PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Idiopathic Pulmonary Fibrosis Agents
    Interstitial Lung Disease Associated with Systemic Sclerosis or Scleroderma (SSc-ILD) Agents

    DEA CLASS

    Rx

    DESCRIPTION

    A kinase inhibitor; blocks multiple pathways involved in the scarring of lung tissue
    Used for adults with idiopathic pulmonary fibrosis (IPF), chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype, and systemic sclerosis-associated interstitial lung disease (SSc-ILD)
    Avoid in moderate to severe hepatic disease or severe renal impairment; women who may become pregnant must use highly effective contraception during and for 3 months following the last dose

    COMMON BRAND NAMES

    Ofev

    HOW SUPPLIED

    Ofev Oral Cap: 100mg, 150mg

    DOSAGE & INDICATIONS

    For the treatment of idiopathic pulmonary fibrosis (IPF).
    NOTE: The FDA has granted orphan drug status to nintedanib for this indication.
    Oral dosage
    Adults

    150 mg PO twice daily, administered approximately every 12 hours. In 3 randomized, double-blind, placebo-controlled clinical trials (n = 1,231), patients with idiopathic pulmonary fibrosis (IPF) treated with nintedanib had a significantly reduced annual rate of decline of FVC (-60 to -115 mL) vs. placebo (-191 to -240 mL), after adjusting for gender, height, and age. In 2 of the 3 clinical trials, nintedanib also improved the percent change in forced vital capacity (FVC) from baseline over 52 weeks. A phase II and phase III clinical trial demonstrated a significantly reduced risk of first acute IPF exacerbation in patients treated with nintedanib (HR 0.16; 95% CI, 0.04 to 0.71) vs. placebo; a third clinical trial (phase III) found no difference between treatment groups. Nintedanib did not affect all-cause mortality.

    For the treatment of scleroderma (systemic sclerosis)-associated interstitial lung disease (SSc-ILD).
    Oral dosage
    Adults

    150 mg PO twice daily, administered approximately every 12 hours. In a randomized, double-blind, placebo-controlled clinical trial (n = 580) of patients with SSc-ILD, there was a significantly reduced annual rate of decline of FVC by 41 mL in patients treated with nintedanib (-52 mL) vs. placebo (-93 mL), corresponding to a relative treatment effect of 44%. There were no benefits observed in the modified Rodnan skin score (mRSS) or difference in survival at week 52.

    For the treatment of chronic fibrosing interstitial lung disease (ILD) with a progressive phenotype.
    Oral dosage
    Adults

    150 mg PO twice daily, administered approximately every 12 hours. In a 52 week, randomized, double-blind, placebo-controlled clinical trial of patients with chronic fibrosing ILDs with a progressive phenotype (n = 662), there was a statistically significant reduction in the annual rate of decline in FVC (107 mL; 95% CI: 65, 148) in patients treated with nintedanib (-81 mL) versus placebo (-188 mL). There was no statistically significant difference observed in overall survival.

    MAXIMUM DOSAGE

    Adults

    300 mg/day PO.

    Geriatric

    300 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    Neonates

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline hepatic impairment
    Child Pugh Class A: Reduce the dose of nintedanib to 100 mg PO every 12 hours.
    Child Pugh Class B or C: Nintedanib treatment is not recommended. Safety and efficacy have not been studied in patients with severe hepatic impairment.
     
    Treatment-induced hepatotoxicity
    Mild hepatic impairment (Child Pugh A): Consider an interruption or discontinuation of therapy for management of adverse reactions.
    AST / ALT 3 to 5 times the upper limit of normal (ULN) without signs of severe liver damage: Hold nintedanib therapy or reduce the dose to 100 mg PO twice daily. When liver enzymes return to baseline, treatment with nintedanib may be resumed at a reduced dosage (i.e., 100 mg PO twice daily), and then subsequently increased to the full dose (150 mg PO twice daily).
    AST / ALT greater than 3 times ULN with signs or symptoms of severe liver damage or AST / ALT greater than 5 times ULN: Discontinue nintedanib therapy.

