Ofev

OFEV is a kinase inhibitor indicated in adults for:

• Treatment of idiopathic pulmonary fibrosis (IPF) (
  1.1 Idiopathic Pulmonary Fibrosis

  OFEV is indicated for the treatment of adults with idiopathic pulmonary fibrosis (IPF).
  )
• Treatment of chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype (
  1.2 Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype

  OFEV is indicated for the treatment of adults with chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype

  [see Clinical Studies (14.2)]

  .
  )
• Slowing the rate of decline in pulmonary function in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) (
  1.3 Systemic Sclerosis-Associated Interstitial Lung Disease

  OFEV 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. (
  2.2 Recommended Dosage

  The recommended dosage of OFEV is 150 mg taken orally twice daily administered approximately 12 hours apart.

  Administration Information

  OFEV capsules should be taken with food

  [see Clinical Pharmacology (12.3)]

  and swallowed whole with liquid. OFEV capsules should not be chewed because of a bitter taste.

  OFEV 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 OFEV 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 in patients with mild hepatic impairment (Child Pugh A): 100 mg taken orally twice daily approximately 12 hours apart taken with food. (
  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 OFEV 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 OFEV is not recommended

  [see Warnings and Precautions (5.1)and Use in Specific Populations (8.6)].
  ,
  8.6 Hepatic 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

  [see Clinical Pharmacology (12.3)]

  . In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of OFEV is 100 mg twice daily

  [see Dosage and Administration (2.3)]

  . Monitor for adverse reactions and consider treatment interruption, or discontinuation for management of adverse reactions in these patients

  [see Dosage and Administration (2.4)].

  Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with OFEV is not recommended

  [see Warnings and Precautions (5.1)].
  )
• Consider temporary dose reduction to 100 mg, treatment interruption, or discontinuation for management of adverse reactions. (
  2.4 Dosage Modification due to Adverse Reactions

  In addition to symptomatic treatment, if applicable, the management of adverse reactions of OFEV may require dose reduction or temporary interruption until the specific adverse reaction resolves to levels that allow continuation of therapy

  .

  OFEV 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 OFEV

  [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 OFEV, 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 OFEV 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 OFEV to 100 mg twice daily. Once liver enzymes have returned to baseline values, treatment with OFEV 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.
  ,
  5.2 Elevated Liver Enzymes and Drug-Induced Liver Injury

  Cases of drug-induced liver injury (DILI) have been observed with OFEV 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 OFEV 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 OFEV group and for 0.7% of patients in the placebo group

  [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 OFEV, 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 OFEV and placebo, respectively

  [see Adverse Reactions (6.1)].

  Diarrhea led to permanent dose reduction in 11% of patients treated with OFEV compared to 0 placebo-treated patients. Diarrhea led to discontinuation of OFEV 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 OFEV and placebo, respectively

  [see Adverse Reactions (6.1)].

  Diarrhea led to permanent dose reduction in 16% of patients treated with OFEV compared to less than 1% of placebo-treated patients. Diarrhea led to discontinuation of OFEV 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 OFEV and placebo, respectively

  [see Adverse Reactions (6.1)].

  Diarrhea led to permanent dose reduction in 22% of patients treated with OFEV compared to 1% of placebo-treated patients. Diarrhea led to discontinuation of OFEV 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

  [see Dosage and Administration (2.4)].

  OFEV 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 OFEV.

  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 OFEV 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 OFEV 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 OFEV 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 OFEV in 2% of patients and vomiting led to discontinuation of OFEV in 1% of the patients. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), nausea led to discontinuation of OFEV in less than 1% of patients and vomiting led to discontinuation of OFEV in 1% of the patients. In the SSc-ILD study (Study 4), nausea led to discontinuation of OFEV in 2% of patients and vomiting led to discontinuation of OFEV 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

  [see Dosage and Administration (2.4)]

  . OFEV 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 OFEV.
  ,
  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.

