Treatment with OFEV® is not recommended in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Patients with mild hepatic impairment (Child Pugh A) can be treated with a reduced dose of OFEV®
 

Cases of drug-induced liver injury (DILI) have been observed with OFEV® 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 OFEV® 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. In the SSc-ILD study (Study 4), a maximum ALT and/or AST greater than or equal to 3 times ULN was observed for 4.9% of patients in the OFEV® group and for 0.7% of patients in the placebo group. 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. Conduct liver function tests (ALT, AST, and bilirubin) prior to initiation of treatment with OFEV®, 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.
 

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 OFEV® and placebo, respectively [see Adverse Reactions (6.1)]. Diarrhea led to permanent dose reduction in 11% of patients treated with OFEV® compared to 0 placebo-treated patients. Diarrhea led to discontinuation of OFEV® 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 OFEV® and placebo, respectively [see Adverse Reactions (6.1)]. Diarrhea led to permanent dose reduction in 16% of patients treated with OFEV® compared to less than 1% of placebo-treated patients. Diarrhea led to discontinuation of OFEV® in 6% of the patients compared to less than 1% of placebo-treated patients. In the SSc-ILD study (Study 4), diarrhea was reported in 76% versus 32% of patients treated with OFEV® and placebo, respectively. Diarrhea led to permanent dose reduction in 22% of patients treated with OFEV® compared to 1% of placebo-treated patients. Diarrhea led to discontinuation of OFEV® 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. OFEV® 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 OFEV®.

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 OFEV® 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 OFEV® and placebo, respectively. In the SSc-ILD study (Study 4), nausea was reported in 32% versus 14% and vomiting was reported in 25% versus 10% of patients treated with OFEV® and placebo, respectively. 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 of OFEV® in 2% of patients and vomiting led to discontinuation of OFEV® in 1% of the patients. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), nausea led to discontinuation of OFEV® in less than 1% of patients and vomiting led to discontinuation of OFEV® in 1% of the patients. In the SSc-ILD study (Study 4), nausea led to discontinuation of OFEV® in 2% of patients and vomiting led to discontinuation of OFEV® in 1% of the patients. For nausea or vomiting that persists despite appropriate supportive care including anti-emetic therapy, dose reduction or treatment interruption may be required. OFEV® 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 nausea or vomiting does not resolve, discontinue treatment with OFEV®. 

Based on findings from animal studies and its mechanism of action, OFEV® can cause fetal harm when administered to a pregnant woman. Nintedanib caused embryo-fetal deaths and structural abnormalities in rats and rabbits when administered during organogenesis at less than (rats) and approximately 5 times (rabbits) the maximum recommended human dose (MRHD) in adults. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to avoid becoming pregnant while receiving treatment with OFEV® and to use highly effective contraception during treatment and at least 3 months after the last dose of OFEV®. It is currently unknown whether nintedanib may reduce the effectiveness of hormonal contraceptives, therefore advise women using hormonal contraceptives to add a barrier method. Verify pregnancy status prior to treatment with OFEV® and during treatment as appropriate. 

Arterial thromboembolic events have been reported in patients taking OFEV®. In IPF studies (Study 1, Study 2, and Study 3), arterial thromboembolic events were reported in 2.5% of patients treated with OFEV® and less than 1% of placebo-treated patients. Myocardial infarction was the most common adverse reaction under arterial thromboembolic events, occurring in 1.5% of OFEV®-treated patients compared to less than 1% of placebo treated patients. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), arterial thromboembolic events were reported in less than 1% of patients in both treatment arms. Myocardial infarction was observed in less than 1% of patients in both treatment arms. In the SSc-ILD study (Study 4), arterial thromboembolic events were reported in 0.7% of patients in both treatment arms. There were 0 cases of myocardial infarction in OFEV®-treated patients compared to 0.7% of placebo-treated patients. Use caution when treating patients at higher cardiovascular risk including known coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia. 

Based on the mechanism of action (VEGFR inhibition), OFEV® may increase the risk of bleeding. In IPF studies (Study 1, Study 2, and Study 3), bleeding events were reported in 10% of patients treated with OFEV® and in 7% of patients treated with placebo. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), bleeding events were reported in 11% of patients treated with OFEV® and in 13% of patients treated with placebo. In the SSc-ILD study (Study 4), bleeding events were reported in 11% of patients treated with OFEV® and in 8% of patients treated with placebo. In clinical trials, epistaxis was the most frequent bleeding event reported. In the postmarketing period non-serious and serious bleeding events, some of which were fatal, have been observed. Use OFEV® in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.

Based on the mechanism of action, OFEV® may increase the risk of gastrointestinal perforation. In IPF studies (Study 1, Study 2, and Study 3), gastrointestinal perforation was reported in less than 1% of patients treated with OFEV®, compared to 0 cases in the placebo-treated patients. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), gastrointestinal perforation was not reported in any patients in any treatment arm. In the SSc-ILD study (Study 4), no cases of gastrointestinal perforation were reported in patients treated with OFEV® or in placebo-treated patients. In the postmarketing period, cases of gastrointestinal perforations have been reported, some of which were fatal. Use caution when treating patients who have had recent abdominal surgery, previous history of diverticular disease or receiving concomitant corticosteroids or NSAIDs. Discontinue therapy with OFEV® in patients who develop gastrointestinal perforation. Only use OFEV® in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk.