nintedanib

1 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).

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 da …

3 DOSAGE FORMS AND STRENGTHS Capsules: 150 mg, brown, opaque, oblong soft gelatin capsule, free from surface defect, laser imprinted “DG3” containing bright greenish yellow to pale yellow suspension. 100 mg, peach, opaque, oblong soft gelatin capsule, free from surface defect, laser imprinted “DG2” containing bright greenish yellow to pale yellow suspension. Capsules: 150 mg and 100 mg ( 3 )

4 CONTRAINDICATIONS None None ( 4 )

6 ADVERSE REACTIONS 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 Cipla Ltd at 1-866-604-3268 or FDA at 1-800-FDA-1088 o r 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, and over 280 patients with SSc-ILD. Over 200 IPF patients were exposed to nintedanib for more than 2 years in clinical trials. Idiopathic Pulmonary Fibrosis Nintedanib capsule was 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 capsule-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 capsule-treated patients and 15% of placebo-treated patients. The most frequent adverse reactions that led to discontinuation in nintedanib capsule-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. Table 1 Adverse Reactions Occurring in ≥5% of Nintedanib Capsule-treated Patients with Idiopathic Pulmonary Fibrosis and More Commonly Than Placebo in Study 1, Study 2, and Study 3 Adverse Reaction Nintedanib Capsule, 150 mg n=723 Placebo n=508 c Includes hypertension, blood pressure increased, hypertensive crisis, and hypertensive cardiomyopathy. Gastrointestinal disorders Diarrhea 62% 18% Nausea 24% 7% Abdominal pain a 15% 6% Vomiting 12% 3% Hepatobiliary disorders Liver enzyme elevation b 14% 3% Metabolism and nutrition diso …

7 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 )] .

8 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 con …

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 to 3, vascular endothelial growth factor receptor (VEGFR) 1 to 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.

11 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-,methylester, (3 Z )-, ethanesulfonate (1:1). Its structural formula is: Nintedanib esylate is a bright yellow powder with an empirical formula of C 31 H 33 N 5 O 4 ∙C 2 H 6 O 3 S 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 esylate, respectively). The inactive ingredients of nintedanib capsules are the following: Fill Material : hard fat, medium-chain triglycerides, polyglyceryl-3 dioleate. Capsule Shell : gelatin, glycerin, titanium dioxide, red ferric oxide, yellow ferric oxide, water, ink (ammonium hydroxide, carmine, ferrosoferric oxide, isopropyl alcohol, N-butyl alcohol, propylene glycol, shellac, simethicone). chemical-structure

10 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 150 mg: Brown, opaque, oblong soft gelatin capsule, free from surface defect, laser imprinted “DG3” containing bright greenish yellow to pale yellow suspension. They are packaged in HDPE bottles with a child-resistant closure, available as follows: Bottles of 60 NDC: 60505-4819-6 100 mg: Peach, opaque, oblong soft gelatin capsule, free from surface defect, laser imprinted “DG2” containing bright greenish yellow to pale yellow suspension. They are packaged in HDPE bottles with a child-resistant closure, available as follows: Bottles of 60 NDC: 60505-4818-6 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.