Otezla

Patient Information

Administration Instructions

Instruct patients to take OTEZLA only as prescribed.

Advise patients that OTEZLA can be taken with or without food, and that the tablets should not be crushed, split, or chewed [see DOSAGE AND ADMINISTRATION].

Hypersensitivity

Inform patients that hypersensitivity reactions can occur following administration of OTEZLA. Instruct patients to contact their healthcare provider if they experience symptoms of an allergic reaction [see WARNINGS AND PRECAUTIONS].

Diarrhea, Nausea, And Vomiting

Advise patients of the potential complications of severe diarrhea, nausea, or vomiting and instruct them to contact their healthcare provider if they experience these adverse reactions, especially if the patient is 65 years of age or older [see WARNINGS AND PRECAUTIONS].

Depression

Inform patients that treatment with OTEZLA is associated with an increased incidence of depression. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider [see WARNINGS AND PRECAUTIONS].

Weight Decrease

Instruct patients to have their weight monitored regularly and, if unexplained or clinically significant weight loss occurs, to contact their healthcare provider for evaluation of the weight loss [see WARNINGS AND PRECAUTIONS].

Pregnancy

Inform patients that there is a pregnancy registry for pregnant women who have taken OTEZLA during pregnancy. Advise patients to contact the registry at 1-877-311-8972 to enroll or visit https://mothertobaby.org/ongoing-study/otezla/ [see Use In Specific Populations]. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their prescriber of a known or suspected pregnancy.

Description

The active ingredient in OTEZLA tablets is apremilast. Apremilast is a phosphodiesterase 4 (PDE4) inhibitor. Apremilast is known chemically as N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide. Its empirical formula is C₂₂H₂₄N₂O₇S and the molecular weight is 460.5.

The chemical structure is:

 

 

OTEZLA tablets are supplied in 10-, 20-, and 30-mg strengths for oral administration. Each tablet contains apremilast as the active ingredient and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide red, iron oxide yellow (20 and 30 mg only) and iron oxide black (30 mg only).

Indications

Psoriatic Arthritis

OTEZLA is indicated for the treatment of adult patients with active psoriatic arthritis.

Plaque Psoriasis

OTEZLA 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 is indicated for the treatment of adult patients with oral ulcers associated with Behçet’s Disease.

Dosage And Administration

Dosage In Psoriatic Arthritis, Plaque Psoriasis, And 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.

OTEZLA can be administered without regard to meals. Do not crush, split, or chew the tablets.

Table 1: Dosage Titration Schedule

Day 1	Day 2		Day 3		Day 4		Day 5		Day 6 & thereafter
AM	AM	PM	AM	PM	AM	PM	AM	PM	AM	PM
10 mg	10 mg	10 mg	10 mg	20 mg	20 mg	20 mg	20 mg	30 mg	30 mg	30 mg

 

Dosage Adjustment In Patients With Severe Renal Impairment

OTEZLA dosage should be reduced to 30 mg once daily in patients with severe renal impairment (creatinine clearance (CLcr) of less than 30 mL per minute estimated by the Cockcroft–Gault equation) [see Use In Specific Populations and CLINICAL PHARMACOLOGY]. For initial dosage titration in this group, it is recommended that OTEZLA be titrated using only the AM schedule listed in Table 1 and the PM doses be skipped.

How Supplied

Dosage Forms And Strengths

OTEZLA is available as diamond shaped, film coated tablets in the following dosage strengths:

• 10-mg pink tablet engraved with “APR” on one side and “10” on the other side
• 20-mg brown tablet engraved with “APR” on one side and “20” on the other side
• 30-mg beige tablet engraved with “APR” on one side and “30” on the other side

OTEZLA is available as diamond-shaped, film-coated tablets in the following dosage strengths: 10-mg pink tablet engraved with “APR” on one side and “10” on the other side; 20-mg brown tablet engraved with “APR” on one side and “20” on the other side; 30-mg beige tablet engraved with “APR” on one side and “30” on the other side.

