Apremilast

5 WARNINGS AND PRECAUTIONS Hypersensitivity : Cases of angioedema and anaphylaxis have been reported during post marketing surveillance. Avoid the use of OTEZLA/OTEZLA XR 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/OTEZLA XR and institute appropriate therapy ( 5.1 ) Diarrhea, Nausea, and Vomiting : Consider OTEZLA/OTEZLA XR dosage 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/OTEZLA XR in patients with a 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/OTEZLA XR ( 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 ) 5.1 Hypersensitivity Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported during post marketing surveillance. Avoid the use of OTEZLA/OTEZLA XR 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/OTEZLA XR 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 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/OTEZLA XR dosage reduction or suspension if patients develop severe diarrhea, nausea, or vomiting. 5.3 Depression Treatment with apremilast is associated with an increased incidence of depression. Before using OTEZLA/OTEZLA XR in patients with a history of depression and/or suicidal thoughts or behavior, carefully weigh the risks and benefits of treatment with OTEZLA/OTEZLA XR. Advise patients, their caregivers, and families 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. Carefully evaluate the risks and benefits of continuing treatment with OTEZLA/OTEZLA XR if such events occur. Psoriatic Arthritis : During the 16-week placebo-controlled period of the 3 controlled clinical trials, 1.0% (10/998) of subjects treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1441) of subjects treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated subjects (0/495). Depression was reported as serious in 0.2% (3/1441) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1441) of subjects while receiving OTEZLA, compared to none in placebo treated subjects (0/495). In the clinical trials, 2 subjects who received placebo committed suicide compared to none in OTEZLA-treated subjects. Plaque Psoriasis : During the 16-week placebo-controlled period of the 3 controlled clinical trials in adult subjects with moderate to severe plaque psoriasis, 1.3% (12/920) of subjects treated with OTEZLA reported depression compared to 0.4% (2/506) treated with placebo. During the clinical trials, 0.1% (1/1308) of subjects treated with OTEZLA discontinued treatment due to depression compared with none in placebo-treated subjects (0/506). Depression was reported as serious in 0.1% (1/1308) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/506). Instances of suicidal behavior have been observed in 0.1% (1/1308) of subjects while receiving OTEZLA, compared to 0.2% (1/506) in placebo-treated subjects. In the clinical trials, one subject treated with OTEZLA attempted suicide while one who received placebo committed suicide. During the 16-week placebo-controlled period of the clinical trial in adults with mild to moderate plaque psoriasis, the incidence of subjects reporting depression was similar to what was observed in the adult moderate to severe plaque psoriasis trials. Behçet’s Disease : During the placebo-controlled period of the phase 3 trial, 1% (1/104) of subjects treated with OTEZLA reported depression/depressed mood compared to 1% (1/103) treated with placebo. None of these reports of depression was serious or led to discontinuation from the trial. No instances of suicidal ideation or behavior were reported during the placebo-controlled period of the phase 3 trial in subjects treated with OTEZLA (0/104) or treated with placebo (0/103). 5.4 Weight Decrease Weight loss may occur in adult or pediatric patients treated with OTEZLA/OTEZLA XR. Regularly monitor the weight of patients treated with OTEZLA/OTEZLA XR. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of OTEZLA/OTEZLA XR [see Adverse Reactions (6.1) ] . Weight Loss in Adult Patients During the placebo-controlled period of the trials in psoriatic arthritis (PsA), weight decrease between 5%-10% of body weight was reported in 10% (49/497) of subjects treated with OTEZLA 30 mg twice daily compared to 3.3% (16/495) treated with placebo. During the placebo-controlled period of the trials in adults with moderate to severe plaque psoriasis, weight decrease between 5%-10% of body weight occurred in 12% (96/784) of subjects treated with OTEZLA compared to 5% (19/382) treated with placebo. Weight decrease of ≥ 10% of body weight occurred in 2% (16/784) of subjects treated with OTEZLA 30 mg twice daily compared to 1% (3/382) subjects treated with placebo. During the placebo-controlled period of the clinical trial in adults with mild to moderate plaque psoriasis, weight decrease was similar to what was observed in the trials of adults with moderate to severe plaque psoriasis. During the placebo-controlled period of the phase 3 trial in Behçet’s Disease, weight decrease > 5% of body weight was reported in 4.9% (5/103) of subjects treated with OTEZLA 30 mg twice daily compared to 3.9% (4/102) subjects treated with placebo. Weight Loss in Pediatric Patients During the placebo-controlled period of the clinical trial in pediatric subjects 6 years of age and older with moderate to severe plaque psoriasis, weight decrease between 5%-10% of body weight occurred in 12% (19/163) of pediatric subjects treated with OTEZLA compared to 2.5% (2/80) of pediatric subjects treated with placebo. Weight decrease of ≥ 10% of body weight occurred in 1% (1/163) of pediatric subjects treated with OTEZLA twice daily compared to 0% (0/80) of pediatric subjects treated with placebo. Closely monitor growth (height and weight) in pediatric patients treated with OTEZLA/OTEZLA XR. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted. 5.5 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/OTEZLA XR. Therefore, the use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA/OTEZLA XR is not recommended [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] .

