effects occur, management may require interruption, dose reduction, or discontinuation of therapy .lonafarnibMonitor Closely (1)lonafarnib will increase the level or effect of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Lonafarnib is a weak P-gp inhibitor. Monitor for adverse reactions if coadministered with P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. Reduce P-gp substrate dose if needed.lopinavirMonitor Closely (1)lopinavir increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .mefloquineMonitor Closely (1)mefloquine increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .nefazodoneSerious - Use Alternative (1)nefazodone will increase the level or effect of nintedanib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.nelfinavirMonitor Closely (1)nelfinavir increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .nicardipineMonitor Closely (1)nicardipine increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy.nifedipineMonitor Closely (1)nifedipine increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy.nilotinibMonitor Closely (1)nilotinib increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy.paliperidoneMonitor Closely (1)paliperidone increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy.phenobarbitalSerious - Use Alternative (1)phenobarbital decreases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Avoid coadministration, particularly for P-gp inducers that are also CYP3A4 inducers; nintedanib is a substrate of P-gp and to a less extent CYP3A4.phenytoinSerious - Use Alternative (1)phenytoin decreases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Avoid coadministration, particularly for P-gp inducers that are also CYP3A4 inducers; nintedanib is a substrate of P-gp and to a less extent CYP3A4.ponatinibMonitor Closely (1)ponatinib increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .posaconazoleMonitor Closely (1)posaconazole increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .primidoneSerious - Use Alternative (1)primidone decreases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Avoid coadministration, particularly for P-gp inducers that are also CYP3A4 inducers; nintedanib is a substrate of P-gp and to a less extent CYP3A4.progesterone micronizedMonitor Closely (1)progesterone micronized increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .propafenoneMonitor Closely (1)propafenone increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .propranololMonitor Closely (1)propranolol increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .quinidineMonitor Closely (1)quinidine increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .quinineMonitor Closely (1)quinine increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .ranolazineMonitor Closely (1)ranolazine increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .rifampinSerious - Use Alternative (1)rifampin decreases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Avoid coadministration, particularly for P-gp inducers that are also CYP3A4 inducers; nintedanib is a substrate of P-gp and to a less extent CYP3A4.ritonavirMonitor Closely (1)ritonavir increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .rivaroxabanMonitor Closely (1)nintedanib increases effects of rivaroxaban by anticoagulation. Use Caution/Monitor. Nintedanib is a VEGFR inhibitor, and may increase the risk of bleeding; monitor patients on full anticoagulation therapy; monitor closely for bleeding and adjust therapy as needed .saquinavirMonitor Closely (1)saquinavir increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .sarecyclineMonitor Closely (1)sarecycline will increase the level or effect of nintedanib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor for toxicities of P-gp substrates that may require dosage reduction when coadministered with P-gp inhibitors.St John's WortSerious - Use Alternative (1)St John's Wort decreases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Avoid coadministration, particularly for P-gp inducers that are also CYP3A4 inducers; nintedanib is a substrate of P-gp and to a less extent CYP3A4.stiripentolMonitor Closely (1)stiripentol will increase the level or effect of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Consider reducing the dose of P-glycoprotein (P-gp) substrates, if adverse reactions are experienced when administered concomitantly with stiripentol.sunitinibMonitor Closely (1)sunitinib increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .suvorexantMonitor Closely (1)suvorexant increases effects of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .tacrolimusMonitor Closely (1)tacrolimus increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .tamoxifenMonitor Closely (1)tamoxifen increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .tenofovir DFSerious - Use Alternative (1)tenofovir DF decreases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Avoid coadministration, particularly for P-gp inducers that are also CYP3A4 inducers; nintedanib is a substrate of P-gp and to a less extent CYP3A4.ticagrelorMonitor Closely (1)ticagrelor increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .tipranavirSerious - Use Alternative (1)tipranavir decreases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Avoid coadministration, particularly for P-gp inducers that are also CYP3A4 inducers; nintedanib is a substrate of P-gp and to a less extent CYP3A4.tucatinibMonitor Closely (1)tucatinib will increase the level or effect of nintedanib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Consider reducing the dosage of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities.ulipristalMonitor Closely (1)ulipristal increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .vandetanibMonitor Closely (1)vandetanib increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .vemurafenibMonitor Closely (1)vemurafenib increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .verapamilMonitor Closely (1)verapamil increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .vinblastineSerious - Use Alternative (1)vinblastine decreases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Avoid coadministration, particularly for P-gp inducers that are also CYP3A4 inducers; nintedanib is a substrate of P-gp and to a less extent CYP3A4.warfarinMonitor Closely (1)nintedanib increases effects of warfarin by anticoagulation. Use Caution/Monitor. >10% Idiopathic pulmonary fibrosis Diarrhea (62%) Nausea (24%) Abdominal pain (15%) Elevated liver enzymes (14%) Vomiting (12%) Decreased appetite (11%) SSc-ILD Diarrhea (76%) Nausea (32%) Vomiting (25%) Skin ulcer (18%) Abdominal pain (18%) Liver enzyme elevation (13%) Decreased weight (12%) Fatigue (11%) 1-10% Idiopathic pulmonary fibrosis Decreased weight (10%) Bleeding events (10%) Headache (8%) Hypertension (5%) Arterial thromboembolic events (2.5%) Myocardial infarction (1.5%) Bronchitis (1.5%) Hypothyroidism (1.1%) SSc-ILD Decreased appetite (9%) Headache (9%) Pyrexia (6%) Back pain (6%) Dizziness (6%) Hypertension (5%) <1% Idiopathic pulmonary fibrosis Pneumonia (0.7%) Lung neoplasm malignant (0.3%) Gastrointestinal perforation (0.3%) Postmarketing Reports Pancreatitis Thrombocytopenia Drug-induced liver injury Rash Pruritus Alopecia Nephrotic range proteinuria Contraindications None Cautions Severe liver injury with fatal outcome reported; majority of hepatic events occur within first 3 months of treatment; conduct liver function tests (ALT, AST, and bilirubin) before initiating, monthly for 3 months, and then q3months thereafter and as clinically indicated Not recommended in patients with moderate or severe hepatic impairment (Child Pugh B or C); reduced dose for patients with mild hepatic impairment (Child Pugh A) Nausea, and/or vomiting may occur; treat with adequate hydration and antidiarrheal/antiemetic medications; if persists, treatment interruption and dose reduction may be needed Diarrhea may occur; treat at first signs with adequate hydration and antidiarrheal medication (eg, loperamide); consider treatment interruption if diarrhea continues; treatment may be resumed at full dosage (150 mg twice daily), or at reduced dosage (100 mg twice daily); may subsequently increase to full dosage; if severe diarrhea persists despite symptomatic treatment, discontinue treatment Arterial thromboembolic events reported, including myocardial infarction; caution when treatment patients at higher cardiovascular risk May increased risk of bleeding or gastrointestinal perforation (based on mechanism of action [VEGFR inhibition]); monitor for bleeding if on full anticoagulant therapy and adjust anticoagulation treatment as needed Smoking associated with decreased systemic exposure; encourage patients to quit smoking Can cause fetal harm; use adequate contraception during treatment and for at least 3 months after the last dose In postmarketing period non-serious and serious bleeding events reported; use therapy in patients with known risk of bleeding only if anticipated benefit outweighs potential risk In postmarketing period, cases of gastrointestinal perforations reported; use caution when treating patients who have had recent abdominal surgery, previous history of diverticular disease or receiving concomitant corticosteroids or NSAIDs; discontinue therapy in patients who develop gastrointestinal perforation; only use in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk Cases of proteinuria within nephrotic range reported in postmarketing period; histological findings, when available, were consistent with glomerular microangiopathy with or without renal thrombi; improvement in proteinuria observed after therapy was discontinued; however, in some cases, residual proteinuria persisted; consider treatment interruption in patients who develop new or worsening proteinuria Drug interaction overview Nintedanib is a substrate of CYP3A4 and P-gp transporter Coadministration with potent P-gp or CYP3A4 inhibitors may increase systemic exposure of nintedanib (monitor closely) Coadministration with P-gp or CYP3A4 inducers may decrease systemic exposure to nintedanib by 50%; avoid coadministration Nintedanib is a VEGFR inhibitor and may increase bleeding risk; monitor patients on full anticoagulation for bleeding and adjust anticoagulation treatment if needed Pregnancy Based on findings from animal studies and its mechanism of action, can cause fetal harm when administered to pregnant women; counsel patients on pregnancy prevention and planning Verify pregnancy status of females of reproductive potential prior to treatment and during treatment as appropriate Animal data In animal studies of pregnant rats and rabbits treated during organogenesis, nintedanib caused embryofetal deaths and structural abnormalities at less than (rats) and ~5 times (rabbits) the maximum recommended human dose Contraception Advise females of reproductive potential to avoid becoming pregnant while receiving nintedanib Use effective contraception during treatment, and for at least 3 months after taking the last dose Drug does not change exposure to oral contraceptive containing ethinylestradiol and levonorgestrel in patients with SSc-ILD; however, efficacy of oral hormonal contraceptives may be compromised by vomiting and/or diarrhea or other conditions where drug absorption may be reduced Advise women taking oral hormonal contraceptives experiencing vomiting and/or diarrhea to use alternative highly effective contraception; verify pregnancy status prior to treatment and during treatment as appropriate Infertility Based on