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  • CLASSES

    Small Molecule Antineoplastic Multikinase Inhibitors

    BOXED WARNING

    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) 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 < 3 times the upper limit of normal or baseline. No initial dosage adjustment is needed in patients with pre-existing mild or moderate hepatic disease; however, regorafenib has not been studied in patients with severe hepatic disease and use in this population is not recommended. Therapy interruption and dose reduction or drug discontinuation may be necessary in patients who develop elevated LFTs or hepatocellular necrosis. Monitor patients with hepatic impairment closely for adverse reactions.

    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 (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: No dosage adjustment is necessary.
    Severe hepatic impairment (Child-Pugh class C): Use not recommended; regorafenib has not been studied in patients with severe hepatic impairment.
    Treatment-Related Hepatotoxicity:
    Grade 1 or 2 AST/ALT elevations (less than or equal to 5 times ULN) with bilirubin less than or equal to 2 times ULN: No dosage adjustment necessary.
    Grade 1 AST/ALT elevations (less than or equal to 3 times upper limit of normal (ULN) with grade 3 or 4 increase in total bilirubin (more than 3 times ULN): Hold regorafenib therapy. Upon recovery, resume therapy at a reduced dose of 120 mg for the first occurrence, and 80 mg for the second recurrence. If a serious increase in total bilirubin occurs after reducing the dose to 80 mg, permanently discontinue regorafenib therapy.
    Grade 2 or higher AST/ALT elevations (more than 3 times ULN) with bilirubin more than 2 times ULN: Permanently discontinue regorafenib therapy.
    Grade 3 AST/ALT elevations (AST/ALT 5.1 to 20 times upper limit of normal (ULN)) with bilirubin less than or equal to 2 times ULN: Hold regorafenib therapy. Upon recovery, consider the risk/benefits of continuing therapy. If therapy is continued, reduce the regorafenib dose to 120 mg. Permanently discontinue therapy in patients who have a recurrence of grade 3 transaminase elevations despite a dose reduction to 120 mg.
    Grade 4 AST/ALT elevations (AST/ALT more than 20 times ULN) with any bilirubin: Permanently discontinue regorafenib therapy.

    Renal Impairment

    Baseline Renal Impairment:
    Mild, moderate, or severe renal impairment (CrCL greater than or equal to 15 mL/min): No dosage adjustment is necessary.
    End-stage renal disease: Regorafenib has not been studied in patients with severe renal impairment or end-stage renal disease.
    Treatment-Related Nephrotoxicity:
    Grade 3 or 4 (SCr more than 3 times baseline or upper limit of normal (ULN)): Hold regorafenib therapy. Upon recovery, resume regorafenib at a reduced dose of 120 mg; evaluate the risks and benefits of continuing therapy in patients who experienced a grade 4 reaction. If the grade 3 or 4 toxicity recurs, again hold therapy until resolution, then reduce the dose to 80 mg. Permanently discontinue therapy in patients who do not tolerate a regorafenib dose of 80 mg.

    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

    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) 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 < 3 times the upper limit of normal or baseline. No initial dosage adjustment is needed in patients with pre-existing mild or moderate hepatic disease; however, regorafenib has not been studied in patients with severe hepatic disease and use in this population is not recommended. Therapy interruption and dose reduction or drug discontinuation may be necessary in patients who develop elevated LFTs or hepatocellular necrosis. Monitor patients with hepatic impairment closely for adverse reactions.

    Bleeding, GI bleeding

    Fatal bleeding has been reported with regorafenib use, including GI bleeding and bleeding from the respiratory and genitourinary tracts. Permanently discontinue regorafenib therapy in patients who develop severe or life-threatening bleeding.

    Skin disease

    Skin toxicity has been reported frequently with regorafenib use, including palmar-plantar erythrodysesthesia (hand and foot syndrome) rash, and toxic epidermal necrolysis (TEN). Therapy interruption and/or dose reduction or drug discontinuation may be necessary in patients who develop skin disease (see Dosage); initiate treatment to relieve symptoms.

    Hypertension

    Hypertension including hypertensive crisis has been reported with regorafenib use. In patients with pre-existing hypertension, do not start regorafenib therapy until blood pressure is adequately controlled. 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. Temporarily or permanently discontinue therapy in patients who develop severe or uncontrolled hypertension.

    Acute myocardial infarction, cardiac disease

    Myocardial ischemia and infarction have been reported with regorafenib use. Hold therapy in patients who develop new or acute onset cardiac disease (ischemia) or acute myocardial infarction. Following symptom resolution, consider the risk/benefits of continuing regorafenib therapy.

    Fistula, GI perforation

    GI perforation or fistula has been reported rarely with regorafenib use; some cases were fatal. Discontinue therapy if patients develop GI perforation or fistula.

    Surgery, wound dehiscence

    Impaired wound healing may occur with vascular endothelial growth factor receptor inhibitors, such as regorafenib. Therefore, temporary suspension of therapy is recommended at least 2 weeks before elective surgery. Resume regorafenib therapy based on clinical judgement of adequate wound healing. Discontinue therapy in patients who develop wound dehiscence.