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) ] 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 ) Behçet’s 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. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Psoriatic Arthritis Clinical Trials OTEZLA was evaluated in three multicenter, randomized, double-blind, placebo-controlled trials (PsA-1, PsA-2, and PsA-3) of similar design in adult subjects with active psoriatic arthritis [see Clinical Studies (14.1) ] . Across the three trials, there were 1493 subjects randomized equally to placebo, OTEZLA 20 mg twice daily or OTEZLA 30 mg twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1) ] . Placebo subjects whose tender and swollen joint counts had not improved by at least 20% were re-randomized 1:1 in a blinded fashion to either OTEZLA 20 mg twice daily or 30 mg twice daily at week 16 while OTEZLA subjects remained on their initial treatment. Subjects ranged in age from 18 to 83 years, with an overall median age of 51 years. The majority of the most common adverse reactions presented in Table 3 occurred within the first 2 weeks of treatment and tended to resolve over time with continued dosing. Diarrhea, headache, and nausea were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for subjects taking OTEZLA were nausea (1.8%), diarrhea (1.8%), and headache (1.2%). The proportion of subjects with psoriatic arthritis who discontinued treatment due to any adverse reaction was 4.6% for subjects taking OTEZLA 30 mg twice daily and 1.2% for placebo-treated subjects. Table 3. Adverse Reactions Reported in ≥ 2% of Adult Subjects with Active Psoriatic Arthritis on OTEZLA 30 mg Twice Daily and ≥ 1% than That Observed in Subjects on Placebo up to Day 112 (Week 16) Placebo OTEZLA 30 mg BID BID = twice daily. Adverse Reactions Day 1 to 5 (N = 495) n (%) n (%) indicates number of subjects and percent. Day 6 to Day 112 (N = 490) n (%) Day 1 to 5 (N = 497) n (%) Day 6 to Day 112 (N = 493) n (%) Diarrhea 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. 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 respiratory tract infection Of the reported adverse drug reactions none were serious. 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) Moderate to Severe Plaque Psoriasis Clinical Trials Adverse Reactions from Clinical Trials in Adults The safety of OTEZLA was assessed in 1426 subjects in three randomized, double-blind, placebo-controlled trials in adult subjects with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy. Subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1) ] . 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 4 ). 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 4. Adverse Reactions Reported in ≥ 1% of Adult Subjects with Moderate to Severe Plaque Psoriasis on OTEZLA and With Greater Frequency Than in Subjects on Placebo up to Day 112 (Week 16) Adverse Reactions Placebo (N = 506) n (%) OTEZLA 30 mg BID BID = twice daily. (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 Two subjects treated with OTEZLA experienced serious adverse reaction of 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 (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 a 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) ] . 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. OTEZLA was evaluated in a Phase 3, multicenter, randomized, placebo-controlled trial (PSOR-5) in adults with moderate to severe plaque psoriasis of the genital area [see Clinical Studies (14.2) ] . A total of 289 subjects were randomized to receive OTEZLA 30 mg twice daily or placebo 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. Adverse Reactions from Clinical Trials in Pediatric Subjects 6 to 17 Years of Age OTEZLA was evaluated in a Phase 3, multicenter, randomized, placebo-controlled trial (PSOR-6) in pediatric subjects 6 to 17 years of age with moderate to severe plaque psoriasis [see Clinical Studies (14.3) ] . A total of 245 subjects were randomized to receive OTEZLA (163 subjects, at a dosage of 20 mg twice daily or 30 mg twice daily, based on body weight) or placebo (82 subjects) twice daily during the 16-week placebo-controlled phase of the trial. The trial also included a 36-week extension phase during which all subjects received OTEZLA 20 mg or 30 mg twice daily. Overall, the safety profile observed in pediatric subjects treated with OTEZLA during the study was consistent with the safety profile established in adult subjects with moderate to severe plaque psoriasis. Mild to Moderate Plaque Psoriasis Clinical Trial in Adults OTEZLA