  
  
  

  To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 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 OFEV was evaluated in over 1000 IPF patients, 332 patients with chronic fibrosing ILDs with a progressive phenotype, and over 280 patients with SSc-ILD. Over 200 IPF patients were exposed to OFEV for more than 2 years in clinical trials.

  Idiopathic Pulmonary Fibrosis

  OFEV 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 OFEV 150 mg twice daily and 508 patients received placebo. The median duration of exposure was 10 months for patients treated with OFEV 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 OFEV, 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 OFEV, 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 OFEV-treated patients and 1.8% of placebo-treated patients.

  Adverse reactions leading to permanent dose reductions were reported in 16% of OFEV-treated patients and 1% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with OFEV was diarrhea (11%).

  Adverse reactions leading to discontinuation were reported in 21% of OFEV-treated patients and 15% of placebo-treated patients. The most frequent adverse reactions that led to discontinuation in OFEV-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 OFEV than placebo treatment group are listed in Table 1.

  Table 1 Adverse Reactions Occurring in ≥5% of OFEV-treated Patients with Idiopathic Pulmonary Fibrosis and More Commonly Than Placebo in Study 1, Study 2, and Study 3

  Adverse Reaction	OFEV, 150 mg n=723	Placebo n=508
  aIncludes abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain and abdominal tenderness. bIncludes 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. cIncludes hypertension, blood pressure increased, hypertensive crisis, and hypertensive cardiomyopathy.
  Gastrointestinal disorders
  Diarrhea	62%	18%
  Nausea	24%	7%
  Abdominal paina	15%	6%
  Vomiting	12%	3%
  Hepatobiliary disorders
  Liver enzyme elevationb	14%	3%
  Metabolism and nutrition disorders
  Decreased appetite	11%	5%
  Nervous system disorders
  Headache	8%	5%
  Investigations
  Weight decreased	10%	3%
  Vascular disorders
  Hypertensionc	5%	4%

  In addition, hypothyroidism was reported in patients treated with OFEV, more than placebo (1.1% vs. 0.6%). Alopecia was also reported in more patients treated with OFEV 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

  OFEV 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 OFEV 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 OFEV, more than placebo, was pneumonia (4% vs. 3%). Adverse events leading to death were reported in 3% of patients treated with OFEV 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 OFEV-treated patients and 4% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with OFEV was diarrhea (16%).

  Adverse reactions leading to discontinuation were reported in 20% of OFEV-treated patients and 10% of placebo-treated patients. The most frequent adverse reaction that led to discontinuation in OFEV-treated patients was diarrhea (6%).

  The safety profile in patients with chronic fibrosing ILDs with a progressive phenotype treated with OFEV was consistent with that observed in IPF patients. In addition, the following adverse events were reported in OFEV 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

  OFEV was studied in a phase 3, randomized, double-blind, placebo-controlled trial (Study 4) in which 576 patients with SSc-ILD received OFEV 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 OFEV 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 OFEV, 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 OFEV (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 OFEV-treated patients and 4% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with OFEV was diarrhea (22%).

  Adverse reactions leading to discontinuation were reported in 16% of OFEV-treated patients and 9% of placebo-treated patients. The most frequent adverse reactions that led to discontinuation in OFEV-treated patients were diarrhea (7%), nausea (2%), vomiting (1%), abdominal pain (1%), and interstitial lung disease (1%).

  The safety profile in patients treated with OFEV with or without mycophenolate at baseline was comparable.

  The most common adverse reactions with an incidence of greater than or equal to 5% in OFEV-treated patients and more commonly than in placebo are listed in Table 2.

