PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionApremilast when taken orally is absorbed with an absolute bioavailability of ~73%, with peak plasma concentrations (Cmax) occurring at median time (tmax) of ~2.5 hours. Co-administration with food does not alter the extent of absorption of apremilast.. DistributionHuman 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 major circulating component (45%) followed by inactive metabolite M12 (39%), 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. EliminationThe plasma clearance of apremilast is about 10 L/hr in healthy subjects, with 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 subjects with severe renal impairment administered single dose of 30 mg apremilast, the AUC and Cmax of apremilast increased by approximately 88% and 42%, respectively [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].. Age: 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 (8.5)].. 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 substrate, but not an inhibitor of P-glycoprotein (P-gp) and is not 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 single oral dose of 30-mg apremilast resulted in reduction of apremilast AUC and Cmax by 72% and 43%, respectively [see Warnings and Precautions (5.5) and Drug Interactions (7.1)].

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is 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 SummaryAvailable pharmacovigilance data with OTEZLA use in pregnant women have not established 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 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 dose-related increase in spontaneous abortions, with most abortions occurring during Weeks to 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 dose approximately 1.4-times the MRHD (on an AUC basis at dose of 20 mg/kg/day). Although, there was no evidence for 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 through 15). In 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 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 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 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 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 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 dose of 300 mg/kg/day).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are described elsewhere in the labeling:Hypersensitivity [see Warnings and Precautions (5.1)] Diarrhea, Nausea, and Vomiting [see Warnings and Precautions (5.2)] Depression [see Warnings and Precautions (5.3)] Weight Decrease [see Warnings and Precautions (5.4)] Drug Interactions [see Warnings and Precautions (5.5)] Hypersensitivity [see Warnings and Precautions (5.1)] Diarrhea, Nausea, and Vomiting [see Warnings and Precautions (5.2)] Depression [see Warnings and Precautions (5.3)] Weight Decrease [see Warnings and Precautions (5.4)] Drug Interactions [see Warnings and Precautions (5.5)] Psoriatic Arthritis: The most common adverse reactions (>= 5%) are diarrhea, nausea, and headache (6.1)Plaque Psoriasis: The most common adverse reactions (>= 5%) are diarrhea, nausea, upper respiratory tract infection, and headache, including tension headache (6.1)Behcets Disease: The most common adverse reactions (>= 10%) are diarrhea, nausea, headache, and upper respiratory tract infection (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Psoriatic Arthritis: The most common adverse reactions (>= 5%) are diarrhea, nausea, and headache (6.1). Plaque Psoriasis: The most common adverse reactions (>= 5%) are diarrhea, nausea, upper respiratory tract infection, and headache, including tension headache (6.1). Behcets Disease: The most common adverse reactions (>= 10%) are diarrhea, nausea, headache, and upper respiratory tract infection (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 TrialsOTEZLA was evaluated in 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 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 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 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 occurred within the first 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)PlaceboOTEZLA 30 mg BIDBID twice daily. Adverse Reactions Day to 5(N 495)n (%)n (%) indicates number of subjects and percent. Day to Day 112(N 490)n (%)Day to 5(N 497)n (%)Day to Day 112(N 493)n (%)DiarrheaOf the reported gastrointestinal adverse reactions, subject experienced serious adverse reaction of nausea and vomiting