Futibatinib is an oral small molecule kinase inhibitor that targets fibroblast growth factor receptors (FGFR) 1, 2, 3, and 4. It is indicated for the treatment of adults with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement. Comprehensive ophthalmological examinations are necessary prior to and during treatment due to the risk of retinal pigment epithelial detachment. Increases in serum phosphate levels are also a pharmacodynamic effect of futibatinib; monitor for hyperphosphatemia.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Take futibatinib with or without food at approximately the same time every day.
-Swallow tablets whole; do not crush, chew, split, or dissolve the tablet.
-If a patient misses a dose by more than 12 hours or if vomiting occurs, skip the dose and resume dosing with the next scheduled dose.
Ocular toxicity (e.g., retinal pigment epithelial detachment (RPED), blurred vision) has been reported with futibatinib therapy. Perform a comprehensive ophthalmological examination including optical coherence tomography (OCT) of the macula prior to beginning treatment with futibatinib, every 2 months for the first 6 months of treatment, and every 3 months thereafter during treatment. If visual symptoms occur, urgently refer patients for an ophthalmologic evaluation, with follow-up every 3 weeks until resolution or discontinuation of futibatinib. An interruption of therapy or dose reduction may be necessary if RPED occurs. Treat patients who develop dry eyes or corneal keratitis with ocular demulcents (artificial tears) as needed. RPED/retinal detachment (9%) and xerophthalmia/dry eyes (15%) occurred in patients with cholangiocarcinoma or other advanced solid tumors who received futibatinib in a pooled safety population analysis (n = 318). Evaluation with OCT was not routinely done in patients included in this analysis. The median time to RPED onset was 40 days. A dose reduction was required in 1.6% of patients and permanent discontinuation of therapy was necessary in 0.3% of patients. RPED (7.8%) and dry eyes (25%; grade 3, 1%) were reported in patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103). The term dry eyes included increased lacrimation, keratitis, photokeratitis, punctate keratitis, and ulcerative keratitis.
High phosphate levels, which may lead to soft-tissue mineralization, calcinosis, non-uremic calciphylaxis, and vascular calcification, have been reported with futibatinib therapy. Increases in phosphate levels are a pharmacodynamic effect of futibatinib due to fibroblast growth factor (FGFR) inhibition. Monitor patients for hyperphosphatemia during treatment with futibatinib. If the serum phosphate level is 5.5 mg/dL or greater, begin a low phosphate diet, start phosphate-lowering therapy, and monitor serum phosphate levels weekly. If the serum phosphate level is greater than 7 mg/dL, initiate or optimize phosphate lowering therapy; therapy interruption, a dose reduction, or discontinuation of therapy may be necessary. Hyperphosphatemia (based on laboratory values above the upper limit of normal) occurred in 88% of patients with cholangiocarcinoma or other advanced solid tumors who received futibatinib in a pooled safety population analysis (n = 318). The median time to hyperphosphatemia onset was 5 (range, 1 to 117) days; 77% of patients required the use of phosphate binding agents. Increased phosphate level that worsened from baseline was reported in 97% (grade 3 or 4, 39%) of patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103). In this trial, other electrolyte abnormalities that worsened from baseline included increased calcium level/hypercalcemia (51%; grade 3 or 4, 1.2%), decreased sodium level/hyponatremia (51%; grade 3 or 4, 15%), decreased phosphate level/hypophosphatemia (50%; grade 3 or 4, 20%), decreased potassium level/hypokalemia (22%; grade 3 or 4, 2.1%), and increased potassium level/hyperkalemia (16%; grade 3 or 4, 2%).
Glucose level alterations that worsened from baseline including increased glucose level/hyperglycemia (52%; grade 3 or 4, 4.9%) and decreased glucose level/hypoglycemia (25%) occurred in patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103).
Decreased appetite/anorexia (23%; grade 3, 2.9%) and weight loss (18%; grade 3, 3.9%) were reported in patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103).
Dysgeusia including ageusia and taste disorder occurred in 25% of patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103).
Alopecia occurred in 34% of patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103).
Xerosis/dry skin (29%) and palmar-plantar erythrodysesthesia (hand and foot syndrome) (21%; grade 3, 4.9%) were reported in patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103).