  Table 2 Adverse Reactions Occurring in ≥5% of OFEV-treated Patients with Systemic Sclerosis-Associated Interstitial Lung Disease and More Commonly Than Placebo in Study 4

  Adverse Reaction	OFEV, 150 mg n=288	Placebo n=288
  aIncludes abdominal pain, abdominal pain upper, abdominal pain lower, and esophageal pain.
  bIncludes alanine aminotransferase increased, gamma-glutamyltransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, blood alkaline phosphatase increased, transaminase increased, and hepatic function abnormal.
  cIncludes hypertension, blood pressure increased, and hypertensive crisis.
  Diarrhea	76%	32%
  Nausea	32%	14%
  Vomiting	25%	10%
  Skin ulcer	18%	17%
  Abdominal paina	18%	11%
  Liver enzyme elevationb	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%
  Hypertensionc	5%	2%

  In addition, alopecia was reported in patients treated with OFEV, more than placebo (1.4% vs. 1.0%).

  6.2 Postmarketing Experience

  The following adverse reactions have been identified during postapproval use of OFEV. 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
  )
• Prior to treatment initiation, conduct liver function tests in all patients and a pregnancy test in females of reproductive potential. (
  2.1 Testing Prior to OFEV Administration

  Conduct liver function tests in all patients and a pregnancy test in females of reproductive potential prior to initiating treatment with OFEV

  [see Warnings and Precautions (5.2, 5.4)].
  ,
  5.2 Elevated Liver Enzymes and Drug-Induced Liver Injury

  Cases of drug-induced liver injury (DILI) have been observed with OFEV 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 OFEV 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 OFEV group and for 0.7% of patients in the placebo group

  [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 OFEV, 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)]

  .
  ,
  5.4 Embryo-Fetal Toxicity

  Based on findings from animal studies and its mechanism of action, OFEV 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 OFEV and to use highly effective contraception at initiation of, during treatment, and at least 3 months after the last dose of OFEV. 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 OFEV and during treatment as appropriate

  [see Use in Specific Populations (8.1, 8.3)and Clinical Pharmacology (12.1, 12.3)].
  )

Capsules:

• 150 mg, brown, opaque, oblong, soft capsules marked in dark gray with the Boehringer Ingelheim company symbol and "150".
• 100 mg, peach, opaque, oblong, soft capsules marked in dark gray with the Boehringer Ingelheim company symbol and "100".

• Lactation: Breastfeeding is not recommended. (
  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 OFEV, advise women that breastfeeding is not recommended during treatment with OFEV.

  Data

  Milk and plasma of lactating rats have similar concentrations of nintedanib and its metabolites.
  )
• Renal impairment: The safety and efficacy of OFEV have not been studied in patients with severe renal impairment and end-stage renal disease. (
  8.7 Renal Impairment

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

  [see Clinical Pharmacology (12.3)]

  . 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.
  ,
  12.3 Pharmacokinetics

  The PK properties of nintedanib were similar in healthy volunteers, patients with IPF, patients with chronic fibrosing ILDs with a progressive phenotype, patients with SSc-ILD, and cancer patients. The PK of nintedanib is linear. Dose proportionality was shown by an increase of nintedanib exposure with increasing doses (dose range 50 to 450 mg once daily and 150 to 300 mg twice daily). Accumulation upon multiple administrations in patients with IPF was 1.76-fold for AUC. Steady-state plasma concentrations were achieved within one week of dosing. Nintedanib trough concentrations remained stable for more than one year. The inter-individual variability in the PK of nintedanib was moderate to high (coefficient of variation of standard PK parameters in the range of 30% to 70%), intra-individual variability low to moderate (coefficients of variation below 40%).

  Absorption

  Nintedanib reached maximum plasma concentrations approximately 2 to 4 hours after oral administration as a soft gelatin capsule under fed conditions. The absolute bioavailability of a 100 mg dose was 4.7% (90% CI: 3.62 to 6.08) in healthy volunteers. Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism.

  After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions (90% CI: 95.3% to 152.5%) and absorption was delayed (median t_maxfasted: 2.00 hours; fed: 3.98 hours), irrespective of the food type.

  Distribution

  Nintedanib follows bi-phasic disposition kinetics. After intravenous infusion, a high volume of distribution which was larger than total body volume (V_ss: 1050 L) was observed.