    Asian patients

    Based on pooled data from three placebo-controlled trials, a higher incidence of hand and foot skin reaction, also known as palmar-plantar erythrodysesthesia, and hepatic impairment occurred in Asian patients compared with Caucasian patients.

    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 months 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 / 22.0-32.0
    hypertension / Early / 8.0-28.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 17.0-22.0
    GI bleeding / Delayed / 0-21.0
    asthenia / Delayed / 4.0-15.0
    fatigue / Early / 4.0-15.0
    hyperbilirubinemia / Delayed / 4.0-13.0
    infection / Delayed / 5.0-9.0
    lymphopenia / Delayed / 8.0-9.0
    diarrhea / Early / 8.0-8.0
    hyponatremia / Delayed / 8.0-8.0
    rash / Early / 6.0-7.0
    elevated hepatic enzymes / Delayed / 4.0-6.0
    anemia / Delayed / 6.0-6.0
    anorexia / Delayed / 0-5.0
    bleeding / Early / 2.0-4.0
    prolonged bleeding time / Delayed / 4.0-4.0
    hypokalemia / Delayed / 3.0-4.0
    thrombocytopenia / Delayed / 1.0-3.0
    hyperamylasemia / Delayed / 3.0-3.0
    proteinuria / Delayed / 0-3.0
    alopecia / Delayed / 0-2.0
    nausea / Early / 2.0-2.0
    fever / Early / 0-2.0
    neutropenia / Delayed / 1.0-2.0
    hypocalcemia / Delayed / 2.0-2.0
    hepatic failure / Delayed / 0.8-1.6
    myocardial infarction / Delayed / 1.2-1.2
    vomiting / Early / 0-1.0
    weight loss / Delayed / 0-1.0
    headache / Early / 0-1.0
    abdominal pain / Early / 0-1.0
    musculoskeletal pain / Early / 0-1.0
    dyspnea / Early / 0-1.0
    GI perforation / Delayed / 0.6-0.6
    gastrointestinal fistula / Delayed / 0.6-0.6
    hypertensive crisis / Early / 0.3-0.3
    Stevens-Johnson syndrome / Delayed / 0.2-0.2
    toxic epidermal necrolysis / Delayed / 0.2-0.2
    erythema multiforme / Delayed / 0.2-0.2
    leukoencephalopathy / Delayed / 0-0.1
    new primary malignancy / Delayed / 0-0.1
    hepatotoxicity / Delayed / Incidence not known

    Moderate

    dysphonia / Delayed / 30.0-39.0
    hypothyroidism / Delayed / 0-18.0
    constipation / Delayed / 0-8.0

