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Stivarga

Generic Name: Regorafenib
Class: Antineoplastic Agents
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 on Aug 6, 2018

Warning

    Hepatic Toxicity
  • Severe or fatal hepatotoxicity reported;1 2 evaluate hepatic function before and regularly during therapy.1 (See Hepatic Toxicity under Cautions.)

  • If hepatotoxicity occurs, interrupt therapy and then reduce dosage or permanently discontinue the drug depending on the severity and persistence of the toxicity.1 (See Hepatotoxicity under Dosage and Administration.)

Introduction

See also: Xeloda

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

Uses for Stivarga

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

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

Stivarga Dosage and Administration

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

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 (See Hepatotoxicity and also see Infectious Complications under Dosage and Administration.)

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
Recommended Dosage Modifications for Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome)

Toxicity

Occurrence

Recommended Dosage Modification

Grade 2

First occurrence (of any duration)

Reduce dosage to 120 mg daily1 13

No improvement within 7 days of initial dosage reduction or second occurrence

Interrupt therapy; when resuming therapy, further reduce dosage to 80 mg daily1 13

Third occurrence

If 80 mg daily is not tolerated, permanently discontinue therapy1 13

Grade 3

First occurrence

Interrupt therapy for ≥7 days; following recovery, may resume at reduced dosage of 120 mg daily1 13

Second occurrence

Interrupt therapy again for ≥7 days; following recovery, may resume at further reduced dosage of 80 mg daily1 13

Third occurrence

If 80 mg daily is not tolerated, permanently discontinue therapy1 13

Grade 4

See Grade 3 or 4 Toxicity under Dosage and Administration1 13

Hepatotoxicity
Recommended Dosage Modifications for Hepatotoxicity

Toxicity

Occurrence

Recommended Dosage Modification

Grade 3 (AST and/or ALT >5 times ULN but ≤20 times ULN)

First occurrence

Interrupt therapy; following recovery, may resume at reduced dosage of 120 mg daily only if potential benefits outweigh risk1 13

Recurrence

Permanently discontinue therapy1 13

Grade 4 (AST and/or ALT >20 times ULN)

Any occurrence

Permanently discontinue therapy1 13

Grade 2 or higher (AST and/or ALT >3 times ULN) with bilirubin >2 times ULN

Any occurrence

Permanently discontinue therapy1 13

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

Asian Patients

No initial dosage adjustment required.1 (See Hepatic Toxicity and also see Dermatologic Effects under Cautions.)

Cautions for Stivarga

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Warnings

Hepatic Toxicity

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 (See Hepatotoxicity under Dosage and Administration.)

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 (See Infectious Complications under Dosage and Administration.)

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 (See Specific Drugs and Foods under Interactions.)

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 (See Dosage Modification for Toxicity under Dosage and Administration.)

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 (See Dosage Modification for Toxicity under Dosage and Administration.)

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

Discontinue regorafenib in patients with wound dehiscence.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 (See Advice to Patients.)

Impairment of Fertility

Decreased fertility observed in male and female animals; may impair fertility in humans.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

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

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 (see Absorption: Special Populations, under Pharmacokinetics); 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 (Clcr 15–29 mL/minute).1

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

Common Adverse Effects

Patients receiving regorafenib for the treatment of metastatic colorectal cancer following failure of prior therapy: Asthenia/fatigue,1 2 6 pain,1 6 decreased appetite,1 2 6 palmar-plantar erythrodysesthesia (hand-foot syndrome),1 2 6 diarrhea,1 2 6 mucositis,1 2 6 weight loss,1 2 6 infection,1 dysphonia,1 2 6 hypertension,1 2 6 fever,1 2 rash,1 2 6 hemorrhage,1 headache,1 nausea,2 proteinuria,1 anemia,1 elevated concentrations of hepatic enzymes (e.g., AST, ALT),1 hypocalcemia,1 hypophosphatemia,1 lymphopenia,1 elevated concentrations of pancreatic enzymes (e.g., amylase, lipase),1 hyperbilirubinemia,1 thrombocytopenia,1 2 6 hyponatremia,1 hypokalemia,1 increased INR.1

Patients receiving regorafenib for the treatment of locally advanced, unresectable, or metastatic GIST following failure of prior therapy: Palmar-plantar erythrodysesthesia,1 3 4 pain,1 hypertension,1 3 4 asthenia/fatigue,1 3 4 diarrhea,1 3 4 mucositis,1 3 4 dysphonia,1 3 infection,1 decreased appetite,1 3 4 rash,1 3 alopecia,1 3 4 fever,1 nausea,1 3 4 hypothyroidism,1 vomiting,1 headache,1 4 muscle spasms,1 weight loss,1 hemorrhage,1 myalgia,3 4 constipation,3 hoarseness,3 4 proteinuria,1 elevated concentrations of hepatic enzymes (e.g., AST, ALT),1 hypophosphatemia,1 4 hyperbilirubinemia,1 lymphopenia,1 hypokalemia.1