in OTEZLA 30 mg twice daily; subject treated with OTEZLA 20 mg twice daily experienced serious adverse reaction of diarrhea; subject treated with OTEZLA 30 mg twice daily experienced serious adverse reaction of headache. (1.2)8 (1.6)46 (9.3)38 (7.7)Nausea (1.4)15 (3.1)37 (7.4)44 (8.9)Headache (1.8)11 (2.2)24 (4.8)29 (5.9)Upper respiratory tract infectionOf the reported adverse drug reactions none were serious. (0.6)9 (1.8)3 (0.6)19 (3.9)Vomiting (0.4)2 (0.4)4 (0.8)16 (3.2)Nasopharyngitis (0.2)8 (1.6)1 (0.2)13 (2.6)Abdominal pain upper (0.0)1 (0.2)3 (0.6)10 (2.0). Moderate to Severe Plaque Psoriasis Clinical TrialsThe safety of OTEZLA was assessed in 1426 subjects in 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 days [see Dosage and Administration (2.1)]. 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 ReactionsPlacebo (N=506)n (%)OTEZLA 30 mg BIDBID twice daily. (N=920)n (%)Diarrhea32 (6)160 (17)Nausea35 (7)155 (17)Upper respiratory tract infection31 (6)84 (9)Tension headache21 (4)75 (8)Headache19 (4)55 (6)Abdominal painTwo subjects treated with OTEZLA experienced serious adverse reaction of abdominal pain. 11 (2)39 (4)Vomiting8 (2)35 (4)Fatigue9 (2)29 (3)Dyspepsia6 (1)29 (3)Decreased appetite5 (1)26 (3)Insomnia4 (1)21 (2)Back pain4 (1)20 (2)Migraine5 (1)19 (2)Frequent bowel movements1 (0)17 (2)Depression2 (0)12 (1)Bronchitis2 (0)12 (1)Tooth abscess0 (0)10 (1)Folliculitis0 (0)9 (1)Sinus headache0 (0)9 (1)Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) subjects following discontinuation of treatment with OTEZLA.OTEZLA was evaluated in Phase 3, multicenter, randomized, placebo-controlled trial (PSOR-3) in adults with moderate to severe plaque psoriasis of the scalp [see Clinical Studies (14.2)]. 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 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. %) in the OTEZLA group compared to placebo.. Mild to Moderate Plaque Psoriasis Clinical Trial OTEZLA was evaluated in Phase 3, multicenter, randomized, placebo-controlled trial (PSOR-4) in adult subjects with mild to moderate plaque psoriasis [see Clinical Studies (14.3)]. 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.. Behcets Disease Clinical TrialsOTEZLA was evaluated in Phase 3, multicenter, randomized, placebo-controlled trial (BCT-002) in adult subjects with Behcets Disease (BD) with active oral ulcers [see Clinical Studies (14.4)]. total of 207 subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. Titration was used over the first 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 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 12Adverse ReactionsPlacebo(N=103)n (%)OTEZLA 30 mg twice daily (N=104)n (%)DiarrheaThere were no serious adverse reactions of diarrhea, nausea or vomiting. 21 (20.4)43 (41.3)Nausea 11 (10.7)20 (19.2)Headache11 (10.7)15 (14.4)Upper respiratory tract infection5 (4.9)12 (11.5)Abdominal pain upper2 (1.9)9 (8.7)Vomiting (1.9)9 (8.7)Back pain6 (5.8)8 (7.7)Viral upper respiratory tract infection5 (4.9)7 (6.7)Arthralgia3 (2.9)6 (5.8). Other adverse reactions reported in subjects on OTEZLA in psoriatic arthritis, plaque psoriasis, and Behcets Disease clinical trials are:Gastrointestinal Disorders: Gastroesophageal reflux diseaseImmune System Disorders: HypersensitivityInvestigations: Weight decreaseMetabolism and Nutrition Disorders: Decreased appetite1 subject treated with OTEZLA 30 mg twice daily experienced serious adverse reaction. Nervous System Disorders: MigraineRespiratory, Thoracic, and Mediastinal Disorders: CoughSkin and Subcutaneous Tissue Disorders: Rash. Gastrointestinal Disorders: Gastroesophageal reflux disease. Immune System Disorders: Hypersensitivity. Investigations: Weight decrease. Metabolism and Nutrition Disorders: Decreased appetite1 subject treated with OTEZLA 30 mg twice daily experienced serious adverse reaction. Nervous System Disorders: Migraine. Respiratory, Thoracic, and Mediastinal Disorders: Cough. Skin and Subcutaneous Tissue Disorders: Rash.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Apremilast is an oral small-molecule inhibitor of phosphodiesterase (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.. 12.3 Pharmacokinetics. AbsorptionApremilast when taken orally is absorbed with an absolute bioavailability of ~73%, with peak plasma concentrations (Cmax) occurring at median time (tmax) of ~2.5 hours. Co-administration with food does not alter the extent of absorption of apremilast.. DistributionHuman 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 major circulating component (45%) followed by inactive metabolite M12 (39%), 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. EliminationThe plasma clearance of apremilast is about 10 L/hr in healthy subjects, with 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 subjects with severe renal impairment administered single dose of 30 mg apremilast, the AUC and Cmax of apremilast increased by approximately 88% and 42%, respectively [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].. Age: 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 (8.5)].. 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 substrate, but not an inhibitor of P-glycoprotein (P-gp) and is not 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 single oral dose of 30-mg apremilast resulted in reduction of apremilast AUC and Cmax by 72% and 43%, respectively [see Warnings and Precautions (5.5) and Drug Interactions (7.1)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Psoriatic Arthritis. The safety and efficacy of OTEZLA was evaluated in multicenter, randomized, double-blind, placebo-controlled trials (PsA-1 [NCT01172938], PsA-2 [NCT01212757], and PsA-3 [NCT01212770]) of similar design. total of 1493 adult subjects with active PsA (>= swollen joints and >= tender joints) despite prior or current treatment with disease-modifying antirheumatic drug (DMARD) therapy were randomized. Subjects enrolled in these trials had diagnosis of PsA for at least months. One qualifying psoriatic skin lesion of at least cm in diameter was required in Trial PsA-3. Previous treatment with biologic, including TNF-blockers was allowed (up to 10% could be TNF-blocker therapeutic failures). Across the 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 days [see Dosage and Administration (2.1)]. Subjects were allowed to receive stable doses of concomitant methotrexate [MTX (<=25 mg/week)], sulfasalazine [SSZ (<= g/day)], leflunomide [LEF (<=20 mg/day)], low dose oral corticosteroids (equivalent to <=10 mg of prednisone 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. Placebo-controlled 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 blinded fashion to either OTEZLA 20 mg twice daily or 30 mg twice daily following the titration schema [see Dosage and Administration (2.1)]. 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 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 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 ArthritisThe percent of subjects achieving ACR 20, 50 and 70 responses in Trials PsA-1, PsA-2, and PsA-3 are presented in Table below. OTEZLA +- DMARDs, compared with Placebo +- DMARDs resulted in 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-3PsA-1PsA-2PsA-3NN is number of randomized and treated subjects. Placebo +- DMARDsN=168OTEZLA 30 mg twice daily +- DMARDsN=168Placebo +- DMARDsN=159OTEZLA 30 mg twice daily +- DMARDsN=162Placebo +- DMARDsN=169OTEZLA 30 mg twice daily +- DMARDsN=167ACR 20 Week 1619%38% Statistically significantly different from placebo (p<0.05). 19%32% 18%41% ACR 50 Week 166%16%5%11%8%15%ACR 70 Week 161%4%1%1%2%4%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- 1Placebo(NN reflects randomized subjects; actual number of subjects evaluable for each endpoint may vary by timepoint. =168)OTEZLA 30 mg twice daily(N=168)Mean changes from baseline are least square means from analyses of covariance.Number of tender jointsScale 0-78. Sample Size166164 Baseline2323 Mean Change at Week 16-2-7Number of swollen jointsScale 0-76. Sample Size166164 Baseline1313 Mean Change at Week 16-2-5Patients assessment of painVAS Visual Analog Scale; = best, 100 worst. Sample Size165159 Baseline6158 Mean Change at Week 16-6-14Patients global assessment of disease activity Sample Size165159 Baseline5956 Mean Change at Week 16-3-10Physicians global assessment of disease activity Sample Size158159 Baseline5556 Mean Change at Week 16-8-19HAQ-DIHAQ-DI Health Assessment Questionnaire-Disability Index; = best, = worst; measures the subjects ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity. score Sample Size165159 Baseline1.21.2 Mean Change at Week 16-0.09-0.2CRPCRP C-reactive protein; Reference range 0-0.5 mg/dL. Sample Size166167 Baseline1.10.8 Mean Change at Week 160.1-0.1Treatment 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 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.. 