nintedanib
Capsule · Oral
Uses
Nintedanib Capsules is a kinase inhibitor indicated in adults for: Treatment of idiopathic pulmonary fibrosis (IPF) ( 1.1 ) Treatment of chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype ( 1.2 ) 1.1 Idiopathic Pulmonary Fibrosis Nintedanib Capsules is indicated for the treatment of adults with idiopathic pulmonary fibrosis (IPF). 1.2 Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype Nintedanib Capsules is indicated for the treatment of adults with chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype [see Clinical Studies (14.2) ].
Dosage and administration
Recommended dosage: 150 mg taken orally twice daily approximately 12 hours apart taken with food. ( 2.2 ) Recommended dosage in patients with mild hepatic impairment (Child Pugh A): 100 mg taken orally twice daily approximately 12 hours apart taken with food. ( 2.3 , 8.6 ) Consider temporary dose reduction to 100 mg, treatment interruption, or discontinuation for management of adverse reactions. ( 2.4 , 5.2 , 5.3 , 6 ) Prior to treatment initiation, conduct liver function tests in all patients and a pregnancy test in females of reproductive potential. ( 2.1 , 5.2 , 5.4 ) 2.1 Testing Prior to Nintedanib Capsules Administration Conduct liver function tests in all patients and a pregnancy test in females of reproductive potential prior to initiating treatment with Nintedanib Capsules [see Warnings and Precautions (5.2 , 5.4) ] . 2.2 Recommended Dosage The recommended dosage of Nintedanib Capsules is 150 mg taken orally twice daily administered approximately 12 hours apart. Administration Information Nintedanib Capsules should be taken with food [see Clinical Pharmacology (12.3) ] and swallowed whole with liquid. Nintedanib Capsules should not be chewed because of a bitter taste. Nintedanib Capsules should not be opened or crushed. If contact with the content of the capsule occurs, wash hands immediately and thoroughly. The effect of chewing or crushing of the capsule on the pharmacokinetics of nintedanib is not known. Information for Missed Dose If a dose of Nintedanib Capsules is missed, the next dose should be taken at the next scheduled time. Advise the patient to not make up for a missed dose. Do not exceed the recommended maximum daily dosage of 300 mg. 2.3 Recommended Dosage for Patients with Hepatic Impairment Mild Hepatic Impairment In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of Nintedanib Capsules is 100 mg orally twice daily approximately 12 hours apart taken with food [see Use in Specific Populations (8.6) ] . Moderate or Severe Hepatic Impairment Treatment with Nintedanib Capsules is not recommended [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6) ] . 2.4 Dosage Modification due to Adverse Reactions In addition to symptomatic treatment, if applicable, the management of adverse reactions of Nintedanib Capsules may require dose reduction or temporary interruption until the specific adverse reaction resolves to levels that allow continuation of therapy. 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 a patient does not tolerate 100 mg twice daily, discontinue treatment with Nintedanib Capsules [see Warnings and Precautions (5.2 , 5.3 , 5.5 , 5.7) and Adverse Reactions (6.1) ] . Elevated Liver Enzymes Dose modifications or interruptions may be necessary for liver enzyme elevations. Conduct liver function tests (aspartate aminotransferase (AST), alanine aminotransferase (ALT), 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. Discontinue Nintedanib Capsules in patients with AST or ALT greater than 3 times the upper limit of normal (ULN) with signs or symptoms of liver injury and for AST or ALT elevations greater than 5 times the upper limit of normal. For AST or ALT greater than 3 times to less than 5 times the ULN without signs of liver damage, interrupt treatment or reduce Nintedanib Capsules to 100 mg twice daily. Once liver enzymes have returned to baseline values, treatment with Nintedanib Capsules may be reintroduced at a reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage (150 mg twice daily) [see Warnings and Precautions (5.2) and Adverse Reactions (6.1) ] . In patients with mild hepatic impairment (Child Pugh A), consider treatment interruption, or discontinuation for management of adverse reactions.
