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 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 and institute appropriate therapy ( 5.1 ). Diarrhea, Nausea, and Vomiting : Consider apremilast 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 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. ( 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 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 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. 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 generally improved quickly. Consider apremilast dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting. 5.3 Depression Treatment with apremilast is associated with an increase incidence of depression. Before using apremilast in patients with a history of depression and/or suicidal thoughts or behavior, carefully weigh the risks and benefits of treatment with apremilast. 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 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 reported depression compared to 0.4% (2/506) treated with placebo. During the clinical trials, 0.1% (1/1,308) of subjects treated with apremilast discontinued treatment due to depression compared with none in placebo-treated subjects (0/506). Depression was reported as serious in 0.1% (1/1,308) of subjects exposed to apremilast, compared to none in placebo-treated subjects (0/506). Instances of suicidal behavior have been observed in 0.1% (1/1,308) of subjects while receiving apremilast, compared to 0.2% (1/506) in placebo-treated subjects. In the clinical trials, one subject treated with apremilast 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. Regularly monitor the weight of patients treated with apremilast. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of apremilast [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% to 10% of body weight occurred in 12% (96/784) of subjects treated with apremilast 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 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. Therefore, the use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with apremilast is not recommended [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] .