    Mild

    epistaxis / Delayed / 0-7.0
    dysgeusia / Early / 0-7.0

    DRUG INTERACTIONS

    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and clarithromycin, a strong CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and clarithromycin, a strong CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    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%.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if regorafenib and aprepitant, fosaprepitant are used concurrently and monitor for an increase in regorafenib-related adverse effects for several days after administration of a multi-day aprepitant regimen. Regorafenib is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of regorafenib. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Regorafenib is also a weak in vitro CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Information is not available regarding the use of aprepitant with weak CYP3A4 inhibitors.
    Atazanavir: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and atazanavir, a CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of regorafenib with cobicistat due to increased plasma concentrations of regorafenib and cobicistat, 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. Cobicistat is also a CYP2D6 substrate. An active metabolite of regorafenib, M-2, inhibits CYP2D6 in vitro. (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and atazanavir, a CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and phenobarbital, a strong CYP3A4 inducer, as the exposure of regorafenib may decrease and the exposure of the active metabolite M-5 may increase.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and phenobarbital, a strong CYP3A4 inducer, as the exposure of regorafenib may decrease and the exposure of the active metabolite M-5 may increase.
    Boceprevir: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and boceprevir, a strong CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Canagliflozin: (Moderate) Regorafenib is a mild UGT enzyme inhibitor in vitro. Therefore, regorafenib may theoretically interact with canagliflozin (UGT substrate) to increase the effects of canagliflozin leading to potential hypoglycemia. Patients should be monitored for changes in glycemic control.
    Canagliflozin; Metformin: (Moderate) Regorafenib is a mild UGT enzyme inhibitor in vitro. Therefore, regorafenib may theoretically interact with canagliflozin (UGT substrate) to increase the effects of canagliflozin leading to potential hypoglycemia. Patients should be monitored for changes in glycemic control.
    Carbamazepine: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and carbamazepine, a strong CYP3A4 inducer, as the exposure of regorafenib may decrease and the exposure of the active metabolite M-5 may increase.
    Ceritinib: (Major) Avoid coadministration of ceritinib with regorafenib due to increased regorafenib exposure; additive QT prolongation may also occur. If coadministration is unavoidable, monitor for regorafenib-related adverse reactions. Periodically monitor electrolytes and ECGs; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib is a CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval. regorafenib is primarily metabolized by CYP3A4 and is also associated with QT prolongation.
    Clarithromycin: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and clarithromycin, a strong CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Clopidogrel: (Major) Regorafenib may reduce the antiplatelet activity of clopidogrel by inhibiting clopidogrel's metabolism to its active metabolite. Use clopidogrel and regorafenib together with caution and monitor for reduced efficacy of clopidogrel. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps. The CYP3A4 isoenzyme is involved in one of the metabolic steps, and the CYP2C19 isoenzyme is involved in both steps. In vitro studies indicate regorafenib is an inhibitor of CYP2C19 and CYP3A4.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Cobicistat: (Major) Avoid coadministration of regorafenib with cobicistat due to increased plasma concentrations of regorafenib and cobicistat, 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. Cobicistat is also a CYP2D6 substrate. An active metabolite of regorafenib, M-2, inhibits CYP2D6 in vitro.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of regorafenib with cobicistat due to increased plasma concentrations of regorafenib and cobicistat, 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. Cobicistat is also a CYP2D6 substrate. An active metabolite of regorafenib, M-2, inhibits CYP2D6 in vitro. (Moderate) Use caution if coadministration of regorafenib with elvitegravir is necessary, and monitor for an increase in elvitegravir-related adverse reactions. Elvitegravir is a substrate of UGT1A1 and 1A3. Regorafenib, M-2, and M-5 all competitively inhibit UGT1A9 and 1A1 in vitro.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of regorafenib with cobicistat due to increased plasma concentrations of regorafenib and cobicistat, 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. Cobicistat is also a CYP2D6 substrate. An active metabolite of regorafenib, M-2, inhibits CYP2D6 in vitro. (Moderate) Use caution if coadministration of regorafenib with elvitegravir is necessary, and monitor for an increase in elvitegravir-related adverse reactions. Elvitegravir is a substrate of UGT1A1 and 1A3. Regorafenib, M-2, and M-5 all competitively inhibit UGT1A9 and 1A1 in vitro. (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.
    Cobimetinib: (Moderate) If concurrent use of cobimetinib and regorafenib is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro as well as a P-glycoprotein (P-gp) substrate; in vitro, regorafenib is a weak inhibitor of both CYP3A and P-gp. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
    Conivaptan: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and conivaptan, a strong CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with regorafenib, a mild P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. 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 with P-gp inhibitors like regorafenib in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with regorafenib, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Darunavir: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and darunavir, a CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Darunavir; Cobicistat: (Major) Avoid coadministration of regorafenib with cobicistat due to increased plasma concentrations of regorafenib and cobicistat, 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. Cobicistat is also a CYP2D6 substrate. An active metabolite of regorafenib, M-2, inhibits CYP2D6 in vitro. (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and darunavir, a CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of regorafenib with cobicistat due to increased plasma concentrations of regorafenib and cobicistat, 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. Cobicistat is also a CYP2D6 substrate. An active metabolite of regorafenib, M-2, inhibits CYP2D6 in vitro. (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and darunavir, a CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of regorafenib with ritonavir, due to increased regorafenib exposure; coadministration may also result in elevated plasma concentrations of ritonavir. Ritonavir is a strong CYP3A4 inhibitor and regorafenib is a CYP3A4 substrate. Ketoconazole, another strong CYP3A4 inhibitor, increased the mean AUC of regorafenib by 33%, and decreased the mean AUC of active metabolites M-2 and M-5 by 93%; concomitant use with other strong CYP3A4 inhibitors may lead to an increase in regorafenib-related adverse reactions. In addition, regorafenib is a mild in vitro inhibitor of CYP2D6, while ritonavir is partially metabolized via CYP2D6. Coadministration of ritonavir with another CYP2D6 inhibitor, fluoxetine, increased the ritonavir AUC by 19%.
