The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Elevated Liver Enzymes and Drug-Induced Liver Injury [see Warnings and Precautions (5.2) ] Gastrointestinal Disorders [see Warnings and Precautions (5.3) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.4) ] Arterial Thromboembolic Events [see Warnings and Precautions (5.5) ] Risk of Bleeding [see Warnings and Precautions (5.6) ] Gastrointestinal Perforation [see Warnings and Precautions (5.7) ] Nephrotic Range Proteinuria [see Warnings and Precautions (5.8) ] Most common adverse reactions (≥5%) are: diarrhea, nausea, abdominal pain, vomiting, liver enzyme elevation, decreased appetite, headache, weight decreased, and hypertension.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Edenbridge Pharmaceuticals, LLC., DBA Dexcel Pharma USA, at 1-877-381-3336 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical 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 practice. The safety of nintedanib capsules was evaluated in over 1000 IPF patients, and 332 patients with chronic fibrosing ILDs with a progressive phenotype. Over 200 IPF patients were exposed to nintedanib capsules for more than 2 years in clinical trials.
Idiopathic Pulmonary Fibrosis Nintedanib capsules were studied in three randomized, double-blind, placebo-controlled, 52-week trials. In the phase 2 (Study 1) and phase 3 (Study 2 and Study 3) trials, 723 patients with IPF received nintedanib capsules 150 mg twice daily and 508 patients received placebo. The median duration of exposure was 10 months for patients treated with nintedanib capsules and 11 months for patients treated with placebo.
Subjects ranged in age from 42 to 89 years (median age of 67 years). Most patients were male (79%) and Caucasian (60%). The most frequent serious adverse reactions reported in patients treated with nintedanib capsules, more than placebo, were bronchitis (1.2% vs. 0.8%) and myocardial infarction (1.5% vs. 0.4%). The most common adverse events leading to death in patients treated with nintedanib capsules, more than placebo, were pneumonia (0.7% vs. 0.6%), lung neoplasm malignant (0.3% vs. 0%), and myocardial infarction (0.3% vs. 0.2%).
In the predefined category of major adverse cardiovascular events (MACE) including MI, fatal events were reported in 0.6% of nintedanib capsules- treated patients and 1.8% of placebo-treated patients. Adverse reactions leading to permanent dose reductions were reported in 16% of nintedanib capsules-treated patients and 1% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with nintedanib capsules was diarrhea (11%).
Adverse reactions leading to discontinuation were reported in 21% of nintedanib capsules-treated patients and 15% of placebo-treated patients. The most frequent adverse reactions that led to discontinuation in nintedanib capsules-treated patients were diarrhea (5%), nausea (2%), and decreased appetite (2%). The most common adverse reactions with an incidence of greater than or equal to 5% and more frequent in the nintedanib capsules than placebo treatment group are listed in Table 1.
In addition, hypothyroidism was reported in patients treated with nintedanib capsules, more than placebo (1.1% vs. 0.6%). Alopecia was also reported in more patients treated with nintedanib capsules than placebo (0.8% vs. 0.4%). Combination with Pirfenidone Concomitant treatment with nintedanib and pirfenidone was investigated in an exploratory open-label, randomized (1:1) trial of nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times a day) compared to nintedanib 150 mg twice daily alone in 105 randomized patients for 12 weeks.
The primary endpoint was the percentage of patients with gastrointestinal adverse events from baseline to Week 12. Gastrointestinal adverse events were in line with the established safety profile of each component and were experienced in 37 (70%) patients treated with pirfenidone added to nintedanib versus 27 (53%) patients treated with nintedanib alone. Diarrhea, nausea, vomiting, and abdominal pain (includes upper abdominal pain, abdominal discomfort, and abdominal pain) were the most frequent adverse events reported in 20 (38%) versus 16 (31%), in 22 (42%) versus 6 (12%), in 15 (28%) versus 6 (12%), and in 15 (28%) versus 7 (14%) patients treated with pirfenidone added to nintedanib versus nintedanib alone, respectively.
More subjects reported AST or ALT elevations (greater than or equal to 3 times the upper limit of normal) when using pirfenidone in combination with nintedanib (n=3 (6%)) compared to nintedanib alone (n=0) [see Warnings and Precautions (5.2 , 5.3) ] . Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype Nintedanib capsules were studied in a phase 3, double-blind, placebo-controlled trial (Study 5) in which 663 patients with chronic fibrosing ILDs with a progressive phenotype were randomized to receive nintedanib capsules 150 mg twice daily (n=332) or placebo (n=331) for at least 52 weeks.
At 52 weeks, the median duration of exposure was 12 months for patients in both treatment arms. Subjects ranged in age from 27 to 87 years (median age of 67 years). The majority of patients were Caucasian (74%) or Asian (25%). Most patients were male (54%). The most frequent serious adverse event reported in patients treated with nintedanib capsules, more than placebo, was pneumonia (4% vs. 3%). Adverse events leading to death were reported in 3% of patients treated with nintedanib capsules and in 5% of patients treated with placebo.
No pattern was identified in the adverse events leading to death. Adverse reactions leading to permanent dose reductions were reported in 33% of nintedanib capsules-treated patients and 4% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with nintedanib capsules was diarrhea (16%). Adverse reactions leading to discontinuation were reported in 20% of nintedanib capsules-treated patients and 10% of placebo-treated patients.
The most frequent adverse reaction that led to discontinuation in nintedanib capsules-treated patients was diarrhea (6%). The safety profile in patients with chronic fibrosing ILDs with a progressive phenotype treated with nintedanib capsules was consistent with that observed in IPF patients. In addition, the following adverse events were reported in nintedanib capsules more than placebo in chronic progressive fibrosing ILD: nasopharyngitis (13% vs. 12%), upper respiratory tract infection (7% vs 6%), urinary tract infection (6% vs. 4%), fatigue (10% vs. 6%), and back pain (6% vs. 5%). 1
