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  • CLASSES

    Small Molecule Antineoplastic Multikinase Inhibitors

    BOXED WARNING

    Hepatic disease, hepatotoxicity

    Severe and sometimes fatal hepatotoxicity has been reported with regorafenib use, usually within the first 2 months of therapy. Obtain liver function tests (LFTs) including ALT, AST, and bilirubin prior to starting regorafenib and then at least every 2 weeks for the first 2 months of therapy. Thereafter, monitor LFTs monthly or more often as clinically indicated. If LFT elevations occur, increase the frequency of monitoring to weekly until levels improve to less than 3 times the upper limit of normal or baseline. An interruption of therapy, dose reduction, or treatment discontinuation may be necessary for patients who develop elevated LFTs or hepatocellular necrosis. Closely monitor patients with hepatic impairment for adverse reactions. While an initial dose adjustment is not necessary for patients with mild or moderate hepatic impairment at baseline, it has not been studied in patients with severe hepatic disease and is not recommended for use in these patients.[51883]

    DEA CLASS

    Rx

    DESCRIPTION

    Oral multikinase inhibitor
    Used for the treatment of gastrointestinal stromal tumor, metastatic colorectal cancer, and hepatocellular cancer in patients who have previously received certain treatments
    Serious adverse reactions include hepatotoxicity, infections, hemorrhage, GI perforation/fistula, hypertension, and dermatologic toxicities

    COMMON BRAND NAMES

    Stivarga

    HOW SUPPLIED

    Stivarga Oral Tab: 40mg

    DOSAGE & INDICATIONS

    For the treatment of metastatic colorectal cancer in patients who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF therapy; and an anti-EGFR therapy if RAS wild type.
    Oral dosage
    Adults

    160 mg PO once daily with a low-fat breakfast on days 1 to 21 of each 28-day cycle until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In an interim analysis, median overall survival (OS) (primary endpoint) was significantly improved with regorafenib plus best supportive care (BSC) compared with placebo plus BSC (6.4 months vs. 5 months) in 760 patients with mCRC who had previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; bevacizumab; and panitumumab or cetuximab (KRAS mutation-negative patients only) in a multinational, randomized, double-blind, phase 3 trial (the CORRECT trial). In this study, 48% of patients had received 4 or more previous therapies. The median duration of regorafenib therapy was 2.8 months. Regorafenib significantly improved OS in the subgroup of 495 patients with colon cancer but not in the subgroups of 220 patients with rectal cancer or 44 patients with combined colon and rectum cancer. Progression-free survival was also significantly improved with regorafenib compared with placebo in this trial (1.9 months vs. 1.7 months).

    For the treatment of locally advanced, unresectable or metastatic gastrointestinal stromal tumors (GIST) in patients who have previously received imatinib and sunitinib.
    The FDA has designated regorafenib as an orphan drug for the treatment of GIST.
    Oral dosage
    Adults

    160 mg PO once daily with a low-fat breakfast on days 1 to 21 of each 28-day cycle until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Median progression-free survival (primary endpoint) was significantly improved with regorafenib plus best supportive care (BSC) compared with placebo plus BSC (4.8 months vs. 0.9 months) in patients with metastatic or unresectable GIST progressing after failure of at least imatinib and sunitinib therapy in a multinational, randomized, double-blind, phase 3 trial (the GRID trial; n = 199). In this study, 43% of patients had failed 3 or more lines of previous therapy. The median duration of regorafenib therapy was 22.9 weeks. Most patients in the placebo arm (88%) crossed over to the regorafenib arm at progression. Median overall survival was not significantly different between treatment arms (17.4 months vs. 17.4 months).

    For the treatment of hepatocellular cancer in patients who have previously been treated with sorafenib.
    NOTE: The FDA has designated regorafenib as an orphan drug for the treatment of hepatocellular carcinoma.
    Oral dosage
    Adults

    160 mg PO once daily with a low-fat breakfast on days 1 to 21 of each 28-day cycle until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In an international, randomized, double-blind, phase 3 clinical trial (RESORCE), treatment with regorafenib significantly improved median overall survival compared with placebo (10.6 months vs. 7.8 months) in patients with advanced hepatocellular carcinoma after failure of sorafenib therapy.

