FDA label 091cf7e8-8192-96c3-e063-6394a90a35eb

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 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 ( 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 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 a higher risk of complications from severe diarrhea, nausea, or vomiting. Monitor patients who are more susceptible to complications of diarrhea or vomiting. Patients who reduced dosage or discontinued OTEZLA generally improved quickly. Consider OTEZLA dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting. 5.3 Depression Treatment with OTEZLA is associated with an increased incidence of depression. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with OTEZLA. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur. Psoriatic Arthritis : During the 0 to 16-week placebo-controlled period of the 3 controlled clinical trials, 1.0% (10/998) of subjects treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1441) of subjects treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated subjects (0/495). Depression was reported as serious in 0.2% (3/1441) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1441) of subjects while receiving OTEZLA, compared to none in placebo treated subjects (0/495). In the clinical trials, 2 subjects who received placebo committed suicide compared to none in OTEZLA-treated subjects. Plaque Psoriasis : During the 0 to 16-week placebo-controlled period of the 3 controlled clinical trials in subjects with moderate to severe plaque psoriasis, 1.3% (12/920) of subjects treated with OTEZLA reported depression compared to 0.4% (2/506) treated with placebo. During the clinical trials, 0.1% (1/1308) of subjects treated with OTEZLA discontinued treatment due to depression compared with none in placebo-treated subjects (0/506). Depression was reported as serious in 0.1% (1/1308) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/506). Instances of suicidal behavior have been observed in 0.1% (1/1308) of subjects while receiving OTEZLA, compared to 0.2% (1/506) in placebo-treated subjects. In the clinical trials, one subject treated with OTEZLA attempted suicide while one who received placebo committed suicide. During the 0 to 16-week placebo-controlled period of the mild to moderate plaque psoriasis clinical trial, the incidence of subjects reporting depression was similar to what was observed in the moderate to severe plaque psoriasis trials. Behçet's Disease : During the placebo-controlled period of the phase 3 trial, 1% (1/104) of subjects treated with OTEZLA reported depression/depressed mood compared to 1% (1/103) treated with placebo. None of these reports of depression was serious or led to discontinuation from the trial. No instances of suicidal ideation or behavior were reported during the placebo-controlled period of the phase 3 trial in subjects treated with OTEZLA (0/104) or treated with placebo (0/103). 5.4 Weight Decrease During the placebo-controlled period of the trials in psoriatic arthritis (PsA), weight decrease between 5%-10% of body weight was reported in 10% (49/497) of subjects treated with OTEZLA 30 mg twice daily compared to 3.3% (16/495) treated with placebo. During the placebo-controlled period of the trials in moderate to severe plaque psoriasis, weight decrease between 5%-10% of body weight occurred in 12% (96/784) of subjects treated with OTEZLA compared to 5% (19/382) treated with placebo. Weight decrease of ≥ 10% of body weight occurred in 2% (16/784) of subjects treated with OTEZLA 30 mg twice daily compared to 1% (3/382) subjects treated with placebo. During the placebo-controlled period of the mild to moderate plaque psoriasis clinical trial, weight decrease was similar to what was observed in the moderate to severe plaque psoriasis trials. During the placebo-controlled period of the phase 3 trial in Behçet's Disease, weight decrease >5% of body weight was reported in 4.9% (5/103) of subjects treated with OTEZLA 30 mg twice daily compared to 3.9% (4/102) subjects treated with placebo. Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered [see Adverse Reactions (6.1) ] . 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. 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) ] .

