Brand name: Stivarga
Drug class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
Chemical name: 4-[4-[[[[4-Chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-3-fluorophenoxy]-N-methyl-2-pyridinecarboxamide
Molecular formula: C₂₁H₁₅ClF₄N₄O₃
CAS number: 755037-03-7

Medically reviewed by Drugs.com on Apr 7, 2025. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases.^{1 2 3 4 5}

Uses for Regorafenib

Colorectal Cancer

Treatment of metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens; a vascular endothelial growth factor inhibitor (anti-VEGF therapy); and, in patients with tumors bearing wild-type (nonmutated) KRAS gene, an epidermal growth factor receptor inhibitor (anti-EGFR therapy).^{1 2}

American Society of Clinical Oncology (ASCO) states that regorafenib or trifluridine/tipiracil may be considered in the third- or fourth-line setting in patients with late-stage colorectal cancer with any RAS/BRAF status; however, the drugs are recommended in patients with wild-type RAS metastatic colorectal cancer previously treated with fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, and anti-EGFR therapy.¹⁷

GI Stromal Tumor (GIST)

Treatment of locally advanced, unresectable, or metastatic GIST previously treated with imatinib and sunitinib therapy (designated an orphan drug by FDA for treatment of this cancer).^{1 3 4 8}

Hepatocellular Carcinoma

Treatment of hepatocellular carcinoma previously treated with sorafenib therapy (designated an orphan drug by FDA for treatment of this cancer).^{1 8 14}

Other Uses

Has been studied in patients with gastric cancer^{† [off-label]}, osteosarcoma^{† [off-label]}, soft-tissue sarcoma^{† [off-label]}, and glioblastoma^{† [off-label]}.^{19 21 22 23}

Regorafenib Dosage and Administration

General

Pretreatment Screening

• Blood pressure; control blood pressure prior to initiating therapy.¹

• Assess serum aminotransferase (ALT and AST) and bilirubin concentrations prior to initiating therapy.¹

• Verify pregnancy status in females of reproductive potential.¹

Patient Monitoring

• Monitor blood pressure weekly during the first 6 weeks of therapy and then every cycle, or more frequently, as clinically indicated.¹

• Monitor serum aminotransferase (ALT and AST) and bilirubin concentrations at least every 2 weeks for the first 2 months of therapy, and then monthly thereafter or more frequently as clinically indicated.¹

Other General Considerations

• Withhold therapy for at least 2 weeks prior to elective surgery.¹ Do not administer for ≥2 weeks following major surgery and until adequate wound healing has occurred.¹

• If regorafenib is used in patients receiving a coumarin-derivative anticoagulant (e.g., warfarin), monitor international normalized ratio (INR) more frequently.¹

Administration

Oral Administration

Administer orally with water following a low-fat meal (<600 calories and <30% fat) at the same time each day.¹

Swallow tablets whole.¹

If a dose is missed, take the prescribed dose as soon as possible on the same day; do not take two doses on the next day to replace the missed dose.¹

Dosage

Available as regorafenib monohydrate; dosage expressed in terms of anhydrous regorafenib.¹

Adults

Colorectal Cancer

Oral

160 mg once daily on days 1–21 of each 28-day cycle.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

GIST

Oral

160 mg once daily on days 1–21 of each 28-day cycle.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Hepatocellular Carcinoma

Oral

160 mg once daily on days 1–21 of each 28-day cycle.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Dosage Modification for Toxicity

Grade 3 or 4 Toxicity

If grade 3 or 4 toxicity occurs, interrupt therapy.¹ If toxicity is grade 4, the manufacturer recommends permanent discontinuance of therapy; the manufacturer states that therapy may be resumed following recovery from grade 4 toxicity only if the potential benefits outweigh the risks.^{1 13}

When resuming therapy following recovery from first episode of grade 3 or 4 toxicity (except hepatotoxicity or infection), use reduced dosage of 120 mg daily.¹