    MAXIMUM DOSAGE

    Adults

    160 mg per day PO on days 1 to 21, every 28 days.

    Geriatric

    160 mg per day PO on days 1 to 21, every 28 days.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment:
    Mild to moderate hepatic impairment (total bilirubin less than or equal to the upper limit of normal (ULN) and AST greater than ULN; total bilirubin 1 to 1.5 times ULN; total bilirubin 1.6 to 3 times ULN and any AST): No dosage adjustment necessary.
    Severe hepatic impairment (total bilirubin greater than 3 times ULN): Regorafenib is not recommended as it has not been studied in this population.[51883]
     
    Treatment-Related Hepatotoxicity:
    Grade 2 AST/ALT elevation (3.1 to 5 times ULN) with concurrent bilirubin 2 times ULN or LESS: No dosage adjustment necessary.
    Grade 2 AST/ALT elevation (3.1 to 5 times ULN) with concurrent bilirubin MORE THAN 2 times ULN: Permanently discontinue regorafenib therapy.
    Grade 3 AST/ALT elevation (5.1 to 20 times upper limit of normal (ULN)) with bilirubin 2 times ULN or LESS: Hold regorafenib therapy. Upon recovery, consider the risk/benefits of continuing therapy. If therapy is continued, reduce the daily dose of regorafenib from 160 mg to 120 mg. Permanently discontinue therapy in patients who have grade 3 transaminase elevations despite a dose reduction to 120 mg.
    Grade 3 AST/ALT elevation (5.1 to 20 times upper limit of normal (ULN)) with concurrent bilirubin MORE THAN 2 times ULN: Permanently discontinue regorafenib therapy.
    Grade 4 AST/ALT elevation (more than 20 times ULN) with any bilirubin: Permanently discontinue regorafenib therapy.[51883]

    Renal Impairment

    Baseline Renal Impairment:
    Mild, moderate, or severe renal impairment (CrCL 15 mL/min or more): No dosage adjustment is necessary.
    End-stage renal failure on dialysis: There is no recommended dose as regorafenib has not been studied in this population.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Regorafenib should be taken at the same time each day with a low-fat meal that contains less than 600 calories and 30% fat.
    Swallow tablets whole with water.
    If a dose is missed, take as soon as possible that day. Do not take 2 doses of regorafenib on the same day.
    Discard any unused tablets in accordance with local requirements 7 weeks after opening the bottle.

    STORAGE

    Stivarga:
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in original container
    - Use within 7 weeks of first opening the bottle

    CONTRAINDICATIONS / PRECAUTIONS

    Hepatic disease, hepatotoxicity

    Severe and sometimes fatal hepatotoxicity has been reported with regorafenib use, usually within the first 2 months of therapy. Obtain liver function tests (LFTs) including ALT, AST, and bilirubin prior to starting regorafenib and then at least every 2 weeks for the first 2 months of therapy. Thereafter, monitor LFTs monthly or more often as clinically indicated. If LFT elevations occur, increase the frequency of monitoring to weekly until levels improve to less than 3 times the upper limit of normal or baseline. An interruption of therapy, dose reduction, or treatment discontinuation may be necessary for patients who develop elevated LFTs or hepatocellular necrosis. Closely monitor patients with hepatic impairment for adverse reactions. While an initial dose adjustment is not necessary for patients with mild or moderate hepatic impairment at baseline, it has not been studied in patients with severe hepatic disease and is not recommended for use in these patients.[51883]

    Anticoagulant therapy, bleeding, GI bleeding

    Fatal bleeding has been reported with regorafenib use, including bleeding of the central nervous system or the respiratory, genitourinary, or gastrointestinal (GI bleeding) tracts. Permanently discontinue regorafenib therapy in patients who develop severe or life-threatening bleeding. Use caution in patients receiving anticoagulant therapy and monitor INR levels more frequently in patients receiving warfarin.