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 3 multicenter, randomized, double-blind, placebo-controlled trials (PsA-1, PsA-2, and PsA-3) of similar design in adult subjects with active psoriatic arthritis [see Clinical Studies (14.1) ] . Across the 3 trials, there were 1493 subjects randomized equally to placebo, OTEZLA 20 mg twice daily or OTEZLA 30 mg twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1) ] . Placebo subjects whose tender and swollen joint counts had not improved by at least 20% were re-randomized 1:1 in a blinded fashion to either OTEZLA 20 mg twice daily or 30 mg twice daily at week 16 while OTEZLA subjects remained on their initial treatment. Subjects ranged in age from 18 to 83 years, with an overall median age of 51 years. The majority of the most common adverse reactions presented in Table 2 occurred within the first 2 weeks of treatment and tended to resolve over time with continued dosing. Diarrhea, headache, and nausea were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for subjects taking OTEZLA were nausea (1.8%), diarrhea (1.8%), and headache (1.2%). The proportion of subjects with psoriatic arthritis who discontinued treatment due to any adverse reaction was 4.6% for subjects taking OTEZLA 30 mg twice daily and 1.2% for placebo-treated subjects. Table 2: Adverse Reactions Reported in ≥ 2% of Subjects on OTEZLA 30 mg Twice Daily and ≥ 1% Than That Observed in Subjects on Placebo up to Day 112 (Week 16) 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 The safety of OTEZLA was assessed in 1426 subjects in 3 randomized, double-blind, placebo-controlled trials in adult subjects with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy. Subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. Titration was used over the first 5 days [see Dosage and Administration (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 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. Mild to Moderate Plaque Psoriasis Clinical Trial OTEZLA was evaluated in a Phase 3, multicenter, randomized, placebo-controlled trial (PSOR-4) in adult subjects with mild to moderate plaque psoriasis [see Clinical Studies (14.3) ] . A total of 595 subjects were randomized to receive OTEZLA 30 mg twice daily (297 subjects) or placebo twice daily (298 subjects) during the placebo-controlled phase of the trial. The trial also included an open-label extension phase during which all subjects received OTEZLA 30 mg twice daily. Overall, the safety profile observed in the OTEZLA group during the placebo-controlled phase was consistent with the safety profile previously established in adult subjects with moderate to severe plaque psoriasis. Behçet's Disease Clinical Trials OTEZLA was evaluated in a Phase 3, multicenter, randomized, placebo-controlled trial (BCT-002) in adult subjects with Behçet's Disease (BD) with active oral ulcers [see Clinical Studies (14.4) ] . A total of 207 subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1) ] . After Week 12, all subjects received treatment with OTEZLA 30 mg twice daily. Subjects ranged in age from 19 to 72, with a mean age of 40 years. Diarrhea, nausea, headache, and upper respiratory tract infection were the most commonly reported adverse reactions (see Table 4 ). The proportion of subjects with BD who discontinued treatment due to any adverse reaction during the placebo-controlled period of the trial, was 2.9% for subjects treated with OTEZLA 30 mg twice daily and 4.9% for placebo-treated subjects. Table 4: Adverse Reactions Reported in ≥ 5% of Subjects on OTEZLA and with at least 1% Greater Frequency than Subjects on Placebo up to Week 12 Adverse Reactions Placebo (N = 103) n (%) OTEZLA 30 mg twice daily (N = 104) n (%) Diarrhea 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 1 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

<table width="85%" ID="table2"><caption>Table 2: Adverse Reactions Reported in &#x2265; 2% of Subjects on OTEZLA 30 mg Twice Daily and &#x2265; 1% Than That Observed in Subjects on Placebo up to Day 112 (Week 16)</caption><col width="25%" align="left" valign="top"/><col width="16%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="19%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule"/><th colspan="2" styleCode="Lrule" valign="bottom">Placebo</th><th colspan="2" styleCode="Lrule Rrule" valign="bottom">OTEZLA 30 mg BID <footnote ID="K1167">BID = twice daily.</footnote></th></tr><tr><th align="center" styleCode="Lrule" valign="bottom">Adverse Reactions</th><th styleCode="Lrule" valign="bottom">Day 1 to 5 (N = 495) n (%) <footnote ID="K1183">n (%) indicates number of subjects and percent.</footnote></th><th styleCode="Lrule" valign="bottom">Day 6 to Day 112 (N = 490) n (%) </th><th styleCode="Lrule" valign="bottom">Day 1 to 5 (N = 497) n (%) </th><th styleCode="Lrule Rrule" valign="bottom">Day 6 to Day 112 (N = 493) n (%) </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule">Diarrhea <footnote ID="t2fa">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.</footnote></td><td styleCode="Lrule">6 (1.2)</td><td styleCode="Lrule">8 (1.6)</td><td styleCode="Lrule">46 (9.3)</td><td styleCode="Lrule Rrule">38 (7.7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Nausea <footnoteRef IDREF="t2fa"/></td><td styleCode="Lrule">7 (1.4)</td><td styleCode="Lrule">15 (3.1)</td><td styleCode="Lrule">37 (7.4)</td><td styleCode="Lrule Rrule">44 (8.9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Headache <footnoteRef IDREF="t2fa"/></td><td styleCode="Lrule">9 (1.8)</td><td styleCode="Lrule">11 (2.2)</td><td styleCode="Lrule">24 (4.8)</td><td styleCode="Lrule Rrule">29 (5.9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Upper respiratory tract infection <footnote ID="t2fb">Of the reported adverse drug reactions none were serious.</footnote></td><td styleCode="Lrule">3 (0.6)</td><td styleCode="Lrule">9 (1.8)</td><td styleCode="Lrule">3 (0.6)</td><td styleCode="Lrule Rrule">19 (3.9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Vomiting <footnoteRef IDREF="t2fa"/></td><td styleCode="Lrule">2 (0.4)</td><td styleCode="Lrule">2 (0.4)</td><td styleCode="Lrule">4 (0.8)</td><td styleCode="Lrule Rrule">16 (3.2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule">Nasopharyngitis <footnoteRef IDREF="t2fb"/></td><td styleCode="Lrule">1 (0.2)</td><td styleCode="Lrule">8 (1.6)</td><td styleCode="Lrule">1 (0.2)</td><td styleCode="Lrule Rrule">13 (2.6)</td></tr><tr><td styleCode="Lrule">Abdominal pain upper <footnoteRef IDREF="t2fb"/></td><td styleCode="Lrule">0 (0.0)</td><td styleCode="Lrule">1 (0.2)</td><td styleCode="Lrule">3 (0.6)</td><td styleCode="Lrule Rrule">10 (2.0)</td></tr></tbody></table>