Tablets are supplied in the following strengths and package configurations:

 

Package configuration	Tablet strength	NDC number
Bottles of 60	30 mg	55513-137-60 59572-631-06
Bottles of 500	30 mg	55513-137-50
Two-week starter pack	13 -ta blet blister titration pack containing: (4) 10-mg, (4) 20-mg, and (5) 3 0-mg tablets with an additional (14) 30-mg ta blets	59572-630-27
28-count carton	Two 30-mg blister ca rds containing (14) 30-mg ta blets	55513-137-28 59572-631-28
28-day starter pack	13 -ta blet blister titration pack containing: (4) 10-mg, (4) 20-mg, and (5) 3 0-mg tablets with an additional (42) 30-mg ta blets	55513-369-55 59572-632-55

 

Storage And Handling

Store tablets below 30°C (86°F).

Manufactured for: Amgen Inc., Thousand Oaks, CA 91320-1799 U.S.A. Revised: Dec 2021

The following adverse reactions are described elsewhere in the labeling:

• Hypersensitivity [see WARNINGS AND PRECAUTIONS]
• Diarrhea, Nausea, and Vomiting [see WARNINGS AND PRECAUTIONS]
• Depression [see WARNINGS AND PRECAUTIONS]
• Weight Decrease [see WARNINGS AND PRECAUTIONS]
• Drug Interactions [see WARNINGS AND PRECAUTIONS]

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 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]. 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]. 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 2 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 2: Adverse Reactions Reported in ≥ 2% of Subjects on OTEZLA 30 mg Twice Daily and ≥ 1% Than That Observed in Subjects on Placebo up to Day 112 (Week 16)

Adverse Reactions	Placebo		OTEZLA 30 mg BID*
	Day 1 to 5 (N = 495)† n(%)	Day 6 to Day 112 (N = 490) n(%)	Day 1 to 5 (N = 497) n(%)	Day 6 to Day 112 (N = 493) n(%)
Diarrhea ‡	6(1.2)	8(1.6)	46 (9.3)	38 (7.7)
Nausea‡	7(1.4)	15 (3.1)	37 (7.4)	44 (8.9)
Headache‡	9(1.8)	11 (2.2)	24 (4.8)	29 (5.9)
Upper respira tory tract infection§	3 (0.6)	9(1.8)	3 (0.6)	19 (3.9)
Vomiting‡	2 (0.4)	2(0.4)	4(0.8)	16 (3.2)
Nasopharyngitis§	1 (0.2)	8(1.6)	1 (0.2)	13 (2.6)
Abdominal pain upper§	0(0.0)	1 (0.2)	3 (0.6)	10 (2.0)
*BID = twice daily. †n (%) indicates number of subjects and percent. ‡Of the reported gastrointestinal adverse reactions, 1 subject experienced a serious adverse reaction of nausea and vomiting in OTEZLA 30 mg twice daily; 1 subject treated with OTEZLA 20 mg twice daily experienced a serious adverse reaction of diarrhea; 1 subject treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction of headache. § Of the reported adverse drug reactions none were serious.

 

Moderate To Severe Plaque Psoriasis Clinical Trials

The safety of OTEZLA was assessed in 1426 subjects in 3 randomized, double-blind, placebo-controlled trials in adult subjects with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy. 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]. Subjects ranged in age from 18 to 83 years, with an overall median age of 46 years.

Diarrhea, nausea, and upper respiratory tract infection were the most commonly reported adverse reactions (see Table 3). The most common adverse reactions leading to discontinuation for subjects taking OTEZLA were nausea (1.6%), diarrhea (1.0%), and headache (0.8%). The proportion of subjects with plaque psoriasis who discontinued treatment due to any adverse reaction was 6.1% for subjects treated with OTEZLA 30 mg twice daily and 4.1% for placebo-treated subjects.

Table 3: Adverse Reactions Reported in ≥ 1% of Subjects on OTEZLA and With Greater Frequency Than in Subjects on Placebo up to Day 112 (Week 16)

Adverse Reactions	Placebo (N=506) n (%)	OTEZLA 30 mg BID* (N=920) n (%)
Diarrhea	32 (6)	160 (17)
Nausea	35 (7)	155 (17)
Upper respiratory tract infection	31 (6)	84 (9)
Tension headache	21 (4)	75 (8)
Headache	19 (4)	55 (6)
Abdominal pain†	11 (2)	39 (4)
Vomiting	8 (2)	35 (4)
Fatigue	9 (2)	29 (3)
Dyspepsia	6 (1)	29 (3)
Decreased appetite	5 (1)	26 (3)
Insomnia	4 (1)	21 (2)
Back pain	4 (1)	20 (2)
Migraine	5 (1)	19 (2)
Frequent bowel movements	1 (0)	17 (2)
Depression	2 (0)	12 (1)
Bronchitis	2 (0)	12 (1)
Tooth abscess	0 (0)	10 (1)
Folliculitis	0 (0)	9 (1)
Sinus headache	0 (°)	9 (1)
*BID = twice daily. † Two subjects treated with OTEZLA experienced serious adverse reaction of abdominal pain.

