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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 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 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 behaviour, prescribers should carefully weigh the risks and benefits of treatment with apremilast tablets. 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 apremilast tablets 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 apremilast tablets reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1,441) of subjects treated with apremilast tablets 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% (3/1,441) of subjects exposed to apremilast tablets, compared to none in placebo-treated subjects (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1,441) of subjects while receiving apremilast tablets, compared to none in placebo treated subjects (0/495). In the clinical trials, 2 subjects who received placebo committed suicide compared to none in apremilast tablets-treated subjects. 5.4 Weight Decrease During the placebo-controlled period of the trials in psoriatic arthritis (PsA), weight decrease between 5% to 10% of body weight was reported in 10% (49/497) of subjects treated with apremilast tablets 30 mg twice daily compared to 3.3% (16/495) treated with placebo. Patients treated with apremilast tablets should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of apremilast tablets 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 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 )] • Psoriatic Arthritis: The most common adverse reactions (≥ 5%) are diarrhea, nausea, and headache ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Annora Pharma Private Limited at 1-866-495-1995 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 Apremilast 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 1,493 subjects randomized equally to placebo, apremilast 20 mg twice daily or apremilast 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 apremilast 20 mg twice daily or 30 mg twice daily at week 16 while apremilast 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 apremilast 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 apremilast 30 mg twice daily and 1.2% for placebo-treated subjects. Table 2: Adverse Reactions Reported in ≥ 2% of Subjects on Apremilast 30 mg Twice Daily and ≥ 1% Than That Observed in Subjects on Placebo up to Day 112 (Week 16) Placebo Apremilast 30 mg BID d Adverse Reactions Day 1 to 5 (N = 495) n (%) c Day 6 to Day 112 (N = 490) n (%) Day 1 to 5 (N = 497) n (%) Day 6 to Day 112 (N = 493) n (%) Diarrhea a 6 (1.2) 8 (1.6) 46 (9.3) 38 (7.7) Nausea a 7 (1.4) 15 (3.1) 37 (7.4) 44 (8.9) Headache a 9 (1.8) 11 (2.2) 24 (4.8) 29 (5.9) Upper respiratory tract infection b 3 (0.6) 9 (1.8) 3 (0.6) 19 (3.9) Vomiting a 2 (0.4) 2 (0.4) 4 (0.8) 16 (3.2) Nasopharyngitis b 1 (0.2) 8 (1.6) 1 (0.2) 13 (2.6) Abdominal pain upper b 0 (0.0) 1 (0.2) 3 (0.6) 10 (2.0) a Of the reported gastrointestinal adverse reactions, 1 subject experienced a serious adverse reaction of nausea and vomiting in apremilast 30 mg twice daily; 1 subject treated with apremilast 20 mg twice daily experienced a serious adverse reaction of diarrhea; 1 subject treated with apremilast 30 mg twice daily experienced a serious adverse reaction of headache. b Of the reported adverse drug reactions none were serious. c n (%) indicates number of subjects and percent. d BID = twice daily. Other adverse reactions reported in subjectson apremilast inpsoriatic arthritis clinicaltrials are: • Gastrointestinal Disorders: Gastroesophageal reflux disease • Immune System Disorders: Hypersensitivity • Investigations: Weight decrease • Metabolism and Nutrition Disorders: Decreasedappetite* • Nervous System Disorders: Migraine • Respiratory, Thoracic, and Mediastinal Disorders: Cough • Skin and Subcutaneous Tissue Disorders: Rash *1 subjecttreated with apremilast 30 mg twice daily experienced a serious adverse reaction.