If grade 3 or 4 toxicity (except hepatotoxicity or infection) occurs at a dosage of 120 mg daily, interrupt therapy again; when resuming therapy following recovery, use further reduced dosage of 80 mg daily.¹

If dosage of 80 mg daily is not tolerated, permanently discontinue therapy.¹

Dermatologic Toxicity

Hepatotoxicity

Hypertension

If symptomatic grade 2 hypertension occurs, temporarily interrupt therapy.¹

For grade 3 or 4 hypertension, see Grade 3 or 4 Toxicity under Dosage and Administration.¹

Infectious Complications

If grade 3 or 4 infection develops or worsening infection of any grade occurs, temporarily interrupt therapy; following resolution of infection, resume therapy at same dosage.¹

Special Populations

Hepatic Impairment

Mild (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN or total bilirubin concentration exceeding the ULN, but ≤1.5 times the ULN) or moderate (total bilirubin concentration >1.5 times, but ≤3 times the ULN with any AST concentration) preexisting hepatic impairment: No dosage adjustment required.¹ Closely monitor for adverse effects.¹

Severe preexisting hepatic impairment (total bilirubin concentration >3 times the ULN): Use not recommended.¹

Renal Impairment

Mild, moderate, or severe renal impairment: No dosage adjustment required.¹

End-stage renal disease requiring dialysis: Appropriate dosage not established.¹

Geriatric Patients

No specific dosage recommendations at this time.¹

Race

No initial dosage adjustment required in Asian patients.¹

Cautions for Regorafenib

Contraindications

• Manufacturer states none known.¹

Warnings/Precautions

Warnings

Hepatic Toxicity

Boxed warning regarding risk of hepatotoxicity is included in the prescribing information.¹ Severe and sometimes fatal hepatotoxicity, usually characterized by a hepatocellular pattern of injury, reported; generally occurs during initial 2 months of therapy.^{1 2} Liver function test abnormalities reported more frequently in Asian patients compared with Caucasian patients.¹

Monitor serum ALT, AST, and bilirubin concentrations prior to initiation of therapy, at least every 2 weeks for the first 2 months of therapy, and monthly thereafter or more frequently as clinically indicated.¹ If concentrations rise above pretreatment levels, monitor liver function tests weekly until the concentrations return to baseline or improve to <3 times the ULN.¹

If hepatotoxicity occurs, interrupt therapy and then reduce dosage or permanently discontinue therapy depending on the severity and persistence of the toxicity.¹

Other Warnings and Precautions

Infectious Complications

Infections, sometimes fatal, reported.¹ Most common infections include urinary tract infections, nasopharyngitis, mucocutaneous and systemic fungal infections, and pneumonia.¹

If infection occurs, interrupt therapy depending on the severity of the infection.¹

Hemorrhage

Increased risk of hemorrhage; some fatal events reported.¹

Permanently discontinue therapy if severe or life-threatening hemorrhage occurs.¹

Monitor INR more frequently in patients receiving concomitant warfarin therapy.¹

GI Perforation and Fistula Formation

GI perforation (including 8 deaths) reported in 0.6% of 4518 regorafenib-treated patients in clinical trials.¹ GI fistula formation also reported.¹

Discontinue therapy if GI perforation or fistula formation occurs.¹

Dermatologic Effects

Skin and subcutaneous reactions, including palmar-plantar erythrodysesthesia (hand-foot syndrome) and severe rash requiring dosage modification, reported frequently.¹ Palmar-plantar erythrodysesthesia generally appears during the first cycle of therapy.¹ Palmar-plantar erythrodysesthesia reported more frequently in Asian patients compared with Caucasian patients.¹

If dermatologic toxicity occurs, employ supportive measures; temporary interruption of therapy, dosage reduction, or permanent discontinuance of therapy may be necessary depending on the severity and persistence of the toxicity.¹

Hypertension

Increased risk of hypertension; onset generally occurs during the first treatment cycle.¹

