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Treatment with nintedanib is not recommended for patients with moderate
hepatic impairment (Child-Pugh Class B) or severe hepatic impairment (Child-Pugh
Class C). Patients with mild hepatic impairment (Child-Pugh Class A) may receive
nintedanib at a reduced dose.
Cases of drug-induced liver injury (DILI) have been observed in patients
treated with nintedanib. Both non-serious and serious DILI cases have been
reported in clinical trials and post-marketing settings; fatal cases of severe
liver injury have also been reported during the post-marketing period. Most
hepatic events occur within the first three months of treatment. In clinical
trials, nintedanib administration was associated with elevations in liver
enzymes (ALT, AST, ALKP, GGT) and bilirubin. In most cases, these elevations are
reversible with dose adjustment or treatment interruption.In IPF studies
(Studies 1, 2, and 3), the majority (94%) of patients with elevated ALT and/or
AST had levels less than 5 times the upper limit of normal (ULN), and the
majority (95%) of patients with elevated bilirubin had levels less than 2 times
the ULN.In the study of chronic fibrosing ILD with a progressive phenotype
(Study 5), the majority (95%) of patients with elevated ALT and/or AST had
levels less than 5 times the ULN, and the majority (94%) of patients with
elevated bilirubin had levels less than 2 times the ULN.In the SSc-ILD study
(Study 4), maximum ALT and/or AST levels ≥ 3 times the ULN were observed in 4.9%
of patients in the nintedanib group and 0.7% of patients in the placebo
group.
Patients with low body weight (less than 65 kg), Asian ethnicity, and female
sex may be at a higher risk of elevated liver enzymes. Nintedanib exposure
increases with age, which may also contribute to an increased risk of elevated
liver enzymes.
Perform liver function tests (ALT, AST, and bilirubin) prior to the
initiation of nintedanib treatment, periodically during the first three months
of treatment, and thereafter at regular intervals or as clinically indicated.
Measure liver function promptly in patients reporting symptoms that may indicate
liver injury, including fatigue, anorexia, right upper quadrant discomfort, dark
urine, or jaundice. Dose adjustment or treatment interruption may be required
for elevated liver enzymes.
Diarrhea was the most frequently reported gastrointestinal event in clinical
trials. In most patients, the events were mild to moderate in severity and
occurred within the first three months of treatment.In IPF studies (Studies 1,
2, and 3), diarrhea was reported in 62% of patients receiving nintedanib versus
18% of patients receiving placebo. Diarrhea led to permanent dose reduction in
11% of nintedanib-treated patients versus 0% of placebo-treated patients, and
treatment discontinuation in 5% of nintedanib-treated patients versus less than
1% of placebo-treated patients.In the study of chronic fibrosing ILD with a
progressive phenotype (Study 5), diarrhea was reported in 67% of patients
receiving nintedanib versus 24% of patients receiving placebo. Diarrhea led to
permanent dose reduction in 16% of nintedanib-treated patients versus less than
1% of placebo-treated patients, and treatment discontinuation in 6% of
nintedanib-treated patients versus less than 1% of placebo-treated patients.In
the SSc-ILD study (Study 4), diarrhea was reported in 76% of patients receiving
nintedanib versus 32% of patients receiving placebo. Diarrhea led to permanent
dose reduction in 22% of nintedanib-treated patients versus 1% of
placebo-treated patients, and treatment discontinuation in 7% of
nintedanib-treated patients versus 0.3% of placebo-treated patients.
Dose adjustment or treatment interruption may be required for patients who
develop diarrhea as an adverse reaction. Treat diarrhea at the first sign of
onset, including adequate hydration and the use of antidiarrheal agents (e.g.,
loperamide). If diarrhea persists, consider dose reduction or treatment
interruption. Nintedanib therapy may be resumed at the full dose (150 mg twice
daily) or the reduced dose (100 mg twice daily), with subsequent escalation back
to the full dose if tolerated. Discontinue nintedanib treatment if severe
diarrhea persists despite symptomatic management.