14.2Moderate to Severe Plaque Psoriasis. Two multicenter, randomized, double-blind, placebo-controlled trials (PSOR-1 [NCT01194219] and PSOR-2 [NCT01232283]) enrolled 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 >= (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 (moderate) and (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. total of 18% of subjects had history of psoriatic arthritis.. Clinical Response in Subjects with Moderate to Severe Plaque PsoriasisThe 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-2Trial PSOR-1Trial PSOR-2PlaceboOTEZLA30 mg BIDPlaceboOTEZLA30 mg BIDBID twice daily. NN is number of randomized and treated subjects. N=282N=562N=137N=274PASIPASI Psoriasis Area and Severity Index. -75, (%)15 (5.3)186 (33.1)8 (5.8)79 (28.8)sPGAsPGA Static Physician Global Assessment. of Clear or Almost Clear, (%)11 (3.9)122 (21.7)6 (4.4)56 (20.4)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 AreaA 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 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 >= [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 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 Scalp Itch NRS response (defined as >= 4-point reduction from baseline).Subjects had 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 naive, and 58.8% had failed or 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 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 displays the proportion of subjects achieving Whole Body Itch NRS response at each visit, while Figure 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 ScalpTrial PSOR-3PlaceboOTEZLA 30 mg twice dailyTreatment DifferenceOTEZLA Placebo. Adjusted difference in proportions is the weighted average of the treatment differences across baseline ScPGA scores with the Cochran-Mantel-Haenszel weights. (95% CICI confidence interval.)Number of subjects randomizedN 102N 201 ScPGA responseScPGA score of clear [0] or almost clear [1] with at least 2-point reduction from baseline. 13.7%43.3%29.6%(19.5%, 39.7%)Number of subjects with baseline Whole Body Itch NRS Score >=4N 94N 185 Whole Body Itch NRS response22.5%45.5%23.0%(11.5%, 34.6%)Number of subjects with baseline Scalp Itch NRS Score >=4N 90N 175 Scalp Itch NRS response21.1%47.1%26.2%(13.9%, 38.5%)NRS Numeric Rating Scale; SE standard errorFigure 1: Proportion (+- SE) of Subjects Achieving Whole Body Itch NRS Response through Week 16NRS Numeric Rating Scale; SE standard errorFigure 2: Proportion (+- SE) of Subjects Achieving Scalp Itch NRS Response through Week 16. Figure 1. Figure 2. 14.3Mild to Moderate Plaque Psoriasis. 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 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 Whole Body Itch NRS response (defined as >= 4-point reduction from baseline) at Week 16 among subjects with baseline Whole Body Itch NRS >= and the proportion of subjects with an ScPGA response (defined as an ScPGA score of clear [0] or almost clear [1] with at least 2-point reduction from baseline) at Week 16 among subjects with 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 (mild) and (moderate) at baseline were 30.6% and 69.4%, respectively.. Clinical Response in Subjects with Mild to Moderate Plaque PsoriasisThe 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 PsoriasisTrial PSOR-4PlaceboOTEZLA 30 mg twice dailyTreatment DifferenceOTEZLA Placebo. Adjusted difference in proportions is the weighted average of the treatment differences across baseline sPGA scores with the Cochran-Mantel-Haenszel weights. (95% CICI confidence interval.)Number of Subjects RandomizedN 298N 297 sPGA ResponsesPGA score of clear [0] or almost clear [1] with at least 2-point reduction from baseline. 4.1%21.6%17.5%(12.2%, 22.8%)Number of Subjects with Baseline Whole Body Itch NRS Score >= 4N 249N 253 Whole Body Itch NRS ResponseWhole Body Itch NRS score reduction of >= 4-points from baseline. 18.6%43.2%24.7%(16.5%, 32.8%)Number of Subjects with Baseline ScPGA Score >= 2N 199N 212 ScPGA ResponseScPGA score of clear [0] or almost clear [1] with at least 2-point reduction from baseline. 16.6%44.0%27.4%(18.6%, 36.3%). 