    Renal Impairment

    CrCl greater than or equal to 30 mL/minute: Dosage adjustment is not required.
    CrCl less than 30 mL/minute or end-stage renal disease: Safety and efficacy of nintedanib have not been studied.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Nintedanib capsules must be administered with food.
    Administer capsules whole with liquid; the patient should not chew or crush the capsule because of a bitter taste and an unknown impact to the drug's efficacy.
    If a dose is missed, take the next dose at the next scheduled time; do not take 2 doses at the same time.

    STORAGE

    Ofev:
    - Avoid excessive heat (above 104 degrees F)
    - Avoid excessive humidity
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Asian patients, females, geriatric, hepatic disease, hepatotoxicity, jaundice

    Reduce the dose of nintedanib in patients with mild hepatic disease (Child Pugh A). Nintedanib is not recommended in patients with moderate or severe hepatic disease (Child Pugh B or C); it has not been studied in patients with severe hepatic disease. Nintedanib therapy may cause elevated bilirubin and liver enzymes, but increases in liver enzymes are usually reversible with dose modification or interruption of therapy. During postmarketing surveillance, non-serious and serious cases of drug-induced hepatotoxicity, including severe liver injury with fatal outcome, were reported. Patients with a low body weight (weighing less than 65 kg), Asian patients, and females may have a higher risk of elevations in liver enzymes. Since nintedanib exposure increases with patient age, geriatric patients may also be at a higher risk of increased liver enzymes. Check liver function tests (LFTS) and bilirubin concentrations before starting treatment, at regular intervals during the first 3 months, and periodically thereafter, and as clinically indicated. Dosage modification or interruption of nintedanib therapy may be necessary for elevated liver enzymes. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during nintedanib therapy, promptly interrupt therapy.

    Anticoagulant therapy, bleeding

    Use nintedanib in patients with a known risk of bleeding only if the benefits of therapy outweigh the risks. For patients receiving nintedanib concurrently with anticoagulant therapy, closely monitor for bleeding and adjust anticoagulation treatment as necessary. Nintedanib may increase the risk of bleeding, based on its mechanism of action as a VEGFR inhibitor. In the idiopathic pulmonary fibrosis (IPF) clinical trials, bleeding events occurred more often in patients treated with nintedanib than in the placebo group (10% vs. 7%). Similarly, in the systemic sclerosis-associated interstitial lung disease (SSc-ILD) clinical trial, bleeding events were reported by 11% of nintedanib recipients compared to 8% of patients who received a placebo. However, in the chronic fibrosing interstitial lung diseases (ILDs) trial, a higher percentage of placebo recipients experienced a bleeding event compared with the nintedanib treatment group (13% vs. 11%). Bleeding events, both non-serious and serious (some fatal), have also been reported during postmarketing use of the drug.[58203]

    Acute myocardial infarction, coronary artery disease, myocardial infarction, stroke

    Serious arterial events, including myocardial infarction (MI), have been reported with nintedanib use. Nintedanib should be used with caution in patients at increased cardiovascular risk, including known coronary artery disease or ischemia. Encourage patients receiving nintedanib to seek immediate medical attention if they experience symptoms suggesting a heart attack (e.g., chest pain or pressure, pain in their arms, back, neck or jaw, or shortness of breath) or symptoms of a stroke (e.g., numbness or weakness on one side of the body, trouble talking, or severe head pain). Consider treatment interruption in patients who develop signs or symptoms of acute myocardial infarction, stroke, or other serious arterial events.

