Otezla Drug Information

Psoriatic Arthritis OTEZLA is indicated for the treatment of adult patients and pediatric patients 6 years of age and older and weighing at least 20 kg with active psoriatic arthritis.

Plaque Psoriasis OTEZLA/OTEZLA XR is indicated for the treatment of adult patients with plaque psoriasis who are candidates for phototherapy or systemic therapy.

Oral Ulcers Associated with Behçet's Disease OTEZLA/OTEZLA XR is indicated for the treatment of adult patients with oral ulcers associated with Behçet's Disease.

Recommended Dosage in Adult and Pediatric Patients with Psoriatic Arthritis, Plaque Psoriasis, and Behçet's Disease Adult Patients with Psoriatic Arthritis, Plaque Psoriasis, or Behçet's Disease The recommended initial dosage titration from Day 1 to Day 5 is shown in Table 1. Following the 5-day titration with OTEZLA, the recommended maintenance dosage is OTEZLA 30 mg twice daily or OTEZLA XR 75 mg once daily taken orally starting on Day 6. This titration is intended to reduce the gastrointestinal symptoms associated with initial therapy.

Table 1. Dosage Titration Schedule for Adult Patients with Psoriatic Arthritis, Plaque Psoriasis, or Behçet's Disease Pediatric Patients 6 Years of Age and Older and Weighing at Least 20 kg with Psoriatic Arthritis Moderate to Severe Plaque Psoriasis The recommended dosage for pediatric patients 6 years of age and older and weighing at least 20 kg with psoriatic arthritis or moderate to severe plaque psoriasis is based on body weight. Table 2.

Switching Between OTEZLA and OTEZLA XR

Patients treated with OTEZLA 30 mg twice daily may be switched to OTEZLA XR 75 mg once daily the day following the last dose of OTEZLA 30 mg.

Dosage Adjustment in Adult and Pediatric Patients with Severe Renal Impairment Adult Patients with Psoriatic Arthritis, Plaque Psoriasis, or Behçet's Disease For initial dosage titration in adult patients with severe renal impairment (creatinine clearance of less than 30 mL per minute estimated by the Cockcroft–Gault equation), titrate OTEZLA using only the AM schedule listed in Table 1 and skip the PM doses. The recommended maintenance dosage in this group is OTEZLA 30 mg once daily. OTEZLA XR is not recommended for adult patients with severe renal impairment; the appropriate dosage for these patients has not been determined.

Pediatric Patients 6 Years of Age and Older and Weighing at Least 20 kg with Psoriatic Arthritis or Moderate to Severe Plaque Psoriasis For initial dosage titration in pediatric patients 6 years of age and older and weighing at least 20 kg with psoriatic arthritis or moderate to severe plaque psoriasis and severe renal impairment (CLcr of less than 30 mL per minute estimated by the Cockcroft–Gault equation), titrate OTEZLA using only the AM schedule listed in Table 2 for the appropriate body weight category and skip the PM doses.

Important Administration Instructions Administer OTEZLA/OTEZLA XR with or without food. Swallow tablets whole. Do not crush, split, or chew.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Psoriatic Arthritis Clinical Trials OTEZLA was evaluated in three multicenter, randomized, double-blind, placebo-controlled trials (PsA-1, PsA-2, and PsA-3) of similar design in adult subjects with active psoriatic arthritis. Across the three trials, there were 1493 subjects randomized equally to placebo, OTEZLA 20 mg twice daily or OTEZLA 30 mg twice daily.

Titration was used over the first 5 days. Placebo subjects whose tender and swollen joint counts had not improved by at least 20% were re-randomized 1:1 in a blinded fashion to either OTEZLA 20 mg twice daily or 30 mg twice daily at week 16 while OTEZLA subjects remained on their initial treatment. Subjects ranged in age from 18 to 83 years, with an overall median age of 51 years.

The majority of the most common adverse reactions presented in Table 3 occurred within the first 2 weeks of treatment and tended to resolve over time with continued dosing. Diarrhea, headache, and nausea were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for subjects taking OTEZLA were nausea (1.8%), diarrhea (1.8%), and headache (1.2%).

