Ofev

None None ( 4 )

• Hepatic impairment:
• OFEV is 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.
• ( 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 OFEV, 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.
• ( 2.1 , 2.4 , 5.2 ) Gastrointestinal disorders:
• Diarrhea, nausea, and vomiting have occurred with OFEV.
• Treat patients at first signs with adequate hydration and antidiarrheal medicine (e.g., loperamide) or anti-emetics.
• Discontinue OFEV 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 OFEV in patients with known bleeding risk only if anticipated benefit outweighs the potential risk.
• ( 5.6 ) Gastrointestinal perforation has been reported.
• Use OFEV with caution when treating patients with recent abdominal surgery, previous history of diverticular disease or receiving concomitant corticosteroids or NSAIDs.
• Discontinue 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.
• ( 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 OFEV 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 OFEV [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 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 [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 OFEV, at regular intervals during the first three months of treatment, and periodically thereafter or as clinically indicated.
• 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 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 [see Adverse Reactions (6.1) ].
• 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 [see Dosage and Administration (2.4) ].
• 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 [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 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 [see Dosage and Administration (2.4) ] .
• If severe nausea or vomiting does not resolve, discontinue treatment with OFEV.
• 5.4 Embryo-Fetal Toxicity 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.
• avoid becoming pregnant while receiving treatment with OFEV and to use highly effective contraception at initiation of, during treatment, and at least 3 months after the last dose of OFEV.
• Verify pregnancy status prior to treatment with OFEV and during treatment as appropriate [see Use in Specific Populations (8.1 , 8.3) and Clinical Pharmacology (12.1 , 12.3) ].
• 5.5 Arterial Thromboembolic Events 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.
• 5.6 Risk of Bleeding 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.
• 5.7 Gastrointestinal Perforation 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.
• 5.8 Nephrotic Range Proteinuria Cases of proteinuria within the nephrotic range have been reported in the postmarketing period.
• Histological findings, when available, were consistent with glomerular microangiopathy with or without renal thrombi.
• Improvement in proteinuria has been observed after OFEV was discontinued; however, in some cases, residual proteinuria persisted.
• Consider treatment interruption in patients who develop new or worsening proteinuria.

• Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , OFEV can cause fetal harm when administered to a pregnant woman.
• There are no data on the use of OFEV during pregnancy.
• In animal studies of pregnant rats and rabbits treated during organogenesis, nintedanib caused embryo-fetal deaths and structural abnormalities at less than (rats) and approximately 5 times (rabbits) the maximum recommended human dose [see Data ] .
• Advise pregnant women of the potential risk to a fetus.
• The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
• In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and miscarriage in clinically recognized pregnancies is 15% to 20%.
• Data Animal Data In animal reproduction toxicity studies, nintedanib caused embryo-fetal deaths and structural abnormalities in rats and rabbits at less than and approximately 5 times the maximum recommended human dose (MRHD) in
• adults (on a plasma AUC basis at maternal oral doses of 2.5 and 15 mg/kg/day in rats and rabbits, respectively).
• Malformations included abnormalities in the vasculature, urogenital, and skeletal systems.
• Vasculature anomalies included missing or additional major blood vessels.
• Skeletal anomalies included abnormalities in the thoracic, lumbar, and caudal vertebrae (e.g., hemivertebra, missing, or asymmetrically ossified), ribs (bifid or fused), and sternebrae (fused, split, or unilaterally ossified).
• In some fetuses, organs in the urogenital system were missing.
• In rabbits, a significant change in sex ratio was observed in fetuses (female:male ratio of approximately 71%:29%) at approximately 15 times the MRHD in
• adults (on an AUC basis at a maternal oral dose of 60 mg/kg/day).
• Nintedanib decreased post-natal viability of rat pups during the first 4 post-natal days when dams were exposed to less than the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).
• IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended.
• ( 8.2 ) Renal impairment:
• The safety and efficacy of OFEV have not been studied in patients with severe renal impairment and end-stage renal disease.
• ( 8.7 , 12.3 ) Smokers:
• Decreased exposure has been noted in smokers which may alter the efficacy profile of OFEV.
• ( 8.8 )
• 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , OFEV can cause fetal harm when administered to a pregnant woman.
• There are no data on the use of OFEV during pregnancy.
• In animal studies of pregnant rats and rabbits treated during organogenesis, nintedanib caused embryo-fetal deaths and structural abnormalities at less than (rats) and approximately 5 times (rabbits) the maximum recommended human dose [see Data ] .
• Advise pregnant women of the potential risk to a fetus.
• The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
• In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and miscarriage in clinically recognized pregnancies is 15% to 20%.
• Data Animal Data In animal reproduction toxicity studies, nintedanib caused embryo-fetal deaths and structural abnormalities in rats and rabbits at less than and approximately 5 times the maximum recommended human dose (MRHD) in
• adults (on a plasma AUC basis at maternal oral doses of 2.5 and 15 mg/kg/day in rats and rabbits, respectively).
• Malformations included abnormalities in the vasculature, urogenital, and skeletal systems.
• Vasculature anomalies included missing or additional major blood vessels.
• Skeletal anomalies included abnormalities in the thoracic, lumbar, and caudal vertebrae (e.g., hemivertebra, missing, or asymmetrically ossified), ribs (bifid or fused), and sternebrae (fused, split, or unilaterally ossified).
• In some fetuses, organs in the urogenital system were missing.
• In rabbits, a significant change in sex ratio was observed in fetuses (female:male ratio of approximately 71%:29%) at approximately 15 times the MRHD in
• adults (on an AUC basis at a maternal oral dose of 60 mg/kg/day).
• Nintedanib decreased post-natal viability of rat pups during the first 4 post-natal days when dams were exposed to less than the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).
• 8.2 Lactation Risk Summary There is no information on the presence of nintedanib in human milk, the effects on the breast-fed infant or the effects on milk production.
• Nintedanib and/or its metabolites are present in the milk of lactating rats [see Data ] .
• Because of the potential for serious adverse reactions in nursing infants from OFEV, advise women that breastfeeding is not recommended during treatment with OFEV.
• Data Milk and plasma of lactating rats have similar concentrations of nintedanib and its metabolites.
• 8.3 Females and Males of Reproductive Potential Based on findings from animal studies and its mechanism of action, OFEV can cause fetal harm when administered to a pregnant woman and may reduce fertility in females of reproductive potential [see Use in Specific Populations (8.1) , Clinical Pharmacology (12.1 , 12.3) , and Nonclinical Toxicology (13.1) ] .
• Counsel patients on pregnancy prevention and planning.
• Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to treatment with OFEV and during treatment as appropriate [see Dosage and Administration (2.1) , Warnings and Precautions (5.4) , and Use in Specific Populations (8.1) ].
• Contraception OFEV can cause fetal harm when administered to a pregnant woman.
• Advise females of reproductive potential to
• avoid becoming pregnant while receiving treatment with OFEV.
• Advise females of reproductive potential to use highly effective contraception at initiation of, during treatment, and for at least 3 months after taking the last dose of OFEV.
• Nintedanib does not change the exposure to oral contraceptive containing ethinylestradiol and levonorgestrel in patients with SSc-ILD.
• However, the efficacy of oral hormonal contraceptives may be compromised by vomiting and/or diarrhea or other conditions where the drug absorption may be reduced.
• Advise women taking oral hormonal contraceptives experiencing these conditions to use alternative highly effective contraception.
• Infertility Based on animal data, OFEV may reduce fertility in females of reproductive potential [see Nonclinical Toxicology (13.1) ].
• 8.4 Pediatric Use The safety and effectiveness of OFEV have not been established in pediatric patients for the treatment of fibrosing interstitial lung diseases.
• Effectiveness was not demonstrated in a randomized, double-blind, placebo-controlled study conducted in 26 OFEV-treated pediatric patients aged 6 to 17 years with fibrosing interstitial lung diseases, who were treated with OFEV based on weight.
• Animal Toxicity Data In repeat-dose toxicology studies, young animals (mice, rats, and monkeys) dosed with nintedanib showed changes in the bone and fast-growing teeth.
• Bone changes include thickening of the growth plate in all species.
• These changes were fully or at least partially reversible in rats and monkeys; reversibility in mice has not been studied.
• Tooth changes include broken incisors and discoloration in rodents.
• These changes were irreversible after discontinuation of nintedanib treatment .
• 8.5 Geriatric Use Of the total number of subjects in phase 2 and 3 clinical studies of OFEV in IPF (Study 1, Study 2, and Study 3), 61% were 65 and over, while 16% were 75 and over.
• In the chronic fibrosing ILDs with a progressive phenotype clinical study (Study 5), 61% were 65 and over, while 19% were 75 and older.
• In SSc-ILD (Study 4), 21.4% were 65 and over, while 1.9% were 75 and older.
• In phase 3 studies, no overall differences in effectiveness were observed between subjects who were 65 and over and younger subjects; no overall differences in safety were observed between subjects who were 65 and over or 75 and over and younger subjects, but greater sensitivity of some older individuals cannot be ruled out .
• 8.6 Hepatic Impairment Nintedanib is predominantly eliminated via biliary/fecal excretion (greater than 90%).
• In a PK study performed in patients with hepatic impairment (Child Pugh A, Child Pugh B), exposure to nintedanib was increased [see Clinical Pharmacology (12.3) ] .
• In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of OFEV is 100 mg twice daily [see Dosage and Administration (2.3) ] .
• Monitor for adverse reactions and consider treatment interruption, or discontinuation for management of adverse reactions in these patients [see Dosage and Administration (2.4) ].
• Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with OFEV is not recommended [see Warnings and Precautions (5.1) ].
• 8.7 Renal Impairment Based on a single-dose study, less than 1% of the total dose of nintedanib is excreted via the kidney [see Clinical Pharmacology (12.3) ] .
• Adjustment of the starting dose in patients with mild to moderate renal impairment is not required.
• The safety, efficacy, and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment (less than 30 mL/min CrCl) and end-stage renal disease.
• 8.8 Smokers Smoking was associated with decreased exposure to OFEV [see Clinical Pharmacology (12.3) ], which may alter the efficacy profile of OFEV .
• Encourage patients to stop smoking prior to treatment with OFEV and to
• avoid smoking
• when using OFEV.