    Skin disease

    Serious rash and skin disease, including palmar-plantar erythrodysesthesia (hand and foot syndrome), erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported in patients treated with regorafenib in clinical trials. Monitor for dermatologic toxicities and implement supportive measures for supportive relief; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary.[51883]

    Geriatric, hypertension

    Use regorafenib with caution in patients with pre-existing hypertension, as hypertension including hypertensive crisis has been reported with regorafenib use. Do not start regorafenib therapy until blood pressure is adequately controlled. Grade 3 hypertension was more common in geriatric patients (age 65 years and older) treated with regorafenib compared to younger patients in the placebo-controlled clinical trials (18% vs. 9%); additionally, one grade 4 hypertension event has been reported in the 65 years and older age group and none in the younger age group. Monitor blood pressure weekly for the first 6 weeks of therapy. Thereafter, monitor blood pressure at the start of every cycle or more often as clinically indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for severe or uncontrolled hypertension.[51883]

    Acute myocardial infarction, cardiac disease

    Use regorafenib with caution in patients with a history of cardiac disease. Myocardial ischemia and infarction have been reported with regorafenib use at an increased incidence compared to placebo. Hold therapy in patients who develop new or acute onset cardiac ischemia or acute myocardial infarction. Following symptom resolution, consider the risk/benefits of continuing regorafenib therapy.

    Fistula, GI perforation

    GI perforation and GI fistula have been reported with regorafenib use; some cases were fatal. Permanently discontinue therapy if patients develop GI perforation or fistula.

    Impaired wound healing, surgery

    Impaired wound healing can occur in patients treated with vascular endothelial growth factor (VEGF) receptor inhibitors such as regorafenib. Therefore, temporarily hold regorafenib therapy for at least 2 weeks before elective surgery; do not administer regorafenib for at least 2 weeks following major surgery and until adequate wound healing. The safety of resuming regorafenib after the resolution of wound healing complications has not been established.[51883]

    Asian patients

    Based on pooled data from three placebo-controlled trials, a higher incidence of palmar-plantar erythrodysesthesia (hand and foot syndrome) and liver function test abnormalities occurred in Asian patients compared with White patients. No starting dose adjustment is necessary based on race.

    Encephalopathy

    Reversible Posterior Leukoencephalopathy Syndrome (RPLS), also known as Posterior Reversible Encephalopathy Syndrome (PRES), has been reported with regorafenib use. Symptoms of RPLS include seizures, severe headache, visual disturbances, confusion, and altered mental status. Discontinue regorafenib therapy if RPLS is suspected or diagnosed; this syndrome may be confirmed on magnetic resonance imaging.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during regorafenib treatment and for at least 2 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, regorafenib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving regorafenib should be apprised of the potential hazard to the fetus. A total loss of pregnancy occurred with regorafenib doses that were much lower than the recommended human doses in rats (about 6% of the human dose based on body surface area) and rabbits (about 25% of the human exposure). Other embryo-fetal toxicity included delayed ossification and a dose-dependent increase in skeletal malformations (e.g., cleft palate, enlarged fontanelle), cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal pelvis in pregnant rats and ventricular septal defects and a dose-dependent increase in cardiovascular malformations, skeletal anomalies, missing kidney/ureter, kidney malformations, and hydronephrosis in pregnant rabbits.