 

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 [see Clinical Studies]. A total of 302 subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. The most commonly reported adverse reactions that occurred at a higher rate in the OTEZLA group than in the placebo group were: diarrhea (31% vs. 11%), nausea (22% vs. 6%), headache (12% vs. 5%), and vomiting (6% vs. 2%). 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. Gastrointestinal adverse reactions that led to discontinuation of treatment were diarrhea (3% vs. 0%), nausea (1.5% vs. 1%), and vomiting (1.5% vs. 0 %) in the OTEZLA group compared to placebo.

Mild To Moderate Plaque Psoriasis Clinical Trial

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]. 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]. 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]. 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 4). 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 4: Adverse Reactions Reported in ≥ 5% of Subjects on OTEZLA and with at least 1% Greater Frequency than Subjects on Placebo up to Week 12

Adverse Reactions	Placebo (N=103) n (%)	OTEZLA 30 mg twice daily (N=104) n (%)
Diarrhea*	21 (20.4)	43 (41.3)
Nausea*	11 (10.7)	20 (19.2)
Headache	11 (10.7)	15 (14.4)
Upper respiratory tract infection	5 (4.9)	12 (11.5)
Abdominal pain upper	2(1.9)	9(8.7)
Vomiting*	2(1.9)	9(8.7)
Back pain	6 (5.8)	8 (7.7)
Viral upper respiratory tract infection	5 (4.9)	7(6.7)
Arthralgia	3 (2.9)	6 (5.8)
* There were no serious adverse reactions of diarrhea, nausea or vomiting.

 

Other adverse reactions reported in subjects on OTEZLA in psoriatic arthritis, plaque psoriasis, and Behcet’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

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

Drug Interactions

Strong CYP450 Inducers

Apremilast exposure is decreased when OTEZLA is co-administered with strong CYP450 inducers (such as rifampin) and may result in loss of efficacy [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Included as part of the PRECAUTIONS section.

Precautions

Hypersensitivity

Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported during post marketing surveillance. Avoid the use of OTEZLA in patients with known hypersensitivity to apremilast or to any of the excipients in the formulation. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue OTEZLA and institute appropriate therapy.

Diarrhea, Nausea, And Vomiting

There have been reports of severe diarrhea, nausea, and vomiting associated with the use of OTEZLA. Most events occurred within the first few weeks of treatment. In some cases, patients were hospitalized. Patients 65 years of age or older and patients taking medications that can lead to volume depletion or hypotension may be at a higher risk of complications from severe diarrhea, nausea, or vomiting. Monitor patients who are more susceptible to complications of diarrhea or vomiting. Patients who reduced dosage or discontinued OTEZLA generally improved quickly. Consider OTEZLA dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting.

Depression

Treatment with OTEZLA is associated with an increased incidence of depression. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with OTEZLA. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur.

Psoriatic Arthritis

During the 0 to 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 0 to 16-week placebo-controlled period of the 3 controlled clinical trials in 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 0 to 16-week placebo-controlled period of the mild to moderate plaque psoriasis clinical trial, the incidence of subjects reporting depression was similar to what was observed in the 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 Decrease

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 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 mild to moderate plaque psoriasis clinical trial, weight decrease was similar to what was observed in the moderate to severe plaque psoriasis trials.

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.

Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered [see ADVERSE REACTIONS].

Drug Interactions

Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of OTEZLA. Therefore, the use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not recommended [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term studies were conducted in mice and rats with apremilast to evaluate its carcinogenic potential. No evidence of apremilast-induced tumors was observed in mice at oral doses up to 8.8-times the Maximum Recommended Human Dose (MRHD) on an AUC basis (1000 mg/kg/day) or in rats at oral doses up to approximately 0.08- and 1.1-times the MRHD, (20 mg/kg/day in males and 3 mg/kg/day in females, respectively).

