and OATP1B3, or breast cancer resistance protein (BCRP).

Drug interaction studies were performed with apremilast and CYP3A4 substrates (oral contraceptive containing ethinyl estradiol and norgestimate), CYP3A and P-gp inhibitor (ketoconazole), CYP450 inducer (rifampin) and frequently co-administered drug in this patient population (methotrexate).

No significant pharmacokinetic interactions were observed when 30-mg oral apremilast was administered with either oral contraceptive, ketoconazole, or methotrexate. Co-administration of the CYP450 inducer rifampin (600 mg once daily for 15 days) with a single oral dose of 30-mg apremilast resulted in reduction of apremilast AUC and Cmax by 72% and 43%, respectively [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

Clinical Studies

Psoriatic Arthritis

The safety and efficacy of OTEZLA was evaluated in 3 multi-center, randomized, double-blind, placebo-controlled trials (Studies PsA-1, PsA-2, and PsA-3) of similar design. A total of 1493 adult patients with active PsA ( ≥ 3 swollen joints and ≥ 3 tender joints) despite prior or current treatment with disease-modifying antirheumatic drug (DMARD) therapy were randomized. Patients enrolled in these studies had a diagnosis of PsA for at least 6 months. One qualifying psoriatic skin lesion of at least 2 cm in diameter was required in Study PsA- 3. Previous treatment with a biologic, including TNF-blockers was allowed (up to 10% could be TNF-blocker therapeutic failures). Across the 3 studies, patients were randomly assigned to placebo (n=496), OTEZLA 20 mg (n=500), or OTEZLA 30 mg (n=497) given orally twice daily. Titration was used over the first 5 days [see DOSAGE AND ADMINISTRATION]. Patients were allowed to receive stable doses of concomitant methotrexate [MTX ( ≤ 25 mg/week)], sulfasalazine [SSZ ( ≤ 2 g/day)], leflunomide [LEF ( ≤ 20 mg/day)], low dose oral corticosteroids (equivalent to ≤ 10 mg of prednisone a day), and/or nonsteroidal anti-inflammatory drugs (NSAIDs) during the trial. Treatment assignments were stratified based on small-molecule DMARD use at baseline in Studies PsA-1, PsA-2 and PsA-3. There was an additional stratification of BSA > 3% with psoriasis in study PsA-3. The patients who were therapeutic failures of > 3 agents for PsA (small molecules or biologics), or > 1 biologic TNF blocker were excluded.

The primary endpoint was the percentage of patients achieving American College of Rheumatology (ACR) 20 response at Week 16. Placebo-controlled efficacy data were collected and analyzed through Week 24. Patients whose tender and swollen joint counts had not improved by at least 20% were considered non-responders at Week 16. Placebo non-responders were re-randomized 1:1 in a blinded fashion to either OTEZLA 20 mg twice daily or 30 mg twice daily following the titration schema [see DOSAGE AND ADMINISTRATION]. OTEZLA patients remained on their initial treatment. At Week 24, all remaining placebo patients were re-randomized to either 20 mg twice daily or 30 mg twice daily.

Patients with subtypes of PsA were enrolled across the 3 studies, including symmetric polyarthritis (62.0%), asymmetric oligoarthritis (27.0%), distal interphalangeal (DIP) joint arthritis (6.0%), arthritis mutilans (3.0%), and predominant spondylitis (2.1%). The median duration of PsA disease was 5 years. Patients received concomitant therapy with at least one DMARD (65.0%), MTX (55.0%), SSZ (9.0%), LEF (7.0%), low dose oral corticosteroids (14.0%), and NSAIDs (71.0%). Prior treatment with small-molecule DMARDs only was reported in 76.0% of patients and prior treatment with biologic DMARDs was reported in 22.0% of patients, which includes 9.0% who had failed prior biologic DMARD treatment.

Clinical Response in Patients With Psoriatic Arthritis

The percent of patients achieving ACR 20, 50 and 70 responses in Studies PsA-1, PsA-2, and PsA-3 are presented in Table 4 below. OTEZLA ± DMARDs, compared with Placebo ± DMARDs resulted in a greater improvement in signs and symptoms of psoriatic arthritis as demonstrated by the proportion of patients with an ACR 20 response at Week 16.

Table 4: Proportion of Patients With ACR Responses in Studies PsA-1, PsA-2 and PsA-3

Na PsA-1 PsA-2 PsA-3
Placebo ± DMARDs
N=168
Otezla 30 mg twice daily ± DMARDs
N=168
Placebo ± DMARDs
N=159
Otezla 30 mg twice daily ± DMARDs
N=162
Placebo ± DMARDs
N=169
Otezla 30 mg twice daily ± DMARDs
N=167
ACR 20 Week 16 19% 38%b 19% 32%b 18% 41%b
ACR 50 Week 16 6% 16% 5% 11% 8% 15%
ACR 70 Week 16 1% 4% 1% 1% 2% 4%
a N is number of randomized and treated patients.
b Statistically significantly different from placebo (p < 0.05).

OTEZLA 30 mg twice daily resulted in improvement for each ACR component, compared to placebo at Week 16 in Study PsA-1 (Table 5). Consistent results were observed in Studies PsA-2 and PsA-3.