was evaluated in a Phase 3, multicenter, randomized, placebo-controlled trial (PSOR-4) in adult subjects with mild to moderate plaque psoriasis [see Clinical Studies (14.4) ] . A total of 595 subjects were randomized to receive OTEZLA 30 mg twice daily (297 subjects) or placebo twice daily (298 subjects) during the placebo-controlled phase of the trial. The trial also included an open label extension phase during which all subjects received OTEZLA 30 mg twice daily. Overall, the safety profile observed in the OTEZLA group during the placebo-controlled phase was consistent with the safety profile previously established in adult subjects with moderate to severe plaque psoriasis. Behçet’s Disease Clinical Trials OTEZLA was evaluated in a Phase 3, multicenter, randomized, placebo-controlled trial (BCT-002) in adult subjects with Behçet’s Disease (BD) with active oral ulcers [see Clinical Studies (14.5) ] . A total of 207 subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1) ] . After Week 12, all subjects received treatment with OTEZLA 30 mg twice daily. Subjects ranged in age from 19 to 72, with a mean age of 40 years. Diarrhea, nausea, headache, and upper respiratory tract infection were the most commonly reported adverse reactions (see Table 5 ). The proportion of subjects with BD who discontinued treatment due to any adverse reaction during the placebo-controlled period of the trial, was 2.9% for subjects treated with OTEZLA 30 mg twice daily and 4.9% for placebo-treated subjects. Table 5. Adverse Reactions Reported in ≥ 5% of Adult Subjects with BD with Active Oral Ulcers on OTEZLA and with at Least 1% Greater Frequency than Subjects on Placebo up to Week 12 Adverse Reactions Placebo (N = 103) n (%) OTEZLA 30 mg twice daily (N = 104) n (%) Diarrhea There were no serious adverse reactions of diarrhea, nausea or vomiting. 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) Other adverse reactions reported in subjects on OTEZLA in psoriatic arthritis, plaque psoriasis, and Behçet’s Disease clinical trials are : Gastrointestinal Disorders: Gastroesophageal reflux disease Immune System Disorders: Hypersensitivity Investigations: Weight decrease Metabolism and Nutrition Disorders: Decreased appetite One subject treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction. Nervous System Disorders: Migraine Respiratory, Thoracic, and Mediastinal Disorders: Cough Skin and Subcutaneous Tissue Disorders: Rash

8 USE IN SPECIFIC POPULATIONS Severe Renal Impairment : Increased systemic exposure of OTEZLA has been observed. For adults and for pediatric patients weighing 50 kg or more, reduce dosage to OTEZLA 30 mg once daily. For pediatric patients weighing 20 kg to less than 50 kg, reduce dosage to OTEZLA 20 mg once daily ( 2.3 , 8.6 ). 8.1 Pregnancy Risk Summary Available data with OTEZLA use in pregnant women have not identified a drug-associated risk of major birth defects or adverse maternal or fetal outcomes (see Data ) . In animal embryo-fetal development studies, the administration of apremilast to pregnant cynomolgus monkeys during organogenesis resulted in dose-related increases in abortion/embryo-fetal death at dose exposures approximately 2-times the maximum recommended human therapeutic dose (MRHD) and no adverse effect at an exposure of 1.4-times the MRHD. When apremilast was administered to pregnant mice during organogenesis, there were no apremilast-induced malformations up to exposures 4-times the MRHD. Based on findings from animal reproduction studies, OTEZLA/OTEZLA XR may increase the risk for fetal loss (see Data ) . Advise pregnant women of the potential risk of fetal loss. The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data A pregnancy registry conducted by the Organization of Teratology Information Specialists (OTIS) in the United States and Canada assessed the risk of major birth defects in liveborn infants of women with psoriatic arthritis, psoriasis, or Behçet’s Disease exposed to apremilast in the first trimester. The study compared pregnant women treated with apremilast (n = 15) with disease matched pregnant women who were not exposed to apremilast (n = 106). In the apremilast-exposed cohort, there were no reports of liveborn infants with major birth defects nor miscarriages. One stillbirth was reported in the apremilast exposed cohort. These data are limited by the small sample size of apremilast-exposed pregnancies. Animal Data In an embryo-fetal developmental study, pregnant cynomolgus monkeys were administered apremilast at doses of 20, 50, 200, or 1000 mg/kg/day during the