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  • CLASSES

    Protein Kinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    A kinase inhibitor; blocks multiple pathways.
    Used for the treatment of idiopathic pulmonary fibrosis (IPF); significantly reduces the decline in forced vital capacity compared with placebo.
    Investigational for treating lung cancer and other cancers.
    Not recommended for moderate to severe liver disease or in women who may become pregnant; use adequate contraception during and for at least 3 months after 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 = 1231), patients with idiopathic pulmonary fibrosis (IPF) treated with nintedanib 150 mg PO twice daily had a significantly reduced annual rate of decline of FVC (-60 to -115 mL) compared with placebo (-191 to -240 mL), after adjusting for gender, height, and age. In 2 of the 3 clinical trials (both phase III), nintedanib also improved the percent change in forced vital capacity (FVC) from baseline over 52 weeks. A phase II and phase III clinical trial each demonstrated a significantly reduced risk of first acute IPF exacerbation over 52 weeks in patients treated with nintedanib (HR 0.16; 95% CI, 0.04 to 0.71) compared with placebo (HR 0.20; 95% CI, 0.07 to 0.56); a third clinical trial (phase III) found no difference between treatment groups. Nintedanib did not affect all-cause mortality.

    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 by mouth 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/min: Dosage adjustment is not required.
    CrCl less than 30 mL/min 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

    Hepatic disease

    Nintedanib is not recommended in patients with moderate hepatic disease (Child Pugh B); it has not been studied in patients with severe hepatic disease (Child Pugh C) and is also not recommended in these patients. Reduce the dose of nintedanib in patients with mild hepatic disease (Child Pugh A). Nintedanib therapy may cause elevated bilirubin and liver enzymes, but was not associated with clinical signs or symptoms of liver injury during clinical trials. Increases in liver enzymes were reversible after dose reduction or interruption of therapy. Check liver function tests (e.g., AST, ALT, and bilirubin) before starting treatment, monthly for 3 months, every 3 months thereafter, and as clinically indicated.

    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.

    Anticoagulant therapy, bleeding

    Nintedanib may increase the risk of bleeding, based on its mechanism of action as a VEGFR inhibitor. In clinical trials, bleeding events occurred more often in patients treated with nintedanib compared with placebo (10% vs 7%). Monitor patients on anticoagulant therapy closely for bleeding and adjust anticoagulation treatment as necessary. Use nintedanib in patients with a known risk of bleeding only if the benefits of therapy outweigh the risks.

    Diarrhea, GI perforation, surgery, vomiting

    Gastrointestinal (GI) events such as diarrhea and nausea/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/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. In clinical trials, GI perforation occurred more often in patients treated with nintedanib compared with placebo (0.3% vs 0%). Nintedanib therapy should be permanently discontinued in patients with GI perforation; use caution when treating patients who have recently had abdominal surgery. The typical presentation may include abdominal pain associated with symptoms such as constipation, fever, nausea, and vomiting. Use nintedanib in patients with a known risk of GI perforation only if the benefits of therapy outweigh the risks.

    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.

    Females, pregnancy

    Although there are no adequate and well-controlled studies in pregnant women, fetal harm may occur if nintedanib is administered during pregnancy. Females of reproductive potential should avoid becoming pregnant during nintedanib therapy. In animal reproduction toxicity studies, nintedanib was teratogenic and embryofetocidal in rats and rabbits at exposures <= 5 times that of the maximum recommended human dose in adults (MRHD). 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 patients about the reproductive risk and contraception requirements during nintedanib treatment. Nintedanib can be teratogenic if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 3 months after the last dose of nintedanib. Females of reproductive potential should undergo pregnancy testing prior to initiation of nintedanib. Women who become pregnant while receiving nintedanib should be apprised of the potential hazard to the fetus. Female fertility in rats was reduced, resulting in possible infertility, at nintedanib exposures of approximately 3 times the MRHD based on AUC, including increased resorption, post-implantation loss, and a decrease in gestation index; an increase in the number of females with resorptions only was observed at exposures approximately equal to the MHRD. The number and size of corpora lutea in the ovaries were observed in chronic toxicity studies in both rats and mice. Nintedanib did not affect male fertility in rats and exposures of approximately 3 times the MRHD based on AUC.

    Breast-feeding

    According to the manufacturer, it is not known if nintedanib is excreted into human milk. Because of the potential of serious adverse reactions in nursing infants, women should be advised to discontinue nintedanib or discontinue breast-feeding.

