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Apotex is pleased to offer financial assistance with cost-sharing for nintedanib capsules labeled and distributed by Apotex to eligible commercially insured patients through the nintedanib instant savings* program:

TO REPORT SUSPECT OR ADVERSE SIDE EFFECTS

Contact Apotex at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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For questions about enrolling in the program and processing the card, please call toll free at 833-393-5673.

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WARNINGS AND PRECAUTIONS

 
 

INDICATIONS

Nintedanib capsules are indicated in adults for:

  • Treatment of idiopathic pulmonary fibrosis (IPF)
  • Treatment of chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

  • Hepatic Impairment: Nintedanib capsules are 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.
  • Elevated Liver Enzymes and Drug-Induced Liver Injury
    • Cases of drug-induced liver injury (DILI) have been observed with nintedanib capsules treatment.
    • In the clinical trials and postmarketing period, non-serious and serious cases of DILI were reported. Cases of severe liver injury with fatal outcome have been reported in the postmarketing period. The majority of hepatic events occur within the first three months of treatment. In clinical trials, administration of nintedanib capsules were 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.
    • 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.
  • Gastrointestinal Disorders
    Diarrhea
    • In clinical trials, diarrhea was the most frequent gastrointestinal event reported. In most patients, the event was of mild to moderate intensity and occurred within the first 3 months of treatment.
    • In IPF studies (Study 1, Study 2, and Study 3), diarrhea was reported in 62% versus 18% of patients treated with nintedanib capsules and placebo, respectively. 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.
    • 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.
      • 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:
      • Was reported in 29% versus 9% and vomiting was reported in 18% versus 5% of patients treated with nintedanib capsules and placebo, respectively.
      • 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 most patients, these events were of mild to moderate intensity. 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.
  • Embryo-Fetal Toxicity
    • Nintedanib capsules can cause fetal harm when administered to a pregnant woman. 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. 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.
  • Arterial 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-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.
    • 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.
  • Risk of Bleeding
    • 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 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.
  • Gastrointestinal Perforation
    • Nintedanib capsules 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 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.
  • 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 nintedanib capsules were discontinued; however, in some cases, residual proteinuria persisted. Consider treatment interruption in patients who develop new or worsening proteinuria.

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 were evaluated in over 1,000 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

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 were diarrhea, nausea, abdominal pain, vomiting, liver enzyme elevation, decreased appetite, headache, decrease in weight, and hypertension.

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-treated patients and 1.8% of placebo-treated patients.


Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype

The safety profile in patients with chronic fibrosing ILDs with a progressive phenotype treated with nintedanib capsules were 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%).

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.


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

DRUG INTERACTIONS

  • 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.

USE IN SPECIFIC POPULATIONS

  • Nursing Mothers: Because of the potential for serious adverse reactions in nursing infants from nintedanib capsules, advise women that breastfeeding is not recommended during treatment with nintedanib capsules.
  • Females and Males of Reproductive Potential: Nintedanib capsules 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 capsules and during treatment as appropriate.
    • Contraception: Nintedanib capsules can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid becoming pregnant while receiving treatment with nintedanib capsules. Advise females of reproductive potential to use highly effective contraception at initiation of, during treatment, and for at least 3 months after taking the last dose of nintedanib capsules. 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 capsules may reduce fertility in females of reproductive potential.
  • Smokers: Smoking was associated with decreased exposure to nintedanib capsules, 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.
  • Pediatric Use: The safety and effectiveness of nintedanib capsules have not been established in pediatric patients for the treatment of fibrosing interstitial lung diseases.
  • Geriatric Use: In phase 3 studies, no overall differences in safety were observed between subjects who were 60 and over or 75 and over and younger subjects taking nintedanib capsules, but greater sensitivity of some older individuals cannot be ruled out.
  • Hepatic Impairment: In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of nintedanib capsules is 100 mg twice daily. Treatment interruption or discontinuation for management of adverse reactions may be warranted in these patients. Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with nintedanib capsules 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.

To report SUSPECTED ADVERSE REACTIONS, contact Apotex, Inc. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information