  The

  in vitro

  protein binding of nintedanib in human plasma was high, with a bound fraction of 97.8%. Serum albumin is considered to be the major binding protein. Nintedanib is preferentially distributed in plasma with a blood to plasma ratio of 0.87.

  Elimination

  The effective half-life of nintedanib in patients with IPF was 9.5 hours (gCV 31.9%). Total plasma clearance after intravenous infusion was high (CL: 1390 mL/min; gCV 28.8%). Urinary excretion of unchanged drug within 48 hours was about 0.05% of the dose after oral and about 1.4% of the dose after intravenous administration; the renal clearance was 20 mL/min.

  Metabolism

  The prevalent metabolic reaction for nintedanib is hydrolytic cleavage by esterases resulting in the free acid moiety BIBF 1202. BIBF 1202 is subsequently glucuronidated by UGT enzymes, namely UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to BIBF 1202 glucuronide. Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways, with CYP3A4 being the predominant enzyme involved. The major CYP-dependent metabolite could not be detected in plasma in the human absorption, distribution, metabolism, and elimination study.

  In vitro

  , CYP-dependent metabolism accounted for about 5% compared to about 25% ester cleavage.

  Excretion

  The major route of elimination of drug-related radioactivity after oral administration of [¹⁴C] nintedanib was via fecal/biliary excretion (93.4% of dose), and the majority of OFEV was excreted as BIBF 1202. The contribution of renal excretion to the total clearance was low (0.65% of dose). The overall recovery was considered complete (above 90%) within 4 days after dosing.

  Specific Populations

  Age, Body Weight, and Sex

  Based on population PK analysis, age and body weight were correlated with nintedanib exposure. However, the effects on exposure are not sufficient to warrant a dose adjustment. There was no influence of sex on the exposure of nintedanib.

  Patients with Renal Impairment

  Based on a population PK analysis of data from 933 patients with IPF, exposure to nintedanib was not influenced by mild (CrCl: 60 to 90 mL/min; n=399) or moderate (CrCl: 30 to 60 mL/min; n=116) renal impairment. Data in severe renal impairment (CrCl below 30 mL/min) was limited.

  Patients with Hepatic Impairment

  A dedicated single-dose phase I pharmacokinetics study of OFEV compared 8 subjects with mild hepatic impairment (Child Pugh A) and 8 subjects with moderate hepatic impairment (Child Pugh B) to 17 subjects with normal hepatic function. In subjects with mild hepatic impairment, the mean exposure to nintedanib was 2.4-fold higher based on C_max(90% CI: 1.6 to 3.6) and 2.2-fold higher based on AUC_0-inf(90% CI: 1.4 to 3.5). In subjects with moderate hepatic impairment, exposure was 6.9-fold higher based on C_max(90% CI: 4.4 to 11.0) and 7.6-fold higher based on AUC_0-inf(90% CI: 5.1 to 11.3). Subjects with severe hepatic impairment (Child Pugh C) have not been studied.

  Smokers

  In the population PK analysis, the exposure of nintedanib was 21% lower in current smokers compared to ex- and never-smokers. The effect is not sufficient to warrant a dose adjustment.

  Drug Interaction Studies

  Potential for Nintedanib to Affect Other Drugs

  Effect of nintedanib coadministration on pirfenidone AUC and C_maxwas evaluated in a multiple-dose study. Nintedanib did not have an effect on the exposure of pirfenidone.

  Fifteen female patients with SSc-ILD received a single dose of a combination of 30 mcg ethinylestradiol and 150 mcg levonorgestrel before and after twice daily dosing of 150 mg nintedanib for at least 10 days. Co-administration of nintedanib did not change the exposure of ethinylestradiol and levonorgestrel

  [see Warnings and Precautions (5.4)and Use in Specific Populations (8.3)]

  .

  In

  in vitro

  studies, nintedanib was shown not to be an inhibitor of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, or MRP-2.