Dosage forms and strengths
Capsules: 150 mg, red-brown, opaque, oblong, soft capsules imprinted in black with "150". 100 mg, yellow to peach, opaque, oblong, soft capsules imprinted in black with "100". Capsules: 150 mg and 100 mg ( 3 )
Contraindications
None None ( 4 )
Warnings and precautions
Hepatic impairment: Nintedanib Capsules 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. 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 capsules, 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 capsules. 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 capsules 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 capsules 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 capsules and placebo, respectively [see Adverse Reactions (6.1) ] . Diarrhea led to permanent dose reduction in 11% of patients treated with nintedanib capsules compared to 0 placebo-treated patients.
Side effects
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 . 6.1 Clinical 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.
Drug interactions
Coadministration of P-gp and CYP3A4 inhibitors may increase nintedanib exposure. Monitor patients closely for tolerability of Nintedanib Capsules. ( 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 Nintedanib Capsules may increase exposure to nintedanib [see Clinical Pharmacology (12.3) ] . In such cases, patients should be monitored closely for tolerability of Nintedanib Capsules. Management of adverse reactions may require interruption, dose reduction, or discontinuation of therapy with Nintedanib Capsules [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 Nintedanib Capsules 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) ] .
Use in specific populations
Lactation: Breastfeeding is not recommended. ( 8.2 ) Renal impairment: The safety and efficacy of nintedanib capsules 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 nintedanib capsules. ( 8.8 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , nintedanib capsules can cause fetal harm when administered to a pregnant woman. There are no data on the use of nintedanib capsules 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 Nintedanib Capsules, advise women that breastfeeding is not recommended during treatment with Nintedanib Capsules. 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, nintedanib capsules 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 Nintedanib Capsules and during treatment as appropriate [see Dosage and Administration (2.1) , Warnings and Precautions (5.4) , and Use in Specific Populations (8.1) ] . Contraception Nintedanib capsules can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid becoming pregnant while receiving treatment with Nintedanib Capsules. 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 Nintedanib Capsules. 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, nintedanib capsules may reduce fertility in females of reproductive potential [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and effectiveness of nintedanib capsules 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 nintedanib capsules-treated pediatric patients aged 6 to 17 years with fibrosing interstitial lung diseases, who were treated with nintedanib capsules 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 nintedanib capsules 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.
Pregnancy
8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , nintedanib capsules can cause fetal harm when administered to a pregnant woman. There are no data on the use of nintedanib capsules 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).
Pediatric use
8.4 Pediatric Use The safety and effectiveness of nintedanib capsules 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 nintedanib capsules-treated pediatric patients aged 6 to 17 years with fibrosing interstitial lung diseases, who were treated with nintedanib capsules 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.
Geriatric use
8.5 Geriatric Use Of the total number of subjects in phase 2 and 3 clinical studies of nintedanib capsules 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 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.
Overdosage
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 nintedanib capsules. Both patients recovered. In case of overdosage, interrupt treatment and initiate general supportive measures as appropriate.
