nintedanib 150 MG Oral Capsule

INDICATIONS AND USAGE Nintedanib capsules are 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 ) • Slowing the rate of decline in pulmonary function in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) ( 1.3 ) 1.1 Idiopathic Pulmonary Fibrosis Nintedanib capsules are indicated for the treatment of adults with idiopathic pulmonary fibrosis (IPF). 1.2 Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype Nintedanib capsules are indicated for the treatment of adults with chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype [see Clinical Studies ( 14.2 )] . 1.3 Systemic Sclerosis-Associated Interstitial Lung Disease Nintedanib capsules are indicated to slow the rate of decline in pulmonary function in adult patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD).

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.

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. Diarrhea led to discontinuation of nintedanib capsules 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 capsules and placebo, respectively [see Adverse Reactions (6.1) ] . Diarrhea led to permanent dose reduction in 16% of patients treated with nintedanib capsules compared to less than 1% of placebo-treated patients. Diarrhea led to discontinuation of nintedanib capsules in 6% of the patients compared to less than 1% 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 capsules 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 capsules 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 nintedanib capsules in 2% of patients and vomiting led to discontinuation of nintedanib capsules in 1% of the patients. In the chronic fibrosing I

CONTRAINDICATIONS None None ( 4 )

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 to 3, vascular endothelial growth factor receptor (VEGFR) 1 to 3, colony stimulating factor1 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 tissueremodeling 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.