  In vitro

  studies also showed that nintedanib has weak inhibitory potential on OCT-1, BCRP, and P-gp; these findings are considered to be of low clinical relevance. Nintedanib and its metabolites, BIBF 1202 and BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes

  in

  vitro

  .

  Potential for Other Drugs to Affect Nintedanib

  Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4. Coadministration with the P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib 1.61-fold based on AUC and 1.83-fold based on C_maxin a dedicated drug-drug interaction study. In a drug-drug interaction study with the P-gp and CYP3A4 inducer, rifampicin, exposure to nintedanib decreased to 50.3% based on AUC and to 60.3% based on C_maxupon coadministration with rifampicin compared to administration of nintedanib alone.

  Effect of pirfenidone coadministration on nintedanib AUC and C_maxwas evaluated in a multiple-dose drug-drug interaction study. Pirfenidone did not have an effect on the exposure of nintedanib. Concomitant treatment with nintedanib and pirfenidone was also investigated in a separate trial, which was 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. Similar nintedanib trough plasma concentrations were observed when comparing patients receiving nintedanib alone with patients receiving nintedanib with add-on pirfenidone.

  Healthy volunteers received a single dose of 150 mg nintedanib before and after multiple dosing of 125 mg bosentan twice daily at steady state. Coadministration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib.

  Nintedanib displays a pH-dependent solubility profile with increased solubility at acidic pH less than 3. However, in the clinical trials, coadministration with proton pump inhibitors or histamine H2 antagonists did not influence the exposure (trough concentrations) of nintedanib.

  In

  in vitro

  studies, nintedanib was shown not to be a substrate of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, MRP-2, or BCRP.

  In vitro

  studies also showed that nintedanib was a substrate of OCT-1; these findings are considered to be of low clinical relevance.
  )
• Smokers: Decreased exposure has been noted in smokers which may alter the efficacy profile of OFEV. (
  8.8 Smokers

  Smoking was associated with decreased exposure to OFEV

  [see Clinical Pharmacology (12.3)],

  which may alter the efficacy profile of OFEV

  .

  Encourage patients to stop smoking prior to treatment with OFEV and to avoid smoking when using OFEV.
  )

• Hepatic impairment: OFEV 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 Recommended Dosage for Patients with Hepatic Impairment

  Mild Hepatic Impairment

  In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of OFEV 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 OFEV 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 OFEV may require dose reduction or temporary interruption until the specific adverse reaction resolves to levels that allow continuation of therapy

  .

  OFEV 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 OFEV

  [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 OFEV, 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 OFEV 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 OFEV to 100 mg twice daily. Once liver enzymes have returned to baseline values, treatment with OFEV 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.
  ,
  5.1 Hepatic Impairment

  Treatment with OFEV 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 OFEV

  [see Dosage and Administration (2.3)].
  ,
  8.6 Hepatic 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

  [see Clinical Pharmacology (12.3)]

  . In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of OFEV is 100 mg twice daily

  [see Dosage and Administration (2.3)]

  . Monitor for adverse reactions and consider treatment interruption, or discontinuation for management of adverse reactions in these patients

  [see Dosage and Administration (2.4)].

  Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with OFEV is not recommended

  [see Warnings and Precautions (5.1)].
  ,
  12.3 Pharmacokinetics

  The PK properties of nintedanib were similar in healthy volunteers, patients with IPF, patients with chronic fibrosing ILDs with a progressive phenotype, patients with SSc-ILD, and cancer patients. The PK of nintedanib is linear. Dose proportionality was shown by an increase of nintedanib exposure with increasing doses (dose range 50 to 450 mg once daily and 150 to 300 mg twice daily). Accumulation upon multiple administrations in patients with IPF was 1.76-fold for AUC. Steady-state plasma concentrations were achieved within one week of dosing. Nintedanib trough concentrations remained stable for more than one year. The inter-individual variability in the PK of nintedanib was moderate to high (coefficient of variation of standard PK parameters in the range of 30% to 70%), intra-individual variability low to moderate (coefficients of variation below 40%).