• Coadministration of P-gp and CYP3A4 inhibitors may increase nintedanib exposure.
• Monitor patients closely for tolerability of OFEV.
• ( 7.1 )
• 7.1 P-glycoprotein (P-gp) and CYP3A4 Inhibitors and Inducers Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4 [see Clinical Pharmacology (12.3) ] .
• Coadministration with oral doses of a P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib by 60%.
• Concomitant use of P-gp and CYP3A4 inhibitors (e.g., erythromycin) with OFEV may increase exposure to nintedanib [see Clinical Pharmacology (12.3) ] .
• In such cases, patients should be monitored closely for tolerability of OFEV.
• Management of adverse reactions may require interruption, dose reduction, or discontinuation of therapy with OFEV [see Dosage and Administration (2.4) ] .
• Coadministration with oral doses of a P-gp and CYP3A4 inducer, rifampicin, decreased exposure to nintedanib by 50%.
• Concomitant use of P-gp and CYP3A4 inducers (e.g., carbamazepine, phenytoin, and St.
• John's wort) with OFEV should be avoided as these drugs may decrease exposure to nintedanib [see Clinical Pharmacology (12.3) ].
• 7.2 Anticoagulants Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding.
• Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary [see Warnings and Precautions (5.6) ].
• 7.3 Pirfenidone In a multiple-dose study conducted to assess the pharmacokinetic effects of concomitant treatment with nintedanib and pirfenidone, the coadministration of nintedanib with pirfenidone did not alter the exposure of either agent [see Clinical Pharmacology (12.3) ] .
• Therefore, no dose adjustment is necessary during concomitant administration of nintedanib with pirfenidone.
• 7.4 Bosentan Coadministration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib [see Clinical Pharmacology (12.3) ] .

• In IPF trials, one patient was inadvertently exposed to a dose of 600 mg daily for a total of 21 days.
• A non-serious adverse event (nasopharyngitis) occurred and resolved during the period of incorrect dosing, with no onset of other reported events.
• Overdosage was also reported in two patients in oncology studies who were exposed to a maximum of 600 mg twice daily for up to 8 days.
• Adverse events reported were consistent with the existing safety profile of OFEV.
• Both patients recovered.
• In case of overdosage, interrupt treatment and initiate general supportive measures as appropriate.