Ensure that BP is controlled prior to initiation of therapy.¹

Monitor BP weekly during the first 6 weeks of therapy; thereafter, monitor every cycle or more frequently as clinically indicated.¹ If hypertension is severe or uncontrolled, temporarily or permanently discontinue therapy.¹

Cardiac Ischemia

Cardiac ischemia and infarction reported.¹

Interrupt therapy if new or acute-onset cardiac ischemia or cardiac infarction occurs.¹ Upon resolution of acute cardiac ischemic events, may resume therapy if the potential benefits outweigh the risk.¹

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS reported in 1 of 4800 regorafenib-treated patients in clinical trials.¹

Consider possible RPLS in patients presenting with headache, seizures, visual disturbances, confusion, or altered mental function.¹ Magnetic resonance imaging (MRI) is necessary to confirm diagnosis.¹

In patients who develop RPLS, discontinue regorafenib.¹

Wound Healing Complications

Effect of regorafenib on wound healing not specifically studied; however, VEGFR inhibitors may impair wound healing.¹

Discontinue regorafenib ≥2 weeks prior to scheduled surgery.¹ Decision to resume therapy postoperatively should be based on clinical assessment of adequacy of wound healing.¹

Safety of resuming therapy after wound healing unknown.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.¹ Embryolethality and teratogenicity demonstrated in animals.¹ Pregnancy should be avoided during therapy and for 2 months after drug discontinuance.¹ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹

Specific Populations

Pregnancy

May cause fetal harm.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Effects on nursing infant or on milk production also unknown.¹ Discontinue nursing during therapy and for 2 weeks after drug discontinuance.¹

Females and Males of Reproductive Potential

Females and males of reproductive potential should use effective contraception during therapy and for 2 months after discontinuance of therapy.¹

Impaired fertility observed in male and female animals.¹

Pediatric Use

Safety and efficacy not established.¹

Dose-dependent dentin alteration and angiectasis, as well as persistent growth and thickening of the femoral epiphyseal growth plate, observed in animals receiving repeated doses at exposure levels lower than those associated with the recommended human dosage.¹

Geriatric Use

No overall differences in safety and efficacy relative to younger adults, but grade 3 or 4 hypertension occurred more frequently in geriatric patients.¹

Hepatic Impairment

Systemic exposure not affected by mild or moderate hepatic impairment; however, monitor closely for adverse effects.¹

Not studied and not recommended in patients with severe hepatic impairment (total bilirubin concentration >3 times the ULN).¹

Renal Impairment

Systemic exposure not affected by severe renal impairment (Cl_cr 15–29 mL/minute).¹

Not studied in patients with end-stage renal disease requiring dialysis.¹

Race

Higher incidence of palmar-plantar erythrodysesthesia (hand-foot syndrome) and liver function abnormalities in Asian patients.¹ No dosage adjustment recommended.¹

Common Adverse Effects

Adverse reactions occurring in ≥20% of patients: Pain (including GI and abdominal pain), palmar-plantar erythrodysesthesia (hand-foot syndrome), asthenia/fatigue, diarrhea, decreased appetite/food intake, hypertension, infection, dysphonia, hyperbilirubinemia, fever, mucositis, weight loss, rash, nausea.¹

Drug Interactions

Metabolized mainly by CYP3A4 and UGT1A9.^{1 9} CYP3A4 mediates conversion of regorafenib to active M-2 metabolite.¹²

Regorafenib inhibits CYP isoenzymes 2B6, 2C8, 2C9, 2C19, and 3A4) and the metabolite M-2 inhibits isoenzymes 2C8, 2C9, 2D6, and 3A4 and M-5 inhibits isoenzyme 2C8.¹ Regorafenib does not induce CYP isoenzymes 1A2, 2B6, 2C19, or 3A4.¹

Regorafenib, M-2, and M-5 competitively inhibit UGT1A1 and UGT1A9 in vitro at clinically relevant concentrations.¹