  Absorption

  Nintedanib reached maximum plasma concentrations approximately 2 to 4 hours after oral administration as a soft gelatin capsule under fed conditions. The absolute bioavailability of a 100 mg dose was 4.7% (90% CI: 3.62 to 6.08) in healthy volunteers. Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism.

  After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions (90% CI: 95.3% to 152.5%) and absorption was delayed (median t_maxfasted: 2.00 hours; fed: 3.98 hours), irrespective of the food type.

  Distribution

  Nintedanib follows bi-phasic disposition kinetics. After intravenous infusion, a high volume of distribution which was larger than total body volume (V_ss: 1050 L) was observed.

  The

  in vitro

  protein binding of nintedanib in human plasma was high, with a bound fraction of 97.8%. Serum albumin is considered to be the major binding protein. Nintedanib is preferentially distributed in plasma with a blood to plasma ratio of 0.87.

  Elimination

  The effective half-life of nintedanib in patients with IPF was 9.5 hours (gCV 31.9%). Total plasma clearance after intravenous infusion was high (CL: 1390 mL/min; gCV 28.8%). Urinary excretion of unchanged drug within 48 hours was about 0.05% of the dose after oral and about 1.4% of the dose after intravenous administration; the renal clearance was 20 mL/min.

  Metabolism

  The prevalent metabolic reaction for nintedanib is hydrolytic cleavage by esterases resulting in the free acid moiety BIBF 1202. BIBF 1202 is subsequently glucuronidated by UGT enzymes, namely UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to BIBF 1202 glucuronide. Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways, with CYP3A4 being the predominant enzyme involved. The major CYP-dependent metabolite could not be detected in plasma in the human absorption, distribution, metabolism, and elimination study.

  In vitro

  , CYP-dependent metabolism accounted for about 5% compared to about 25% ester cleavage.

  Excretion

  The major route of elimination of drug-related radioactivity after oral administration of [¹⁴C] nintedanib was via fecal/biliary excretion (93.4% of dose), and the majority of OFEV was excreted as BIBF 1202. The contribution of renal excretion to the total clearance was low (0.65% of dose). The overall recovery was considered complete (above 90%) within 4 days after dosing.

  Specific Populations

  Age, Body Weight, and Sex

  Based on population PK analysis, age and body weight were correlated with nintedanib exposure. However, the effects on exposure are not sufficient to warrant a dose adjustment. There was no influence of sex on the exposure of nintedanib.

  Patients with Renal Impairment

  Based on a population PK analysis of data from 933 patients with IPF, exposure to nintedanib was not influenced by mild (CrCl: 60 to 90 mL/min; n=399) or moderate (CrCl: 30 to 60 mL/min; n=116) renal impairment. Data in severe renal impairment (CrCl below 30 mL/min) was limited.

  Patients with Hepatic Impairment

  A dedicated single-dose phase I pharmacokinetics study of OFEV compared 8 subjects with mild hepatic impairment (Child Pugh A) and 8 subjects with moderate hepatic impairment (Child Pugh B) to 17 subjects with normal hepatic function. In subjects with mild hepatic impairment, the mean exposure to nintedanib was 2.4-fold higher based on C_max(90% CI: 1.6 to 3.6) and 2.2-fold higher based on AUC_0-inf(90% CI: 1.4 to 3.5). In subjects with moderate hepatic impairment, exposure was 6.9-fold higher based on C_max(90% CI: 4.4 to 11.0) and 7.6-fold higher based on AUC_0-inf(90% CI: 5.1 to 11.3). Subjects with severe hepatic impairment (Child Pugh C) have not been studied.

  Smokers

  In the population PK analysis, the exposure of nintedanib was 21% lower in current smokers compared to ex- and never-smokers. The effect is not sufficient to warrant a dose adjustment.