    Corticosteroid therapy, diarrhea, diverticulitis, GI perforation, surgery, vomiting

    Gastrointestinal (GI) events such as diarrhea and nausea and/or vomiting are common with nintedanib therapy and may require supportive measures to control. Treat diarrhea at first signs with adequate hydration and antidiarrheal medication (e.g., loperamide); use supportive care for nausea and vomiting, including anti-emetic treatment. Consider treatment interruption if diarrhea or vomiting continues despite support measures, until resolution, after which nintedanib may be resumed at full or reduced dosage, followed by titration. If severe symptoms persist, consider permanent discontinuation of treatment. Nintedanib may increase the risk of GI perforation based on its mechanism of action as a VEGFR inhibitor. Use nintedanib in patients with a known risk of GI perforation only if the benefits of therapy outweigh the risks. Use caution when treating patients who have recently had abdominal surgery, have a previous history of diverticular disease (diverticulitis), or who are receiving concomitant corticosteroid therapy or NSAIDs. In the idiopathic pulmonary fibrosis (IPF) clinical trials, GI perforation occurred more often in patients treated with nintedanib than in the placebo group (0.3% vs 0%). No cases of GI perforation were associated with the use of nintedanib during the chronic fibrosing interstitial lung diseases (ILDs) or systemic sclerosis-associated interstitial lung disease (SSc-ILD) clinical trials. During postmarketing surveillance, cases of GI perforation have been reported, some of which were fatal. The typical presentation may include abdominal pain associated with symptoms such as constipation, fever, nausea, and vomiting. Nintedanib therapy should be permanently discontinued in patients with GI perforation.

    Tobacco smoking

    Tobacco smoking was associated with decreased nintedanib exposure, which may decrease the efficacy of treatment. Patients should be encouraged to stop smoking before initiating nintedanib treatment and to avoid smoking during therapy.

    Pregnancy

    Do not use nintedanib during pregnancy; rule out pregnancy in a female of childbearing potential prior to initiation of nintedanib. Females of reproductive potential should avoid becoming pregnant during nintedanib therapy and for at least 3 months after the last dose of nintedanib. In animal reproduction toxicity studies, nintedanib was teratogenic and embryofetocidal in rats and rabbits at exposures 5 times or less that of the maximum recommended human dose (MRHD) in adults. Malformations included abnormalities in the vasculature (missing or additional major blood vessels), urogenital (missing organs), and skeletal systems. 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 rabbits, a significant change in sex ratio was observed in fetuses (female:male of approximately 71%:29%) at an AUC equivalent to approximately 15 times the MRHD. The post-natal viability of rat pups during the first 4 post-natal days was also reduced when dams were exposed to an AUC equivalent to less than the MRHD.

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Counsel female patients about the reproductive risk and contraception requirements during nintedanib treatment. Females of reproductive potential should undergo pregnancy testing prior to initiation of nintedanib and during treatment as appropriate and avoid pregnancy while taking the drug. Women who become pregnant while receiving nintedanib should be apprised of the potential hazard to the fetus. Females of childbearing potential should use highly effective contraception during and for at least 3 months after the final dose of nintedanib. It is currently unknown whether nintedanib may reduce the effectiveness of hormonal contraceptives, therefore advise women using hormonal contraceptives to add a barrier method. Based on animal data, female fertility may be reduced, resulting in possible infertility, with the use of nintedanib. Nintedanib did not affect male fertility in animal studies.

    Breast-feeding

    Breast-feeding is not recommended during nintedanib treatment, because of the potential for serious adverse reactions in a nursing infant. 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; the milk and plasma of lactating rats have similar concentrations of nintedanib and its metabolites.

    Children, infants

    The safety and efficacy of nintedanib have not been established in adolescents, children or infants.

    ADVERSE REACTIONS

    Severe

    thromboembolism / Delayed / 0.7-2.5
    myocardial infarction / Delayed / 0-1.5
    GI perforation / Delayed / 0.3-0.3
    new primary malignancy / Delayed / 0.3-0.3
    pancreatitis / Delayed / Incidence not known
    hypertensive crisis / Early / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    stroke / Early / Incidence not known