    Contraception requirements, infertility, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during regorafenib treatment. Regorafenib can be teratogenic if taken by the mother during pregnancy. Females and males with female partners of reproductive potential should avoid pregnancy and use effective contraception during and for at least 2 months after treatment with regorafenib. Females of reproductive potential should undergo pregnancy testing prior to initiation of regorafenib. Women who become pregnant while receiving regorafenib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of regorafenib on human fertility, male and female infertility has been observed in animal studies.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from regorafenib, advise women to discontinue breast-feeding during treatment and for 2 weeks after the final dose. It is not known whether regorafenib is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    hypophosphatemia / Delayed / 22.0-34.0
    hypertension / Early / 8.0-28.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 12.0-22.0
    elevated hepatic enzymes / Delayed / 4.0-18.0
    lymphopenia / Delayed / 8.0-18.0
    proteinuria / Delayed / 2.0-17.0
    hyperbilirubinemia / Delayed / 4.0-16.0
    asthenia / Delayed / 4.0-15.0
    fatigue / Early / 4.0-15.0
    infection / Delayed / 5.0-9.0
    abdominal pain / Early / 0-8.0
    diarrhea / Early / 3.0-8.0
    hyponatremia / Delayed / 0-8.0
    rash / Early / 3.0-7.0
    thrombocytopenia / Delayed / 0-6.0
    anemia / Delayed / 0-6.0
    bleeding / Early / 2.0-5.0
    anorexia / Delayed / 0-5.0
    prolonged bleeding time / Delayed / 0-4.0
    stomatitis / Delayed / 1.0-4.0
    hypokalemia / Delayed / 0-4.0
    hyperamylasemia / Delayed / 0-4.0
    neutropenia / Delayed / 1.0-3.0
    alopecia / Delayed / 0-2.0
    nausea / Early / 0-2.0
    weight loss / Delayed / 0-2.0
    fever / Early / 0-2.0
    hypocalcemia / Delayed / 0-2.0
    hepatic failure / Delayed / 0-1.6
    pancreatitis / Delayed / 0-1.6
    exfoliative dermatitis / Delayed / 0-1.3
    headache / Early / 0-1.0
    vomiting / Early / 0-1.0
    myocardial infarction / Delayed / 0.3-0.9
    erythema multiforme / Delayed / 0-0.8
    gastrointestinal fistula / Delayed / 0.3-0.8
    GI perforation / Delayed / 0.6-0.6
    hypertensive crisis / Early / 0.2-0.2
    Stevens-Johnson syndrome / Delayed / 0.1-0.1
    toxic epidermal necrolysis / Delayed / 0-0.1
    leukoencephalopathy / Delayed / 0-0.1
    hepatotoxicity / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    nephrotic syndrome / Delayed / Incidence not known
    aortic dissection / Delayed / Incidence not known