14.4 Oral Ulcers Associated with Behcets Disease. multicenter, randomized, placebo-controlled trial (BCT-002 [NCT02307513]) enrolled 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 oral ulcers at screening and at least 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 mean age of 40 years. The mean duration of BD was 6.84 years. All subjects had history of recurrent oral ulcers that were currently active. Subjects had 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 UlcersImprovements 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 (ITTITT intent to treat. Population)EndpointPlaceboN=103OTEZLA 30 mg twice dailyN=104Treatment DifferenceOTEZLA Placebo. (95% CICI confidence interval.)ChangeMean 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. from baseline in the pain of oral ulcers as measured by VASVAS visual analog scale; = no pain, 100 worst possible pain. at Week 12-18.7-42.7-24.1(-32.4, -15.7)ProportionSubjects for whom data are not available to determine response status are considered non-responders. of subjects achieving oral ulcer complete response (oral ulcer-free) at Week 1222.3%52.9%30.6%Adjusted difference in proportions is the weighted average of the treatment differences across the strata of combined sex and region factors with the Cochran-Mantel-Haenszel weights. (18.1%, 43.1%)Proportion of subjects achieving oral ulcer complete response (oral ulcer-free) by Week 6, and who remained oral ulcer-free for at least additional weeks during the 12-week Placebo-controlled Treatment Phase4.9%29.8%25.1% (15.5%, 34.6%)Daily averageMean daily averages are least squares means from analysis of covariance, after adjusting for sex, region, and baseline number of oral ulcers. Based on oral ulcer counts measured at baseline and at Weeks 1, 2, 4, 6, 8, 10, and 12. number of oral ulcers during the 12-week Placebo-controlled Treatment Phase2.61.5-1.1(-1.6, -0.7)Figure displays the mean number of oral ulcers for each treatment group at each visit, while Figure displays the mean oral ulcer pain on 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)ITT intent-to-treat; SE standard error.Weeks0124681012Placebo, n10398979391868382OTEZLA 30 mg twice daily, n10410110110198949497Figure 4: Mean (+- SE) Oral Ulcer Pain on Visual Analog Scale by Time Point Through Week 12 (ITT Population) ITT intent-to-treat; SE standard error. Oral ulcer pain was assessed on 100-mm Visual Analog Scale with = 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. Weeks0124681012Placebo, n10195969190858281OTEZLA 30 mg twice daily, n10295979997929395. Figure 3. Figure 4.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 TrialsOTEZLA was evaluated in 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 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 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 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 occurred within the first 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)PlaceboOTEZLA 30 mg BIDBID twice daily. Adverse Reactions Day to 5(N 495)n (%)n (%) indicates number of subjects and percent. Day to Day 112(N 490)n (%)Day to 5(N 497)n (%)Day to Day 112(N 493)n (%)DiarrheaOf the reported gastrointestinal adverse reactions, subject experienced serious adverse reaction of nausea and vomiting in OTEZLA 30 mg twice daily; subject treated with OTEZLA 20 mg twice daily experienced serious adverse reaction of diarrhea; subject treated with OTEZLA 30 mg twice daily experienced serious adverse reaction of headache. (1.2)8 (1.6)46 (9.3)38 (7.7)Nausea (1.4)15 (3.1)37 (7.4)44 (8.9)Headache (1.8)11 (2.2)24 (4.8)29 (5.9)Upper respiratory tract infectionOf the reported adverse drug reactions none were serious. (0.6)9 (1.8)3 (0.6)19 (3.9)Vomiting (0.4)2 (0.4)4 (0.8)16 (3.2)Nasopharyngitis (0.2)8 (1.6)1 (0.2)13 (2.6)Abdominal pain upper (0.0)1 (0.2)3 (0.6)10 (2.0). Moderate to Severe Plaque Psoriasis Clinical TrialsThe safety of OTEZLA was assessed in 1426 subjects in 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 days [see Dosage and Administration (2.1)]. 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 ReactionsPlacebo (N=506)n (%)OTEZLA 30 mg BIDBID twice daily. (N=920)n (%)Diarrhea32 (6)160 (17)Nausea35 (7)155 (17)Upper respiratory tract infection31 (6)84 (9)Tension headache21 (4)75 (8)Headache19 (4)55 (6)Abdominal painTwo subjects treated with OTEZLA experienced serious adverse reaction of abdominal pain. 11 (2)39 (4)Vomiting8 (2)35 (4)Fatigue9 (2)29 (3)Dyspepsia6 (1)29 (3)Decreased appetite5 (1)26 (3)Insomnia4 (1)21 (2)Back pain4 (1)20 (2)Migraine5 (1)19 (2)Frequent bowel movements1 (0)17 (2)Depression2 (0)12 (1)Bronchitis2 (0)12 (1)Tooth abscess0 (0)10 (1)Folliculitis0 (0)9 (1)Sinus headache0 (0)9 (1)Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) subjects following discontinuation of treatment with OTEZLA.OTEZLA was evaluated in Phase 3, multicenter, randomized, placebo-controlled trial (PSOR-3) in adults with moderate to severe plaque psoriasis of the scalp [see Clinical Studies (14.2)]. 