Apremilast tested negative in the Ames assay, in vitro chromosome aberration assay of human peripheral blood lymphocytes, and the in vivo mouse micronucleus assay.

In a fertility study of male mice, apremilast at oral doses up to approximately 3-times the MRHD based on AUC (up to 50 mg/kg/day) produced no effects on male fertility. In a fertility study of female mice, apremilast was administered at oral doses of 10, 20, 40, or 80 mg/kg/day. At doses ≥ 1.8- times the MRHD (≥ 20 mg/kg/day), estrous cycles were prolonged, due to lengthening of diestrus which resulted in a longer interval until mating. Mice that became pregnant at doses of 20 mg/kg/day and greater also had increased incidences of early postimplantation losses. There was no effect of apremilast approximately 1.0-times the MRHD (10 mg/kg/day).

Use In Specific Populations

Pregnancy

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

Animal Data

In an embryo-fetal developmental study, pregnant cynomolgus monkeys were administered apremilast at doses of 20, 50, 200, or 1000 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 2.1-times the MRHD and greater (on an area under the curve [AUC] 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 an embryo-fetal development study in mice, apremilast was administered at doses of 250, 500, or 750 mg/kg/day to dams during organogenesis (gestation Day 6 through 15). In a combined fertility and embryo-fetal development study in mice, apremilast was administered at doses of 10, 20, 40, or 80 mg/kg/day starting 15 days before cohabitation and continuing through gestation Day 15. No teratogenic findings attributed to apremilast were observed in either study; however, there was an increase in postimplantation loss at doses corresponding to a systemic exposure of 2.3-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.

In a pre-and post-natal study in mice, apremilast was administered to pregnant female mice at doses of 10, 80, or 300 mg/kg/day from Day 6 of gestation through Day 20 of lactation, with weaning on Day 21. Dystocia, reduced viability, and reduced birth weights occurred at doses corresponding to ≥ 4.0-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).

Lactation

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.

Pediatric Use

The safety and effectiveness of OTEZLA in pediatric patients less than 18 years of age have not been established.

Geriatric Use

Of the 1493 patients who enrolled in Trials PsA-1, PsA-2, and PsA-3, a total of 146 psoriatic arthritis patients were 65 years of age and older, including 19 patients 75 years and older. No overall differences were observed in the safety profile of geriatric patients ≥ 65 years of age and younger adult patients < 65 years of age in the clinical trials.

Of the 1257 subjects who enrolled in two placebo-controlled plaque psoriasis trials (PSOR 1 and PSOR 2), a total of 108 plaque psoriasis patients were 65 years of age and older, including 9 patients who were 75 years of age and older. No overall differences were observed in the safety or effectiveness in geriatric patients ≥ 65 years of age and younger adult patients < 65 years of age in the clinical trials.

Because patients 65 years of age or older may be at a higher risk of complications such as volume depletion or hypotension from severe diarrhea, nausea, or vomiting, monitor geriatric patients closely for such complications [see WARNINGS AND PRECAUTIONS].

Renal Impairment

Apremilast pharmacokinetics were characterized in subjects with mild, moderate, and severe renal impairment as defined by a creatinine clearance of 60-89, 30-59, and less than 30 mL per minute, respectively, by the Cockcroft–Gault equation. While no dosage adjustment is needed in patients with mild or moderate renal impairment, the dosage of OTEZLA should be reduced to 30 mg once daily in patients with severe renal impairment [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Hepatic Impairment

Apremilast pharmacokinetics were characterized in subjects with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment. No dosage adjustment is necessary in these patients.

No Information provided

Contraindications

OTEZLA is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation [see ADVERSE REACTIONS].