    ADVERSE REACTIONS

    Severe

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

    Moderate

    elevated hepatic enzymes / Delayed / 14.0-14.0
    bleeding / Early / 10.0-10.0
    hypertension / Early / 5.0-5.0
    hypothyroidism / Delayed / 1.1-1.1
    secondary malignancy / Delayed / 0.3-0.3
    dehydration / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    diarrhea / Early / 62.0-62.0
    nausea / Early / 24.0-24.0
    abdominal pain / Early / 15.0-15.0
    vomiting / Early / 12.0-12.0
    anorexia / Delayed / 11.0-11.0
    weight loss / Delayed / 10.0-10.0
    headache / Early / 8.0-8.0
    infection / Delayed / 0.7-1.2

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Major) Barbiturates are CYP3A4 inducers and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as barbiturates should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Some barbiturates, such as phenobarbital, may also induce the P-glycoprotein (P-gp) metabolism of nintedanib.
    Acetaminophen; Butalbital; Caffeine: (Major) Barbiturates are CYP3A4 inducers and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as barbiturates should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Some barbiturates, such as phenobarbital, may also induce the P-glycoprotein (P-gp) metabolism of nintedanib.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Barbiturates are CYP3A4 inducers and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as barbiturates should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Some barbiturates, such as phenobarbital, may also induce the P-glycoprotein (P-gp) metabolism of nintedanib.
    Aldesleukin, IL-2: (Moderate) The safety and efficacy of aldesleukin, IL-2 in combination with any antineoplastic agents have not been established; however, concurrent or sequential use of these agents is common but results in various pharmacodynamic drug interaction risks. Aldesleukin, IL-2 is associated with serious adverse reactions affecting many organ systems In addition, adesleukin, IL-2 is a mild inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of aldesleukin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Alogliptin; Pioglitazone: (Major) Pioglitazone is a mild CYP3A4 inducer and nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with CYP3A4 inducers such as pioglitazone should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Amiodarone: (Moderate) Amiodarone is a moderate inhibitor of P-glycoprotein (P-gp) and CYP3A4; 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 concomitant use of amiodarone and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Amobarbital: (Major) Barbiturates are CYP3A4 inducers and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as barbiturates should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Some barbiturates, such as phenobarbital, may also induce the P-glycoprotein (P-gp) metabolism of nintedanib.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) Clarithromycin is a moderate P-glycoprotein (P-gp) inhibitor and a potent inhibitor of CYP3A4; nintedanib is a P-gp substrate as well as a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of clarithromycin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary. (Moderate) Lansoprazole is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of lansoprazole and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Clarithromycin is a moderate P-glycoprotein (P-gp) inhibitor and a potent inhibitor of CYP3A4; nintedanib is a P-gp substrate as well as a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of clarithromycin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary. (Moderate) Omeprazole is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of omeprazole and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    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.
    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.
    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.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if nintedanib and aprepitant, fosaprepitant are used concurrently and monitor for an increase in nintedanib-related adverse effects for several days after administration of a multi-day aprepitant regimen. Nintedanib is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of nintedanib. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    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.
    Armodafinil: (Major) In vitro, armodafinil is a mild inducer of CYP3A4; nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as armodafinil should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Barbiturates are CYP3A4 inducers and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as barbiturates should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Some barbiturates, such as phenobarbital, may also induce the P-glycoprotein (P-gp) metabolism of nintedanib.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Barbiturates are CYP3A4 inducers and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as barbiturates should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Some barbiturates, such as phenobarbital, may also induce the P-glycoprotein (P-gp) metabolism of nintedanib.
    Aspirin, ASA; Omeprazole: (Moderate) Omeprazole is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of omeprazole and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Atazanavir: (Moderate) Atazanavir is a potent inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of atazanavir and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Atazanavir; Cobicistat: (Moderate) Atazanavir is a potent inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of atazanavir and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary. (Moderate) Cobicistat is a mild inhibitor of both P-glycoprotein (P-gp) and CYP3A4; nintedanib is a P-gp substrate as well as a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Barbiturates are CYP3A4 inducers and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as barbiturates should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Some barbiturates, such as phenobarbital, may also induce the P-glycoprotein (P-gp) metabolism of nintedanib.
    Azithromycin: (Moderate) Azithromycin is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of azithromycin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Barbiturates: (Major) Barbiturates are CYP3A4 inducers and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as barbiturates should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Some barbiturates, such as phenobarbital, may also induce the P-glycoprotein (P-gp) metabolism of nintedanib.