    Daunorubicin: (Moderate) Use caution if coadministration of regorafenib with daunorubicin is necessary, and monitor for an increase in daunorubicin-related adverse reactions. Daunorubicin is a BCRP substrate and regorafenib is a BCRP inhibitor. Administration of regorafenib for 14 days prior to a single dose of rosuvastatin, another BCRP substrate, increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and a 4.6-fold, respectively; regorafenib-mediated BCRP inhibition may also increase exposure to daunorubicin.
    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.
    Doxorubicin: (Moderate) Use caution if coadministration of regorafenib with doxorubicin is necessary, and monitor for an increase in doxorubicin-related adverse reactions. Doxorubicin is a BCRP substrate and regorafenib is a BCRP inhibitor. Administration of regorafenib for 14 days prior to a single dose of rosuvastatin, another BCRP substrate, increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and a 4.6-fold, respectively; regorafenib-mediated BCRP inhibition may also increase exposure to doxorubicin. Doxorubicin is also a CYP2D6 substrate. An active metabolite of regorafenib, M-2, inhibits CYP2D6 in vitro which may further increase exposure to doxorubicin.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with regorafenib is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; regorafenib is a weak inhibitor of CYP2C9 and 3A4 in vitro. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Edoxaban: (Moderate) Coadministration of edoxaban and regorafenib may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and regorafenib is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of regorafenib; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    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.
    Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with regorafenib may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Regorafenib is a substrate and mild inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity. (Moderate) Use caution if coadministration of regorafenib with grazoprevir is necessary, and monitor for an increase in regorafenib-related adverse reactions. Grazoprevir is a weak CYP3A4 inhibitor and regorafenib is a CYP3A4 substrate. Ketoconazole, a strong CYP3A4 inhibitor, increased the mean AUC of regorafenib by 33%, and decreased the mean AUC of active metabolites M-2 and M-5 by 93%; information is not available for coadministration of regorafenib with weak CYP3A4 inhibitors such as grazoprevir, but regorafenib exposure may increase.
    Elvitegravir: (Moderate) Use caution if coadministration of regorafenib with elvitegravir is necessary, and monitor for an increase in elvitegravir-related adverse reactions. Elvitegravir is a substrate of UGT1A1 and 1A3. Regorafenib, M-2, and M-5 all competitively inhibit UGT1A9 and 1A1 in vitro.
    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%.
    Fosamprenavir: (Major) Avoid coadministration of regorafenib with fosamprenavir, due to altered regorafenib exposure and possible increases in fosamprenavir exposure. Fosamprenavir is a strong CYP3A4 inhibitor, but also a CYP3A4 inducer; regorafenib is a CYP3A4 substrate. Ketoconazole, another strong CYP3A4 inhibitor, increased the mean AUC of regorafenib by 33%, and decreased the mean AUC of active metabolites M-2 and M-5 by 93%; this may lead to increased regorafenib-related adverse reactions. Rifampin, a strong CYP3A4 inducer, decreased the mean AUC of regorafenib by 50%, and increased the mean AUC of active metabolite M-5 by 264%; no change in the mean AUC of M-2 was observed. Information is not available for coadministration of regorafenib with moderate CYP3A4 inducers, but regorafenib efficacy may be affected. Fosamprenavir is also a substrate of CYP2C9 and CYP2D6, while regorafenib inhibits these isoenzymes in vitro. Regorafenib increased the mean AUC of a sensitive CYP2C9 substrate, warfarin, by 25% (n = 8).
    Fosphenytoin: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and phenytoin or fosphenytoin, a strong CYP3A4 inducer, as the exposure of regorafenib may decrease and the exposure of the active metabolite M-5 may increase.
    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) Caution is advised with the coadministration of pibrentasvir and regorafenib as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of breast cancer resistance protein (BCRP); regorafenib is an inhibitor of BCRP.
    Grapefruit juice: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and grapefruit juice, a CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with regorafenib, a CYP3A substrate, as regorafenib toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Imatinib: (Moderate) Use caution if coadministration of regorafenib with imatinib, STI-571 is necessary, and monitor for an increase in imatinib- and regorafenib-related adverse reactions. Imatinib is a BCRP substrate and CYP3A4 inhibitor. Regorafenib is metabolized primarily by CYP3A4 and UGT1A9, and it is a BCRP inhibitor. Administration of regorafenib for 14 days prior to a single dose of rosuvastatin, another BCRP substrate, increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and a 4.6-fold, respectively; regorafenib-mediated BCRP inhibition may also increase exposure to imatinib. Ketoconazole, a strong CYP3A4 inhibitor, increased the mean AUC of regorafenib by 33%, and decreased the mean AUC of active metabolites M-2 and M-5 by 93%; information is not available for coadministration of regorafenib with moderate CYP3A4 inhibitors such as imatinib, but regorafenib exposure may increase. Coadministration of imatinib with another CYP3A4 substrate, simvastatin, increased the simvastatin Cmax and AUC by 2-fold and 3.5-fold, respectively. Imatinib is also a CYP2C9 substrate. Regorafenib and active metabolite, M-2, are CYP2C9 inhibitors in vitro. Regorafenib increased the mean AUC of a sensitive CYP2C9 substrate, warfarin, by 25% (n = 8); this may also affect exposure to imatinib.
    Indinavir: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and indinavir, a strong CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with regorafenib may result in increased serum concentrations of both drugs. Regorafenib is a substrate and inhibitor of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and rifampin, a strong CYP3A4 inducer, as the exposure of regorafenib may decrease and the exposure of the active metabolite M-5 may increase. In 22 healthy volunteers who received a single oral dose of regorafenib 160 mg once and then again after 7 days of oral rifampin 600 mg/day, the mean AUC of regorafenib decreased by 50% and the mean AUC of M-5 increased by 264%.
    Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and rifampin, a strong CYP3A4 inducer, as the exposure of regorafenib may decrease and the exposure of the active metabolite M-5 may increase. In 22 healthy volunteers who received a single oral dose of regorafenib 160 mg once and then again after 7 days of oral rifampin 600 mg/day, the mean AUC of regorafenib decreased by 50% and the mean AUC of M-5 increased by 264%.
    Itraconazole: (Major) Avoid regorafenib use during and for up to 2 weeks after discontinuation of itraconazole treatment. Taking regorafenib, a CYP3A4 substrate, and itraconazole, a strong CYP3A4 inhibitor, may increase exposure of regorafenib and decrease exposure to the active metabolites, M-2 and M-5, and may lead to increased toxicity.
    Ketoconazole: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and ketoconazole, a strong CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease. In 18 healthy volunteers who received a single oral dose of regorafenib 160 mg once and then again after 5 days of oral ketoconazole 400 mg/day, the mean AUC of regorafenib increased by 33% and the mean AUC of M-2 and M-5 both decreased by 93%.
    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.
    Ledipasvir; Sofosbuvir: (Moderate) Use caution if coadministration of regorafenib with ledipasvir is necessary, and monitor for an increase in ledipasvir-related adverse reactions. Ledipasvir is a BCRP substrate, and regorafenib is a BCRP inhibitor. Administration of regorafenib for 14 days prior to a single dose of rosuvastatin, another BCRP substrate, increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and a 4.6-fold, respectively. Concomitant use may increase exposure to ledipasvir. (Moderate) Use caution if coadministration of regorafenib with sofosbuvir is necessary, and monitor for an increase in sofosbuvir-related adverse reactions. Sofosbuvir is a BCRP substrate, and regorafenib is a BCRP inhibitor. Administration of regorafenib for 14 days prior to a single dose of rosuvastatin, another BCRP substrate, increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and a 4.6-fold, respectively. Concomitant use may increase exposure to sofosbuvir.
    Lesinurad: (Moderate) Use lesinurad and regorafenib together with caution; regorafenib may increase the systemic exposure of lesinurad. Regorafenib is a mild inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate.
    Lesinurad; Allopurinol: (Moderate) Use lesinurad and regorafenib together with caution; regorafenib may increase the systemic exposure of lesinurad. Regorafenib is a mild inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate.
    Letermovir: (Moderate) An increase in the serum concentration of regorafenib may occur if given with letermovir. Avoid this combination in patients who are also receiving treatment with cyclosporine because the magnitude of this interaction may be amplified. 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. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased the mean exposure (AUC) of regorafenib by 33%, and decreased the mean AUC of M-2 and M-5 by 93%.
    Loperamide: (Moderate) Use caution if coadministration of regorafenib with loperamide is necessary, and monitor for an increase in loperamide-related adverse reactions including cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and CNS effects. Loperamide is a CYP2B6 and CYP2D6 substrate. Regorafenib is an in vitro inhibitor of CYP2B6, while an active metabolite of regorafenib, M-2, inhibits CYP2D6 in vitro. Exposure to loperamide may increase. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Loperamide; Simethicone: (Moderate) Use caution if coadministration of regorafenib with loperamide is necessary, and monitor for an increase in loperamide-related adverse reactions including cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and CNS effects. Loperamide is a CYP2B6 and CYP2D6 substrate. Regorafenib is an in vitro inhibitor of CYP2B6, while an active metabolite of regorafenib, M-2, inhibits CYP2D6 in vitro. Exposure to loperamide may increase. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of regorafenib with lopinavir; ritonavir, due to increased regorafenib exposure; coadministration may also result in elevated plasma concentrations of ritonavir, which could lead to serious adverse events. Ritonavir and lopinavir are both strong CYP3A4 inhibitors, and regorafenib is a CYP3A4 substrate. Ketoconazole, another strong CYP3A4 inhibitor, increased the mean AUC of regorafenib by 33%, and decreased the mean AUC of active metabolites M-2 and M-5 by 93%; concomitant use with other strong CYP3A4 inhibitors may lead to an increase in regorafenib-related adverse reactions. In addition, regorafenib is a mild in vitro inhibitor of CYP2D6, while ritonavir is partially metabolized via CYP2D6. Coadministration of ritonavir with another CYP2D6 inhibitor, fluoxetine, increased the ritonavir AUC by 19%. (Major) Avoid coadministration of regorafenib with ritonavir, due to increased regorafenib exposure; coadministration may also result in elevated plasma concentrations of ritonavir. Ritonavir is a strong CYP3A4 inhibitor and regorafenib is a CYP3A4 substrate. Ketoconazole, another strong CYP3A4 inhibitor, increased the mean AUC of regorafenib by 33%, and decreased the mean AUC of active metabolites M-2 and M-5 by 93%; concomitant use with other strong CYP3A4 inhibitors may lead to an increase in regorafenib-related adverse reactions. In addition, regorafenib is a mild in vitro inhibitor of CYP2D6, while ritonavir is partially metabolized via CYP2D6. Coadministration of ritonavir with another CYP2D6 inhibitor, fluoxetine, increased the ritonavir AUC by 19%.
    Mitotane: (Major) Use caution if mitotane and repaglinide are used concomitantly, and monitor for decreased efficacy of repaglinide and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and repaglinide is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of repaglinide. When administered with another strong CYP3A inducer, rifampin, repaglinide AUC decreased by 31% and Cmax by 26%.
    Mitoxantrone: (Moderate) Use caution if coadministration of regorafenib with mitoxantrone is necessary, and monitor for an increase in mitoxantrone-related adverse reactions. Mitoxantrone is a BCRP substrate and regorafenib is a BCRP inhibitor. Administration of regorafenib for 14 days prior to a single dose of rosuvastatin, another BCRP substrate, increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and a 4.6-fold, respectively; regorafenib-mediated BCRP inhibition may also increase exposure to mitoxantrone.