Nausea (24%; grade 3, 1.9%) and vomiting (20%; grade 3, 1%) including hematemesis occurred in patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103).[
Diarrhea including colitis and gastroenteritis (39%; grade 3, 1%), constipation (39%), and abdominal pain (30%; grade 3, 2.9%) were reported in patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103).
Stomatitis (30%; grade 3, 6%) and xerostomia/dry mouth (35%) were reported in patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103). Futibatinib therapy was permanently discontinued due to oral dysesthesia and esophagitis in 1 patient each in this trial. The term stomatitis included glossitis, mouth or tongue/oral ulceration, mucosal inflammation, and pharyngeal inflammation.
Elevated hepatic enzymes that worsened from baseline included increased ALT (50%; grade 3 or 4, 7%), AST (46%; grade 3 or 4, 13%), and alkaline phosphatase (47%; grade 3 or 4, 4.9%) occurred in patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103). Increased bilirubin level/hyperbilirubinemia (28%) that worsened from baseline, serious ascites (2.9%), and bile duct/biliary obstruction (2.9%) were also reported in this trial. Additionally, futibatinib therapy was permanently discontinued due to bile duct obstruction in 1 patient.
Hypoalbuminemia was reported in 31% (grade 3 or 4, 2.4%) of patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103).
Nephrotoxicity, specifically increased serum creatinine level that worsened from baseline, was reported in 58% of patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103).
Hematologic toxicities the worsened from baseline including decreased hemoglobin level/anemia (52%; grade 3 or 4, 6%), decreased lymphocytes level/lymphopenia (46%; grade 3 or 4, 10%), decreased platelet count/thrombocytopenia (42%; grade 3 or 4, 1%), decreased leukocyte count/leukopenia (33%; grade 3 or 4, 1.1%), and decreased neutrophil count/neutropenia (31%; grade 3 or 4, 1.6%) were reported in patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103). Futibatinib therapy was permanently discontinued due to anemia in 1 patient in this trial.
Fatigue including asthenia was reported in 37% (grade 3 or 4, 8%) of patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103).
Urinary tract infection including cystitis and dysuria (23%; grade 3 or 4, 2.9%) and serious fever (3.9%) were reported in patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103).
Nail toxicity was reported in 47% (grade 3 or 4, 1.9%) of patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103). The term nail toxicity included nail disorder, nail discoloration, nail dystrophy, nail hypertrophy, nail infection, nail pigmentation, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomycosis, and paronychia.
Musculoskeletal pain (43%; grade 3 or 4, 3.9%), arthralgia including arthritis (25%), and increased creatine kinase (CK) level that worsened from baseline (31%; grade 3 or 4, 5%) were reported in patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103). The term musculoskeletal pain included back pain, bone pain/spinal pain, musculoskeletal or non-cardiac chest pain, musculoskeletal discomfort or stiffness, myalgia, neck pain, and extremity pain.
Prolonged bleeding time that worsened from baseline including increased activated partial thromboplastin time (36%; grade 3 or 4, 8%) and increased prothrombin international normalized ratio (25%) occurred in patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103).
Serious GI bleeding was reported in 3.9% of patients with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103).
Futibatinib therapy was permanently discontinued due to dizziness in 1 patient with locally advanced or metastatic cholangiocarcinoma who received futibatinib in a clinical trial (n = 103).
Retinal pigment epithelial detachment (RPED) (retinal detachment) has been reported with futibatinib therapy. Perform a comprehensive ophthalmological examination including optical coherence tomography (OCT) of the macula prior to beginning treatment with futibatinib, every 2 months for the first 6 months of treatment, and every 3 months thereafter during treatment. If visual symptoms occur, urgently refer patients for an ophthalmologic evaluation, with follow-up every 3 weeks until resolution or discontinuation of futibatinib. An interruption of therapy or dose reduction may be necessary if RPED occurs.