    Basiliximab: (Moderate) Basiliximab is a mild inhibitor of CYP3A4 and nintedanib is a mild CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of basiliximab and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Barbiturates are CYP3A4 inducers and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as barbiturates should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Some barbiturates, such as phenobarbital, may also induce the P-glycoprotein (P-gp) metabolism of nintedanib.
    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.
    Bexarotene: (Major) Bexarotene is a CYP3A4 inducer and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as bexarotene should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    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.
    Boceprevir: (Moderate) Boceprevir is a potent inhibitor of CYP3A4 and a mild 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 concomitant use of boceprevir and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Bosentan: (Major) Bosentan is a CYP3A4 inducer and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as bosentan should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Bosutinib: (Moderate) In vitro, bosutinib is a moderate inhibitor of P-glycoprotein (P-gp); nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of bosutinib and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Butabarbital: (Major) Barbiturates are CYP3A4 inducers and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as barbiturates should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Some barbiturates, such as phenobarbital, may also induce the P-glycoprotein (P-gp) metabolism of nintedanib.
    Cabozantinib: (Moderate) Monitor for an increase in nintedanib-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of nintedanib may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and nintedanib is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Canagliflozin: (Moderate) Canagliflozin is a mild inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of canagliflozin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Canagliflozin; Metformin: (Moderate) Canagliflozin is a mild inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of canagliflozin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Carbamazepine: (Major) Carbamazepine is a potent CYP3A4 and P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as carbamazepine should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Carvedilol: (Moderate) Increased concentrations of nintedanib may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and nintedanib is a P-gp substrate.
    Chloramphenicol: (Moderate) Chloramphenicol is a moderate inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of chloramphenicol and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Cimetidine: (Moderate) Cimetidine is a mild inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of cimetidine and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Clarithromycin: (Moderate) Clarithromycin is a moderate P-glycoprotein (P-gp) inhibitor and a potent inhibitor of CYP3A4; nintedanib is a P-gp substrate as well as a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of clarithromycin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Clobazam: (Major) Clobazam is a mild CYP3A4 inducer and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as clobazam should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Cobicistat: (Moderate) Cobicistat is a mild inhibitor of both P-glycoprotein (P-gp) and CYP3A4; nintedanib is a P-gp substrate as well as a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Cobicistat is a mild inhibitor of both P-glycoprotein (P-gp) and CYP3A4; nintedanib is a P-gp substrate as well as a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Cobicistat is a mild inhibitor of both P-glycoprotein (P-gp) and CYP3A4; nintedanib is a P-gp substrate as well as a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Conivaptan: (Moderate) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and nintedanib, a CYP3A4/P-gp substrate. Concurrent use may result in elevated nintedanib serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as nintedanib, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with lansoprazole. Treatment with nintedanib may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Crizotinib: (Moderate) Closely monitor for nintedanib-related adverse reactions if coadministration with crizotinib is necessary; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for nintedanib patients due to adverse reactions. Nintedanib is a substrate of P-glycoprotein (P-gp) and, to a minor extent, CYP3A4. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp, and is also a moderate inhibitor of CYP3A4. Coadministration another P-gp/CYP3A4 inhibitor increased exposure to nintedanib by 60%.
    Cyclosporine: (Moderate) Cyclosporine is a moderate inhibitor of both P-glycoprotein (P-gp) and CYP3A4; 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 concomitant use of cyclosporine and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    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.
    Dabrafenib: (Major) Dabrafenib is a CYP3A4 inducer and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as dabrafenib should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Daclatasvir: (Moderate) Systemic exposure of nintedanib, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of nintedanib; monitor patients for potential adverse effects.
    Dalfopristin; Quinupristin: (Moderate) Quinupristin is a potent inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of dalfopristin; quinupristin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    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.
    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.
    Danazol: (Moderate) Danazol is a moderate inhibitor of CYP3A4 and nintedanib is a substrate of P-glycoprotein (P-gp) and to a minor extent, CYP3A4. Concomitant use of P-gp and CYP3A4 inhibitors with nintedanib may increase exposure to nintedanib. It is not clear to what extent danazol might affect nintedanib exposure. If concomitant use of danazol and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary.