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 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

Patients With Hepatic Impairment

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

Patients With Renal Impairment

The pharmacokinetics of apremilast is not affected by mild or moderate renal impairment. In 8 subjects with severe renal impairment administered a single dose of 30 mg apremilast, the AUC and C of apremilast increased by approximately 88% and 42%, respectively [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

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 trials 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 P-glycoprotein (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 trials 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 C 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 multicenter, randomized, double-blind, placebo-controlled trials (PsA-1 [NCT01172938], PsA-2 [NCT01212757], and PsA-3 [NCT01212770]) of similar design. A total of 1493 adult subjects with active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite prior or current treatment with disease-modifying antirheumatic drug (DMARD) therapy were randomized. Subjects enrolled in these trials 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 Trial PsA-3. Previous treatment with a biologic, including TNF-blockers was allowed (up to 10% could be TNF-blocker therapeutic failures). Across the 3 trials, subjects 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]. Subjects 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 Trials PsA-1, PsA-2 and PsA-3. There was an additional stratification of body surface area (BSA) > 3% with psoriasis in Trial PsA-3. The subjects 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 subjects achieving American College of Rheumatology (ACR) 20 response at Week 16. Placebocontrolled efficacy data were collected and analyzed through Week 24. Subjects 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 subjects remained on their initial treatment. At Week 24, all remaining placebo subjects were re-randomized to either 20 mg twice daily or 30 mg twice daily.

Subjects with subtypes of PsA were enrolled across the 3 trials, 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. Subjects 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 subjects and prior treatment with biologic DMARDs was reported in 22.0% of subjects, which includes 9.0% who had failed prior biologic DMARD treatment.

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 5 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.

Table 5: Proportion of Subjects With ACR Responses in Trials PsA-1, PsA-2 and PsA-3

N*	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% †	19%	32% †	18%	41% †
ACR 50 Week 16	6%	16%	5%	11%	8%	15%
ACR 70 Week 16	1%	4%	1%	1%	2%	4%
*N is number of randomized and treated subjects. † 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 Trial PsA-1 (Table 6). Consistent results were observed in Trials PsA-2 and PsA-3.

Table 6: ACR Components Mean Change from Baseline at Week 16 in Trial PsA- 1

	Placebo (N*=168)	OTEZLA30 mg twice daily (N*=168)
Number of tender joints†
Sample Size	166	164
Ba seline	23	23
Mean Change at Week 16	-2	-7
Number of swollen joints‡
Sample Size	166	164
Baseline	13	13
Mean Change at Week 16	-2	-5
Patient’s assessment of pain§
Sample Size	165	159
Ba seline	61	58
Mean Change at Week 16	-6	-14
Patient’s global assessment of disease activity§
Sample Size	165	159
Ba seline	59	56
Mean Change at Week 16	-3	-10
Physician’s global assessment of disease activity§
Sample Size	158	159
Ba seline	55	56
Mean Change at Week 16	-8	-19
HAQ-DI¶ score
Sample Size	165	159
Ba seline	1.2	1.2
Mean Change at Week 16	-0.09	-0.2
CRP#
Sample Size	166	167
Ba seline	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. *N reflects randomized subjects; actual number of subjects evaluable for each endpoint may vary by timepoint. †Scale 0-78. ‡Scale 0-76. §VAS = Visual Analog Scale; 0 = best, 100 = worst. ¶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. #CRP = C-reactive protein; Reference range 0-0.5 mg/dL.

 

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 (HAQ-DI) score at Week 16 [-0.244 vs. -0.086, respectively; 95% CI for the difference was (-0.26, -0.06)] in Trial 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 Trial PsA-1. Consistent results were observed in Trials PsA-2 and PsA-3.

Moderate To Severe Plaque Psoriasis

Two multicenter, randomized, double-blind, placebo-controlled trials (PSOR-1 [NCT01194219] and PSOR-2 [NCT01232283]) 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 plaque psoriasis of the scalp were allowed to use coal tar shampoo and/or salicylic acid scalp preparations on scalp lesions.

Trial PSOR-1 enrolled 844 subjects and Trial PSOR-2 enrolled 413 subjects. In both trials, subjects were randomized 2:1 to OTEZLA 30 mg twice daily (BID) or placebo for 16 weeks. Both trials assessed the proportion of subjects who achieved PASI-75 at Week 16 and the proportion of subjects who achieved an sPGA score of clear (0) or almost clear (1) at Week 16. Across both trials, subjects ranged in age from 18 to 83 years, with an overall median age of 46 years. The mean baseline BSA involvement was 25.2% (median 21.0%), the mean baseline PASI score was 19.1 (median 16.8), and the proportion of subjects with an 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 onethird 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 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 7.