    Moderate

    skin ulcer / Delayed / 0-18.0
    elevated hepatic enzymes / Delayed / 4.9-14.0
    bleeding / Early / 10.0-11.0
    hypertension / Early / 5.0-5.0
    hypothyroidism / Delayed / 1.1-1.1
    dehydration / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    diarrhea / Early / 62.0-76.0
    nausea / Early / 24.0-32.0
    vomiting / Early / 12.0-25.0
    abdominal pain / Early / 15.0-18.0
    pharyngitis / Delayed / 0-13.0
    weight loss / Delayed / 10.0-12.0
    anorexia / Delayed / 9.0-11.0
    fatigue / Early / 10.0-11.0
    headache / Early / 8.0-9.0
    infection / Delayed / 0.7-7.0
    back pain / Delayed / 6.0-6.0
    fever / Early / 0-6.0
    dizziness / Early / 0-6.0
    alopecia / Delayed / 0.8-1.4
    pruritus / Rapid / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Amiodarone: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as amiodarone, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Amiodarone is a moderate inhibitor of P-gp and CYP3A4; nintedanib is a P-gp substrate, and also a minor substrate of CYP3A4. Administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Amobarbital: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as clarithromycin, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Clarithromycin is a moderate P-gp inhibitor and a potent inhibitor of CYP3A4; nintedanib is a P-gp substrate, and a minor CYP3A4 substrate. Administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Anticoagulants: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Antithrombin III: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Apalutamide: (Major) Avoid coadministration of nintedanib with apalutamide due to decreased plasma concentrations of nintedanib. Nintedanib is a substrate of P-glycoprotein (P-gp) and, to a minor extent, CYP3A4. Apalutamide is a strong CYP3A4 inducer as well as a weak P-gp inducer. Coadministration with oral doses of another P-gp and CYP3A4 inducer decreased exposure to nintedanib by 50%.
    Apixaban: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Argatroban: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Atazanavir; Cobicistat: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as cobicistat, may increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Cobicistat is a mild inhibitor of both P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Barbiturates: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Betrixaban: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Bivalirudin: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Boceprevir: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as boceprevir, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Boceprevir is a potent inhibitor of CYP3A4 and a mild P--gp inhibitor; nintedanib is a P-gp substrate, and a minor substrate of CYP3A4. Administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Butabarbital: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Butalbital; Acetaminophen: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Butalbital; Acetaminophen; Caffeine: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Carbamazepine: (Major) Avoid the use of carbamazepine with nintedanib, as carbamazepine is expected to decrease the exposure of nintedanib and compromise its efficacy. Carbamazepine is a potent P-glycoprotein (P-gp) and CYP3A4 inducer; nintedanib is a P-gp substrate and a minor substrate of CYP3A4. In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Clarithromycin: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as clarithromycin, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Clarithromycin is a moderate P-gp inhibitor and a potent inhibitor of CYP3A4; nintedanib is a P-gp substrate, and a minor CYP3A4 substrate. Administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Cobicistat: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as cobicistat, may increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Cobicistat is a mild inhibitor of both P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Conivaptan: (Moderate) Monitor for nintedanib-related adverse reactions if concomitant use of conivaptan is necessary. Concomitant use may increase nintedanib exposure. Nintedanib is a P-gp substrate, and a minor substrate of CYP3A and conivaptan is a dual P-gp and CYP3A inhibitor. Coadministration with another dual P-gp and CYP3A inhibitor increased nintedanib AUC by 60%.
    Cyclosporine: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as cyclosporine, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Cyclosporine is a moderate inhibitor of both P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Dabigatran: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Dalteparin: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Danaparoid: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Darunavir; Cobicistat: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as cobicistat, may increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Cobicistat is a mild inhibitor of both P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as cobicistat, may increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Cobicistat is a mild inhibitor of both P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as ritonavir, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Desirudin: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Dronedarone: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as dronedarone, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Dronedarone is a moderate inhibitor of P-gp and a mild inhibitor of CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Edoxaban: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as ivacaftor, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Ivacaftor