nintedanib esylate

Important safety information

Hepatic impairment: Nintedanib capsules are not recommended for use in patients with moderate or severe hepatic impairment. In patients with mild hepatic impairment (Child Pugh A), the recommended dosage is 100 mg twice daily approximately 12 hours apart taken with food. Consider treatment interruption, or discontinuation for management of adverse reactions in these patients. ( 2.3 , 2.4 , 5.1 , 8.6 , 12.3 ) Elevated liver enzymes and drug-induced liver injury: ALT, AST, and bilirubin elevations have occurred with nintedanib, including cases of drug-induced liver injury. In the postmarketing period, non-serious and serious cases of drug-induced liver injury, including severe liver injury with fatal outcome, have been reported. The majority of hepatic events occur within the first three months of treatment. Liver enzyme and bilirubin increases were reversible with dose modification or interruption in the majority of cases. Monitor ALT, AST, and bilirubin prior to initiation of treatment, at regular intervals during the first three months of treatment, and periodically thereafter or as clinically indicated. Temporary dosage reductions or discontinuations may be required. ( 2.1 , 2.4 , 5.2 ) Gastrointestinal disorders: Diarrhea, nausea, and vomiting have occurred with nintedanib. Treat patients at first signs with adequate hydration and antidiarrheal medicine (e.g., loperamide) or anti-emetics. Discontinue nintedanib capsules if severe diarrhea, nausea, or vomiting persists despite symptomatic treatment. ( 5.3 ) Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use highly effective contraception. Advise women taking oral hormonal contraceptives experiencing vomiting, diarrhea, or other conditions where the drug absorption may be reduced to use alternative highly effective contraception. ( 5.4 , 8.1 , 8.3 ) Arterial thromboembolic events have been reported. Use caution when treating patients at higher cardiovascular risk including known coronary artery disease. ( 5.5 ) Bleeding events have been reported. Use nintedanib capsules in patients with known bleeding risk only if anticipated benefit outweighs the potential risk. ( 5.6 ) Gastrointestinal perforation has been reported. Use nintedanib capsules with caution when treating patients with recent abdominal surgery, previous history of diverticular disease or receiving concomitant corticosteroids or NSAIDs. Discontinue nintedanib capsules in patients who develop gastrointestinal perforation. Only use nintedanib capsules in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk. ( 5.7 ) Nephrotic range proteinuria has been reported. Consider treatment interruption in patients who develop new or worsening proteinuria. ( 5.8 ) 5.1 Hepatic Impairment Treatment with nintedanib capsules is not recommended in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] . Patients with mild hepatic impairment (Child Pugh A) can be treated with a reduced dose of nintedanib capsules [see Dosage and Administration ( 2.3 )]. 5.2 Elevated Liver Enzymes and Drug-Induced Liver Injury Cases of drug-induced liver injury (DILI) have been observed with nintedanib treatment. In the clinical trials and postmarketing period, non-serious and serious cases of DILI were reported. Cases of severe liver injury with fatal outcome have been reported in the postmarketing period. The majority of hepatic events occur within the first three months of treatment. In clinical trials, administration of nintedanib was associated with elevations of liver enzymes (ALT, AST, ALKP, GGT) and bilirubin. Liver enzyme and bilirubin increases were reversible with dose modification or interruption in the majority of cases. In IPF studies (Study 1, Study 2, and Study 3), the majority (94%) of patients with ALT and/or AST elevations had elevations less than 5 times ULN and the majority (95%) of patients with bilirubin elevations had elevations less than 2 times ULN. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), the majority (95%) of patients with ALT and/or AST elevations had elevations less than 5 times ULN and the majority (94%) of patients with bilirubin elevations had elevations less than 2 times ULN [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] . Patients with a low body weight (less than 65 kg), Asian, and female patients may have a higher risk of elevations in liver enzymes. Nintedanib exposure increased with patient age, which may also result in a higher risk of increased liver enzymes [see Clinical Pharmacology ( 12.3 )]. Conduct liver function tests (ALT, AST, and bilirubin) prior to initiation of treatment with nintedanib capsules, at regular intervals during the first three months of treatment, and periodically thereafter or as clinically indicated. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. Dosage modifications or interruption may be necessary for liver enzyme elevations [see Dosage and Administration ( 2.1 , 2.4 )]. 5.3 Gastrointestinal Disorders Diarrhea In clinical trials, diarrhea was the most frequent gastrointestinal event reported. In most patients, the event was of mild to moderate intensity and occurred within the first 3 months of treatment. In IPF studies (Study 1, Study 2, and Study 3), diarrhea was reported in 62% versus 18% of patients treated with nintedanib and placebo, respectively [see Adverse Reactions ( 6.1 )] . Diarrhea led to permanent dose reduction in 11% of patients treated with nintedanib compared to 0 placebo-treated patients. Diarrhea led to discontinuation of nintedanib in 5% of the patients compared to less than 1% of placebo-treated patients. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), diarrhea was reported in 67% versus 24% of patients treated with nintedanib and placebo, respectively [see Adverse Reactions ( 6.1 )]. Diarrhea led to permanent dose reduction in 16% of patients treated with nintedanib compared to less than 1% of placebo-treated patients. Diarrhea led to discontinuation of nintedanib in 6% of the patients compared to less than 1% of placebo-treated patients [see Adverse Reactions ( 6.1 )]. Diarrhea led to permanent dose reduction in 22% of patients treated with nintedanib compared to 1% of placebo-treated patients. Diarrhea led to discontinuation of nintedanib in 7% of the patients compared to 0.3% of placebo-treated patients. Dosage modifications or treatment interruptions may be necessary in patients with adverse reactions of diarrhea. Treat diarrhea at first signs with adequate hydration and antidiarrheal medication (e.g., loperamide), and consider dose reduction or treatment interruption if diarrhea continues [see Dosage and Administration ( 2.4 )] . Nintedanib capsules treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe diarrhea persists despite symptomatic treatment, discontinue treatment with nintedanib capsules. Nausea and Vomiting In IPF studies (Study 1, Study 2, and Study 3), nausea was reported in 24% versus 7% and vomiting was reported in 12% versus 3% of patients treated with nintedanib and placebo, respectively. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), nausea was reported in 29% versus 9% and vomiting was reported in 18% versus 5% of patients treated with nintedanib and placebo, respectively [see Adverse Reactions ( 6.1 )] . In most patients, these events were of mild to moderate intensity. In IPF studies (Study 1, Study 2, and Study 3), nausea led to discontinuation…