Table 7: Clinical Response at Week 16 in Trials PSOR-1 and PSOR-2

	Trial PSOR-1		Trial PSOR-2
	Placebo	OTEZLA 30 mg BID	Placebo	OTEZLA 30 mg BID*
N†	N=282	N=562	N=137	N=274
PASI‡ -75, n (%)	15 (5.3)	186 (33.1)	8 (5.8)	79 (28.8)
sPGA§ of Clear or Almost Clear, n (%)	11 (3.9)	122 (21.7)	6 (4.4)	56 (20.4)
*BID = twice daily. †N is number of randomized and treated subjects. ‡PASI = Psoriasis Area and Severity Index. §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.

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 8.

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.

Table 8: Efficacy Results at Week 16 in Adults with Plaque Psoriasis of the Scalp

	Trial PSOR-3
	Placebo	OTEZLA 30 mg twice daily	Treatment Difference*,† (95% CI‡)
Number of subjects randomized	N = 102	N = 201
ScPGA response§	13.7%	43.3%	29.6% (19.5%, 39.7%)
Number of subjects with baseline Whole Body Itch NRS Score ≥4	N = 94	N = 185
Whole Body Itch NRS response	22.5%	45.5%	23.0% (11.5%, 34.6%)
Number of subjects with baseline Scalp Itch NRS Score ≥4	N = 90	N = 175
Scalp Itch NRS response	21.1%	47.1%	26.2% (13.9%, 38.5%)
*OTEZLA – Placebo. †Adjusted difference in proportions is the weighted average of the treatment differences across baseline ScPGA scores with the Cochran-Mantel-Haenszel weights. ‡CI = confidence interval. §ScPGA score of clear [0] or almost clear [1] with at least a 2-point reduction from baseline.

 

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

Mild To Moderate Plaque Psoriasis

A multicenter, randomized, double-blind, placebo-controlled trial (PSOR-4 [NCT03721172]) was conducted in 595 adult subjects with mild to moderate plaque psoriasis (BSA involvement of 2-15%, sPGA score of 2-3 [mild or moderate disease], and PASI score of 2–15). Enrolled subjects had an inadequate response or were intolerant to at least one topical therapy and had not received prior biologic therapy. Subjects were allowed to use unmedicated emollients for lesions on non-scalp areas of the body and non-medicated shampoos for lesions on the scalp.

Subjects were randomized 1:1 to receive either OTEZLA 30 mg twice daily (n = 297) or placebo twice daily (n = 298) 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 an sPGA response (defined as an sPGA score of clear [0] or almost clear [1] with at least a 2-point reduction from baseline) at Week 16. Subjects with mild disease (sPGA = 2 at baseline) were required to be clear (sPGA = 0) to achieve an sPGA response. Other evaluated endpoints include the proportion of subjects with a Whole Body Itch NRS response (defined as a ≥ 4-point reduction from baseline) at Week 16 among subjects with a baseline Whole Body Itch NRS ≥ 4 and the proportion of subjects with an ScPGA response (defined as an ScPGA score of clear [0] or almost clear [1] with at least a 2-point reduction from baseline) at Week 16 among subjects with a baseline ScPGA score ≥ 2.

Subjects ranged in age from 18 to 85 years, with an overall median age of 50 years. The mean baseline BSA involvement was 6.4%, the mean baseline PASI score was 6.5, and the proportions of subjects with an sPGA score of 2 (mild) and 3 (moderate) at baseline were 30.6% and 69.4%, respectively.

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 9.

Table 9: Efficacy Results at Week 16 in Adults with Mild to Moderate Plaque Psoriasis

	Trial PSOR-4
	Placebo	OTEZLA 30 mg twice daily	Treatment Difference*,† (95% CI‡)
Number of Subjects Randomized	N = 298	N = 297
sPGA Response§	4.1%	21.6%	17.5% (12.2%, 22.8%)
Number of Subjects with Baseline Whole Body Itch NRS Score ≥4	N = 249	N = 253
Whole Body Itch NRS Response¶	18.6%	43.2%	24.7% (16.5%, 32.8%)
Number of Subjects with Baseline ScPGAScore≥ 2	N = 199	N = 212
ScPGA Response#	16.6%	44.0%	27.4% (18.6%, 36.3%)
*OTEZLA – Placebo. †Adjusted difference in proportions is the weighted average of the treatment differences across baseline sPGA scores with the Cochran-Mantel-Haenszel weights. ‡CI = confidence interval. §sPGA score of clear [0] or almost clear [1] with at least a 2-point reduction from baseline. ¶ Whole Body Itch NRS score reduction of ≥ 4-points from baseline. #ScPGA score of clear [0] or almost clear [1] with at least a 2-point reduction from baseline.

