Nintedanib

Nintedanib is a kinase inhibitor indicated in adults for: Treatment of idiopathic pulmonary fibrosis (IPF). Treatment of chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype. Slowing the rate of decline in pulmonary function in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD).

1.1Idiopathic Pulmonary Fibrosis Nintedanib

capsule is indicated for the treatment of adults with idiopathic pulmonary fibrosis (IPF).

1.2Chronic Fibrosing Interstitial Lung Diseases

with a Progressive Phenotype Nintedanib capsule is indicated for the treatment of adults with chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype .

1.3Systemic Sclerosis-Associated Interstitial Lung Disease

Nintedanib capsule is indicated to slow the rate of decline in pulmonary function in adult patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD).

Recommended dosage: 150 mg taken orally twice daily approximately 12 hours apart taken with food. 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 )

2.1Testing 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 .

2.2Recommended Dosage The

recommended dosage of nintedanib capsule is 150 mg taken orally twice daily administered approximately 12 hours apart. Administration Information Nintedanib capsules should be taken with food 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 capsule 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.

2.3Recommended 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 . Moderate or Severe Hepatic Impairment Treatment with nintedanib capsule is not recommended .

2.4Dosage 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 . 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) . In patients with mild hepatic impairment (Child Pugh A), consider treatment interruption, or discontinuation for management of adverse reactions.

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. 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. Bleeding events have been reported. Use nintedanib capsules in patients with known bleeding risk only if anticipated benefit outweighs the potential risk. 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. Nephrotic range proteinuria has been reported. Consider treatment interruption in patients who develop new or worsening proteinuria.

5.1Hepatic Impairment Treatment with

nintedanib capsules is not recommended in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment . Patients with mild hepatic impairment (Child Pugh A) can be treated with a reduced dose of nintedanib capsules

5.2Elevated 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. 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 nintedanib capsules group and for 0.7% of patients in the placebo group . 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 . 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 .

5.3Gastrointestinal 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 . 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 . 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.

In the SSc-ILD study (Study 4), diarrhea was reported in 76% versus 32% of patients treated with nintedanib capsules and placebo, respectively . Diarrhea led to permanent dose reduction in 22% of patients treated with nintedanib capsules compared to 1% of placebo-treated patients. Diarrhea led to discontinuation of nintedanib capsules 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 . 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. 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 nintedanib capsules and placebo, respectively . 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 ILDs with a progressive phenotype study (Study 5), nausea led to discontinuation of nintedanib capsules in less than 1% of patients and vomiting led to discontinuation of nintedanib capsules in 1% of the patients. In the SSc-ILD study (Study 4), nausea led to discontinuation of nintedanib capsules in 2% of patients and vomiting led to discontinuation of nintedanib capsules 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 . 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 nausea or vomiting does not resolve, discontinue treatment with nintedanib capsules.

5.4Embryo-Fetal Toxicity Based on

findings from animal studies and its mechanism of action, nintedanib capsules 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. Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to avoid becoming pregnant while receiving treatment with nintedanib capsules and to use highly effective contraception at initiation of, during treatment, and at least 3 months after the last dose of nintedanib capsules. 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.

Verify pregnancy status prior to treatment with nintedanib capsules and during treatment as appropriate .

5.5Arterial Thromboembolic Events Arterial

thromboembolic events have been reported in patients taking nintedanib capsules. In IPF studies (Study 1, Study 2, and Study 3), arterial thromboembolic events were reported in 2.5% of patients treated with nintedanib capsules 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 nintedanib capsule-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 nintedanib capsule-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.

5.6Risk of Bleeding Based on the

mechanism of action (VEGFR inhibition), nintedanib capsules 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 nintedanib capsules 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 nintedanib capsules 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 nintedanib capsules 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 nintedanib capsules in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.

5.7Gastrointestinal Perforation Based on the

mechanism of action, nintedanib 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 nintedanib capsules, 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 nintedanib capsules 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 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.

5.8Nephrotic 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 nintedanib capsules was discontinued; however, in some cases, residual proteinuria persisted.

Consider treatment interruption in patients who develop new or worsening proteinuria.

None None

Lactation: Breastfeeding is not recommended. 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.

8.1Pregnancy Risk Summary Based on

findings from animal studies and its mechanism of action , nintedanib can cause fetal harm when administered to a pregnant woman. There are no data on the use of nintedanib 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 . 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).

8.2Lactation 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 . Because of the potential for serious adverse reactions in nursing infants from nintedanib, 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.

8.3Females and Males of Reproductive Potential Based

on findings from animal studies and its mechanism of action, nintedanib can cause fetal harm when administered to a pregnant woman and may reduce fertility in females of reproductive potential . Counsel patients on pregnancy prevention and planning. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to treatment with nintedanib and during treatment as appropriate . Contraception Nintedanib 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. 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, nintedanib may reduce fertility in females of reproductive potential .

8.4Pediatric Use The

safety and effectiveness of nintedanib 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 capsule-treated pediatric patients aged 6 to 17 years with fibrosing interstitial lung diseases, who were treated with nintedanib 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.

8.5Geriatric Use Of the

total number of subjects in phase 2 and 3 clinical studies of nintedanib capsule 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 .

8.6Hepatic 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 . In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of nintedanib capsules is 100 mg twice daily . Monitor for adverse reactions and consider treatment interruption, or discontinuation for management of adverse reactions in these patients . Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with nintedanib capsules is not recommended .

8.7Renal Impairment Based on a

single-dose study, less than 1% of the total dose of nintedanib is excreted via the kidney . 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.

8.8Smokers Smoking

was associated with decreased exposure to nintedanib , which may alter the efficacy profile of nintedanib . Encourage patients to stop smoking prior to treatment with nintedanib capsules and to avoid smoking when using nintedanib capsules.

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 Gastrointestinal Disorders Embryo-Fetal Toxicity Arterial Thromboembolic Events Risk of Bleeding Gastrointestinal Perforation Nephrotic Range Proteinuria Most common adverse reactions (≥5%) are: diarrhea, nausea, abdominal pain, vomiting, liver enzyme elevation, decreased appetite, headache, weight decreased, and hypertension. To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1Clinical 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 disorders Decreased appetite 11% 5% Nervous system disorders Headache 8% 5% Investigations Weight decreased 10% 3% Vascular disorders Hypertension c 5% 4% a Includes abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain and abdominal tenderness. b Includes gamma-glutamyltransferase increased, hepatic enzyme increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic function abnormal, liver function test abnormal, transaminase increased, blood alkaline phosphatase-increased, alanine aminotransferase abnormal, aspartate aminotransferase abnormal, and gamma-glutamyltransferase abnormal. 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 3x the upper limit of normal) when using pirfenidone in combination with nintedanib (n=3 (6%)) compared to nintedanib alone (n=0) . Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype Nintedanib capsules was 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. Adverse reactions leading to permanent dose reductions were reported in 33% of nintedanib capsule-treated patients and 4% of placebo-treated patients.

The most frequent adverse reaction that led to permanent dose reduction in the patients treated with nintedanib capsules was diarrhea (16%). Adverse reactions leading to discontinuation were reported in 20% of nintedanib capsule-treated patients and 10% of placebo-treated patients. The most frequent adverse reaction that led to discontinuation in nintedanib capsule-treated patients was diarrhea (6%).

The safety profile in patients with chronic fibrosing ILDs with a progressive phenotype treated with nintedanib capsules was consistent with that observed in IPF patients. In addition, the following adverse events were reported in nintedanib capsules more than placebo in chronic progressive fibrosing ILD: nasopharyngitis (13% vs. 12%), upper respiratory tract infection (7% vs 6%), urinary tract infection (6% vs. 4%), fatigue (10% vs. 6%), and back pain (6% vs. 5%). Systemic Sclerosis-Associated Interstitial Lung Disease Nintedanib capsule was studied in a phase 3, randomized, double-blind, placebo-controlled trial (Study 4) in which 576 patients with SSc-ILD received nintedanib capsules 150 mg twice daily (n=288) or placebo (n=288).

Patients were to receive treatment for at least 52 weeks; individual patients were treated for up to 100 weeks. The median duration of exposure was 15 months for patients treated with nintedanib capsules and 16 months for patients treated with placebo. Subjects ranged in age from 20 to 79 years (median age of 55 years).

Most patients were female (75%). Patients were mostly Caucasian (67%), Asian (25%), or Black (6%). At baseline, 49% of patients were on stable therapy with mycophenolate. The most frequent serious adverse events reported in patients treated with nintedanib capsules, more than placebo, were interstitial lung disease (2.4% nintedanib vs. 1.7% placebo) and pneumonia (2.8% nintedanib vs. 0.3% placebo).

Within 52 weeks, 5 patients treated with nintedanib capsules (1.7%) and 4 patients treated with placebo (1.4%) died. There was no pattern among adverse events leading to death in either treatment arm. Adverse reactions leading to permanent dose reductions were reported in 34% of nintedanib capsule-treated patients and 4% of placebo-treated patients.

The most frequent adverse reaction that led to permanent dose reduction in the patients treated with nintedanib capsules was diarrhea (22%). Adverse reactions leading to discontinuation were reported in 16% of nintedanib capsule-treated patients and 9% of placebo-treated patients. The most frequent adverse reactions that led to discontinuation in nintedanib capsule-treated patients were diarrhea (7%), nausea (2%), vomiting (1%), abdominal pain (1%), and interstitial lung disease (1%).

The safety profile in patients treated with nintedanib capsules with or without mycophenolate at baseline was comparable. The most common adverse reactions with an incidence of greater than or equal to 5% in nintedanib capsule-treated patients and more commonly than in placebo are listed in Table 2. Table 2 Adverse Reactions Occurring in ≥5% of Nintedanib Capsule-treated Patients with Systemic Sclerosis-Associated Interstitial Lung Disease and More Commonly Than Placebo in Study 4 Adverse Reaction Nintedanib Capsule , 150mg n=288 Placebo n=288 Diarrhea 76% 32% Nausea 32% 14% Vomiting 25% 10% Skin ulcer 18% 17% Abdominal pain a 18% 11% Liver enzyme elevation b 13% 3% Weight decreased 12% 4% Fatigue 11% 7% Decreased appetite 9% 4% Headache 9% 8% Pyrexia 6% 5% Back pain 6% 4% Dizziness 6% 4% Hypertension c 5% 2% Includes abdominal pain, abdominal pain upper, abdominal pain lower, and esophageal pain.

Includes alanine aminotransferase increased, gamma-glutamyltransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, blood alkaline phosphatase increased, transaminase increased, and hepatic function abnormal. Includes hypertension, blood pressure increased, and hypertensive crisis. In addition, alopecia was reported in patients treated with nintedanib capsules, more than placebo (1.4% vs. 1.0%).

6.2Postmarketing Experience The

following adverse reactions have been identified during postapproval use of nintedanib capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders : Thrombocytopenia Gastrointestinal Disorders : Pancreatitis Hepatobiliary Disorders : Drug-induced liver injury Nervous System Disorders : Posterior reversible encephalopathy syndrome Renal and Urinary Disorders : Proteinuria Skin and Subcutaneous Tissue Disorders : Pruritus, rash Vascular Disorders : Non-serious and serious bleeding events, some of which were fatal