    Darunavir: (Moderate) Darunavir is a moderate P-glycoprotein (P-gp) inhibitor and a potent inhibitor of CYP3A4; 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 concomitant use of darunavir and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Darunavir; Cobicistat: (Moderate) Cobicistat is a mild inhibitor of both P-glycoprotein (P-gp) and CYP3A4; nintedanib is a P-gp substrate as well as a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary. (Moderate) Darunavir is a moderate P-glycoprotein (P-gp) inhibitor and a potent inhibitor of CYP3A4; 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 concomitant use of darunavir and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of nintedanib with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated nintedanib plasma concentrations. Closely monitor the patient for nintedanib adverse effects, including gastrointestinal toxicity, elevated liver enzymes, and hypertension; a dose reduction, interruption of therapy, or discontinuation of therapy may be necessary. Nintedanib is a substrate of CYP3A4 and P-glycoprotein (P-gp). Ritonavir can increase nintedanib concentrations as it is a potent CYP3A4 inhibitor and a P-gp inhibitor. Paritaprevir also inhibits P-gp. (Moderate) Concurrent administration of nintedanib with ritonavir may result in elevated nintedanib plasma concentrations. Closely monitor the patient for nintedanib adverse effects, including gastrointestinal toxicity, elevated liver enzymes, and hypertension; a dose reduction, interruption of therapy, or discontinuation of therapy may be necessary. Nintedanib is a substrate of CYP3A4 and P-glycoprotein (P-gp). Ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor.
    Dasatinib: (Moderate) Dasatinib is a mild inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of dasatinib and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Delavirdine: (Moderate) Delavirdine is a potent inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of delavirdine and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Denosumab: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection and/or osteonecrosis of the jaw, a rare condition that has been reported during denosumab therapy.
    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.
    Dexamethasone: (Major) Dexamethasone is a CYP3A4 inducer and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as dexamethasone should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. In addition, because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen.
    Dextromethorphan; Quinidine: (Moderate) Quinidine is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of quinidine and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Diltiazem: (Moderate) Diltiazem is a moderate inhibitor of both P-glycoprotein (P-gp) and CYP3A4; 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 concomitant use of diltiazem and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Dronedarone: (Moderate) Dronedarone is a moderate inhibitor of P-glycoprotein (P-gp) and a mild CYP3A4 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 concomitant use of dronedarone and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    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.
    Efavirenz: (Major) Efavirenz is a CYP3A4 inducer and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as efavirenz should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Efavirenz is a CYP3A4 inducer and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as efavirenz should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Elbasvir; Grazoprevir: (Moderate) Administering nintedanib with elbasvir; grazoprevir may result in elevated nintedanib plasma concentrations. Nintedanib is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Moderate) Eliglustat is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of eliglustat and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    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.
    Erythromycin: (Moderate) Erythromycin is a moderate inhibitor of P-glycoprotein (P-gp) and CYP3A4; 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 concomitant use of erythromycin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Erythromycin; Sulfisoxazole: (Moderate) Erythromycin is a moderate inhibitor of P-glycoprotein (P-gp) and CYP3A4; 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 concomitant use of erythromycin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Eslicarbazepine: (Major) Eslicarbazepine is a CYP3A4 inducer. Nintedanib is a substrate of P-glycoprotein (P-gp) and to a minor extent, a substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as eslicarbazepine should be avoided as nintedanib exposure may be reduced and nintedanib efficacy may be compromised. Coadministration of nintedanib with a drug that was both a P-gp and CYP3A4 inducer decreased exposure to nintedanib by 50%. It is not clear to what extent eslicarbazepine will decease nintedanib exposure.
    Etravirine: (Major) Etravirine is a CYP3A4 inducer and a P-glycoprotein (P-gp) inhibitor; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as etravirine should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Ezetimibe; Simvastatin: (Moderate) Simvastatin is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of simvastatin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Felbamate: (Major) Felbamate is a mild inducer of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with CYP3A4 inducers such as felbamate should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Fluconazole: (Moderate) Fluconazole is a moderate inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of fluconazole and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Fluoxetine: (Moderate) Fluoxetine is a mild inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of fluoxetine and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Fluoxetine; Olanzapine: (Moderate) Fluoxetine is a mild inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of fluoxetine and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Flutamide: (Major) In vitro, flutamide is a CYP3A4 inducer; nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as flutamide should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    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.
    Fosamprenavir: (Major) Fosamprenavir is a potent inhibitor and a moderate inducer of CYP3A4; nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with a CYP3A4 inhibitor could increase the concentration and clinical effect of nintedanib, while concomitant use of a CYP3A4 inducer could decrease exposure to nintedanib. In addition, nintedanib is a substrate for P-glycoprotein; fosamprenavir is an inducer of P-gp.
    Fosphenytoin: (Major) Fosphenytoin is a potent CYP3A4 and mild P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as fosphenytoin should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and nintedanib as coadministration may increase serum concentrations of nintedanib and increase the risk of adverse effects. Nintedanib is a substrate of P-glycoprotein (P-gp); glecaprevir is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and nintedanib as coadministration may increase serum concentrations of nintedanib and increase the risk of adverse effects. Nintedanib is a substrate of P-glycoprotein (P-gp); pibrentasvir is an inhibitor of P-gp.