Description
Nintedanib Capsules contain nintedanib, a kinase inhibitor [see Mechanism of Action (12.1) ] . Nintedanib is presented as the ethanesulfonate salt (esylate), with the chemical name 1 H -Indole-6-carboxylic acid, 2,3- dihydro-3-[[[4-[methyl[(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo-,methyl ester, (3Z)-, ethanesulfonate (1:1). Its structural formula is: Nintedanib esylate is a bright yellow powder with an empirical formula of C31H33N5O4ꞏC2H6O3S and a molecular weight of 649.76 g/mol. Nintedanib Capsules for oral administration are available in 2 dose strengths containing 100 mg or 150 mg of nintedanib (equivalent to 120.40 mg or 180.60 mg nintedanib ethanesulfonate, respectively). The inactive ingredients of Nintedanib Capsules are the following: Fill Material: Medium-chain triglycerides, lecithin. Capsule Shell: gelatin, glycerin, ferric oxide red, ferric oxide yellow, titanium dioxide, black ink. 1
Mechanism of action
12.1 Mechanism of Action Nintedanib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). Nintedanib inhibits the following RTKs: platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR) 1-3, colony stimulating factor 1 receptor (CSF1R), and Fms-like tyrosine kinase-3 (FLT-3). These kinases except for FLT-3 have been implicated in pathogenesis of interstitial lung diseases (ILD). Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these kinases and blocks the intracellular signaling cascades, which have been demonstrated to be involved in the pathogenesis of fibrotic tissue remodeling in ILD. Nintedanib also inhibits the following nRTKs: Lck, Lyn and Src kinases. The contribution of FLT-3 and nRTK inhibition to nintedanib efficacy in ILD is unknown.
How supplied
150 mg: red-brown, opaque, oblong, soft capsules imprinted in black with "150". They are packaged in HDPE bottles with a child-resistant closure, available as follows: Bottles of 60 NDC: 42799-973-01 100 mg: yellow to peach, opaque, oblong, soft capsules imprinted in black with "100". They are packaged in HDPE bottles with a child-resistant closure, available as follows: Bottles of 60 NDC: 42799-972-01 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from exposure to high humidity and avoid excessive heat. If repackaged, use USP tight container.
Patient information
Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Elevated Liver Enzymes and Drug-Induced Liver Injury Advise patients that they will need to undergo liver function testing periodically. Advise patients to immediately report any symptoms of a liver problem (e.g., skin or the whites of eyes turn yellow, urine turns dark or brown (tea colored), pain on the right side of stomach, bleed or bruise more easily than normal, lethargy, loss of appetite) [see Warnings and Precautions (5.2) ] . Gastrointestinal Disorders Inform patients that gastrointestinal disorders such as diarrhea, nausea, and vomiting were the most commonly reported gastrointestinal events occurring in patients who received nintedanib capsules. Advise patients that their healthcare provider may recommend hydration, antidiarrheal medications (e.g., loperamide), or anti-emetic medications to treat these side effects. Temporary dosage reductions or discontinuations may be required. Instruct patients to contact their healthcare provider at the first signs of diarrhea or for any severe or persistent diarrhea, nausea, or vomiting [see Warnings and Precautions (5.3) and Adverse Reactions (6.1) ] . Embryo-Fetal Toxicity Counsel patients on pregnancy prevention and planning. Advise females of reproductive potential of the potential risk to a fetus and to avoid becoming pregnant while receiving treatment with Nintedanib Capsules. 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 Nintedanib Capsules. Advise women taking oral hormonal contraceptives who experience vomiting and/or diarrhea or other conditions where the drug absorption may be reduced to contact their doctor to discuss alternative highly effective contraception. Advise female patients to notify their doctor if they become pregnant or suspect they are pregnant during therapy with Nintedanib Capsules [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1 , 8.3) ] . Arterial Thromboembolic Events Advise patients about the signs and symptoms of acute myocardial ischemia and other arterial thromboembolic events and the urgency to seek immediate medical care for these conditions [see Warnings and Precautions (5.5) ] . Risk of Bleeding Bleeding events have been reported. Advise patients to report unusual bleeding [see Warnings and Precautions (5.6) ] . Gastrointestinal Perforation Serious gastrointestinal perforation events have been reported. Advise patients to report signs and symptoms of gastrointestinal perforation [see Warnings and Precautions (5.7) ] . Nephrotic Range Proteinuria Nephrotic range proteinuria has been reported. Advise patients to report signs and symptoms of proteinuria (e.g., fluid retention, foamy urine) [see Warnings and Precautions (5.8) ] . Lactation Advise patients that breastfeeding is not recommended while taking Nintedanib Capsules [see Use in Specific Populations (8.2) ] . Smokers Encourage patients to stop smoking prior to treatment with Nintedanib Capsules and to avoid smoking when using Nintedanib Capsules [see Clinical Pharmacology (12.3) ] . Administration Instruct patients to take Nintedanib Capsules with food, to swallow Nintedanib Capsules whole with liquid, and not to chew the capsules due to the bitter taste. Advise patients or caregivers not to open or crush Nintedanib Capsules and to wash hands immediately and thoroughly if contact with the content of the capsule occurs. Advise patients to not make up for a missed dose [see Dosage and Administration (2.2) ] . Distributed by: Edenbridge Pharmaceuticals, LLC, DBA Dexcel Pharma USA, Parsippany, NJ 07054
Label text from the FDA structured product label by Edenbridge Pharmaceuticals LLC. (revised Jul 29, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Nintedanib Esylate in 18 products
nintedanib NDC products (18)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 60505-4818 | Nintedanib Esylate 100 mg/1 Capsule | Apotex Corp. | ANDA |
| 60505-4819 | Nintedanib Esylate 150 mg/1 Capsule | Apotex Corp. | ANDA |
| 73190-097 | Nintedanib Esylate 150 mg/1 Capsule | AvKARE | ANDA |
| 73190-096 | Nintedanib Esylate 100 mg/1 Capsule | AvKARE | ANDA |
| 69097-641 | Nintedanib Esylate 100 mg/1 Capsule | Cipla USA Inc. | ANDA |
| 69097-639 | Nintedanib Esylate 150 mg/1 Capsule | Cipla USA Inc. | ANDA |
| 43598-147 | Nintedanib Esylate 150 mg/1 Capsule | Dr. Reddy's Laboratories Inc. | ANDA |
| 43598-148 | Nintedanib Esylate 100 mg/1 Capsule | Dr. Reddy's Laboratories Inc. | ANDA |
| 42799-972 | Nintedanib Esylate 100 mg/1 Capsule | Edenbridge Pharmaceuticals LLC. | ANDA |
| 42799-973 | Nintedanib Esylate 150 mg/1 Capsule | Edenbridge Pharmaceuticals LLC. | ANDA |
| 42806-568 | Nintedanib Esylate 150 mg/1 Capsule | EPIC PHARMA LLC | ANDA |
| 42806-569 | Nintedanib Esylate 100 mg/1 Capsule | EPIC PHARMA LLC | ANDA |
| 68462-802 | Nintedanib Esylate 100 mg/1 Capsule | Glenmark Pharmaceuticals Inc., USA | ANDA |
| 68462-803 | Nintedanib Esylate 150 mg/1 Capsule | Glenmark Pharmaceuticals Inc., USA | ANDA |
| 51407-985 | Nintedanib Esylate 150 mg/1 Capsule | Golden State Medical Supply, Inc. | ANDA |
| 51407-984 | Nintedanib Esylate 100 mg/1 Capsule | Golden State Medical Supply, Inc. | ANDA |
| 0781-2492 | Nintedanib Esylate 100 mg/1 Capsule | Sandoz Inc | ANDA |
| 0781-2495 | Nintedanib Esylate 150 mg/1 Capsule | Sandoz Inc | ANDA |
Frequently asked questions
What is nintedanib used for?
Nintedanib Capsules is a kinase inhibitor indicated in adults for: Treatment of idiopathic pulmonary fibrosis (IPF) ( 1.1 ) Treatment of chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype ( 1.2 ) 1.1 Idiopathic Pulmonary Fibrosis Nintedanib Capsules is indicated for the treatment of adults with idiopathic pulmonary fibrosis (IPF). 1.2 Chronic Fibrosing Interstitial…
What are the side effects of nintedanib?
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… See the full label for the complete list.
Who makes nintedanib?
nintedanib is listed by 9 labelers in the FDA NDC directory, including Apotex Corp., AvKARE, Cipla USA Inc., Dr. Reddy's Laboratories Inc..