period of organogenesis (gestation Days [GD] 20 through 50). There was a dose -related increase in spontaneous abortions, with most abortions occurring during Weeks 3 to 4 of dosing in the first trimester, at doses approximately 2-times the MRHD and greater (on an area under the curve [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 (GD 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 GD 15. No teratogenic findings attributed to apremilast were observed in either study; however, there was an increase in post-implantation loss at doses corresponding to a systemic exposure of approximately 2-times the MRHD and greater (≥ 20 mg/kg/day). At doses of ≥ 20 mg/kg/day skeletal variations included incomplete ossification sites of tarsals, skull, sternebra, and vertebrae. No effects were observed at a dose approximately 1.3-times the MRHD (10 mg/kg/day). Apremilast distributed across the placenta into the fetal compartment in mice and monkeys. In a pre and postnatal 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-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). 8.2 Lactation Risk Summary There are no data on the presence of apremilast in human milk, its effects on the breastfed infant, or its effects on milk production. However, apremilast was detected in the milk of lactating mice (see Data ). 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/OTEZLA XR and any potential adverse effects on the breastfed infant from OTEZLA/OTEZLA XR 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. 8.4 Pediatric Use OTEZLA Plaque Psoriasis The safety and effectiveness of OTEZLA have been established in pediatric patients 6 years of age and older and weighing at least 20 kg with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Use of OTEZLA in these patients is supported by evidence from a 52-week adequate and well-controlled clinical trial (PSOR-6) in 245 pediatric subjects 6 years of age and older with moderate to severe plaque psoriasis. Weight loss in OTEZLA-treated pediatric subjects was comparable to weight loss observed in adults [see Warnings and Precautions (5.4) , Adverse Reactions (6.1) and Clinical Studies (14.3) ] . Closely monitor growth (height and weight) in pediatric patients treated with OTEZLA. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted. The safety and effectiveness of OTEZLA have not been established in pediatric patients below the age of 6 years or weighing less than 20 kg with moderate to severe plaque psoriasis. Psoriatic Arthritis The safety and effectiveness of OTEZLA have been established for pediatric patients 6 years of age and older and weighing at least 20 kg with psoriatic arthritis. Use of OTEZLA in these patients is supported by evidence from adequate and well controlled trials of OTEZLA in adults with psoriatic arthritis, pharmacokinetic data from adult patients with psoriatic arthritis, adult patients with psoriasis, and pediatric patients with psoriasis, and safety data from a clinical trial in 245 pediatric patients 6 years of age and older with psoriasis. Steady-state exposure of OTEZLA in pediatric patients with psoriatic arthritis is estimated to be comparable to adults with psoriatic arthritis and pediatric patients with psoriasis [see Clinical Pharmacology (12.3) ] . Closely monitor growth (height and weight) in OTEZLA-treated pediatric patients. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.4) ] . The safety and effectiveness of OTEZLA have not been established in pediatric patients below the age of 6 years or weighing less than 20 kg with psoriatic arthritis. Behçet’s Disease The safety and effectiveness of OTEZLA have not been established in pediatric patients with psoriatic arthritis or oral ulcers associated with Behçet’s Disease. OTEZLA XR Plaque Psoriasis and Psoriatic Arthritis The safety and effectiveness of OTEZLA XR have been established for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis in pediatric patients 6 years of age and older and weighing at least 50 kg. Use of OTEZLA XR in these patients is supported by pharmacokinetic data from healthy adults demonstrating comparable PK exposure between OTEZLA XR 75 mg once daily and OTEZLA 30 mg twice daily, which is the recommended OTEZLA dosage for pediatric patients weighing at least 50 kg [see Dosage and Administration (2.1) , Clinical Pharmacology (12.3) ] . Closely monitor growth (height and weight) in pediatric patients treated with OTEZLA XR. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted. The safety and effectiveness of OTEZLA XR have not been established in pediatric patients below the age of 6 years or weighing less than 50 kg with moderate to severe plaque psoriasis or psoriatic arthritis. Behçet’s Disease The safety and effectiveness of OTEZLA XR have not been established in pediatric patients with oral ulcers associated with Behçet’s Disease. 8.5 Geriatric Use Of the 1493 patients who enrolled in Trials PsA-1, PsA-2, and PsA-3, a total of 146 (9.8%) psoriatic arthritis patients were 65 years of age and older, including 19 (1.3%) 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 (8.6%) plaque psoriasis patients were 65 years of age and older, including 9 (0.7%) 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 (5.2) ] . 8.6 Renal Impairment OTEZLA pharmacokinetics were characterized in adult 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. No dosage adjustment is needed in patients with mild or moderate renal impairment. In adult patients with severe renal impairment, reduce the maintenance dosage to OTEZLA 30 mg once daily. In pediatric patients 6 years of age and older and weighing at least 20 kg with psoriatic arthritis or moderate to severe plaque psoriasis and severe renal impairment, reduce the maintenance dosage to OTEZLA 30 mg once daily for pediatric patients weighing at least 50 kg and to OTEZLA 20 mg once daily for pediatric patients weighing 20 kg to less than 50 kg [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ] . The pharmacokinetics of OTEZLA XR has not been evaluated in patients with renal impairment. In patients with severe renal impairment, it is recommended that OTEZLA be used instead of OTEZLA XR [see Dosage and Administration (2.3) 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.

8.1 Pregnancy Risk Summary Available data with OTEZLA use in pregnant women have not identified a drug-associated risk of major birth defects or adverse maternal or fetal outcomes (see Data ) . In animal embryo-fetal development studies, the administration of apremilast to pregnant cynomolgus monkeys during organogenesis resulted in dose-related increases in abortion/embryo-fetal death at dose exposures approximately 2-times the maximum recommended human therapeutic dose (MRHD) and no adverse effect at an exposure of 1.4-times the MRHD. When apremilast was administered to pregnant mice during organogenesis, there were no apremilast-induced malformations up to exposures 4-times the MRHD. Based on findings from animal reproduction studies, OTEZLA/OTEZLA XR may increase the risk for fetal loss (see Data ) . Advise pregnant women of the potential risk of fetal loss. The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data A pregnancy registry conducted by the Organization of Teratology Information Specialists (OTIS) in the United States and Canada assessed the risk of major birth defects in liveborn infants of women with psoriatic arthritis, psoriasis, or Behçet’s Disease exposed to apremilast in the first trimester. The study compared pregnant women treated with apremilast (n = 15) with disease matched pregnant women who were not exposed to apremilast (n = 106). In the apremilast-exposed cohort, there were no reports of liveborn infants with major birth defects nor miscarriages. One stillbirth was reported in the apremilast exposed cohort. These data are limited by the small sample size of apremilast-exposed pregnancies. Animal Data In an embryo-fetal developmental study, pregnant cynomolgus monkeys were administered apremilast at doses of 20, 50, 200, or 1000 mg/kg/day during the period of organogenesis (gestation Days [GD] 20 through 50). There was a dose -related increase in spontaneous abortions, with most abortions occurring during Weeks 3 to 4 of dosing in the first trimester, at doses approximately 2-times the MRHD and greater (on an area under the curve [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 (GD 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 GD 15. No teratogenic findings attributed to apremilast were observed in either study; however, there was an increase in post-implantation loss at doses corresponding to a systemic exposure of approximately 2-times the MRHD and greater (≥ 20 mg/kg/day). At doses of ≥ 20 mg/kg/day skeletal variations included incomplete ossification sites of tarsals, skull, sternebra, and vertebrae. No effects were observed at a dose approximately 1.3-times the MRHD (10 mg/kg/day). Apremilast distributed across the placenta into the fetal compartment in mice and monkeys. In a pre and postnatal 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-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).