    Glimepiride; Pioglitazone: (Major) Pioglitazone is a mild CYP3A4 inducer and nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with CYP3A4 inducers such as pioglitazone should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Grapefruit juice: (Moderate) 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 concomitant use of grapefruit juice and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Griseofulvin: (Major) In vitro, griseofulvin is a mild inducer of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with CYP3A4 inducers such as griseofulvin should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    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.
    Idelalisib: (Moderate) Idelalisib is a potent inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of idelalisib and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Iloperidone: (Moderate) Iloperidone is a mild inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of iloperidone and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Imatinib: (Moderate) Imatinib, STI-571 is a moderate inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of imatinib and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Indinavir: (Moderate) Indinavir is a potent inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of indinavir and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with nintedanib may result in increased serum concentrations of nintedanib. Nintedanib is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4 and P-gp. Caution and close monitoring for increased nintedanib side effects, including gastrointestinal toxicity, elevated liver enzymes, and hypertension, are advised if these drugs are used together. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Isoniazid, INH: (Moderate) Isoniazid, INH is a potent inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of isoniazid and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Rifampin is a potent CYP3A4 inducer a moderate P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration 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. Avoid concomitant use of nintedanib with rifampin, as nintedanib efficacy may be compromised. (Moderate) Isoniazid, INH is a potent inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of isoniazid and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Isoniazid, INH; Rifampin: (Major) Rifampin is a potent CYP3A4 inducer a moderate P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration 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. Avoid concomitant use of nintedanib with rifampin, as nintedanib efficacy may be compromised. (Moderate) Isoniazid, INH is a potent inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of isoniazid and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Itraconazole: (Moderate) Itraconazole 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 concomitant use of itraconazole and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Ivacaftor: (Moderate) Ivacaftor is a mild inhibitor of both P-glycoprotein (P-gp) and CYP3A4; 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 concomitant use of ivacaftor and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Ketoconazole: (Moderate) Ketoconazole is a potent inhibitor of CYP3A4 and, in vitro, a moderate P-glycoprotein (P-gp) inhibitor; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration with ketoconazole increased nintedanib concentrations by 60%; the nintedanib AUC was increased by 1.61-fold and the Cmax by 1.83-fold. If concomitant use of ketoconazole and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Lansoprazole: (Moderate) Lansoprazole is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of lansoprazole and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Lansoprazole; Naproxen: (Moderate) Lansoprazole is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of lansoprazole and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Lapatinib: (Moderate) Lapatinib is a moderate inhibitor of P-glycoprotein (P-gp) and a mild CYP3A4 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 concomitant use of lapatinib and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Ledipasvir; Sofosbuvir: (Moderate) Ledipasvir is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of ledipasvir; sofosbuvir and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    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.
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of nintedanib with ritonavir may result in elevated nintedanib plasma concentrations. Closely monitor the patient for nintedanib adverse effects, including gastrointestinal toxicity, elevated liver enzymes, and hypertension; a dose reduction, interruption of therapy, or discontinuation of therapy may be necessary. Nintedanib is a substrate of CYP3A4 and P-glycoprotein (P-gp). Ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor. (Moderate) Lopinavir is a potent inhibitors of CYP3A4; nintedanib is a minor substrate of CYP3A4. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of lopinavir; ritonavir and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Lovastatin: (Moderate) Lovastatin is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of lovastatin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Lovastatin; Niacin: (Moderate) Lovastatin is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of lovastatin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Lumacaftor; Ivacaftor: (Moderate) Concomitant use of nintedanib and lumacaftor; ivacaftor may alter the therapeutic effects of nintedanib; caution and close monitoring are advised if these drugs are used together. Nintedanib is a substrate of P-glycoprotein (P-gp) and, to a minor extent, CYP3A4. Lumacaftor is a strong CYP3A inducer; in vitro data also suggests lumacaftor; ivacaftor may induce and/or inhibit P-gp. FDA-approved labeling for nintedanib recommends avoiding the concomitant use of drugs that are P-gp and CYP3A inducers; however, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Although the induction of nintedanib through the CYP3A pathway may lead to decreased drug efficacy, this is only a minor metabolic pathway. Monitor the patient for decreased nintedanib efficacy or increased or prolonged therapeutic effects and adverse events.
    Lumacaftor; Ivacaftor: (Moderate) Ivacaftor is a mild inhibitor of both P-glycoprotein (P-gp) and CYP3A4; 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 concomitant use of ivacaftor and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Mefloquine: (Moderate) Mefloquine is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of mefloquine and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Mephobarbital: (Major) Barbiturates are CYP3A4 inducers and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as barbiturates should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Some barbiturates, such as phenobarbital, may also induce the P-glycoprotein (P-gp) metabolism of nintedanib.
    Metformin; Pioglitazone: (Major) Pioglitazone is a mild CYP3A4 inducer and nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with CYP3A4 inducers such as pioglitazone should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Methohexital: (Major) Barbiturates are CYP3A4 inducers and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as barbiturates should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Some barbiturates, such as phenobarbital, may also induce the P-glycoprotein (P-gp) metabolism of nintedanib.
    Metyrapone: (Major) Metyrapone is a CYP3A4 inducer and nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with CYP3A4 inducers such as metyrapone should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Mifepristone, RU-486: (Moderate) Mifepristone, RU-486 is a moderate inhibitor of P-glycoprotein (P-gp) and, in vitro, an inhibitor of CYP3A4. 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 concomitant use of mifepristone, RU-486 and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Mirabegron: (Moderate) Mirabegron is a mild inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of mirabegron and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Mitotane: (Major) Avoid the concomitant use of mitotane with nintedanib; if coadministration cannot be avoided, monitor for decreased efficacy of nintedanib. Mitotane is a strong CYP3A4 inducer and nintedanib is a minor (5%) CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of nintedanib.
    Modafinil: (Major) Modafinil is a CYP3A4 inducer and nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with CYP3A4 inducers such as modafinil should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Nafcillin: (Major) In vitro, nafcillin is a CYP3A4 inducer and nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with CYP3A4 inducers such as nafcillin should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Nefazodone: (Moderate) Nefazodone is a potent inhibitor of CYP3A4 and nintedanib is a CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of nefazodone and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Nelfinavir: (Moderate) Nelfinavir is a moderate inhibitor of P-glycoprotein (P-gp) and a potent CYP3A4 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 concomitant use of nelfinavir and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Nevirapine: (Major) Nevirapine is a CYP3A4 inducer and nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with CYP3A4 inducers such as nevirapine should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Niacin; Simvastatin: (Moderate) Simvastatin is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of simvastatin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Nicardipine: (Moderate) In vitro, nicardipine is a potent inhibitor of P-glycoprotein (P-gp) and a moderate CYP3A4 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 concomitant use of nicardipine and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Nifedipine: (Moderate) Nifedipine is a mild inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of nifedipine and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Nilotinib: (Moderate) Nilotinib is a moderate inhibitor of both P-glycoprotein (P-gp) and CYP3A4; 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 concomitant use of nilotinib and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Octreotide: (Moderate) Octreotide is a moderate inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of octreotide and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of nintedanib with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated nintedanib plasma concentrations. Closely monitor the patient for nintedanib adverse effects, including gastrointestinal toxicity, elevated liver enzymes, and hypertension; a dose reduction, interruption of therapy, or discontinuation of therapy may be necessary. Nintedanib is a substrate of CYP3A4 and P-glycoprotein (P-gp). Ritonavir can increase nintedanib concentrations as it is a potent CYP3A4 inhibitor and a P-gp inhibitor. Paritaprevir also inhibits P-gp. (Moderate) Concurrent administration of nintedanib with ritonavir may result in elevated nintedanib plasma concentrations. Closely monitor the patient for nintedanib adverse effects, including gastrointestinal toxicity, elevated liver enzymes, and hypertension; a dose reduction, interruption of therapy, or discontinuation of therapy may be necessary. Nintedanib is a substrate of CYP3A4 and P-glycoprotein (P-gp). Ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor.
    Omeprazole: (Moderate) Omeprazole is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of omeprazole and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Omeprazole; Sodium Bicarbonate: (Moderate) Omeprazole is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of omeprazole and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Oral Contraceptives: (Moderate) In vitro, ethinyl estradiol (EE) is a mild inhibitor of CYP3A4; nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of oral contraceptives containing EE, including mestranol, and the ethinyl estradiol; etonogestrel vaginal ring, and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction of nintedanib, interruption of therapy, or discontinuation of therapy may be necessary in rare cases. Mestranol rapidly metabolized by demethylation to ethinyl estradiol upon absorption.
    Oritavancin: (Major) Oritavancin is a mild inducer of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with CYP3A4 inducers such as oritavancin should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Oxcarbazepine: (Major) Oxcarbazepine is a CYP3A4 inducer and nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with CYP3A4 inducers such as oxcarbazepine should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Paliperidone: (Moderate) Paliperidone is a mild inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of paliperidone and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Pantoprazole: (Moderate) Pantoprazole is a moderate inhibitor of P-glycoprotein (P-gp) and, in vitro, a moderate CYP3A4 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 concomitant use of pantoprazole and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Pazopanib: (Moderate) Pazopanib is a mild inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of pazopanib and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Pentobarbital: (Major) Barbiturates are CYP3A4 inducers and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as barbiturates should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Some barbiturates, such as phenobarbital, may also induce the P-glycoprotein (P-gp) metabolism of nintedanib.