is a mild inhibitor of both P-glycoprotein (P-gp) and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as cobicistat, may increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Cobicistat is a mild inhibitor of both P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as cobicistat, may increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Cobicistat is a mild inhibitor of both P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Enoxaparin: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Erythromycin: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as erythromycin, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Erythromycin is a moderate inhibitor of P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Erythromycin; Sulfisoxazole: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as erythromycin, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Erythromycin is a moderate inhibitor of P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Fondaparinux: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Fosphenytoin: (Major) Avoid the use of fosphenytoin with nintedanib if possible, as fosphenytoin is expected to decrease the exposure of nintedanib and compromise its efficacy. Fosphenytoin is a potent CYP3A4 and mild P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate and a minor substrate of CYP3A4. In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Fostamatinib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as fostamatinib, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Fostamatinib is an inhibitor of CYP3A4 and P-gp. Nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Grapefruit juice: (Moderate) Patients should limit or avoid grapefruit juice during nintedanib treatment. Grapefruit Juice is a potent inhibitor of CYP3A4 and a moderate P-glycoprotein (P-gp) inhibitor; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration may increase the concentration and clinical effect of nintedanib. If the patient continues to regularly ingest grapefruit juice in the diet, closely monitor for increased nintedanib side effects including nausea, vomiting, diarrhea, gastrointestinal toxicity, or elevated liver enzymes. If these occur, the patient should discontinue use of grapefruit juice.
    Heparin: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Isavuconazonium: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as isavuconazonium, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4 and P-gp. Nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the use of rifampin with nintedanib, as rifampin significantly decreases the exposure of nintedanib and is expected to compromise the efficacy of nintedanib. Rifampin is a potent CYP3A4 inducer a moderate P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate and a minor substrate of CYP3A4. In a drug interaction study, the use of nintedanib with oral doses of rifampin decreased the nintedanib AUC to 50.3% and the Cmax to 60.3% compared with administration of nintedanib alone.
    Isoniazid, INH; Rifampin: (Major) Avoid the use of rifampin with nintedanib, as rifampin significantly decreases the exposure of nintedanib and is expected to compromise the efficacy of nintedanib. Rifampin is a potent CYP3A4 inducer a moderate P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate and a minor substrate of CYP3A4. In a drug interaction study, the use of nintedanib with oral doses of rifampin decreased the nintedanib AUC to 50.3% and the Cmax to 60.3% compared with administration of nintedanib alone.
    Itraconazole: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as itraconazole, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Itraconazole is a potent inhibitor of CYP3A4 and a moderate P-gp inhibitor; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Ivacaftor: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as ivacaftor, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Ivacaftor is a mild inhibitor of both P-glycoprotein (P-gp) and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Ketoconazole: (Moderate) Ketoconaozle, a dual inhibitor of P-glycoprotein (P-gp) and CYP3A4, increases the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Ketoconazole is a potent inhibitor of CYP3A4 and a moderate P-gp inhibitor; nintedanib is a P-gp substrate and a minor substrate of CYP3A4. In drug interaction studies, the use of ketoconazole increased nintedanib AUC by 60% and the Cmax by 1.83-fold.
    Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as clarithromycin, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Clarithromycin is a moderate P-gp inhibitor and a potent inhibitor of CYP3A4; nintedanib is a P-gp substrate, and a minor CYP3A4 substrate. Administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Lapatinib: (Moderate) Monitor for an increase in nintedanib-related adverse reactions if coadministration with lapatinib is necessary. Nintedanib is a substrate of P-glycoprotein (P-gp) and, to a minor extent, CYP3A4. Lapatinib is a P-gp inhibitor as well as a weak CYP3A4 inhibitor. Coadministration with a dual P-gp and strong CYP3A4 inhibitor increased nintedanib exposure by 60%.