Regorafenib inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).¹² The metabolites M-2 and M-5 are P-gp and BCRP substrates.¹⁶

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Possible increased systemic exposure to regorafenib, decreased systemic exposure to M-2 and M-5, and increased incidence of adverse effects.¹ Avoid concomitant use.¹

Potent CYP3A4 inducers: Possible decreased systemic exposure to regorafenib, increased systemic exposure to M-5, and reduced regorafenib efficacy.¹ Avoid concomitant use.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

In vitro studies suggested inhibition of certain CYP isoenzymes by regorafenib and/or its active metabolites; studies in patients revealed no clinically important changes in AUC or concentration of probe substrates for CYP isoenzyme 2C8, 2C19, or 3A4 and a 25% increase in the AUC of a probe substrate for CYP2C9.¹

Drugs Affected by Transport Systems

BCRP substrates: Possible increased systemic exposure to BCRP substrate.¹ Closely monitor for BCRP substrate toxicity.¹

P-gp substrates: No clinically important interactions expected; in vitro studies suggested inhibition of P-gp by regorafenib, but clinical data indicated no change in pharmacokinetics of a probe substrate for P-gp.¹⁶

Drugs Affecting Transport Systems

Drugs affecting P-gp or BCRP: Possible effects on M-2 and M-5 exposure; clinical importance not established.¹⁶

Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase (UGT)

UGT1A1 substrates: Possible increased systemic exposure to the UGT substrate.^{1 7 16}

Specific Drugs and Foods

Regorafenib Pharmacokinetics

Absorption

Bioavailability

Peak plasma regorafenib concentrations are attained about 4 hours after oral administration.¹

Food

Administration with a high-fat meal (945 calories and 54.6 g of fat) increased AUC of regorafenib by 48% and decreased AUC of the active M-2 and M-5 metabolites by 20 and 51%, respectively.¹

Administration with a low-fat meal (319 calories and 8.2 g of fat) increased AUC of regorafenib, M-2, and M-5 by 36, 40, and 23%, respectively.¹

Special Populations

In patients with hepatocellular carcinoma and mild (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN or total bilirubin concentration exceeding the ULN, but not >1.5 times the ULN) or moderate (total bilirubin concentration >1.5 times, but not >3 times the ULN with any AST concentration) hepatic impairment, systemic exposure to regorafenib, M-2, and M-5 was similar to that in patients with normal hepatic function.¹

In patients with mild renal impairment (Cl_cr 60–89 mL/minute), systemic exposure to regorafenib, M-2, and M-5 was similar to that in patients with normal renal function.¹

Distribution

Extent

Not known whether regorafenib is distributed into human milk.¹

Plasma Protein Binding

>99% for regorafenib, M-2, and M-5.¹

Elimination

Metabolism

Metabolized mainly by CYP3A4 and UGT1A9.^{1 9} The main circulating metabolites, M-2 (N-oxide metabolite) and M-5 (N-oxide and N-desmethyl metabolite), have similar steady-state concentrations and in vitro activity as the parent drug.^{1 5 6 9} Metabolism of regorafenib to M-2 is mediated by CYP3A4; the enzyme responsible for conversion of M-2 to M-5 has not been determined to date.¹²

Undergoes enterohepatic circulation.¹

Elimination Route

Eliminated mainly in feces (71%; as unchanged drug [47%] and metabolites [24%]) and to a lesser extent in urine (19%).¹

Half-life

Approximately 28 hours (for regorafenib), 25 hours (for M-2), or 51 hours (for M-5).^{1 6}

Special Populations

Age, weight, ethnicity, and gender do not substantially affect pharmacokinetics of regorafenib.¹

Stability

Storage

Oral

Tablets

25°C (excursions permitted between 15–30°C).¹ Store in original container, tightly closed, with desiccant; discard any unused tablets 7 weeks after container is first opened.¹