Hyperphosphatemia has been reported with futibatinib therapy. High phosphate levels may lead to soft-tissue mineralization, calcinosis, nonuremic calciphylaxis, and vascular calcification. Monitor patients for hyperphosphatemia during treatment with futibatinib. Increases in phosphate levels are a pharmacodynamic effect of futibatinib due to fibroblast growth factor (FGFR) inhibition. If the serum phosphate level is 5.5 mg/dL or greater, begin a low phosphate diet, start phosphate-lowering therapy, and monitor serum phosphate levels weekly. If the serum phosphate level is greater than 7 mg/dL, initiate or optimize phosphate lowering therapy; therapy interruption, a dose reduction, or discontinuation of therapy may be necessary.
Use futibatinib with caution in patients with hepatic disease. Although data are limited, patients with cirrhosis and total bilirubin greater than 1.5 times the upper limit of normal (ULN) to 3 times ULN may have an increased incidence of adverse reactions compared to patients with normal hepatic function due to higher exposure of unbound futibatinib. Cholangiocarcinoma patients with a total bilirubin greater than 3 times ULN were excluded from clinical trials.
Pregnancy should be avoided by females of reproductive potential during futibatinib treatment and for 1 week after the last dose. Although there are no adequately controlled studies in pregnant women, futibatinib may cause fetal harm or pregnancy loss when administered during pregnancy based on its mechanism of action and data from animal studies. Women who are pregnant or who become pregnant while receiving futibatinib should be apprised of the potential hazard to the fetus. Futibatinib given orally once daily at doses approximately 5 times the human recommended dose of 20 mg (based on BSA) to pregnant rats during organogenesis resulted in 100% embryo-fetal mortality due to post-implantation loss. Fetal survival was not affected when futibatinib was given orally once daily at doses approximately 0.2 times the human recommended dose to pregnant rats during organogenesis; however, there were reports of reduced mean fetal body weight, increased fetal skeletal and visceral malformations, major blood vessel variations, and reduced ossification in offspring.
Counsel patients about the reproductive risk and contraception requirements during futibatinib treatment. Females of reproductive potential should avoid pregnancy and use effective contraception during and for 1 week after treatment with futibatinib. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should also use effective contraception during and for 1 week after treatment with futibatinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of futibatinib. Women who become pregnant while receiving futibatinib should be apprised of the potential hazard to the fetus.
Due to the potential for serious adverse reactions in nursing children from futibatinib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known if futibatinib is secreted in human milk or if it has effects on the breast-fed child or on milk production.
For the treatment of cholangiocarcinoma:
NOTE: Futibatinib is designated by the FDA as an orphan drug for this indication.
-for the treatment of previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement:
NOTE: Select patients based on the presence of a FGFR2 gene fusion or rearrangement. At this time, there is not an FDA-approved test for detection of FGFR2 gene fusion or rearrangement in patients with cholangiocarcinoma.
Oral dosage:
Adults: 20 mg orally once daily until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy may need to be interrupted, dose reduced, or discontinued in patients who develop severe toxicity. Treatment with futibatinib resulted in an overall response rate of 42% (all partial responses) in patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma in a multicenter, single-arm, phase 1/2 trial (n = 103); the median time to response was 2.5 (range, 0.7 to 7.4) months. The duration of response was at least 6 months in 72% of patients and at least 12 months in 14% of patients. In this trial, 99% of patients had FGFR2 fusions or other rearrangements; all patients had received at least 1 prior systemic treatment including platinum-based therapy.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Recommended Dose Reductions
First dose reduction: 16 mg PO once daily.
Second dose reduction: 12 mg PO once daily. Permanently discontinue futibatinib therapy if unable to tolerate this dosage.
Hyperphosphatemia
-Serum phosphate level 5.5 mg/dL or higher: Begin a low phosphate diet and start phosphate lowering therapy.
-Serum phosphate level 7.1 to 10 mg/dL: Initiate or adjust phosphate lowering therapy. Continue futibatinib at a reduced dose. If the serum phosphate level resolves to 7 mg/dL or less within 2 weeks after the dose reduction, continue at this reduced dose. If the serum phosphate level is not 7 mg/dL or less within 2 weeks after the initial dose reduction, further reduce to the next lower dose. If the serum phosphate level is still more than 7 mg/dL at 2 weeks after the second dose reduction, hold futibatinib therapy until the serum phosphate level resolves to 7 mg/dL or less and resume futibatinib at the dose prior to suspending.