The proportion of subjects with psoriatic arthritis who discontinued treatment due to any adverse reaction was 4.6% for subjects taking OTEZLA 30 mg twice daily and 1.2% for placebo-treated subjects. Table 3. Adverse Reactions Reported in ≥ 2% of Adult Subjects with Active Psoriatic Arthritis on OTEZLA 30 mg Twice Daily and ≥ 1% than That Observed in Subjects on Moderate to Severe Plaque Psoriasis Clinical Trials Adverse Reactions from Clinical Trials in Adults The safety of OTEZLA was assessed in 1426 subjects in three randomized, double-blind, placebo-controlled trials in adult subjects with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy.

Table 4. Adverse Reactions Reported in ≥ 1% of Adult Subjects with Moderate to Severe Plaque Psoriasis on OTEZLA and With Greater Frequency Than in Subjects on 0 9 Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) subjects following discontinuation of treatment with OTEZLA. OTEZLA was evaluated in a Phase 3, multicenter, randomized, placebo-controlled trial (PSOR-3) in adults with moderate to severe plaque psoriasis of the scalp.

A total of 302 subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. The proportion of subjects who discontinued treatment because of any adverse reaction during the 16-week placebo-controlled period of the trial was 6% for subjects who received OTEZLA 30 mg twice daily and 3% for subjects who received placebo. Overall, the safety profile observed in the OTEZLA group during the placebo-controlled phase was consistent with the safety profile previously established in adult subjects with moderate to severe plaque psoriasis.

Adverse Reactions from Clinical Trials in Pediatric Subjects 6 to 17 Years of Age OTEZLA was evaluated in a Phase 3, multicenter, randomized, placebo-controlled trial (PSOR-6) in pediatric subjects 6 to 17 years of age with moderate to severe plaque psoriasis. The trial also included a 36-week extension phase during which all subjects received OTEZLA 20 mg or 30 mg twice daily. Overall, the safety profile observed in pediatric subjects treated with OTEZLA during the study was consistent with the safety profile established in adult subjects with moderate to severe plaque psoriasis.

Mild to Moderate Plaque Psoriasis Clinical Trial in Adults OTEZLA was evaluated in a Phase 3, multicenter, randomized, placebo-controlled trial (PSOR-4) in adult subjects with mild to moderate plaque psoriasis. The trial also included an open label extension phase during which all subjects received OTEZLA 30 mg twice daily. Behçet's Disease Clinical Trials OTEZLA was evaluated in a Phase 3, multicenter, randomized, placebo-controlled trial (BCT-002) in adult subjects with Behçet's Disease (BD) with active oral ulcers.

After Week 12, all subjects received treatment with OTEZLA 30 mg twice daily. Subjects ranged in age from 19 to 72, with a mean age of 40 years. The proportion of subjects with BD who discontinued treatment due to any adverse reaction during the placebo-controlled period of the trial, was 2.9% for subjects treated with OTEZLA 30 mg twice daily and 4.9% for placebo-treated subjects.

Table 5. Adverse Reactions Reported in ≥ 5% of Adult Subjects with BD with Active Oral Ulcers on OTEZLA and with at Least 1% Greater Frequency than Subjects on 3 6 Other adverse reactions reported in subjects on OTEZLA in psoriatic arthritis, plaque psoriasis, and Behçet's Disease clinical trials are: Gastrointestinal Disorders: Gastroesophageal reflux disease Immune System Disorders: Hypersensitivity Investigations: Weight decrease Metabolism and Nutrition Disorders: Decreased appetite One subject treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction. Nervous System Disorders: Migraine Respiratory, Thoracic, and Mediastinal Disorders: Cough Skin and Subcutaneous Tissue Disorders: Rash

Strong CYP450 Inducers Co-administration with strong

CYP450 inducers (such as rifampin) decreases apremilast exposure and may result in loss of efficacy of OTEZLA/OTEZLA XR.

Pregnancy Risk Summary Available data with OTEZLA use in pregnant women have not identified a drug-associated risk of major birth defects or adverse maternal or fetal outcomes (see Data ). In animal embryo-fetal development studies, the administration of apremilast to pregnant cynomolgus monkeys during organogenesis resulted in dose-related increases in abortion/embryo-fetal death at dose exposures approximately 2-times the maximum recommended human therapeutic dose (MRHD) and no adverse effect at an exposure of 1.4-times the MRHD. When apremilast was administered to pregnant mice during organogenesis, there were no apremilast-induced malformations up to exposures 4-times the MRHD.

