Adult Patients with Psoriatic Arthritis, Plaque Psoriasis, or Behçet's Disease

The recommended initial dosage titration of OTEZLA from Day 1 to Day 5 is shown in Table 1. Following the 5-day titration, the recommended maintenance dosage is 30 mg twice daily taken orally starting on Day 6. This titration is intended to reduce the gastrointestinal symptoms associated with initial therapy.

Pediatric Patients 6 Years of Age and Older and Weighing at Least 20 kg with Moderate to Severe Plaque Psoriasis

The recommended dosage for pediatric patients 6 years of age and older and weighing at least 20 kg with moderate to severe plaque psoriasis is based on body weight. Following the appropriate initial titration schedule shown in Table 2, the recommended maintenance dosage of OTEZLA taken orally is 30 mg twice daily for pediatric patients who weigh at least 50 kg and 20 mg twice daily for pediatric patients who weigh from 20 kg to less than 50 kg. This titration is intended to reduce the gastrointestinal symptoms associated with initial therapy.

Adult Patients with Psoriatic Arthritis, Plaque Psoriasis, or Behçet's Disease

For initial dosage titration in adult patients with severe renal impairment (creatinine clearance [CLcr] 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. Reduce OTEZLA maintenance dosage to 30 mg once daily in this group [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Pediatric Patients 6 Years of Age and Older and Weighing at Least 20 kg with 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 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. Reduce the OTEZLA maintenance dosage to 30 mg once daily for pediatric patients who weigh at least 50 kg and to 20 mg once daily for pediatric patients who weigh 20 kg to less than 50 kg [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Psoriatic Arthritis: During the 16-week placebo-controlled period of the 3 controlled clinical trials, 1.0% (10/998) of subjects treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1441) of subjects treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated subjects (0/495). Depression was reported as serious in 0.2% (3/1441) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1441) of subjects while receiving OTEZLA, compared to none in placebo treated subjects (0/495). In the clinical trials, 2 subjects who received placebo committed suicide compared to none in OTEZLA-treated subjects.

Plaque Psoriasis: During the 16-week placebo-controlled period of the 3 controlled clinical trials in adult subjects with moderate to severe plaque psoriasis, 1.3% (12/920) of subjects treated with OTEZLA reported depression compared to 0.4% (2/506) treated with placebo. During the clinical trials, 0.1% (1/1308) of subjects treated with OTEZLA discontinued treatment due to depression compared with none in placebo-treated subjects (0/506). Depression was reported as serious in 0.1% (1/1308) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/506). Instances of suicidal behavior have been observed in 0.1% (1/1308) of subjects while receiving OTEZLA, compared to 0.2% (1/506) in placebo-treated subjects. In the clinical trials, one subject treated with OTEZLA attempted suicide while one who received placebo committed suicide.

During the 16-week placebo-controlled period of the clinical trial in adults with mild to moderate plaque psoriasis, the incidence of subjects reporting depression was similar to what was observed in the adult moderate to severe plaque psoriasis trials.

Behçet's Disease: During the placebo-controlled period of the phase 3 trial, 1% (1/104) of subjects treated with OTEZLA reported depression/depressed mood compared to 1% (1/103) treated with placebo. None of these reports of depression was serious or led to discontinuation from the trial. No instances of suicidal ideation or behavior were reported during the placebo-controlled period of the phase 3 trial in subjects treated with OTEZLA (0/104) or treated with placebo (0/103).

Weight Loss in Adult Patients

During the placebo-controlled period of the trials in psoriatic arthritis (PsA), weight decrease between 5%-10% of body weight was reported in 10% (49/497) of subjects treated with OTEZLA 30 mg twice daily compared to 3.3% (16/495) treated with placebo.

During the placebo-controlled period of the trials in adults with moderate to severe plaque psoriasis, weight decrease between 5%-10% of body weight occurred in 12% (96/784) of subjects treated with OTEZLA compared to 5% (19/382) treated with placebo. Weight decrease of ≥ 10% of body weight occurred in 2% (16/784) of subjects treated with OTEZLA 30 mg twice daily compared to 1% (3/382) subjects treated with placebo.

During the placebo-controlled period of the clinical trial in adults with mild to moderate plaque psoriasis, weight decrease was similar to what was observed in the trials of adults with moderate to severe plaque psoriasis.

During the placebo-controlled period of the phase 3 trial in Behçet's Disease, weight decrease > 5% of body weight was reported in 4.9% (5/103) of subjects treated with OTEZLA 30 mg twice daily compared to 3.9% (4/102) subjects treated with placebo.

Weight Loss in Pediatric Patients

During the placebo-controlled period of the clinical trial in pediatric subjects 6 to 17 years of age with moderate to severe plaque psoriasis, weight decrease between 5%-10% of body weight occurred in 12% (19/163) of pediatric subjects treated with OTEZLA compared to 2.5% (2/80) of pediatric subjects treated with placebo. Weight decrease of ≥ 10% of body weight occurred in 1% (1/163) of pediatric subjects treated with OTEZLA twice daily compared to 0% (0/80) of pediatric subjects treated with placebo.