-Serum phosphate level higher than 10 mg/dL: Initiate or adjust phosphate lowering therapy. Hold futibatinib therapy until the serum phosphate level resolves to 7 mg/dL or less; resume futibatinib at a reduced dose. Permanently discontinue futibatinib therapy if the serum phosphate level is not 7 mg/dL or less within 2 weeks after 2 dose interruptions and reductions.
Ocular Toxicity
-Retinal Pigment Epithelial Detachment (RPED): Continue futibatinib at the current dose and perform periodic ophthalmic evaluations. If the toxicity resolves within 14 days, continue futibatinib at the current dose. If the toxicity does not resolve within 14 days, hold futibatinib therapy until the toxicity resolves; resume futibatinib at a reduced dose.
Other Adverse Reactions
-Grade 3: Hold futibatinib therapy until the toxicity resolves to grade 1 or baseline. Resume futibatinib at the dose prior to suspending for hematologic toxicities that resolve within 1 week. Resume futibatinib at the next lower dose for non-hematologic toxicities.
-Grade 4: Permanently discontinue futibatinib therapy.
Maximum Dosage Limits:
-Adults
20 mg PO once daily.
-Geriatric
20 mg PO once daily.
-Adolescents
Safety and efficacy not established.
-Children
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with futibatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP and P-gp substrate and futibatinib is a P-gp and BCRP inhibitor.
Afatinib: (Moderate) If the concomitant use of futibatinib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of futibatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-gp substrate and futibatinib is a P-gp inhibitor. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
Alpelisib: (Major) Avoid coadministration of alpelisib with futibatinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and futibatinib is a BCRP inhibitor.
Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with futibatinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; futibatinib is a P-gp and BCRP inhibitor.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concurrent use of futibatinib and clarithromycin. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; clarithromycin is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Apalutamide: (Major) Avoid concurrent use of futibatinib and apalutamide. Concomitant use may decrease futibatinib exposure, which may reduce its efficacy. Futibatinib is a substrate of CYP3A and P-gp; apalutamide is a dual P-gp and strong CYP3A inducer. Coadministration with another dual P-gp and strong CYP3A inducer decreased futibatinib exposure by 64%.
Atazanavir; Cobicistat: (Major) Avoid concurrent use of futibatinib and cobicistat. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; cobicistat is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with futibatinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; futibatinib is a P-gp and BCRP inhibitor.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving futibatinib. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving futibatinib. Concurrent use may increase betrixaban exposure resulting in an increased bleeding risk; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a P-gp substrate; futibatinib is a P-gp inhibitor. Coadministration of other P-gp inhibitors increased betrixaban exposure by 2 to 3-fold.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with futibatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Carbamazepine: (Major) Avoid concurrent use of futibatinib and carbamazepine. Concomitant use may decrease futibatinib exposure, which may reduce its efficacy. Futibatinib is a substrate of CYP3A and P-gp; carbamazepine is a dual P-gp and strong CYP3A inducer. Coadministration with another dual P-gp and strong CYP3A inducer decreased futibatinib exposure by 64%.
Clarithromycin: (Major) Avoid concurrent use of futibatinib and clarithromycin. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; clarithromycin is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Cobicistat: (Major) Avoid concurrent use of futibatinib and cobicistat. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; cobicistat is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Cobimetinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with futibatinib is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-glycoprotein substrate; futibatinib is a P-gp inhibitor.
Colchicine: (Major) Avoid concomitant use of colchicine and futibatinib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and futibatinib is a P-gp inhibitor.
Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with futibatinib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a P-gp substrate and futibatinib is a P-gp inhibitor.
Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with futibatinib is necessary in patients with creatinine clearance (CrCl) greater than 50 mL/minute. Avoid coadministration in patients with CrCl less than 50 mL/minute when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCl less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-gp substrate and futibatinib is a P-gp inhibitor.
Darunavir; Cobicistat: (Major) Avoid concurrent use of futibatinib and cobicistat. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; cobicistat is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concurrent use of futibatinib and cobicistat. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; cobicistat is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%. (Moderate) Coadministration of tenofovir alafenamide with futibatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Digoxin: (Moderate) Increase monitoring of serum digoxin concentrations and watch for potential signs and symptoms of clinical toxicity when starting, adjusting, or discontinuing futibatinib. Concurrent use may increase digoxin exposure. Digoxin is a P-gp substrate with a narrow therapeutic index and futibatinib is a P-gp inhibitor.
Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with futibatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP and P-gp substrate and futibatinib is a P-gp and BCRP inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with futibatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP and P-gp substrate and futibatinib is a P-gp and BCRP inhibitor.
Dolutegravir; Rilpivirine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with futibatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP and P-gp substrate and futibatinib is a P-gp and BCRP inhibitor.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with futibatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Doxorubicin Liposomal: (Major) Avoid coadministration of futibatinib with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and futibatinib is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of futibatinib with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and futibatinib is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Edoxaban: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of futibatinib is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and futibatinib is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with futibatinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of futibatinib. Increased concentrations of edoxaban may occur during concomitant use of futibatinib; monitor for increased adverse effects of edoxaban.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with futibatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with futibatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concurrent use of futibatinib and cobicistat. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; cobicistat is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%. (Moderate) Coadministration of tenofovir alafenamide with futibatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent use of futibatinib and cobicistat. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; cobicistat is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%. (Moderate) Coadministration of tenofovir disoproxil fumarate with futibatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with futibatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with futibatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with futibatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with futibatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with futibatinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-gp substrate and futibatinib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with futibatinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; futibatinib is a P-gp inhibitor.
Fosphenytoin: (Major) Avoid concurrent use of futibatinib and fosphenytoin. Concomitant use may decrease futibatinib exposure, which may reduce its efficacy. Futibatinib is a substrate of CYP3A and P-gp; fosphenytoin is a dual P-gp and strong CYP3A inducer. Coadministration with another dual P-gp and strong CYP3A inducer decreased futibatinib exposure by 64%.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with coadministration of glecaprevir and futibatinib as increased plasma concentrations of glecaprevir may occur resulting in increased risk of glecaprevir-related adverse events. Glecaprevir is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor. (Moderate) Monitor for an increase in pibrentasvir-related adverse effects if concomitant use of futibatinib is necessary. Concomitant use may increase pibrentasvir exposure. Pibrentasvir is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during futibatinib treatment due to the risk of increased futibatinib exposure and adverse reactions. Futibatinib is a substrate of CYP3A and P-gp; grapefruit juice is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concurrent use of futibatinib and rifampin. Concomitant use may decrease futibatinib exposure, which may reduce its efficacy. Futibatinib is a substrate of CYP3A and P-gp; rifampin is a dual P-gp and strong CYP3A inducer. Coadministration with rifampin decreased futibatinib exposure by 64%.
Isoniazid, INH; Rifampin: (Major) Avoid concurrent use of futibatinib and rifampin. Concomitant use may decrease futibatinib exposure, which may reduce its efficacy. Futibatinib is a substrate of CYP3A and P-gp; rifampin is a dual P-gp and strong CYP3A inducer. Coadministration with rifampin decreased futibatinib exposure by 64%.
Itraconazole: (Major) Avoid concurrent use of futibatinib and itraconazole. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; itraconazole is a dual P-gp and strong CYP3A inhibitor. Coadministration with itraconazole increased futibatinib exposure by 41%.
Ketoconazole: (Major) Avoid concurrent use of futibatinib and ketoconazole. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; ketoconazole is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with futibatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concurrent use of futibatinib and clarithromycin. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; clarithromycin is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Lapatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with futibatinib is necessary. Lapatinib is a P-gp substrate and futibatinib is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
Lefamulin: (Major) Avoid coadministration of futibatinib with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; futibatinib may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and futibatinib is a P-gp inhibitor.
Levoketoconazole: (Major) Avoid concurrent use of futibatinib and ketoconazole. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; ketoconazole is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Lonafarnib: (Major) Avoid concurrent use of futibatinib and lonafarnib. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; lonafarnib is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with futibatinib. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and futibatinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with futibatinib. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and futibatinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lopinavir; Ritonavir: (Major) Avoid concurrent use of futibatinib and ritonavir. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; ritonavir is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with futibatinib is necessary. Concomitant use may increase lovastatin exposure. Lovastatin is a P-gp substrate; futibatinib is a P-gp inhibitor.