  Drug Interaction Studies

  Potential for Nintedanib to Affect Other Drugs

  Effect of nintedanib coadministration on pirfenidone AUC and C_maxwas evaluated in a multiple-dose study. Nintedanib did not have an effect on the exposure of pirfenidone.

  Fifteen female patients with SSc-ILD received a single dose of a combination of 30 mcg ethinylestradiol and 150 mcg levonorgestrel before and after twice daily dosing of 150 mg nintedanib for at least 10 days. Co-administration of nintedanib did not change the exposure of ethinylestradiol and levonorgestrel

  [see Warnings and Precautions (5.4)and Use in Specific Populations (8.3)]

  .

  In

  in vitro

  studies, nintedanib was shown not to be an inhibitor of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, or MRP-2.

  In vitro

  studies also showed that nintedanib has weak inhibitory potential on OCT-1, BCRP, and P-gp; these findings are considered to be of low clinical relevance. Nintedanib and its metabolites, BIBF 1202 and BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes

  in

  vitro

  .

  Potential for Other Drugs to Affect Nintedanib

  Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4. Coadministration with the P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib 1.61-fold based on AUC and 1.83-fold based on C_maxin a dedicated drug-drug interaction study. In a drug-drug interaction study with the P-gp and CYP3A4 inducer, rifampicin, exposure to nintedanib decreased to 50.3% based on AUC and to 60.3% based on C_maxupon coadministration with rifampicin compared to administration of nintedanib alone.

  Effect of pirfenidone coadministration on nintedanib AUC and C_maxwas evaluated in a multiple-dose drug-drug interaction study. Pirfenidone did not have an effect on the exposure of nintedanib. Concomitant treatment with nintedanib and pirfenidone was also investigated in a separate trial, which was 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. Similar nintedanib trough plasma concentrations were observed when comparing patients receiving nintedanib alone with patients receiving nintedanib with add-on pirfenidone.

  Healthy volunteers received a single dose of 150 mg nintedanib before and after multiple dosing of 125 mg bosentan twice daily at steady state. Coadministration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib.

  Nintedanib displays a pH-dependent solubility profile with increased solubility at acidic pH less than 3. However, in the clinical trials, coadministration with proton pump inhibitors or histamine H2 antagonists did not influence the exposure (trough concentrations) of nintedanib.

  In

  in vitro

  studies, nintedanib was shown not to be a substrate of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, MRP-2, or BCRP.

  In vitro

  studies also showed that nintedanib was a substrate of OCT-1; these findings are considered to be of low clinical relevance.
  )
• Elevated liver enzymes and drug-induced liver injury: ALT, AST, and bilirubin elevations have occurred with OFEV, 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 Testing Prior to OFEV Administration

  Conduct liver function tests in all patients and a pregnancy test in females of reproductive potential prior to initiating treatment with OFEV

  [see Warnings and Precautions (5.2, 5.4)].
  ,
  2.4 Dosage Modification due to Adverse Reactions

  In addition to symptomatic treatment, if applicable, the management of adverse reactions of OFEV may require dose reduction or temporary interruption until the specific adverse reaction resolves to levels that allow continuation of therapy

  .

  OFEV 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 OFEV

  [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 OFEV, 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 OFEV 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 OFEV to 100 mg twice daily. Once liver enzymes have returned to baseline values, treatment with OFEV 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.
  ,
  5.2 Elevated Liver Enzymes and Drug-Induced Liver Injury

  Cases of drug-induced liver injury (DILI) have been observed with OFEV 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 OFEV 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 OFEV group and for 0.7% of patients in the placebo group

  [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 OFEV, 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)]

  .
  )
• Gastrointestinal disorders: Diarrhea, nausea, and vomiting have occurred with OFEV. Treat patients at first signs with adequate hydration and antidiarrheal medicine (e.g., loperamide) or anti-emetics. Discontinue OFEV if severe diarrhea, nausea, or vomiting persists despite symptomatic treatment. (
  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 OFEV and placebo, respectively

  [see Adverse Reactions (6.1)].