    Moderate

    dysphonia / Delayed / 18.0-39.0
    hypothyroidism / Delayed / 0-18.0

    Mild

    muscle cramps / Delayed / 0-14.0
    pharyngitis / Delayed / 4.0-4.0
    tremor / Early / 0-1.3
    pruritus / Rapid / Incidence not known
    maculopapular rash / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with regorafenib is necessary. Dolutegravir is a BCRP substrate and regorafenib is a BCRP inhibitor.
    Alpelisib: (Major) Avoid coadministration of alpelisib with regorafenib 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 regorafenib is a BCRP inhibitor.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of regorafenib with clarithromycin due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of regorafenib with clarithromycin due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Apalutamide: (Major) Avoid coadministration of regorafenib with apalutamide due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the active metabolite M-5, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased regorafenib exposure by 50% and increased M-5 exposure by 264%.
    Atazanavir: (Major) Avoid coadministration of regorafenib with atazanavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of regorafenib with atazanavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each. (Major) Avoid coadministration of regorafenib with cobicistat due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of regorafenib with phenobarbital due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of regorafenib with phenobarbital due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
    Carbamazepine: (Major) Avoid coadministration of regorafenib with carbamazepine due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
    Ceritinib: (Major) Avoid coadministration of ceritinib with regorafenib due to increased plasma concentrations of regorafenib and decreased exposure to the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Chloramphenicol: (Major) Avoid coadministration of regorafenib with chloramphenicol due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Clarithromycin: (Major) Avoid coadministration of regorafenib with clarithromycin due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Cobicistat: (Major) Avoid coadministration of regorafenib with cobicistat due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Conivaptan: (Major) Avoid coadministration of regorafenib with conivaptan due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Do not initiate therapy with regorafenib for at least 1 week after an infusion of conivaptan. Regorafenib is a CYP3A4 substrate and conivaptan is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Darunavir: (Major) Avoid coadministration of regorafenib with darunavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Darunavir; Cobicistat: (Major) Avoid coadministration of regorafenib with cobicistat due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each. (Major) Avoid coadministration of regorafenib with darunavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of regorafenib with cobicistat due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each. (Major) Avoid coadministration of regorafenib with darunavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of regorafenib with ritonavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each. (Moderate) Monitor for an increase in dasabuvir-related adverse reactions if coadministration with regorafenib is necessary. Dasabuvir is a BCRP substrate and regorafenib is a BCRP inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with regorafenib is necessary. Paritaprevir is a BCRP substrate and regorafenib is a BCRP inhibitor.
    Delavirdine: (Major) Avoid coadministration of regorafenib with delavirdine due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Dolutegravir: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with regorafenib is necessary. Dolutegravir is a BCRP substrate and regorafenib is a BCRP inhibitor.
    Dolutegravir; Lamivudine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with regorafenib is necessary. Dolutegravir is a BCRP substrate and regorafenib is a BCRP inhibitor.
    Dolutegravir; Rilpivirine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with regorafenib is necessary. Dolutegravir is a BCRP substrate and regorafenib is a BCRP inhibitor.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Use caution if coadministration of regorafenib with tenofovir, PMPA is necessary, and monitor for an increase in tenofovir-related adverse reactions. Tenofovir is a BCRP substrate and regorafenib is a BCRP inhibitor. Regorafenib-mediated BCRP inhibition may increase exposure to tenofovir.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Use caution if coadministration of regorafenib with tenofovir, PMPA is necessary, and monitor for an increase in tenofovir-related adverse reactions. Tenofovir is a BCRP substrate and regorafenib is a BCRP inhibitor. Regorafenib-mediated BCRP inhibition may increase exposure to tenofovir.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Use caution if coadministration of regorafenib with tenofovir, PMPA is necessary, and monitor for an increase in tenofovir-related adverse reactions. Tenofovir is a BCRP substrate and regorafenib is a BCRP inhibitor. Regorafenib-mediated BCRP inhibition may increase exposure to tenofovir.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of regorafenib with cobicistat due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of regorafenib with cobicistat due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each. (Moderate) Use caution if coadministration of regorafenib with tenofovir, PMPA is necessary, and monitor for an increase in tenofovir-related adverse reactions. Tenofovir is a BCRP substrate and regorafenib is a BCRP inhibitor. Regorafenib-mediated BCRP inhibition may increase exposure to tenofovir.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Use caution if coadministration of regorafenib with tenofovir, PMPA is necessary, and monitor for an increase in tenofovir-related adverse reactions. Tenofovir is a BCRP substrate and regorafenib is a BCRP inhibitor. Regorafenib-mediated BCRP inhibition may increase exposure to tenofovir.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Use caution if coadministration of regorafenib with tenofovir, PMPA is necessary, and monitor for an increase in tenofovir-related adverse reactions. Tenofovir is a BCRP substrate and regorafenib is a BCRP inhibitor. Regorafenib-mediated BCRP inhibition may increase exposure to tenofovir.