Table 5: ACR Components Mean Change from Baseline at Week 16 in Study PsA- 1

  Placebo
(N*=168)
OTEZLA 30 mg twice daily
(N*=168)
Number of tender jointsa
  Sample Size 166 164
  Baseline 23 23
  Mean Change at Week 16 -2 -7
Number of swollen jointsb
  Sample Size 166 164
  Baseline 13 13
  Mean Change at Week 16 -2 -5
Patient’s assessment of painc
  Sample Size 165 159
  Baseline 61 58
  Mean Change at Week 16 -6 -14
Patient’s global assessment of disease activityc
  Sample Size 165 159
  Baseline 59 56
  Mean Change at Week 16 -3 -10
Physician’s global assessment of disease activityc
  Sample Size 158 159
  Baseline 55 56
  Mean Change at Week 16 -8 -19
HAQ-DId score
  Sample Size 165 159
  Baseline 1.2 1.2
  Mean Change at Week 16 -0.09 -0.2
CRPe
  Sample Size 166 167
  Baseline 1.1 0.8
  Mean Change at Week 16 0.1 -0.1
Mean changes from baseline are least square means from analyses of covariance.
a Scale 0-78.
b Scale 0-76.
c VAS=Visual Analog Scale; 0=best, 100=worst.
d HAQ-DI = Health Assessment Questionnaire-Disability Index; 0=best, 3=worst; measures the subject's ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity.
e CRP = C-reactive protein; Reference range 0-0.5 mg/Dl
* N reflects randomized patients; actual number of patients evaluable for each endpoint may vary by timepoint.

Treatment with OTEZLA resulted in improvement in dactylitis and enthesitis in patients with pre-existing dactylitis or enthesitis.

Physical Function Response

OTEZLA 30 mg twice daily demonstrated a greater improvement compared to placebo in mean change from baseline for the Health Assessment Questionnaire Disability Index (HAQ-DI) score at Week 16 [-0.244 vs. -0.086, respectively; 95% CI for the difference was (-0.26, -0.06)] in Study PsA-1. The proportions of HAQ-DI responders ( ≥ 0.3 improvement from baseline) at Week 16 for the OTEZLA 30 mg twice daily group were 38%, compared to 27%, for the placebo group in Study PsA-1. Consistent results were observed in Studies PsA-2 and PsA-3.

Psoriasis

Two multicenter, randomized, double-blind, placebo-controlled trials (Studies PSOR-1 and PSOR-2) enrolled a total of 1257 subjects 18 years of age and older with moderate to severe plaque psoriasis [ body surface area (BSA) involvement of ≥ 10%, static Physician Global Assessment (sPGA) of ≥ 3 (moderate or severe disease), Psoriasis Area and Severity Index (PASI) score ≥ 12, candidates for phototherapy or systemic therapy]. Subjects were allowed to use low-potency topical corticosteroids on the face, axilla and groin. Subjects with scalp psoriasis were allowed to use coal tar shampoo and/or salicylic acid scalp preparations on scalp lesions.

Study PSOR-1 enrolled 844 subjects and Study PSOR-2 enrolled 413 subjects. In both studies, subjects were randomized 2:1 to OTEZLA 30 mg BID or placebo for 16 weeks. Both studies assessed the proportion of subjects who achieved PASI-75 at Week 16 and the proportion of subjects who achieved a sPGA score of clear (0) or almost clear (1) at Week 16. Across both studies, subjects ranged in age from 18 to 83 years, with an overall median age of 46 years. The mean baseline BSA involvement was 25.19% (median 21.0%), the mean baseline PASI score was 19.07 (median 16.80), and the proportion of subjects with sPGA score of 3 (moderate) and 4 (severe) at baseline were 70.0% and 29.8%, respectively. Approximately 30% of all subjects had received prior phototherapy and 54% had received prior conventional systemic and/or biologic therapy for the treatment of psoriasis with 37% receiving prior conventional systemic therapy and 30% receiving prior biologic therapy. Approximately one-third of subjects had not received prior phototherapy, conventional systemic nor biologic therapy. A total of 18% of subjects had a history of psoriatic arthritis.

Clinical Response in Subjects with Plaque Psoriasis

The proportion of subjects who achieved PASI -75 responses, and sPGA score of clear (0) or almost clear (1), are presented in Table 6.

Table 6: Clinical Response at Week 16 in Studies PSOR-1 and PSOR-2

Na Study PSOR-1 Study PSOR-2
Placebo
N=282
OTEZLA 30 mg BID
N=562
Placebo
N=137
OTEZLA 30 mg BID
N=274
PASIb -75, n (%) 15 (5.3) 186 (33.1) 8 (5.8) 79 (28.8)
sPGAc of Clear or Almost Clear, n (%) 11 (3.9) 122 (21.7) 6 (4.4) 56 (20.4)
a N is number of randomized and treated patients.
b PASI=Psoriasis Area and Severity Index.
c sPGA=Static Physician Global Assessment.

The median time to loss of PASI-75 response among the subjects re-randomized to placebo at Week 32 during the Randomized Treatment Withdrawal Phase was 5.1 weeks.

Last reviewed on RxList: 10/1/2014
This monograph has been modified to include the generic and brand name in many instances.

A A A

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Women's Health

Find out what women really need.