    Lepirudin: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Lopinavir; Ritonavir: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as ritonavir, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Lumacaftor; Ivacaftor: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as ivacaftor, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Ivacaftor is a mild inhibitor of both P-glycoprotein (P-gp) and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Mephobarbital: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Methohexital: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Mifepristone: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as mifepristone, are expected to increase the exposure and clinical effect of nintedanib. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Mifepristone is a moderate inhibitor of P-gp and an inhibitor of CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Nelfinavir: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as nelfinavir, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Nelfinavir is a moderate inhibitor of P-gp and a potent CYP3A4 inhibitor; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as ritonavir, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Pentobarbital: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Pentosan: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Phenobarbital: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Phenytoin: (Major) Avoid the use of phenytoin with nintedanib if possible, as phenytoin is expected to decrease the exposure of nintedanib and compromise its efficacy. Phenytoin is a potent CYP3A4 and mild P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate and a minor substrate of CYP3A4. In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Primidone: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Ranolazine: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as ranolazine, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. In vitro, ranolazine is a moderate inhibitor of P-gp and a mild CYP3A4 inhibitor; nintedanib is a P-gp substrate as well as a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Rifampin: (Major) Avoid the use of rifampin with nintedanib, as rifampin significantly decreases the exposure of nintedanib and is expected to compromise the efficacy of nintedanib. Rifampin is a potent CYP3A4 inducer a moderate P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate and a minor substrate of CYP3A4. In a drug interaction study, the use of nintedanib with oral doses of rifampin decreased the nintedanib AUC to 50.3% and the Cmax to 60.3% compared with administration of nintedanib alone.
    Ritonavir: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as ritonavir, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Rivaroxaban: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Saquinavir: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as saquinavir (when administered with ritonavir), are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Saquinavir is a potent CYP3A4 inhibitor and when combined with ritonavir also inhibits P-gp; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Secobarbital: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Simeprevir: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as simeprevir, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary.Simeprevir is a mild inhibitor of both CYP3A4 and P-gp; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    St. John's Wort, Hypericum perforatum: (Major) Have patients avoid use of St. John's Wort, Hypericum perforatum supplements during nintedanib treatment as this herb is likely to decrease exposure to nintedanib and compromise its efficacy. St. John's Wort is a potent dual CYP3A4 and P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate and a minor substrate of CYP3A4. In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Telaprevir: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as telaprevir, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Telaprevir is a P-glycoprotein (P-gp) and CYP3A4 inhibitor; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Telithromycin: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as telithromycin, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Telithromycin is a potent CYP3A4 inhibitor and a mild inhibitor of P-gp; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Tezacaftor; Ivacaftor: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as ivacaftor, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Ivacaftor is a mild inhibitor of both P-glycoprotein (P-gp) and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Thiopental: (Major) Avoid the use of barbiturates with nintedanib, as these drugs are expected to decrease the exposure of nintedanib and compromise its efficacy. Barbiturates are CYP3A4 inducers and some barbiturates, such as phenobarbital, also induce P-glycoprotein (P-gp). In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
    Ticagrelor: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as ticagrelor, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Ticagrelor is a mild inhibitor of both P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Tinzaparin: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Trandolapril; Verapamil: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as verapamil, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Verapamil is a moderate inhibitor of both P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Tucatinib: (Moderate) Closely monitor for increased nintedanib side effects, including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension, if coadministration with tucatinib is necessary. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Concurrent use may increase the exposure and clinical effect of nintedanib. Nintedanib is a P-gp substrate, and a minor CYP3A4 substrate. Tucatinib is a P-gp inhibitor and a strong CYP3A4 inhibitor. Administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib exposure by 60%.
    Verapamil: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as verapamil, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Verapamil is a moderate inhibitor of both P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Warfarin: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.