Actions

• Inhibits multiple receptor tyrosine kinases, including vascular endothelial growth factor receptors (i.e., VEGFR-1, VEGFR-2, VEGFR-3), platelet-derived growth factor receptors (i.e., PDGFR-α, PDGFR-β), fibroblast growth factor receptors (i.e., FGFR1, FGFR2), and tyrosine kinase with immunoglobulin and epidermal growth factor homology (i.e., TIE-2), in vitro at clinically relevant concentrations.^{1 5 6 10}

• Inhibits other receptor kinases involved in normal cellular functions and pathologic processes (e.g., RET, c-Kit, DDR2, TrkA, EphA-2, Raf-1, b-Raf, mutant b-Raf, SAPK2, Ptk5, Bcr-Abl, CSF-1R).^{1 5 10}

• Inhibits tumor angiogenesis in vivo; inhibits tumor growth and metastasis in mouse models of cancer.^{1 10}

• Main circulating metabolites, M-2 and M-5, were equipotent to regorafenib in biochemical and cellular assays.^{1 5 6 9}

Advice to Patients

• Importance of taking regorafenib with water at the same time each day following a low-fat meal (<600 calories and <30% fat).¹ Importance of avoiding grapefruit juice while taking the drug.¹

• If a dose is missed, importance of administering the missed dose on the same day as soon as it is remembered; do not take 2 doses on the same day to make up for a missed dose.¹

• Risk of severe or life-threatening hepatotoxicity and importance of liver function test monitoring.¹ Importance of promptly informing clinician of signs and symptoms of severe liver damage (e.g., jaundice, nausea, vomiting, dark urine, changes in sleep pattern).¹

• Risk of infection.¹ Importance of promptly informing clinician of signs and symptoms of infection (e.g., fever, severe cough or sore throat, shortness of breath, burning or pain upon urination, unusual vaginal discharge or irritation).¹

• Risk of severe bleeding.¹ Importance of informing clinician of signs and symptoms of unusual bleeding (e.g., bruising, lightheadedness).¹

• Risk of palmar-plantar erythrodysesthesia (hand-foot syndrome) or rash.¹ Importance of informing clinician of skin changes (e.g., redness, pain, blisters, bleeding, swelling).¹

• Risk of hypertension developing or worsening during therapy.¹ Importance of regular monitoring of BP.¹ Importance of informing clinician of signs and symptoms of hypertension (e.g., severe headache, lightheadedness, neurologic symptoms).¹

• Risk of myocardial ischemia and infarction.¹ Importance of seeking immediate medical attention if chest pain, shortness of breath, dizziness, or feelings of faintness occur.¹

• Risk of RPLS.¹ Importance of immediately informing clinician if severe headache, seizure, confusion, or visual and neurologic disturbances occur.¹

• Risk of GI perforation.¹ Importance of promptly informing clinician if severe abdominal pain, persistent abdominal swelling, chills, nausea, vomiting, dehydration, or high fever occurs.¹

• Risk of wound healing complications.¹ Importance of informing clinician of any recent or scheduled surgery.¹

• Risk of fetal harm.¹ Necessity of advising women of childbearing potential and men who are partners of such women to use effective methods of contraception during therapy and for 2 months after drug discontinuance.¹ Importance of patients informing their clinicians if they or their partners are pregnant or think they may be pregnant.¹

• Importance of advising women to avoid breast-feeding while receiving regorafenib therapy and for 2 weeks after the final dose.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses (e.g., hypertension or other cardiovascular disease, hepatic disease, bleeding disorders).¹

• Importance of storing regorafenib tablets in the original container, tightly closed, with the desiccant; do not place tablets in daily or weekly pill boxes.¹ Discard any unused tablets 7 weeks after the container is first opened.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of regorafenib is restricted.²⁴ Regorafenib can only be obtained through designated specialty pharmacies.²⁴ Contact the manufacturer or consult the Stivarga website for specific information.²⁴

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