8.4 Pediatric Use OTEZLA Plaque Psoriasis The safety and effectiveness of OTEZLA have been established in pediatric patients 6 years of age and older and weighing at least 20 kg with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Use of OTEZLA in these patients is supported by evidence from a 52-week adequate and well-controlled clinical trial (PSOR-6) in 245 pediatric subjects 6 years of age and older with moderate to severe plaque psoriasis. Weight loss in OTEZLA-treated pediatric subjects was comparable to weight loss observed in adults [see Warnings and Precautions (5.4) , Adverse Reactions (6.1) and Clinical Studies (14.3) ] . Closely monitor growth (height and weight) in pediatric patients treated with OTEZLA. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted. The safety and effectiveness of OTEZLA have not been established in pediatric patients below the age of 6 years or weighing less than 20 kg with moderate to severe plaque psoriasis. Psoriatic Arthritis The safety and effectiveness of OTEZLA have been established for pediatric patients 6 years of age and older and weighing at least 20 kg with psoriatic arthritis. Use of OTEZLA in these patients is supported by evidence from adequate and well controlled trials of OTEZLA in adults with psoriatic arthritis, pharmacokinetic data from adult patients with psoriatic arthritis, adult patients with psoriasis, and pediatric patients with psoriasis, and safety data from a clinical trial in 245 pediatric patients 6 years of age and older with psoriasis. Steady-state exposure of OTEZLA in pediatric patients with psoriatic arthritis is estimated to be comparable to adults with psoriatic arthritis and pediatric patients with psoriasis [see Clinical Pharmacology (12.3) ] . Closely monitor growth (height and weight) in OTEZLA-treated pediatric patients. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.4) ] . The safety and effectiveness of OTEZLA have not been established in pediatric patients below the age of 6 years or weighing less than 20 kg with psoriatic arthritis. Behçet’s Disease The safety and effectiveness of OTEZLA have not been established in pediatric patients with psoriatic arthritis or oral ulcers associated with Behçet’s Disease. OTEZLA XR Plaque Psoriasis and Psoriatic Arthritis The safety and effectiveness of OTEZLA XR have been established for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis in pediatric patients 6 years of age and older and weighing at least 50 kg. Use of OTEZLA XR in these patients is supported by pharmacokinetic data from healthy adults demonstrating comparable PK exposure between OTEZLA XR 75 mg once daily and OTEZLA 30 mg twice daily, which is the recommended OTEZLA dosage for pediatric patients weighing at least 50 kg [see Dosage and Administration (2.1) , Clinical Pharmacology (12.3) ] . Closely monitor growth (height and weight) in pediatric patients treated with OTEZLA XR. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted. The safety and effectiveness of OTEZLA XR have not been established in pediatric patients below the age of 6 years or weighing less than 50 kg with moderate to severe plaque psoriasis or psoriatic arthritis. Behçet’s Disease The safety and effectiveness of OTEZLA XR have not been established in pediatric patients with oral ulcers associated with Behçet’s Disease.