<table width="85%" ID="table3"><caption>Table 3: Adverse Reactions Reported in &#x2265; 1% of Subjects on OTEZLA and With Greater Frequency Than in Subjects on Placebo up to Day 112 (Week 16)</caption><col width="34%" align="left" valign="bottom"/><col width="33%" align="center" valign="bottom"/><col width="33%" align="center" valign="bottom"/><thead><tr><th styleCode="Lrule Rrule">Adverse Reactions</th><th styleCode="Rrule">Placebo (N = 506) n (%) </th><th styleCode="Rrule">OTEZLA 30 mg BID <footnote ID="K1405"> BID = twice daily.</footnote>(N = 920) n (%) </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">32 (6)</td><td styleCode="Rrule">160 (17)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">35 (7)</td><td styleCode="Rrule">155 (17)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection</td><td styleCode="Rrule">31 (6)</td><td styleCode="Rrule">84 (9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Tension headache</td><td styleCode="Rrule">21 (4)</td><td styleCode="Rrule">75 (8)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">19 (4)</td><td styleCode="Rrule">55 (6)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal pain <footnote ID="K1471">Two subjects treated with OTEZLA experienced serious adverse reaction of abdominal pain.</footnote></td><td styleCode="Rrule">11 (2)</td><td styleCode="Rrule">39 (4)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">8 (2)</td><td styleCode="Rrule">35 (4)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">9 (2)</td><td styleCode="Rrule">29 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspepsia</td><td styleCode="Rrule">6 (1)</td><td styleCode="Rrule">29 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased appetite</td><td styleCode="Rrule">5 (1)</td><td styleCode="Rrule">26 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Insomnia</td><td styleCode="Rrule">4 (1)</td><td styleCode="Rrule">21 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Back pain</td><td styleCode="Rrule">4 (1)</td><td styleCode="Rrule">20 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Migraine</td><td styleCode="Rrule">5 (1)</td><td styleCode="Rrule">19 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Frequent bowel movements</td><td styleCode="Rrule">1 (0)</td><td styleCode="Rrule">17 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Depression</td><td styleCode="Rrule">2 (0)</td><td styleCode="Rrule">12 (1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Bronchitis</td><td styleCode="Rrule">2 (0)</td><td styleCode="Rrule">12 (1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Tooth abscess</td><td styleCode="Rrule">0 (0)</td><td styleCode="Rrule">10 (1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Folliculitis</td><td styleCode="Rrule">0 (0)</td><td styleCode="Rrule">9 (1)</td></tr><tr><td styleCode="Lrule Rrule">Sinus headache</td><td styleCode="Rrule">0 (0)</td><td styleCode="Rrule">9 (1)</td></tr></tbody></table>

<table width="75%" ID="table4"><caption>Table 4: Adverse Reactions Reported in &#x2265; 5% of Subjects on OTEZLA and with at least 1% Greater Frequency than Subjects on Placebo up to Week 12</caption><col width="36%" align="left" valign="middle"/><col width="32%" align="center" valign="middle"/><col width="32%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule">Adverse Reactions</th><th styleCode="Rrule">Placebo (N = 103) n (%) </th><th styleCode="Rrule">OTEZLA 30 mg twice daily (N = 104) n (%) </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea <footnote ID="t4fa">There were no serious adverse reactions of diarrhea, nausea or vomiting.</footnote></td><td styleCode="Rrule">21 (20.4)</td><td styleCode="Rrule">43 (41.3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea <footnoteRef IDREF="t4fa"/></td><td styleCode="Rrule">11 (10.7)</td><td styleCode="Rrule">20 (19.2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">11 (10.7)</td><td styleCode="Rrule">15 (14.4)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection</td><td styleCode="Rrule">5 (4.9)</td><td styleCode="Rrule">12 (11.5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal pain upper</td><td styleCode="Rrule">2 (1.9)</td><td styleCode="Rrule">9 (8.7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting <footnoteRef IDREF="t4fa"/></td><td styleCode="Rrule">2 (1.9)</td><td styleCode="Rrule">9 (8.7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Back pain</td><td styleCode="Rrule">6 (5.8)</td><td styleCode="Rrule">8 (7.7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Viral upper respiratory tract infection</td><td styleCode="Rrule">5 (4.9)</td><td styleCode="Rrule">7 (6.7)</td></tr><tr><td styleCode="Lrule Rrule">Arthralgia</td><td styleCode="Rrule">3 (2.9)</td><td styleCode="Rrule">6 (5.8)</td></tr></tbody></table>