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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypersensitivity: Cases of angioedema and anaphylaxis have been reported during post marketing surveillance. Avoid the use of apremilast tablets 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 apremilast tablets and institute appropriate therapy (5.1). Diarrhea, Nausea, and Vomiting : Consider apremilast tablets 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 apremilast tablets 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 apremilast tablets (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 apremilast tablets 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 apremilast tablets 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 apremilast tablets. 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 apremilast tablets generally improved quickly. Consider apremilast tablets dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting. 5.3 Depression Treatment with apremilast tablets is associated with an increased incidence of depression. Before using apremilast tablets in patients with a history of depression and/or suicidal thoughts or behavior, carefully weigh the risks and benefits of treatment with apremilast tablets. 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 apremilast tablets if such events occur. 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 apremilast tablets reported depression compared to 0.4% (2/506) treated with placebo. During the clinical trials, 0.1% (1/1308) of subjects treated with apremilast tablets 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 apremilast tablets, 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 apremilast tablets, compared to 0.2% (1/506) in placebo- treated subjects. In the clinical trials, one subject treated with apremilast tablets 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. 5.4 Weight Decrease Weight loss may occur in adult or pediatric patients treated with apremilast tablets. Regularly monitor the weight of patients treated with apremilast tablets. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of apremilast tablets [see Adverse Reactions (6.1)] . Weight Loss in Adult Patients 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 apremilast tablets compared to 5% (19/382) treated with placebo. Weight decrease of ≥10% of body weight occurred in 2% (16/784) of subjects treated with apremilast tablets 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. Pediatric use information is approved for Amgen Inc.'s Otezla (apremilast) Tablets. However, due to Amgen Inc.'s marketing exclusivity rights, this drug product is not labeled with that information . 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 apremilast tablets. Therefore, the use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with apremilast tablets 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)] Plaque Psoriasis: The most common adverse reactions (≥5%) are diarrhea, nausea, upper respiratory tract infection, and headache, including tension headache (6.1) ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lifestar Pharma LLC at 1-888-995-4337 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. Moderate to Severe Plaque Psoriasis Clinical Trials Adverse Reactions from Clinical Trials in Adults The safety of apremilast tablets 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 apremilast tablets 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 apremilast tablets 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 apremilast tablets 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 apremilast tablets and With Greater Frequency Than in Subjects on Placebo up to Day 112 (Week 16) a Two subjects treated with apremilast tablets experienced serious adverse reaction of abdominal pain. b BID = twice daily Adverse Reactions Placebo (N=506) n (%) Apremilast tablets 30 mg BID b (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 a 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 apremilast tablets. Apremilast tablets were 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 apremilast tablets 30 mg twice daily or placebo twice daily. The most commonly reported adverse reactions that occurred at a higher rate in the apremilast tablets 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 apremilast tablets 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 apremilast tablets group compared to placebo. Mild to Moderate Plaque Psoriasis Clinical Trial in Adults Apremilast tablets were 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 apremilast tablets 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 apremilast tablets were 30 mg twice daily. Overall, the safety profile observed in the apremilast tablets group during the placebo- controlled phase was consistent with the safety profile previously established in adult subjects with moderate to severe plaque psoriasis. Other adverse reactions reported in subjects on apremilast tablets in plaque psoriasis clinical trials are: Gastrointestinal Disorders: Gastroesophageal reflux disease Immune System Disorders: Hypersensitivity Investigations: Weight decrease Metabolism and Nutrition Disorders: Decreased appetite* Nervous System Disorders: Migraine Respiratory, Thoracic, and Mediastinal Disorders: Cough Skin and Subcutaneous Tissue Disorders: Rash *1 subject treated with apremilast tablets 30 mg twice daily experienced a serious adverse reaction. Pediatric use information is approved for Amgen Inc.'s Otezla (apremilast) Tablets. However, due to Amgen Inc.'s marketing exclusivity rights, this drug product is not labeled with that information .