Lumacaftor; Ivacaftor: (Major) Avoid concurrent use of futibatinib and lumacaftor; ivacaftor. Concomitant use may decrease futibatinib exposure, which may reduce its efficacy. Futibatinib is a substrate of CYP3A and P-gp; lumacaftor; ivacaftor is a dual P-gp and strong CYP3A inducer. Coadministration with another dual P-gp and strong CYP3A inducer decreased futibatinib exposure by 64%.
Lumacaftor; Ivacaftor: (Major) Avoid concurrent use of futibatinib and lumacaftor; ivacaftor. Concomitant use may decrease futibatinib exposure, which may reduce its efficacy. Futibatinib is a substrate of CYP3A and P-gp; lumacaftor; ivacaftor is a dual P-gp and strong CYP3A inducer. Coadministration with another dual P-gp and strong CYP3A inducer decreased futibatinib exposure by 64%.
Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with futibatinib is necessary. Concomitant use may increase maraviroc exposure. Maraviroc is a P-gp substrate; futibatinib is a P-gp inhibitor.
Mefloquine: (Moderate) Monitor for an increase in mefloquine-related adverse effects if concomitant use of futibatinib is necessary. Concomitant use may increase mefloquine exposure. Mefloquine is a P-gp substrate and futibatinib is a P-gp inhibitor.
Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with futibatinib is necessary; decrease the dose of morphine as necessary. Morphine is a P-gp substrate and futibatinib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with futibatinib is necessary; decrease the dose of morphine as necessary. Morphine is a P-gp substrate and futibatinib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Naldemedine: (Moderate) Monitor for naldemedine-related adverse reactions if coadministered with futibatinib. Naldemedine plasma concentrations may increase during concomitant use. Naldemedine is a P-gp substrate and futibatinib is a P-gp inhibitor.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and futibatinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and futibatinib is a P-gp inhibitor.
Nelfinavir: (Major) Avoid concurrent use of futibatinib and nelfinavir. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; nelfinavir is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Nirmatrelvir; Ritonavir: (Major) Avoid concurrent use of futibatinib and ritonavir. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; ritonavir is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Pazopanib: (Major) Avoid coadministration of pazopanib and futibatinib due to the potential for increased pazopanib exposure. Pazopanib is a P-gp and BCRP substrate; futibatinib is a P-gp and BCRP inhibitor. Consider selection of an alternative concomitant medication with no or minimal potential to inhibit P-gp or BCRP.
Phenobarbital: (Major) Avoid concurrent use of futibatinib and phenobarbital. Concomitant use may decrease futibatinib exposure, which may reduce its efficacy. Futibatinib is a substrate of CYP3A and P-gp; phenobarbital is a dual P-gp and strong CYP3A inducer. Coadministration with another dual P-gp and strong CYP3A inducer decreased futibatinib exposure by 64%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concurrent use of futibatinib and phenobarbital. Concomitant use may decrease futibatinib exposure, which may reduce its efficacy. Futibatinib is a substrate of CYP3A and P-gp; phenobarbital is a dual P-gp and strong CYP3A inducer. Coadministration with another dual P-gp and strong CYP3A inducer decreased futibatinib exposure by 64%.
Phenytoin: (Major) Avoid concurrent use of futibatinib and phenytoin. Concomitant use may decrease futibatinib exposure, which may reduce its efficacy. Futibatinib is a substrate of CYP3A and P-gp; phenytoin is a dual P-gp and strong CYP3A inducer. Coadministration with another dual P-gp and strong CYP3A inducer decreased futibatinib exposure by 64%.
Pitavastatin: (Moderate) Monitor for an increase in pitavastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with futibatinib is necessary. Concomitant use may increase pitavastatin exposure. Pitavastatin is a P-gp substrate; futibatinib is a P-gp inhibitor.
Posaconazole: (Major) Avoid concurrent use of futibatinib and posaconazole. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Concomitant use may also increase posaconazole exposure. Futibatinib is a substrate of CYP3A and P-gp and a P-gp inhibitor; posaconazole is a P-gp substrate and dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Pralsetinib: (Major) Avoid concomitant use of futibatinib with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a P-gp substrate and futibatinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased the overall exposure of pralsetinib by 81%.