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 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. %) in the OTEZLA group compared to placebo.. Mild to Moderate Plaque Psoriasis Clinical Trial OTEZLA was evaluated in Phase 3, multicenter, randomized, placebo-controlled trial (PSOR-4) in adult subjects with mild to moderate plaque psoriasis [see Clinical Studies (14.3)]. 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.. Behcets Disease Clinical TrialsOTEZLA was evaluated in Phase 3, multicenter, randomized, placebo-controlled trial (BCT-002) in adult subjects with Behcets Disease (BD) with active oral ulcers [see Clinical Studies (14.4)]. total of 207 subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. Titration was used over the first 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 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 12Adverse ReactionsPlacebo(N=103)n (%)OTEZLA 30 mg twice daily (N=104)n (%)DiarrheaThere were no serious adverse reactions of diarrhea, nausea or vomiting. 21 (20.4)43 (41.3)Nausea 11 (10.7)20 (19.2)Headache11 (10.7)15 (14.4)Upper respiratory tract infection5 (4.9)12 (11.5)Abdominal pain upper2 (1.9)9 (8.7)Vomiting (1.9)9 (8.7)Back pain6 (5.8)8 (7.7)Viral upper respiratory tract infection5 (4.9)7 (6.7)Arthralgia3 (2.9)6 (5.8). Other adverse reactions reported in subjects on OTEZLA in psoriatic arthritis, plaque psoriasis, and Behcets Disease clinical trials are:Gastrointestinal Disorders: Gastroesophageal reflux diseaseImmune System Disorders: HypersensitivityInvestigations: Weight decreaseMetabolism and Nutrition Disorders: Decreased appetite1 subject treated with OTEZLA 30 mg twice daily experienced serious adverse reaction. Nervous System Disorders: MigraineRespiratory, Thoracic, and Mediastinal Disorders: CoughSkin and Subcutaneous Tissue Disorders: Rash. Gastrointestinal Disorders: Gastroesophageal reflux disease. Immune System Disorders: Hypersensitivity. Investigations: Weight decrease. Metabolism and Nutrition Disorders: Decreased appetite1 subject treated with OTEZLA 30 mg twice daily experienced serious adverse reaction. Nervous System Disorders: Migraine. Respiratory, Thoracic, and Mediastinal Disorders: Cough. Skin and Subcutaneous Tissue Disorders: Rash.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Administration InstructionsInstruct 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 (2.1)].. Administration InstructionsInstruct 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 (2.1)].. HypersensitivityInform 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 (5.1)].. HypersensitivityInform 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 (5.1)].. Diarrhea, Nausea, and VomitingAdvise 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 (5.2)].. Diarrhea, Nausea, and VomitingAdvise 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 (5.2)].. DepressionInform 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 (5.3)].. DepressionInform 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 (5.3)].. Weight DecreaseInstruct 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 (5.4)].. Weight DecreaseInstruct 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 (5.4)].. PregnancyInform patients that there is 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 (8.1)]. Advise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females to inform their prescriber of known or suspected pregnancy.. PregnancyInform patients that there is 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 (8.1)]. Advise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females to inform their prescriber of known or suspected pregnancy.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Severe Renal Impairment: Increased systemic exposure of OTEZLA has been observed, reduction in dosage to 30 mg once daily is recommended (2.2, 8.6). 8.1 Pregnancy. Pregnancy Exposure RegistryThere is 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 SummaryAvailable pharmacovigilance data with OTEZLA use in pregnant women have not established 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 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 dose-related increase in spontaneous abortions, with most abortions occurring during Weeks to 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 dose approximately 1.4-times the MRHD (on an AUC basis at dose of 20 mg/kg/day). Although, there was no evidence for 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 through 15). In 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 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 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 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 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 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 dose of 300 mg/kg/day).. 