    Enzalutamide: (Major) Avoid coadministration of regorafenib with enzalutamide due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the active metabolite M-5, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased regorafenib exposure by 50% and increased M-5 exposure by 264%.
    Fluvastatin: (Moderate) Monitor for an increase in fluvastatin-related adverse reactions including myopathy and rhabdomyolysis if coadministration with regorafenib is necessary. Fluvastatin is a BCRP substrate and regorafenib is a BCRP inhibitor.
    Fosamprenavir: (Major) Avoid coadministration of regorafenib with fosamprenavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and fosamprenavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Fosphenytoin: (Major) Avoid coadministration of regorafenib with fosphenytoin due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and regorafenib as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of breast cancer resistance protein (BCRP); regorafenib is an inhibitor of BCRP. (Moderate) Monitor for an increase in pibrentasvir-related adverse reactions if coadministration with regorafenib is necessary. Pibrentasvir is a BCRP substrate and regorafenib is a BCRP inhibitor.
    Grapefruit juice: (Major) Avoid grapefruit juice while taking regorafenib due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Idelalisib: (Major) Avoid coadministration of regorafenib with idelalisib due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Indinavir: (Major) Avoid coadministration of regorafenib with indinavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Irinotecan Liposomal: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with regorafenib is necessary. Irinotecan is a BCRP substrate and regorafenib is a BCRP inhibitor.
    Irinotecan: (Moderate) Monitor for an increase in irinotecan-related adverse reactions if coadministration with regorafenib is necessary. Irinotecan is a BCRP substrate and regorafenib is a BCRP inhibitor.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of regorafenib with rifampin due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of regorafenib with rifampin due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
    Itraconazole: (Major) Avoid coadministration of regorafenib with itraconazole due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Do not initiate treatment with regorafenib for 2 weeks after discontinuation of itraconazole. Regorafenib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Ketoconazole: (Major) Avoid coadministration of regorafenib with ketoconazole due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration of ketoconazole increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Use caution if coadministration of regorafenib with tenofovir, PMPA is necessary, and monitor for an increase in tenofovir-related adverse reactions. Tenofovir is a BCRP substrate and regorafenib is a BCRP inhibitor. Regorafenib-mediated BCRP inhibition may increase exposure to tenofovir.
    Letermovir: (Moderate) Avoid coadministration of regorafenib with letermovir in patients who are also receiving treatment with cyclosporine due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib may be administered with letermovir if the patient is not receiving concomitant cyclosporine. Regorafenib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of regorafenib with ritonavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of regorafenib with lumacaftor; ivacaftor due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of regorafenib with lumacaftor; ivacaftor due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
    Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with regorafenib is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and regorafenib is a weak CYP2C9 inhibitor.
    Mephobarbital: (Major) Avoid coadministration of regorafenib with mephobarbital due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and mephobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
    Methotrexate: (Moderate) Monitor for an increase in methotrexate-related adverse reactions if coadministration with regorafenib is necessary. Methotrexate is a BCRP substrate and regorafenib is a BCRP inhibitor.
    Mifepristone: (Major) Avoid coadministration of regorafenib with mifepristone due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mitotane: (Major) Avoid coadministration of regorafenib with mitotane due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
    Nefazodone: (Major) Avoid coadministration of regorafenib with nefazodone due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Nelfinavir: (Major) Avoid coadministration of regorafenib with nelfinavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Neomycin: (Moderate) Monitor for a decrease in the efficacy of regorafenib if coadministration with neomycin is necessary. Coadministration with neomycin, a non-absorbable antibiotic, did not have a clinically meaningful effect on the mean AUC of single-dose regorafenib in 27 healthy mean; however, the mean AUC of active metabolites M-2 and M-5 decreased by 76% and 86%, respectively.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of regorafenib with ritonavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with regorafenib is necessary. Paritaprevir is a BCRP substrate and regorafenib is a BCRP inhibitor.