    PREGNANCY AND LACTATION

    Pregnancy

    Do not use nintedanib during pregnancy; rule out pregnancy in a female of childbearing potential prior to initiation of nintedanib. Females of reproductive potential should avoid becoming pregnant during nintedanib therapy and for at least 3 months after the last dose of nintedanib. In animal reproduction toxicity studies, nintedanib was teratogenic and embryofetocidal in rats and rabbits at exposures 5 times or less that of the maximum recommended human dose (MRHD) in adults. Malformations included abnormalities in the vasculature (missing or additional major blood vessels), urogenital (missing organs), and skeletal systems. 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 rabbits, a significant change in sex ratio was observed in fetuses (female:male of approximately 71%:29%) at an AUC equivalent to approximately 15 times the MRHD. The post-natal viability of rat pups during the first 4 post-natal days was also reduced when dams were exposed to an AUC equivalent to less than the MRHD.

    Breast-feeding is not recommended during nintedanib treatment, because of the potential for serious adverse reactions in a nursing infant. 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; the milk and plasma of lactating rats have similar concentrations of nintedanib and its metabolites.

    MECHANISM OF ACTION

    Nintedanib is a small molecule inhibitor of multiple receptor tyrosine kinases (RTK), including platelet-derived growth factor receptor (PDGFR) alpha and beta, fibroblast growth factor receptor (FGFR) 1—3, vascular endothelial growth factor receptor (VEGFR) 1—3, and Fms-like tyrosine kinase-3 (FLT3). Additionally, nintedanib inhibits the non-receptor tyrosine kinases (nRTKs) Lck, Lyn, and Src kinase.
     
    The pathogenesis of idiopathic pulmonary fibrosis (IPF) has been associated with FGFR, PDGFR, and VEGFR; the contribution of FLT3 to IPF pathogenesis is unknown. Nintedanib competitively binds to the ATP binding pocket of these receptors, blocking intracellular signaling and inhibiting the proliferation, migration, and transformation of fibroblasts. The contribution of the non-receptor tyrosine kinases inhibition to the efficacy of nintedanib in IPF is unknown.

    PHARMACOKINETICS

    Nintedanib is administered orally. Pharmacokinetic properties of nintedanib were similar in healthy volunteers, patients with idiopathic pulmonary fibrosis (IPF), patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), and cancer patients. The drug exhibits linear pharmacokinetics. Nintedanib has biphasic distribution and is highly (97.8%) protein bound, with serum albumin considered to be the major binding protein. The drug has a volume of distribution that exceeds total body volume. The drug preferentially distributes to plasma, with a plasma-to-blood distribution ratio of 0.87. Steady-state plasma concentrations are achieved within 1 week of dosing, and trough concentrations have remained stable for more than 1 year. Nintedanib has moderate to high inter-patient pharmacokinetic variability (coefficient of variation of standard pharmacokinetic parameters, 30 to 70%) and low to moderate intra-patient variability (coefficients of variation less than 40%). More than 90% of each dose is eliminated via biliary / fecal excretion. Nintedanib undergoes hydrolytic cleavage by esterases, which results in the active metabolite BIBF 1202. While active, BIBF 1202 is substantially less potent than the parent compound and is not a major contributor to the overall effect of nintedanib. BIBF 1202 is then glucuronidated to the inactive metabolite BIBF 1202 glucuronide by UGT1A1, UGT1A7, UGT1A8, and UGT1A10. The isoenzyme CYP3A4 is involved in the biotransformation of nintedanib to a minor extent; in vitro, CYP-dependent metabolism accounted for 5% of metabolism compared to 25% for ester cleavage. Total plasma clearance was 1,390 mL/minute after intravenous (IV) infusion. Urinary excretion of unchanged drug within 48 hours was 0.05% of an oral dose and 1.4% after IV administration; renal clearance was 20 mL/minute. The half-life of nintedanib is 9.5 hours following IV infusion.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: P-glycoprotein (P-gp), CYP3A4
    Nintedanib is a substrate and weak inhibitor of P-gp and a minor substrate of CYP3A4. In vitro, nintedanib is also a weak OCT-1 and BCRP inhibitor; these inhibitory effects are of low clinical relevance.

    Oral Route

    The absolute oral bioavailability was 4.7% (90% CI, 3.62 to 6.08) for an 100 mg dose in healthy volunteers under fed conditions. Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism. Food (regardless of food type) increases nintedanib exposure by approximately 20% and delays the time to maximum concentration (Tmax) from 2 hours to 3.98 hours compared with fasting conditions. When taken with food, peak plasma concentrations (Cmax) of nintedanib is attained within 2 to 4 hours after oral administration. The drug is recommended to be taken orally with food.

    Intravenous Route

    After intravenous infusion, the volume of distribution (1050 L) was observed to be larger than total body volume.