 

Oral Ulcers Associated With Behçet’s Disease

A multicenter, randomized, placebo-controlled trial (BCT-002 [NCT02307513]) enrolled a total of 207 adult subjects with BD with active oral ulcers. Subjects were previously treated with at least one nonbiologic BD medication and were candidates for systemic therapy. Subjects met the International Study Group (ISG) Criteria for BD. Subjects had at least 2 oral ulcers at screening and at least 2 oral ulcers at randomization and without currently active major organ involvement. Concomitant treatment for BD was not allowed.

Subjects were randomized 1:1 to receive either OTEZLA 30 mg twice daily (n = 104) or placebo (n = 103) for 12 weeks. After Week 12, all subjects received OTEZLA 30 mg twice daily.

Efficacy was assessed based on the number and pain of oral ulcers.

Subjects ranged in age from 19 to 72 years, with a mean age of 40 years. The mean duration of BD was 6.84 years. All subjects had a history of recurrent oral ulcers that were currently active. Subjects had a history of skin lesions (98.6%), genital ulcers (90.3%), musculoskeletal manifestations (72.5%), ocular manifestations (17.4%), central nervous system (9.7%), gastrointestinal (GI) manifestations (9.2%) and vascular involvement (1.4%). The mean baseline oral ulcer counts were 4.2 and 3.9 in the OTEZLA and placebo groups, respectively.

Measures Of Oral Ulcers

Improvements in measures of oral ulcers at Week 12 are presented in Table 10.

Table 10: Clinical Response of Oral Ulcers at Week 12 in the BCT-002 Trial (ITT* Population)

Endpoint	Placebo N=103	OTEZLA 30 mg twice daily N=104	Treatment Difference† (95% CI‡)
Change§ from baseline in the pain of oral ulcers asmeasured by VAS¶ at Week 12	-18.7	-42.7	-24.1 (-32.4, -15.7)
Proportion# of subjects achieving oral ulcer complete response (oralulcer-free) at Week 12	22.3%	52.9%	30.6%Þ (18.1%, 43.1%)
Proportion#of subj ects achieving oral ulcer complete response (oralulcer-free) by Week 6, and who remained oral ulcer-free for at least 6 additionalweeks duringthe 12-week Placebo-controlled Treatment Phase	4.9%	29.8%	25. 1 %Þ (15.5%, 34.6%)
Daily averageβ,à number oforal ulcers during the 12 -week Placebo-controlled Treatment Phase	2.6	1.5	-1.1 (-1.6, -0.7)
*ITT = intent to treat. †OTEZLA – Placebo. ‡CI = confidence interval. §Mean changes from baseline are least square means from mixed-effects model for repeated measures, adjusting for sex, region, and baseline pain of oral ulcers as measured by the visual analog scale. ¶VAS = visual analog scale; 0 = no pain, 100 = worst possible pain. #Subjects for whom data are not available to determine response status are considered non-responders. ÞAdjusted difference in proportions is the weighted average of the treatment differences across the 4 strata of combined sex and region factors with the Cochran-Mantel-Haenszel weights. ßMean daily averages are least squares means from analysis of covariance, after adjusting for sex, region, and baseline number of oral ulcers. àBased on oral ulcer counts measured at baseline and at Weeks 1, 2, 4, 6, 8, 10, and 12.

 

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)

 

ITT = intent-to-treat; SE = standard error.

Oral ulcer pain was assessed on a 100-mm Visual Analog Scale with 0 = no pain and 100 = worst possible pain. Mean baseline Visual Analog Scale pain scores were 61.2 and 60.8 in the OTEZLA 30 mg twice daily treatment group and placebo treatment group, respectively.