    Ozanimod: (Major) Coadministration of ozanimod with regorafenib is not recommended. Coadministration may increase the exposure of the active metabolites of ozanimod, which may increase the risk of adverse reactions. Ozanimod is a BCRP substrate and regorafenib is a BCRP inhibitor. Coadministration with another BCRP inhibitor had no effect on ozanimod exposure, but doubled the exposure of the minor active metabolites, RP101988 and RP101075 (the direct precursor of the major active metabolite CC112273). Coadministration of ozanimod with BCRP inhibitors may also increase exposure of CC112273 and CC1084037.
    Pazopanib: (Major) Avoid coadministration of pazopanib and regorafenib due to the potential for increased pazopanib exposure. Pazopanib is a BCRP substrate; regorafenib is a BCRP inhibitor. Consider selection of an alternative concomitant medication with no or minimal potential to inhibit BCRP.
    Phenobarbital: (Major) Avoid coadministration of regorafenib with phenobarbital due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
    Phenytoin: (Major) Avoid coadministration of regorafenib with phenytoin due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
    Posaconazole: (Major) Avoid coadministration of regorafenib with posaconazole due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Primidone: (Major) Avoid coadministration of regorafenib with primidone due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
    Ribociclib: (Major) Avoid coadministration of regorafenib with ribociclib due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Ribociclib; Letrozole: (Major) Avoid coadministration of regorafenib with ribociclib due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Rifampin: (Major) Avoid coadministration of regorafenib with rifampin due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
    Rimegepant: (Major) Avoid coadministration of rimegepant with regorafenib; concurrent use may increase rimegepant exposure. Rimegepant is a substrate of BCRP and regorafenib is a BCRP inhibitor.
    Ritonavir: (Major) Avoid coadministration of regorafenib with ritonavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Rosuvastatin: (Major) Do not exceed a rosuvastatin dose of 10 mg once daily when coadministered with regorafenib. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Rosuvastatin is a substrate of the drug transporter breast cancer resistance protein (BCRP) and regorafenib is a BCRP inhibitor. Coadministration with regorafenib increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and 4.6-fold, respectively. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Saquinavir: (Major) Avoid coadministration of regorafenib with saquinavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of regorafenib with St. John's Wort due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
    Sulfasalazine: (Moderate) Monitor for an increase in sulfasalazine-related adverse reactions if coadministration with regorafenib is necessary. Sulfasalazine is a BCRP substrate and regorafenib is a BCRP inhibitor.
    Talazoparib: (Major) Avoid coadministration of regorafenib with talazoparib due to increased talazoparib exposure. If concomitant use is unavoidable, monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a BCRP substrate and regorafenib is a BCRP inhibitor. The effect of concomitant administration of BCRP inhibitors on the pharmacokinetics of talazoparib has not been studied; however, BCRP inhibitors may increase talazoparib exposure.
    Telithromycin: (Major) Avoid coadministration of regorafenib with telithromycin due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and telithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Tenofovir Alafenamide: (Moderate) Use caution if coadministration of regorafenib with tenofovir alafenamide is necessary, and monitor for an increase in tenofovir alafenamide-related adverse reactions. Tenofovir alafenamide is a BCRP substrate and regorafenib is a BCRP inhibitor. Regorafenib-mediated BCRP inhibition may increase exposure to tenofovir alafenamide. However, when tenofovir alafenamide is administered in combination with cobicistat, other inhibitors of BCRP are not expected to further increase tenofovir alafenamide concentrations.
    Tenofovir, PMPA: (Moderate) Use caution if coadministration of regorafenib with tenofovir, PMPA is necessary, and monitor for an increase in tenofovir-related adverse reactions. Tenofovir is a BCRP substrate and regorafenib is a BCRP inhibitor. Regorafenib-mediated BCRP inhibition may increase exposure to tenofovir.
    Tipranavir: (Major) Avoid coadministration of regorafenib with tipranavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Topotecan: (Major) Avoid coadministration of regorafenib with oral topotecan due to increased topotecan exposure; regorafenib may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and regorafenib is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Tucatinib: (Major) Avoid coadministration of regorafenib with tucatinib due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with regorafenib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP drug transporter; regorafenib is a BCRP inhibitor.
    Voriconazole: (Major) Avoid coadministration of regorafenib with voriconazole due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with regorafenib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Regorafenib is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during regorafenib treatment and for at least 2 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, regorafenib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving regorafenib should be apprised of the potential hazard to the fetus. A total loss of pregnancy occurred with regorafenib doses that were much lower than the recommended human doses in rats (about 6% of the human dose based on body surface area) and rabbits (about 25% of the human exposure). Other embryo-fetal toxicity included delayed ossification and a dose-dependent increase in skeletal malformations (e.g., cleft palate, enlarged fontanelle), cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal pelvis in pregnant rats and ventricular septal defects and a dose-dependent increase in cardiovascular malformations, skeletal anomalies, missing kidney/ureter, kidney malformations, and hydronephrosis in pregnant rabbits.