  Diarrhea led to permanent dose reduction in 11% of patients treated with OFEV compared to 0 placebo-treated patients. Diarrhea led to discontinuation of OFEV 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 OFEV and placebo, respectively

  [see Adverse Reactions (6.1)].

  Diarrhea led to permanent dose reduction in 16% of patients treated with OFEV compared to less than 1% of placebo-treated patients. Diarrhea led to discontinuation of OFEV 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 OFEV and placebo, respectively

  [see Adverse Reactions (6.1)].

  Diarrhea led to permanent dose reduction in 22% of patients treated with OFEV compared to 1% of placebo-treated patients. Diarrhea led to discontinuation of OFEV 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

  [see Dosage and Administration (2.4)].

  OFEV 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 OFEV.

  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 OFEV 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 OFEV 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 OFEV 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 OFEV in 2% of patients and vomiting led to discontinuation of OFEV in 1% of the patients. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), nausea led to discontinuation of OFEV in less than 1% of patients and vomiting led to discontinuation of OFEV in 1% of the patients. In the SSc-ILD study (Study 4), nausea led to discontinuation of OFEV in 2% of patients and vomiting led to discontinuation of OFEV 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

  [see Dosage and Administration (2.4)]

  . OFEV 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 OFEV.
  )
• 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 Embryo-Fetal Toxicity

  Based on findings from animal studies and its mechanism of action, OFEV 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 OFEV and to use highly effective contraception at initiation of, during treatment, and at least 3 months after the last dose of OFEV. 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 OFEV and during treatment as appropriate

  [see Use in Specific Populations (8.1, 8.3)and Clinical Pharmacology (12.1, 12.3)].
  ,
  8.1 Pregnancy

  Risk Summary

  Based on findings from animal studies and its mechanism of action

  [see Clinical Pharmacology (12.1)]

  , OFEV can cause fetal harm when administered to a pregnant woman. There are no data on the use of OFEV 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).
  ,
  8.3 Females and Males of Reproductive Potential

  Based on findings from animal studies and its mechanism of action, OFEV 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 OFEV and during treatment as appropriate

  [see Dosage and Administration (2.1), Warnings and Precautions (5.4), and Use in Specific Populations (8.1)].

  Contraception

  OFEV can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid becoming pregnant while receiving treatment with OFEV. 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 OFEV. 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, OFEV may reduce fertility in females of reproductive potential

  [see Nonclinical Toxicology (13.1)].
  )
• Arterial thromboembolic events have been reported. Use caution when treating patients at higher cardiovascular risk including known coronary artery disease. (
  5.5 Arterial Thromboembolic Events

  Arterial thromboembolic events have been reported in patients taking OFEV. In IPF studies (Study 1, Study 2, and Study 3), arterial thromboembolic events were reported in 2.5% of patients treated with OFEV 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 OFEV-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 OFEV-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.
  )
• Bleeding events have been reported. Use OFEV in patients with known bleeding risk only if anticipated benefit outweighs the potential risk. (
  5.6 Risk of Bleeding

  Based on the mechanism of action (VEGFR inhibition), OFEV 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 OFEV 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 OFEV 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 OFEV 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 OFEV in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
  )
• Gastrointestinal perforation has been reported. Use OFEV with caution when treating patients with recent abdominal surgery, previous history of diverticular disease or receiving concomitant corticosteroids or NSAIDs. Discontinue OFEV in patients who develop gastrointestinal perforation. Only use OFEV in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk. (
  5.7 Gastrointestinal Perforation

  Based on the mechanism of action, OFEV 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 OFEV, 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 OFEV 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 OFEV in patients who develop gastrointestinal perforation. Only use OFEV 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. (
  5.8 Nephrotic 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 OFEV was discontinued; however, in some cases, residual proteinuria persisted. Consider treatment interruption in patients who develop new or worsening proteinuria.
  )