Closely monitor growth (height and weight) in OTEZLA-treated pediatric patients. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted.

Psoriatic Arthritis Clinical Trials

OTEZLA was evaluated in 3 multicenter, randomized, double-blind, placebo-controlled trials (PsA-1, PsA-2, and PsA-3) of similar design in adult subjects with active psoriatic arthritis [see Clinical Studies (14.1)]. Across the 3 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 [see Dosage and Administration (2.1)]. 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.

Moderate to Severe Plaque Psoriasis Clinical Trials

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 [see Clinical Studies (14.3)]. A total of 595 subjects were randomized to receive OTEZLA 30 mg twice daily (297 subjects) or placebo twice daily (298 subjects) during the placebo-controlled phase of the trial. The trial also included an open label extension phase during which all subjects received OTEZLA 30 mg twice daily. 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.

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 [see Clinical Studies (14.4)]. A total of 207 subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1)]. 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.

Diarrhea, nausea, headache, and upper respiratory tract infection were the most commonly reported adverse reactions (see Table 5). 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.

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 appetite1
• Nervous System Disorders: Migraine
• Respiratory, Thoracic, and Mediastinal Disorders: Cough
• Skin and Subcutaneous Tissue Disorders: Rash

1

1 subject treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to OTEZLA during pregnancy. Information about the registry can be obtained by calling 1-877-311-8972 or visiting https://mothertobaby.org/ongoing-study/otezla/.

Risk Summary

Available pharmacovigilance data with OTEZLA use in pregnant women have not established a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes, but these data are extremely limited. Based on findings from animal reproduction studies, OTEZLA may increase the risk for fetal loss. 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 2.1-times the maximum recommended human therapeutic dose (MRHD) and no adverse effect at an exposure of 1.4-times the MRHD. When administered to pregnant mice, during organogenesis there were no apremilast-induced malformations up to exposures 4.0-times the MRHD (see Data). Advise pregnant women of the potential risk of fetal loss. Consider pregnancy planning and prevention for females of reproductive potential.

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 2-4% and 15-20%, respectively.

Data

Risk Summary

There are no data on the presence of apremilast in human milk, the effects on the breastfed infant, or the effects on milk production. However, apremilast was detected in the milk of lactating mice. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for OTEZLA and any potential adverse effects on the breastfed infant from OTEZLA or from the underlying maternal condition.

Data

In mice, following a single oral administration of 10 mg/kg to dams on postpartum Day 13, apremilast concentrations in milk were approximately 1.5-times that of simultaneously collected blood samples.

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 to 17 years of age with moderate to severe plaque psoriasis. Weight loss in OTEZLA-treated pediatric subjects was comparable to weight loss observed in adults. [see Warnings and Precautions (5.4), Adverse Reactions (6.1) and Clinical Studies (14.3)].

Closely monitor growth (height and weight) in OTEZLA-treated pediatric patients. 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.

Psoriatic Arthritis and 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.

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 radiolabeled 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

Drug Interactions

Clinical Response in Subjects with Psoriatic Arthritis

The percent of subjects achieving ACR 20, 50 and 70 responses in Trials PsA-1, PsA-2, and PsA-3 are presented in Table 6 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 subjects with an ACR 20 response at Week 16.

OTEZLA 30 mg twice daily resulted in improvement for each ACR component, compared to placebo at Week 16 in Trial PsA-1 (Table 7). Consistent results were observed in Trials PsA-2 and PsA-3.

Treatment with OTEZLA resulted in improvement in dactylitis and enthesitis in subjects 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 (HAQDI) score at Week 16 [0.244 vs. 0.086, respectively; 95% CI for the difference was (0.26, 0.06)] in Trial PsA1. The proportions of HAQDI 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 Trial PsA1. Consistent results were observed in Trials PsA2 and PsA3.

Clinical Response in Adult Subjects with Moderate to Severe Plaque Psoriasis

The proportion of subjects who achieved PASI-75 responses, and an sPGA score of clear (0) or almost clear (1), are presented in Table 8.

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.

Plaque Psoriasis Involving the Scalp Area

A randomized, double-blind, placebo-controlled trial (PSOR-3 [NCT03123471]) was conducted in 303 adult subjects with moderate to severe plaque psoriasis of the scalp. Enrolled subjects had a Scalp Physician Global Assessment (ScPGA) score of ≥ 3, Scalp Surface Area (SSA) involvement of ≥ 20%, an inadequate response or intolerance to at least one topical therapy for plaque psoriasis of the scalp, and moderate to severe plaque psoriasis (BSA involvement of ≥ 10%, sPGA of ≥ 3 [moderate or severe disease], and PASI score ≥ 12).