    Due to the potential for serious adverse reactions in nursing infants from regorafenib, advise women to discontinue breast-feeding during treatment and for 2 weeks after the final dose. It is not known whether regorafenib is present in human milk, although many drugs are excreted in human milk.

    MECHANISM OF ACTION

    Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and pathologic processes such as oncogenesis, tumor angiogenesis, metastasis, and tumor immunity. Regorafenib or its major active metabolites M-2 and M-5 inhibited RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, Abl, and CSF1R in vitro at concentrations that have been achieved clinically. In vivo, regorafenib demonstrated antiangiogenic activity in a rat tumor model and inhibited tumor growth in several mouse xenograft models including some for human colorectal cancer, GI stromal tumor, and hepatocellular carcinoma. It also demonstrated antimetastatic activity in a mouse xenograft model and 2 mouse orthotopic models of human colorectal cancer.[51883]

    PHARMACOKINETICS

    Regorafenib is administered orally. It is highly (99.5%) bound to human plasma proteins, as are its 2 active metabolites M-2 (99.8%) and M-5 (99.95%). After a single 160-mg dose of regorafenib, the geometric mean elimination half-life for regorafenib was 28 hours (range, 14 to 58 hours) and for the M-2 metabolite was 25 hours (range, 14 to 32 hours); the M-5 metabolite has a longer mean elimination half-life of 51 hours (range, 32 to 70 hours). Within 12 days of administration, approximately 71% of a radiolabeled dose was excreted in the feces (parent compound, 47%; metabolites, 24%) and 19% was excreted in the urine with 17% as glucuronides.[51883]
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, UGT1A9, breast cancer resistance protein (BCRP)
    Regorafenib is metabolized by CYP3A4 and UGT1A9 to two metabolites with similar in vitro pharmacological activity and steady-state concentrations as regorafenib (M-2 and M-5). In vivo, regorafenib is a BCRP inhibitor. In vitro, it also inhibits CYP2C8, CYP2C9, CYP2B6, CYP3A4, and CYP2C19; M-2 inhibits CYP2C8, CYP2C9, CYP3A4, and CYP2D6, while M-5 is an inhibitor of CYP2C8. However, the effects of regorafenib and its metabolites on single oral doses of substrates of CYP3A4 (midazolam; n = 15), CYP2C8 (rosiglitazone; n = 12), and CYP2C19 (omeprazole; n = 11) were not clinically meaningful in patients with advanced solid tumors. Regorafenib, M-2, and M-5 also competitively inhibit UGT1A9 and UGT1A1 at therapeutically relevant concentrations.[51883]

    Oral Route

    The mean relative bioavailability of a regorafenib tablet compared with an oral solution is 69% to 83%. Following a single oral dose of regorafenib 160 mg in patients with advanced solid tumors, the geometric mean peak plasma level (Cmax) of 2.5 mcg/mL occurred at a median time (Tmax) of 4 hours. The geometric mean area under the curve (AUC) was 70.4 mcg x hour/mL and increases less than dose proportionally at steady-state doses greater than 60 mg. At steady-state, the geometric mean Cmax and AUC values were 3.9 mcg/mL and 58.3 mcg x hour/mL, respectively, with a coefficient of variation between 35% and 44%. Regorafenib undergoes enterohepatic circulation and has multiple plasma concentration peaks over a 24-hour dosing period.[51883]
     
    Regorafenib should be administered with a low-fat meal. When administered with a low-fat meal (319 calories and 8.2 g fat), the AUC of regorafenib, M-2, and M-5 were increased by 36%, 40%, and 23%, respectively, compared to fasting conditions. The mean AUC of regorafenib increased by 48% when administered with a high-fat meal (945 calories and 54.6 g fat) compared to a fasting state, while the mean AUC of M-2 and M-5 decreased by 20% and 51%, respectively.[51883]