    Nefazodone: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and nefazodone, a strong CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Nelfinavir: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and nelfinavir a strong CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Neomycin: (Major) Avoid coadministration of neomycin and regorafenib if possible, due to decreased efficacy of regorafenib. A clinically meaningful effect on the mean AUC of regorafenib was not observed when neomycin (1 gram PO three times daily for 5 days), a non-absorbable antibiotic, was administered to healthy men (n = 27) followed by a single dose of regorafenib (160 mg); however, the AUC of active metabolites M-2 and M-5 was decreased by 76% and 86%, respectively.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as regorafenib. The plasma concentrations of regorafenib can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor can significantly increase the systemic exposure to netupitant. Regorafenib has been shown to be a mild CYP3A4 inhibitor in-vitro. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
    Nintedanib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as regorafenib, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. In vitro, regorafenib is a mild inhibitor of P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor substrate of CYP3A4. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of regorafenib with ritonavir, due to increased regorafenib exposure; coadministration may also result in elevated plasma concentrations of ritonavir. Ritonavir is a strong CYP3A4 inhibitor and regorafenib is a CYP3A4 substrate. Ketoconazole, another strong CYP3A4 inhibitor, increased the mean AUC of regorafenib by 33%, and decreased the mean AUC of active metabolites M-2 and M-5 by 93%; concomitant use with other strong CYP3A4 inhibitors may lead to an increase in regorafenib-related adverse reactions. In addition, regorafenib is a mild in vitro inhibitor of CYP2D6, while ritonavir is partially metabolized via CYP2D6. Coadministration of ritonavir with another CYP2D6 inhibitor, fluoxetine, increased the ritonavir AUC by 19%.
    Paclitaxel: (Minor) Paclitaxel is a substrate of CYP2C8 and 3A4; in vitro, regorafenib is a mild inhibitor of CYP2C8 and 3A4. Monitor for increased paclitaxel side effects, including myelosuppression and peripheral neuropathy.
    Pazopanib: (Moderate) Use caution if coadministration of regorafenib with pazopanib is necessary, and monitor for an increase in pazopanib- and regorafenib-related adverse reactions. Pazopanib is a BCRP substrate and a weak CYP3A4 inhibitor; regorafenib is metabolized primarily by CYP3A4 and UGT1A9, and is also a BCRP inhibitor. Administration of regorafenib for 14 days prior to a single dose of rosuvastatin, another BCRP substrate, increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and a 4.6-fold, respectively; regorafenib-mediated BCRP inhibition may also increase exposure to pazopanib. Ketoconazole, a strong CYP3A4 inhibitor, increased the mean AUC of regorafenib by 33%, and decreased the mean AUC of active metabolites M-2 and M-5 by 93%; information is not available for coadministration of regorafenib with weak CYP3A4 inhibitors such as pazopanib, but regorafenib exposure may increase. Pazopanib increased the mean AUC and Cmax of another CYP3A4 substrate, midazolam, by approximately 30% each.
    Phenobarbital: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and phenobarbital, a strong CYP3A4 inducer, as the exposure of regorafenib may decrease and the exposure of the active metabolite M-5 may increase.
    Phenytoin: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and phenytoin, a strong CYP3A4 inducer, as the exposure of regorafenib may decrease and the exposure of the active metabolite M-5 may increase.
    Posaconazole: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and posaconazole, a strong CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    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.
    Rifabutin: (Moderate) Use caution if coadministration of regorafenib with rifabutin is necessary, and monitor for an decrease in the efficacy of regorafenib. Rifabutin is a CYP3A4 inducer and regorafenib is a CYP3A4 substrate. Rifampin, a strong CYP3A4 inducer, decreased the mean AUC of regorafenib by 50% and increased the mean AUC of active metabolite M-5 by 264%, which may lead to decreased efficacy; no change in the mean AUC of M-2 was observed. Information is not available for coadministration of regorafenib with moderate CYP3A4 inducers such as rifabutin, but regorafenib exposure may decrease.
    Rifampin: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and rifampin, a strong CYP3A4 inducer, as the exposure of regorafenib may decrease and the exposure of the active metabolite M-5 may increase. In 22 healthy volunteers who received a single oral dose of regorafenib 160 mg once and then again after 7 days of oral rifampin 600 mg/day, the mean AUC of regorafenib decreased by 50% and the mean AUC of M-5 increased by 264%.
    Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and regorafenib, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Ritonavir: (Major) Avoid coadministration of regorafenib with ritonavir, due to increased regorafenib exposure; coadministration may also result in elevated plasma concentrations of ritonavir. Ritonavir is a strong CYP3A4 inhibitor and regorafenib is a CYP3A4 substrate. Ketoconazole, another strong CYP3A4 inhibitor, increased the mean AUC of regorafenib by 33%, and decreased the mean AUC of active metabolites M-2 and M-5 by 93%; concomitant use with other strong CYP3A4 inhibitors may lead to an increase in regorafenib-related adverse reactions. In addition, regorafenib is a mild in vitro inhibitor of CYP2D6, while ritonavir is partially metabolized via CYP2D6. Coadministration of ritonavir with another CYP2D6 inhibitor, fluoxetine, increased the ritonavir AUC by 19%.
    Rivaroxaban: (Minor) The coadministration of rivaroxaban and regorafenib should be undertaken with caution in patients with renal impairment; it is unclear whether a clinically significant interaction occurs when these two drugs are coadministered to patients with normal renal function. Regorafenib is a combined mild CYP3A4 inhibitor and mild P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Coadministration in patients with renal impairment may result in increased exposure to rivaroxaban compared with patients with normal renal function and no inhibitor use since both pathways of elimination are affected. While an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 mL/minute [HR (95% CI): 1.05 (0.77, 1.42)].
    Rosuvastatin: (Moderate) Use caution if coadministration of regorafenib with rosuvastatin is necessary, and monitor for an increase in rosuvastatin-related adverse reactions. Rosuvastatin is a BCRP substrate and regorafenib is a BCRP inhibitor. Administration of regorafenib for 14 days prior to a single dose of rosuvastatin increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and a 4.6-fold, respectively.