Based on findings from animal reproduction studies, OTEZLA/OTEZLA XR may increase the risk for fetal loss (see Data ). Advise pregnant women of the potential risk of fetal loss. The background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Human Data A pregnancy registry conducted by the Organization of Teratology Information Specialists (OTIS) in the United States and Canada assessed the risk of major birth defects in liveborn infants of women with psoriatic arthritis, psoriasis, or Behçet's Disease exposed to apremilast in the first trimester.

The study compared pregnant women treated with apremilast (n = 15) with disease matched pregnant women who were not exposed to apremilast (n = 106). In the apremilast-exposed cohort, there were no reports of liveborn infants with major birth defects nor miscarriages. One stillbirth was reported in the apremilast exposed cohort.

These data are limited by the small sample size of apremilast-exposed pregnancies. Animal Data In an embryo-fetal developmental study, pregnant cynomolgus monkeys were administered apremilast at doses of mg/kg/day during the period of organogenesis (gestation Days 20 through 50). There was a dose -related increase in spontaneous abortions, with most abortions occurring during Weeks 3 to 4 of dosing in the first trimester, at doses approximately 2-times the MRHD and greater (on an area under the curve basis at doses ≥ 50 mg/kg/day).

No abortifacient effects were observed at a dose approximately 1.4-times the MRHD (on an AUC basis at a dose of 20 mg/kg/day). Although there was no evidence for a teratogenic effect at doses of 20 mg/kg/day and greater when examined at Day 100, aborted fetuses were not examined. In a combined fertility and embryo-fetal development study in mice, apremilast was administered at doses of mg/kg/day starting 15 days before cohabitation and continuing through GD 15.

No teratogenic findings attributed to apremilast were observed in either study; however, there was an increase in post-implantation loss at doses corresponding to a systemic exposure of approximately 2-times the MRHD and greater (≥ 20 mg/kg/day). At doses of ≥ 20 mg/kg/day skeletal variations included incomplete ossification sites of tarsals, skull, sternebra, and vertebrae. No effects were observed at a dose approximately 1.3-times the MRHD (10 mg/kg/day).

Apremilast distributed across the placenta into the fetal compartment in mice and monkeys. Dystocia, reduced viability, and reduced birth weights occurred at doses corresponding to ≥ 4-times the MRHD (on an AUC basis at doses ≥ 80 mg/kg/day). No adverse effects occurred at a dose 1.3-times the MRHD (10 mg/kg/day).

There was no evidence for functional impairment of physical development, behavior, learning ability, immune competence, or fertility in the offspring at doses up to 7.5-times the MRHD (on an AUC basis at a dose of 300 mg/kg/day).

Pediatric Use OTEZLA Plaque Psoriasis The safety and effectiveness of OTEZLA have been established in pediatric patients 6 years of age and older and weighing at least 20 kg with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Use of OTEZLA in these patients is supported by evidence from a 52-week adequate and well-controlled clinical trial (PSOR-6) in 245 pediatric subjects 6 years of age and older with moderate to severe plaque psoriasis. Weight loss in OTEZLA-treated pediatric subjects was comparable to weight loss observed in adults.

Closely monitor growth (height and weight) in pediatric patients treated with OTEZLA. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted. The safety and effectiveness of OTEZLA have not been established in pediatric patients below the age of 6 years or weighing less than 20 kg with moderate to severe plaque psoriasis.

Use of OTEZLA in these patients is supported by evidence from adequate and well controlled trials of OTEZLA in adults with psoriatic arthritis, pharmacokinetic data from adult patients with psoriatic arthritis, adult patients with psoriasis, and pediatric patients with psoriasis, and safety data from a clinical trial in 245 pediatric patients 6 years of age and older with psoriasis. Steady-state exposure of OTEZLA in pediatric patients with psoriatic arthritis is estimated to be comparable to adults with psoriatic arthritis and pediatric patients with psoriasis. Behçet's Disease The safety and effectiveness of OTEZLA have not been established in pediatric patients with psoriatic arthritis or oral ulcers associated with Behçet's Disease.

OTEZLA XR Plaque Psoriasis and Psoriatic Arthritis The safety and effectiveness of OTEZLA XR have been established for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis in pediatric patients 6 years of age and older and weighing at least 50 kg. Use of OTEZLA XR in these patients is supported by pharmacokinetic data from healthy adults demonstrating comparable PK exposure between OTEZLA XR 75 mg once daily and OTEZLA 30 mg twice daily, which is the recommended OTEZLA dosage for pediatric patients weighing at least 50 kg.

OTEZLA/OTEZLA XR is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation.