Nintedanib Drug Information

Idiopathic Pulmonary Fibrosis Nintedanib Capsules is indicated for the treatment of adults

with idiopathic pulmonary fibrosis (IPF).

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.

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 .

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 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.

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 . Moderate or Severe Hepatic Impairment Treatment with Nintedanib Capsules is not recommended .

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 . 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.

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) . 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. Adverse reactions leading to permanent dose reductions were reported in 33% of nintedanib capsules-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 capsules-treated patients and 10% of placebo-treated patients.

The most frequent adverse reaction that led to discontinuation in nintedanib capsules-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%). 1

Postmarketing 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

P-glycoprotein (P-gp) and

CYP3A4 Inhibitors and Inducers Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4 . 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 . 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 . 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 .

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 .

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 . Therefore, no dose adjustment is necessary during concomitant administration of nintedanib with pirfenidone.

Bosentan Coadministration of nintedanib with bosentan did not alter the pharmacokinetics of

nintedanib .

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action , 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 . 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 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.

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.