    Saquinavir: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and saquinavir, a strong CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Selexipag: (Minor) Use caution if coadministration of regorafenib with selexipag is necessary, and monitor for an increase in selexipag-related adverse reactions. Selexipag is a BCRP and UGT substrate. Regorafenib is BCRP inhibitor, while regorafenib, M-2, and M-5 all competitively inhibit UGT1A9 and 1A1 in vitro. Regorafenib-mediated BCRP and UGT1A1 inhibition may increase exposure to selexipag.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and regorafenib. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by regorafenib may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionally, simeprivir, a P-gp inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of regorafenib, a P-gp and CYP3A4 substrate.
    Sofosbuvir: (Moderate) Use caution if coadministration of regorafenib with sofosbuvir is necessary, and monitor for an increase in sofosbuvir-related adverse reactions. Sofosbuvir is a BCRP substrate, and regorafenib is a BCRP inhibitor. Administration of regorafenib for 14 days prior to a single dose of rosuvastatin, another BCRP substrate, increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and a 4.6-fold, respectively. Concomitant use may increase exposure to sofosbuvir.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution if coadministration of regorafenib with sofosbuvir is necessary, and monitor for an increase in sofosbuvir-related adverse reactions. Sofosbuvir is a BCRP substrate, and regorafenib is a BCRP inhibitor. Administration of regorafenib for 14 days prior to a single dose of rosuvastatin, another BCRP substrate, increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and a 4.6-fold, respectively. Concomitant use may increase exposure to sofosbuvir. (Moderate) Use caution when administering velpatasvir with regorafenib. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of BCRP; regorafenib is a BCRP inhibitor. Administration of regorafenib for 14 days prior to a single dose of rosuvastatin, another BCRP substrate, increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and a 4.6-fold, respectively; regorafenib-mediated BCRP inhibition may also increase exposure to velpatasvir. Velpatasvir is also a CYP2B6 substrate and regorafenib inhibits CYP2D6 in vitro, which may further increase exposure to velpatasvir.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution if coadministration of regorafenib with sofosbuvir is necessary, and monitor for an increase in sofosbuvir-related adverse reactions. Sofosbuvir is a BCRP substrate, and regorafenib is a BCRP inhibitor. Administration of regorafenib for 14 days prior to a single dose of rosuvastatin, another BCRP substrate, increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and a 4.6-fold, respectively. Concomitant use may increase exposure to sofosbuvir. (Moderate) Use caution when administering velpatasvir with regorafenib. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of BCRP; regorafenib is a BCRP inhibitor. Administration of regorafenib for 14 days prior to a single dose of rosuvastatin, another BCRP substrate, increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and a 4.6-fold, respectively; regorafenib-mediated BCRP inhibition may also increase exposure to velpatasvir. Velpatasvir is also a CYP2B6 substrate and regorafenib inhibits CYP2D6 in vitro, which may further increase exposure to velpatasvir.
    St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and St. John's Wort, a strong CYP3A4 inducer, as the exposure of regorafenib may decrease and the exposure of the active metabolite M-5 may increase.
    Sulfasalazine: (Moderate) Use caution if coadministration of regorafenib with sulfasalazine is necessary, and monitor for an increase in sulfasalazine-related adverse reactions. Sulfasalazine is a BCRP substrate and regorafenib is a BCRP inhibitor. Regorafenib-mediated BCRP inhibition may increase exposure to sulfasalazine.
    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.
    Telaprevir: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and telaprevir, a strong CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Telithromycin: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and telithromycin, a strong CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and regorafenib is necessary, as the systemic exposure of regorafenib may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of regorafenib. Regorafenib is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    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.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering regorafenib. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C8, CYP2C9, CYP2C19, and CYP3A4; regorafenib is an inhibitor of these enzymes. Monitor patients for adverse reactions if these drugs are coadministered.
    Ticagrelor: (Minor) Coadministration of ticagrelor and regorafenib may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and regorafenib is a mild P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    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.
    Trabectedin: (Minor) Use caution if coadministration of trabectedin and regorafenib is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, regorafenib is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Vemurafenib: (Moderate) Use caution if coadministration of regorafenib with vemurafenib is necessary, and monitor for an increase in vemurafenib-related adverse reactions or a possible decrease in the efficacy of regorafenib. Vemurafenib is a BCRP substrate and regorafenib is a BCRP inhibitor. Regorafenib-mediated BCRP inhibition may increase exposure to vemurafenib. Additionally, vemurafenib is a weak inducer of CYP3A4 and regorafenib is a CYP3A4 substrate. Information is not available for coadministration of regorafenib with weak CYP3A4 inducers such as vemurafenib, but regorafenib exposure may decrease.
    Vincristine Liposomal: (Moderate) In vitro, Regorafenib is both a mild CYP3A4 and P-glycoprotein (P-gp) inhibitor; vincristine is a substrate of both CYP3A and P-gp. Theoretically, concentrations of vincristine may be affected by coadministration. Monitor patients for vincristine toxicity if these drugs are used together.
    Vincristine: (Moderate) In vitro, Regorafenib is both a mild CYP3A4 and P-glycoprotein (P-gp) inhibitor; vincristine is a substrate of both CYP3A and P-gp. Theoretically, concentrations of vincristine may be affected by coadministration. Monitor patients for vincristine toxicity if these drugs are used together.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and regorafenib. Vorapaxar is a CYP3A4 substrate. Regorafenib is a mild CYP3A4 inhibitor in vitro. Increased serum concentrations of vorapaxar are possible when vorapaxar is coadministered with regorafenib. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Voriconazole: (Major) Avoid coadministration of regorafenib with voricoanzole 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: (Major) Concomitant use of regorafenib, a CYP2C9 inhibitor, and warfarin, a CYP2C9 substrate, may result in an increased risk of bleeding. In 8 patients with advanced solid tumors who received a single oral dose of warfarin 10 mg one week before and two weeks after regorafenib 160 mg/day, the mean AUC of warfarin increased by 25%. Fatal hemorrhage has been reported with regorafenib use in clinical trials. If regorafenib and warfain are used together, monitor INR levels more frequently.