Subjects were randomized 2:1 to receive either OTEZLA 30 mg twice daily (n =201) or placebo twice daily (n = 102) for 16 weeks. The primary endpoint was the proportion of subjects who achieved an ScPGA response at Week 16 (defined as ScPGA score of clear [0] or almost clear [1] with at least a 2-point reduction from baseline at Week 16). Secondary endpoints included the proportion of subjects with Whole Body Itch Numeric Rating Scale (NRS) response (defined as ≥ 4-point reduction from baseline) and the proportion of subjects with a Scalp Itch NRS response (defined as ≥ 4-point reduction from baseline).

Subjects had a mean age of 46.9 years, 61.7% were men and 75.6 % were white. At baseline, 76.9% of subjects had moderate plaque psoriasis of the scalp (ScPGA of 3), 23.1% had severe plaque psoriasis of the scalp (ScPGA of 4), 71.6% of subjects were biologic naïve, and 58.8% had failed 1 or 2 topical treatments. At baseline, the mean Whole Body Itch NRS score was 7.2 and the mean Scalp Itch NRS score was 6.7 with the scales ranging from 0 to 10. The mean baseline SSA involvement was 60.6% and the mean baseline BSA involvement was 19.8%.

The proportion of subjects who achieved an ScPGA response, Whole Body Itch NRS response, and Scalp Itch NRS response at Week 16 are presented in Table 9.

Figure 1 displays the proportion of subjects achieving Whole Body Itch NRS response at each visit, while Figure 2 displays the proportion of subjects achieving Scalp Itch NRS response at each visit.

Figure 1: Proportion (± SE) of Subjects Achieving Whole Body Itch NRS Response through Week 16

NRS = Numeric Rating Scale; SE = standard error

Figure 2: Proportion (± SE) of Subjects Achieving Scalp Itch NRS Response through Week 16

NRS = Numeric Rating Scale; SE = standard error

Plaque Psoriasis Involving the Genital Area

A randomized, double-blind, placebo-controlled trial (PSOR-5 [NCT03777436]) was conducted in 289 adult subjects with moderate to severe plaque psoriasis of the genital area. Subjects had a modified static Physician Global Assessment of Genitalia (sPGA-G) score of ≥ 3 (moderate or severe), sPGA score of ≥ 3 (moderate or severe), and had an inadequate response or were intolerant to topical therapy for the treatment of plaque psoriasis of the genital area.

Subjects were randomized 1:1 to receive either apremilast 30 mg twice daily (n = 143) or placebo twice daily (n = 146) for 16 weeks. At Week 16, the placebo group was switched to receive OTEZLA and the OTEZLA group remained on drug through Week 32. The primary endpoint was the proportion of subjects who achieved a modified sPGA-G response (defined as a score of clear [0] or almost clear [1] with at least a 2-point reduction from baseline) at Week 16. Secondary endpoints included the proportion of subjects who achieved an sPGA response (defined as a score of clear [0] or almost clear [1] with at least a 2-point reduction from baseline) at Week 16 and the proportion of subjects who achieved at least a 4-point improvement in the 11-point Genital Psoriasis Itch Numeric Rating Scale (GPI-NRS) item score within the Genital Psoriasis Symptoms Scale (GPSS) at Week 16, among subjects with a baseline GPI-NRS score of ≥ 4.

Subjects ranged in age from 18-81 years, with a median age of 44 years. The proportions of subjects with a modified sPGA-G score of 3 (moderate) and 4 (severe) at baseline were 86.9% and 13.1%, respectively. The proportions of subjects with a sPGA score of 3 (moderate) and 4 (severe) at baseline were 88.6% and 11.1%, respectively. Baseline BSA involvement was < 10% for 57.4% of the subjects and ≥ 10% for 42.6% of the subjects. The mean baseline GPI-NRS score was 6.5. Of the enrolled subjects, 78.9% did not receive prior conventional systemic therapy and 84.4% were biologic-naïve.

The proportions of subjects who achieved a modified sPGA-G response, sPGA response, and GPI-NRS response are presented in Table 10.

Clinical Response in Pediatric Subjects 6 to 17 Years of Age and Weighing at Least 20 kg with Moderate to Severe Plaque Psoriasis

The proportions of subjects who achieved sPGA response and PASI-75 response at Week 16 are presented in Table 11.

Clinical Response in Subjects with Mild to Moderate Plaque Psoriasis

The proportions of subjects who achieved an sPGA response, Whole Body Itch NRS response, and an ScPGA response at Week 16 are presented in Table 12.

Measures of Oral Ulcers

Improvements in measures of oral ulcers at Week 12 are presented in Table 13.

Figure 3 displays the mean number of oral ulcers for each treatment group at each visit, while Figure 4 displays the mean oral ulcer pain on a visual analog scale for each treatment group at each visit.

Figure 3: Mean (± SE) Number of Oral Ulcers by Time Point Through Week 12 (ITT Population)

Figure 4: Mean (± SE) Oral Ulcer Pain on a Visual Analog Scale by Time Point Through Week 12 (ITT Population)