In IPF studies (Studies 1, 2, and 3), nausea was reported in 24% of patients
receiving nintedanib versus 7% of patients receiving placebo, and vomiting was
reported in 12% of patients receiving nintedanib versus 3% of patients receiving
placebo.In the study of chronic fibrosing ILD with a progressive phenotype
(Study 5), nausea was reported in 29% of patients receiving nintedanib versus 9%
of patients receiving placebo, and vomiting was reported in 18% of patients
receiving nintedanib versus 5% of patients receiving placebo.In the SSc-ILD
study (Study 4), nausea was reported in 32% of patients receiving nintedanib
versus 14% of patients receiving placebo, and vomiting was reported in 25% of
patients receiving nintedanib versus 10% of patients receiving placebo.
In most patients, these events were mild to moderate in severity. In IPF
studies (Studies 1, 2, and 3), nausea led to treatment discontinuation in 2% of
nintedanib-treated patients, and vomiting led to treatment discontinuation in 1%
of nintedanib-treated patients. In the study of chronic fibrosing ILD with a
progressive phenotype (Study 5), nausea led to treatment discontinuation in less
than 1% of nintedanib-treated patients, and vomiting led to treatment
discontinuation in 1% of nintedanib-treated patients. In the SSc-ILD study
(Study 4), nausea led to treatment discontinuation in 2% of nintedanib-treated
patients, and vomiting led to treatment discontinuation in 1% of
nintedanib-treated patients.
Dose reduction or treatment interruption may be required for persistent
nausea or vomiting despite appropriate supportive care, including antiemetic
therapy. Nintedanib therapy may be resumed at the full dose (150 mg twice daily)
or the reduced dose (100 mg twice daily), with subsequent escalation back to the
full dose if tolerated. Discontinue nintedanib treatment if severe nausea or
vomiting does not resolve.
Based on findings from animal studies and its mechanism of action, nintedanib
may cause fetal harm when administered to pregnant women. Administration of
nintedanib to rats and rabbits during organogenesis resulted in embryo-fetal
death and structural abnormalities at doses below (rats) and approximately 5
times (rabbits) the maximum recommended human dose (MRHD). Advise pregnant women
of the potential risk to the fetus.Advise females of reproductive potential to
avoid pregnancy during treatment with nintedanib and to use effective
contraception at the start of treatment, during treatment, and for at least 3
months after the last dose. Nintedanib does not alter the exposure to oral
contraceptives containing ethinyl estradiol and levonorgestrel in patients with
SSc-ILD. However, the efficacy of oral hormonal contraceptives may be reduced in
cases of vomiting and/or diarrhea or other conditions that may decrease drug
absorption. Advise females taking oral hormonal contraceptives who experience
these conditions to use an alternative effective contraceptive method. Verify
pregnancy status before and during nintedanib treatment as clinically
appropriate.
Arterial thromboembolic events have been reported in patients treated with
nintedanib. In IPF studies (Studies 1, 2, and 3), arterial thromboembolic events
were reported in 2.5% of patients receiving nintedanib versus less than 1% of
patients receiving placebo. Myocardial infarction was the most common adverse
reaction under the category of arterial thromboembolic events, occurring in 1.5%
of nintedanib-treated patients versus less than 1% of placebo-treated
patients.In the study of chronic fibrosing ILD with a progressive phenotype
(Study 5), arterial thromboembolic events were reported in less than 1% of
patients in both treatment groups, and myocardial infarction was observed in
less than 1% of patients in both treatment groups.In the SSc-ILD study (Study
4), arterial thromboembolic events were reported in 0.7% of patients in both
treatment groups. There were no cases of myocardial infarction in the nintedanib
group versus 0.7% in the placebo group.
Use caution when treating patients with a high cardiovascular risk profile,
including known coronary artery disease. Consider treatment interruption in
patients presenting with signs or symptoms of acute myocardial ischemia.
Based on its mechanism of action (VEGFR inhibition), nintedanib may increase
the risk of bleeding. In IPF studies (Studies 1, 2, and 3), bleeding events were
reported in 10% of patients receiving nintedanib versus 7% of patients receiving
placebo. In the study of chronic fibrosing ILD with a progressive phenotype
(Study 5), bleeding events were reported in 11% of patients receiving nintedanib
versus 13% of patients receiving placebo. In the SSc-ILD study (Study 4),
bleeding events were reported in 11% of patients receiving nintedanib versus 8%
of patients receiving placebo. Epistaxis was the most frequently reported
bleeding event in clinical trials.
Non-serious and serious bleeding events, some of which were fatal, have been
observed during the post-marketing period.
Use nintedanib in patients with known bleeding risk only if the expected
benefit outweighs the potential risk.
FDA，2024.10