Primidone: (Major) Avoid concurrent use of futibatinib and primidone. Concomitant use may decrease futibatinib exposure, which may reduce its efficacy. Futibatinib is a substrate of CYP3A and P-gp; primidone is a dual P-gp and strong CYP3A inducer. Coadministration with another dual P-gp and strong CYP3A inducer decreased futibatinib exposure by 64%.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and futibatinib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and futibatinib is a P-gp inhibitor.
Ranolazine: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with futibatinib is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; futibatinib is a P-gp inhibitor.
Relugolix: (Major) Avoid concomitant use of relugolix and oral futibatinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is necessary, administer futibatinib at least six hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of futibatinib is required; if treatment is interrupted for more than seven days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-gp substrate and futibatinib is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral futibatinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is necessary, administer futibatinib at least six hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of futibatinib is required; if treatment is interrupted for more than seven days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-gp substrate and futibatinib is a P-gp inhibitor.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with futibatinib due to increased repotrectinib exposure which may increase the risk for repotrectinib-related adverse effects. Repotrectinib is a P-gp substrate and futibatinib is a P-gp inhibitor.
Rifampin: (Major) Avoid concurrent use of futibatinib and rifampin. Concomitant use may decrease futibatinib exposure, which may reduce its efficacy. Futibatinib is a substrate of CYP3A and P-gp; rifampin is a dual P-gp and strong CYP3A inducer. Coadministration with rifampin decreased futibatinib exposure by 64%.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with futibatinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and futibatinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with futibatinib; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and futibatinib is a P-gp inhibitor.
Ritonavir: (Major) Avoid concurrent use of futibatinib and ritonavir. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; ritonavir is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Rosuvastatin: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with futibatinib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and futibatinib is a BCRP inhibitor.
Rosuvastatin; Ezetimibe: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with futibatinib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and futibatinib is a BCRP inhibitor.
Saquinavir: (Major) Avoid concurrent use of futibatinib and saquinavir. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Concomitant use may also increase saquinavir exposure. Futibatinib is a substrate of CYP3A and P-gp and a P-gp inhibitor; saquinavir is a P-gp substrate and dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Silodosin: (Major) Avoid coadministration of silodosin and futibatinib due to the potential for increased silodosin exposure. In vitro data indicate that silodosin is a P-glycoprotein substrate; futibatinib is a P-gp inhibitor.
Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with futibatinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; futibatinib is a P-gp inhibitor.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of futibatinib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and futibatinib is a P-gp inhibitor.
St. John's Wort, Hypericum perforatum: (Major) Avoid concurrent use of futibatinib and St. John's wort. Concomitant use may decrease futibatinib exposure, which may reduce its efficacy. Futibatinib is a substrate of CYP3A and P-gp; St. John's wort is a dual P-gp and strong CYP3A inducer. Coadministration with another dual P-gp and strong CYP3A inducer decreased futibatinib exposure by 64%.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of futibatinib is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a P-gp and BCRP substrate; futibatinib is a P-gp and BCRP inhibitor.
Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with futibatinib is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and futibatinib is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with futibatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with futibatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with futibatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with futibatinib as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and futibatinib is a P-gp inhibitor.
Tipranavir: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with futibatinib is necessary. Concomitant use may increase tipranavir exposure. Tipranavir is a P-gp substrate; futibatinib is a P-gp inhibitor.
Topotecan: (Major) Avoid coadministration of futibatinib with oral topotecan due to increased topotecan exposure; futibatinib may be administered with intravenous topotecan. Coadministration increases the risk of topotecan-related adverse reactions. Oral topotecan is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Tucatinib: (Major) Avoid concurrent use of futibatinib and tucatinib. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; tucatinib is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with futibatinib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with futibatinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of futibatinib. Venetoclax is a P-gp substrate; futibatinib is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Vincristine Liposomal: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of futibatinib is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and futibatinib is a P-gp inhibitor.
Vincristine: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of futibatinib is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and futibatinib is a P-gp inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concurrent use of futibatinib and clarithromycin. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; clarithromycin is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Futibatinib is a small molecule kinase inhibitor that covalently binds to fibroblast growth factor receptors (FGFR). It works by inhibiting the phosphorylation and signaling of FGFR 1, 2, 3, and 4 and decreasing cell viability in cancer cell lines with FGFR amplifications, alterations (e.g., fusions), and mutations that result in constitutive activation of FGFR signaling. Constitutive FGFR signaling can support the proliferation and survival of malignant cells. The IC50 values for FGFR 1, 2, 3, and 4 were less than 4 nanomolar. Futibatinib exhibited anti-tumor activity in mouse and rat xenograft models of human tumors with activating FGFR genetic alterations.