    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.
    Perampanel: (Major) In vitro, perampanel is a mild CYP3A4 inducer and nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with CYP3A4 inducers such as perampanel should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Phenobarbital: (Major) Barbiturates are CYP3A4 inducers and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as barbiturates should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Some barbiturates, such as phenobarbital, may also induce the P-glycoprotein (P-gp) metabolism of nintedanib.
    Phentermine; Topiramate: (Major) Coadministration of nintedanib with CYP3A4 inducers such as topiramate should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Topiramate is a mild CYP3A4 inducer and nintedanib is a minor substrate of CYP3A4.
    Phenytoin: (Major) Phenytoin is a potent CYP3A4 and mild P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as phenytoin should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Pioglitazone: (Major) Pioglitazone is a mild CYP3A4 inducer and nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with CYP3A4 inducers such as pioglitazone should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Pirfenidone: (Moderate) In a multiple-dose study in Japanese patients with idiopathic pulmonary fibrosis, coadministration with pirfenidone decreased nintedanib exposure to 68.3% based on AUC and 59.2% based on Cmax compared wtih nintedanib alone. Use caution and monitor closely for nintedanib efficacy if concomitant use of pirfenidone and nintedanib is necessary.
    Posaconazole: (Moderate) Posaconazole is a moderate inhibitor of P-glycoprotein (P-gp) and a potent CYP3A4 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 concomitant use of posaconazole and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Primidone: (Major) Barbiturates are CYP3A4 inducers and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as barbiturates should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Some barbiturates, such as phenobarbital, may also induce the P-glycoprotein (P-gp) metabolism of nintedanib.
    Propafenone: (Moderate) Propafenone is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of propafenone and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Quinidine: (Moderate) Quinidine is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of quinidine and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Quinine: (Major) Quinine is a moderate inhibitor of CYP3A4 and, in vitro, is also a CYP3A4 inducer. Nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with a CYP3A4 inhibitor could increase the concentration and clinical effect of nintedanib, while concomitant use of a CYP3A4 inducer could decrease exposure to nintedanib. Avoid coadministration of nintedanib with CYP3A4 inducers such as quinine as these drugs may compromise nintedanib efficacy.
    Ranolazine: (Moderate) In vitro, ranolazine is a moderate inhibitor of P-glycoprotein (P-gp) and a mild CYP3A4 inhibitor; nintedanib is a P-gp substrate as well as a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of ranolazine and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Regorafenib: (Moderate) In vitro, regorafenib is a mild inhibitor of P-glycoprotein (P-gp) and CYP3A4; 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 concomitant use of regorafenib and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Rifabutin: (Major) Rifabutin is a CYP3A4 inducer and nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with CYP3A4 inducers such as rifabutin should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Rifampin: (Major) Rifampin is a potent CYP3A4 inducer a moderate P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration 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. Avoid concomitant use of nintedanib with rifampin, as nintedanib efficacy may be compromised.
    Rifaximin: (Major) In vitro, rifaximin is a CYP3A4 inducer and a mild P-glycoprotein (P-gp) inhibitor; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration of nintedanib with a CYP3A4 inhibitor could increase the concentration and clinical effect of nintedanib, while concomitant use of a CYP3A4 inducer could decrease exposure to nintedanib. Avoid coadministration of nintedanib with CYP3A4 inducers such as rifaximin as these drugs may compromise nintedanib efficacy.
    Ritonavir: (Moderate) Concurrent administration of nintedanib with ritonavir may result in elevated nintedanib plasma concentrations. Closely monitor the patient for nintedanib adverse effects, including gastrointestinal toxicity, elevated liver enzymes, and hypertension; a dose reduction, interruption of therapy, or discontinuation of therapy may be necessary. Nintedanib is a substrate of CYP3A4 and P-glycoprotein (P-gp). Ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor.
    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.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and nintedanib as coadministration may result in increased systemic exposure of nintedanib. Nintedanib is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of nintedanib, including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Saquinavir: (Moderate) Saquinavir is a moderate inhibitor of P-glycoprotein (P-gp) and a potent CYP3A4 inhibitor; nintedanib is a P-gp substrate and a minor substrate of CYP3A4. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of saquinavir and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Secobarbital: (Major) Barbiturates are CYP3A4 inducers and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as barbiturates should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Some barbiturates, such as phenobarbital, may also induce the P-glycoprotein (P-gp) metabolism of nintedanib.
    Simeprevir: (Moderate) Simeprevir is a mild inhibitor of both CYP3A4 and P-glycoprotein (P-gp); nintedanib is a P-gp substrate and a minor substrate of CYP3A4. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of simeprevir and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Simvastatin: (Moderate) Simvastatin is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of simvastatin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Simvastatin; Sitagliptin: (Moderate) Simvastatin is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of simvastatin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of nintedanib, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently.
    Sorafenib: (Moderate) Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of sorafenib and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary. Sorafenib is an inhibitor of P-glycoprotein (P-gp); nintedanib is a P-gp substrate.