8.2 Lactation. Risk SummaryThere 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 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 mothers clinical need for OTEZLA and any potential adverse effects on the breastfed infant from OTEZLA or from the underlying maternal condition.. DataIn mice, following 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.. 8.4 Pediatric Use. The safety and effectiveness of OTEZLA in pediatric patients less than 18 years of age have not been established.. 8.5 Geriatric Use. Of the 1493 patients who enrolled in Trials PsA-1, PsA-2, and PsA-3, 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 and PSOR 2), total of 108 plaque psoriasis patients were 65 years of age and older, including 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 higher risk of complications such as volume depletion or hypotension from severe diarrhea, nausea, or vomiting, monitor geriatric patients closely for such complications [see Warning and Precautions (5.2)]. 8.6 Renal Impairment. Apremilast pharmacokinetics were characterized in subjects with mild, moderate, and severe renal impairment as defined by 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 (2.2) and Clinical Pharmacology (12.3)].. 8.7 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity: 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 (5.1).Diarrhea, Nausea, and Vomiting: Consider OTEZLA dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting (5.2)Depression: Advise patients, their caregivers, and families 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. Carefully weigh risks and benefits of treatment with OTEZLA in patients with history of depression and/or suicidal thoughts or behavior (5.3)Weight Decrease: Monitor weight regularly. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of OTEZLA (5.4)Drug Interactions: Use with strong cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended because loss of efficacy may occur (5.5, 7.1). Hypersensitivity: 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 (5.1).. Diarrhea, Nausea, and Vomiting: Consider OTEZLA dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting (5.2). Depression: Advise patients, their caregivers, and families 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. Carefully weigh risks and benefits of treatment with OTEZLA in patients with history of depression and/or suicidal thoughts or behavior (5.3). Weight Decrease: Monitor weight regularly. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of OTEZLA (5.4). Drug Interactions: Use with strong cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended because loss of efficacy may occur (5.5, 7.1). 5.1Hypersensitivity. 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.. 5.2 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 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.. 5.3Depression Treatment with OTEZLA is associated with an increased incidence of depression. Before using OTEZLA in patients with 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 to 16-week placebo-controlled period of the 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, subjects who received placebo committed suicide compared to none in OTEZLA-treated subjects.. Plaque Psoriasis: During the to 16-week placebo-controlled period of the 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 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.. Behcets Disease: During the placebo-controlled period of the phase 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 trial in subjects treated with OTEZLA (0/104) or treated with placebo (0/103).. 5.4Weight 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 trial in Behcets 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 (6.1)].. 5.5Drug Interactions. Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in reduction of systemic exposure of apremilast, which may result in 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 (7.1) and Clinical Pharmacology (12.3)].