    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 months 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 diphenylurea oral multikinase inhibitor structurally related to sorafenib. In vitro, regorafenib and its active metabolites, M-2 and M-5, inhibit tyrosine kinases that promote angiogenesis and tumor growth such as vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet derived growth factor (PDGFR)-alfa, PDGFR-beta, and TIE2. Additionally, oncogenic kinases such as c-KIT, REF, and BRAF are inhibited. Other kinases inhibited are fibroblast growth factor receptor (FGFR)-1, FGFR-2, DDR2, Trk2A, Eph2A, SAPK2, PTK5, and Abl. In vivo, regorafenib exhibited antiangiogenic activity in rat tumors and inhibited tumor growth and showed anti-metastatic activity in mouse xenograft models, including some with human colorectal carcinoma.

    PHARMACOKINETICS

    Regorafenib is administered orally. It is metabolized by CYP3A4 and UGT1A9 and undergoes enterohepatic circulation. The circulating active metabolites are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl); both these metabolites have similar in vitro activity to the parent drug. Regorafenib (99.5%) and it's metabolites, M-2 (99.8%) and M-5 (99.95%), are highly bound to plasma proteins. Following a single oral dose of 160 mg, the geometric mean elimination half-lives were 28 hours (hr) (range, 14 to 58 hr), 25 hr (range, 14 to 32 hr), and 51 hr (range, 32 to 70 hr) for the parent drug, M-2 metabolite, and M-5 metabolite, respectively. Following a single radiolabeled oral solution dose of 120 mg, 71% of the dose was recovered in the feces (parent drug, 47%; metabolites, 24%) and 19% of the dose was recovered in the urine (17% as glucuronides) within 12 days.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C9, CYP2B6, CYP2D6, UGT1A9, UGT1A1, breast cancer resistance protein (BCRP)
    Regorafenib is metabolized primarily by the CYP3A4 and UGT1A9 isoenzymes. Avoid concomitant use with strong CYP3A4 inhibitors or inducers. In vitro, it competitively inhibits CYP2C8, CYP2C9, CYP2B6, CYP3A4, and CYP2C19; the active metabolites M-2 (CYP2C8, CYP2C9, CYP3A4, and CYP2D6) and M-5 (CYP2C8) also inhibit hepatic isoenzymes in vitro. 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. Additionally, regorafenib, M-2, and M-5 competitively inhibit UGT1A9 and UGT1A1 at therapeutic concentrations. In vivo, regorafenib, M-2, and M-5 are also inhibitors of BCRP.

    Oral Route

    The mean relative bioavailability of a regorafenib tablet compared with an oral solution is 69% to 83%. Following a single regorafenib 160 mg oral dose, the geometric mean peak plasma level (Cmax) of 2.5 micrograms (mcg)/mL occurred at a median time (Tmax) of 4 hour (hr) in a pharmacokinetic analysis in patients with advanced solid tumors. The geometric mean area under the curve (AUC) was 70.4 mcg X hr/mL. At steady-state regorafenib levels, the geometric mean Cmax and AUC values were 3.9 mcg/mL and 58.3 mcg X hr/mL, respectively. Regorafenib should be administered with a low-fat meal. A single regorafenib 160 mg oral dose was administered under fasting conditions, with a high-fat meal (945 calories; 54.6 grams of fat), and with a low-fat meal (319 calories; 8.2 grams of fat) to 24 healthy male volunteers in a food effect study. Compared with the fasted state, giving regorafenib with a high-fat meal increased the regorafenib mean AUC by 48% and decreased the active metabolites M-2 and M-5 mean AUC values by 20% and 51%, respectively. Giving regorafenib with a low-fat meal increased the regorafenib, M-2 metabolite, and M-5 metabolite mean AUC values by 36%, 40%, and 23%, respectively, compared with the fasted state.