    St. John's Wort, Hypericum perforatum: (Major) St. John's Wort, Hypericum perforatum is a potent CYP3A4 and P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as St. John's Wort should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Streptogramins: (Moderate) Quinupristin is a potent inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of dalfopristin; quinupristin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Tacrolimus: (Moderate) Tacrolimus is a mild inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of tacrolimus and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Tamoxifen: (Moderate) Tamoxifen is a moderate inhibitor of both P-glycoprotein (P-gp) and CYP3A4; 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 concomitant use of tamoxifen and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Telaprevir: (Moderate) Telaprevir is a potent CYP3A4 inhibitor and a mild inhibitor of P-glycoprotein (P-gp); 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 concomitant use of telaprevir and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Telithromycin: (Moderate) Telithromycin is a potent CYP3A4 inhibitor and a mild inhibitor of P-glycoprotein (P-gp); 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 concomitant use of telithromycin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and nintedanib is necessary, as the systemic exposure of nintedanib may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of nintedanib; consider increasing the dose of nintedanib if necessary. Nintedanib is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with nintedanib is necessary, and monitor for an increase in nintedanib-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) inhibitor in vitro, and nintedanib is a P-gp substrate. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp substrates, but exposure to nintedanib is likely to increase.
    Testosterone: (Moderate) Testosterone is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of testosterone and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. Topical preparations of testosterone are unlikely to interact. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Thiopental: (Major) Barbiturates are CYP3A4 inducers and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as barbiturates should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Some barbiturates, such as phenobarbital, may also induce the P-glycoprotein (P-gp) metabolism of nintedanib.
    Ticagrelor: (Moderate) Ticagrelor is a mild inhibitor of both P-glycoprotein (P-gp) and CYP3A4; 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 concomitant use of ticagrelor and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    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.
    Tipranavir: (Major) Tipranavir is a potent inhibitor of CYP3A4 and a potent inducer of P-glycoprotein (P-gp). Nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration of nintedanib with a CYP3A4 inhibitor could increase the concentration and clinical effect of nintedanib, while concomitant use of a CYP3A4 inducer could decrease exposure to nintedanib. Coadministration of nintedanib with P-gp inducers such as tipranavir should be avoided as nintedanib efficacy may be compromised.
    Tolvaptan: (Moderate) Tolvaptan is a mild inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of tolvaptan and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Topiramate: (Major) Coadministration of nintedanib with CYP3A4 inducers such as topiramate should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Topiramate is a mild CYP3A4 inducer and nintedanib is a minor substrate of CYP3A4.
    Trandolapril; Verapamil: (Moderate) Verapamil is a moderate inhibitor of both P-glycoprotein (P-gp) and CYP3A4; 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 concomitant use of verapamil and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Ulipristal: (Moderate) Ulipristal is a P-glycoprotein (P-gp) inhibitor and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of ulipristal and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Valproic Acid, Divalproex Sodium: (Major) In vitro, valproic acid, divalproex sodium is a mild CYP3A4 inducer/inhibitor and a mild P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as valproic acid should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with nintedanib is necessary, due to a possible increase in nintedanib-related adverse reactions. Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4. Coadministration with ketoconazole, a P-gp and CYP3A4 inhibitor, increased the nintedanib AUC by 1.61-fold Cmax by 1.83-fold. Vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate, by 29% and 23%, respectively.
    Vemurafenib: (Major) Vemurafenib is a CYP3A4 inducer and, in vitro, a mild P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as vemurafenib should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Verapamil: (Moderate) Verapamil is a moderate inhibitor of both P-glycoprotein (P-gp) and CYP3A4; 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 concomitant use of verapamil and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Voriconazole: (Moderate) Voriconazole is a moderate inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of voriconazole and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    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.
    Zafirlukast: (Moderate) Zafirlukast is a moderate inhibitor of CYP3A4 and nintedanib is a CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of zafirlukast and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and nintedanib is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, it is not known if nintedanib is excreted into human milk. Because of the potential of serious adverse reactions in nursing infants, women should be advised to discontinue nintedanib or discontinue breast-feeding.

    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 IPF, and cancer patients, and 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 < 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. However, 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. 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. The half-life of nintedanib is 9.5 hours and total plasma clearance 1390 ml/min after intravenous (IV) infusion. Urinary excretion of unchanged drug within 48 hours was 0.05% of the dose after oral administration and 1.4% after IV administration; renal clearance was 20 ml/min.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: P-glycoprotein (P-gp), CYP3A4
    Nintedanib is a substrate and weak inhibitor of (P-gp), as well as 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.