Futibatinib is administered orally. It is 95% bound to human plasma proteins (primarily albumin and alpha 1-acid glycoprotein) at 0.2 to 5 micromol/L in vitro. Following futibatinib 20 mg once daily in patients with advanced solid tumors, the geometric mean apparent volume of distribution was 66 L (coefficient of variation (CV), 18%), the mean elimination half-life was 2.9 hours (CV, 27%), and the geometric mean apparent clearance was 20 L/hour (CV, 23%). After a single 20-mg radiolabeled dose of futibatinib, 91% of the total radioactivity was recovered in feces and 9% of the total radioactivity was recovered in urine. There was minimal unchanged futibatinib observed in the feces or urine; however, unchanged futibatinib was the major drug-related moiety in plasma (59% of radioactivity) in healthy subjects.
Affected cytochrome P450 isoenzymes: CYP3A, P-gp, BCRP
Futibatinib is primarily metabolized by CYP3A; it is also metabolized by CYP2C9 and CYP2D6 to a lesser extent. Drug interactions studies with futibatinib demonstrated no significant drug interactions following coadministration with a proton pump inhibitor (i.e., lansoprazole) or a sensitive CYP3A substrate (i.e., midazolam). In vitro, futibatinib is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and a P-gp and BCRP inhibitor.
-Route-Specific Pharmacokinetics
Oral Route
Following the administration of futibatinib 20 mg PO once daily in patients with advanced solid tumors, the steady-state geometric mean Cmax was 144 nanograms (ng)/mL (CV, 50%) and the AUC value was 790 ng X hour/mL (CV, 45%); there was no drug accumulation after repeat doses. The median Tmax was 2 (range, 1.2 to 22.8) hours. AUC values increased proportionally over a dose range of 4 to 24 mg/day (0.2 to 1.2 times the maximum recommended dosage).
Effects of Food: In healthy subjects, Cmax and AUC values decreased by 42% and 11%, respectively, following the administration of futibatinib with a high-fat and high-calorie meal (approximately 900 to 1,000 calories, with 50% of total calories from fat) compared with the same dose administered under fasted conditions.
-Special Populations
Hepatic Impairment
Mild hepatic impairment (total bilirubin at or below the upper limit of normal [ULN] with an AST more than ULN, or total bilirubin more than 1 to 1.5 times ULN with any AST, or Child-Pugh A) and moderate to severe hepatic impairment (Child-Pugh B to C) in patients with total bilirubin less than 1.5 times ULN have no clinically meaningful impact on the systemic exposure of futibatinib. In subjects with cirrhosis and total bilirubin greater than 1 to 1.5 times ULN, the mean unbound futibatinib AUC and Cmax increased by 1.7-fold compared to subjects with normal hepatic function. The mean unbound futibatinib AUC and Cmax increased by 3.2-fold and 2.4-fold, respectively, in subjects with cirrhosis and total bilirubin greater than 1.5 times ULN compared to healthy subjects. The pharmacokinetic parameters of futibatinib have not been evaluated in patients with moderate or severe hepatic impairment (total bilirubin more than 1.5 times ULN and any AST) without cirrhosis.
Renal Impairment
Mild to moderate renal impairment (CrCl 30 to 89 mL/min) has no clinically meaningful impact on the systemic exposure of futibatinib. Pharmacokinetic parameters of futibatinib have not been evaluated in patients with severe renal impairment (CrCl 15 to 29 mL/min) or end-stage renal disease (CrCl less than 15 mL/min) in patients on dialysis.
Geriatric
Age (18 to 82 years) has no clinically meaningful impact on the systemic exposure of futibatinib.
Gender Differences
Sex has no clinically meaningful impact on the systemic exposure of futibatinib.
Ethnic Differences
Race (White, Asian, and African American) has no clinically meaningful impact on the systemic exposure of futibatinib.
Obesity
Weight (36 to 152 kg) has no clinically meaningful impact on the systemic exposure of futibatinib.