Patients receiving regorafenib for the treatment of hepatocellular carcinoma following failure of prior therapy: Pain,1 palmar-plantar erythrodysesthesia,1 14 asthenia/fatigue,1 14 diarrhea,1 14 decreased appetite,1 14 hypertension,1 14 infection,1 fever,1 dysphonia,1 hemorrhage,1 nausea,1 14 mucositis,1 14 weight loss,1 vomiting,1 muscle spasms,1 elevated concentrations of hepatic enzymes (e.g., AST, ALT),1 hyperbilirubinemia,1 hypophosphatemia,1 lymphopenia,1 thrombocytopenia,1 proteinuria,1 increased INR,1 elevated concentrations of pancreatic enzymes (e.g., amylase, lipase),1 hypokalemia,1 hypocalcemia.1

Interactions for Stivarga

Metabolized mainly by CYP3A4 and UGT1A9.1 9 CYP3A4 mediates conversion of regorafenib to active M-2 metabolite; enzyme responsible for converting M-2 to active M-5 metabolite not determined to date.12

In vitro studies suggested inhibition of certain CYP isoenzymes by regorafenib (isoenzymes 2B6, 2C8, 2C9, 2C19, and 3A4) and its metabolites M-2 (isoenzymes 2C8, 2C9, 2D6, and 3A4) and M-5 (isoenzyme 2C8).1 In vitro studies also suggested that 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

In vitro data indicate regorafenib inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).12 In vitro studies also indicate 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 or UGT1A9 substrates: Possible increased systemic exposure to the UGT substrate.1 7 16

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Antifungals, azoles (e.g., itraconazole, ketoconazole, posaconazole, voriconazole)

Possible increased AUC of regorafenib, decreased AUC of M-2 and M-5, and increased regorafenib toxicity1

Ketoconazole: Increased AUC of regorafenib (by 33%) and decreased AUC of both M-2 and M-5 (by 93%)1 12

Avoid concomitant use1

Antimycobacterials, rifamycins (e.g., rifampin)

Possible decreased AUC of regorafenib, increased AUC of M-5, and reduced regorafenib efficacy1

Rifampin: Decreased AUC of regorafenib (by 50%) and increased AUC of M-5 (by 264%); no substantial effect on AUC of M-21 12

Avoid concomitant use1

Carbamazepine

Possible decreased AUC of regorafenib, increased AUC of M-5, and reduced regorafenib efficacy1

Avoid concomitant use1

Digoxin

No effect on digoxin pharmacokinetics16

Fluorouracil

No substantial effect on pharmacokinetics of fluorouracil7

Grapefruit or grapefruit juice

Possible increased AUC of regorafenib, decreased AUC of M-2 and M-5, and increased regorafenib toxicity1

Avoid concomitant use1

HMG CoA reductase inhibitors (statins) (e.g., atorvastatin, fluvastatin, rosuvastatin)

Possible increased exposure to statins1

Rosuvastatin: Peak plasma concentration and AUC of rosuvastatin increased by 4.6- and 3.8-fold, respectively1

Closely monitor for statin toxicity1

Irinotecan

Increased AUC of irinotecan (by 28%) and its active metabolite SN-38 (by 44%)1 7

Macrolides (clarithromycin, telithromycin)

Possible increased AUC of regorafenib, decreased AUC of M-2 and M-5, and increased regorafenib toxicity1

Avoid concomitant use1

Methotrexate

Possible increased methotrexate exposure1

Closely monitor for methotrexate toxicity1

Midazolam

No substantial effect on AUC of midazolam1

Nefazodone

Possible increased AUC of regorafenib, decreased AUC of M-2 and M-5, and increased regorafenib toxicity1

Avoid concomitant use1

Neomycin

No substantial effect on AUC of regorafenib; decreased AUC of M-2 and M-5 by 76 and 86%, respectively1 15

Omeprazole

No substantial effect on omeprazole concentration1

Oxaliplatin

Increased AUC of total platinum (by 39%) and unbound platinum (by 17%)7

Phenobarbital

Possible decreased AUC of regorafenib, increased AUC of M-5, and reduced regorafenib efficacy1

Avoid concomitant use1

Phenytoin

Possible decreased AUC of regorafenib, increased AUC of M-5, and reduced regorafenib efficacy1

Avoid concomitant use1

Rosiglitazone

No substantial effect on AUC of rosiglitazone1

St. John’s wort (Hypericum perforatum)

Possible decreased AUC of regorafenib, increased AUC of M-5, and reduced regorafenib efficacy1

Avoid concomitant use1

Warfarin

Increased risk of bleeding or INR elevations1

Increased AUC of warfarin (by 25%)1

Monitor INR more frequently1

Stivarga 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 (See Administration under Dosage and Administration.)

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 (Clcr 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 (may be exposed to 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.

Regorafenib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

40 mg

Stivarga

Bayer

AHFS DI Essentials™. © Copyright 2018, Selected Revisions August 6, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Bayer Healthcare. Stivarga (regorafenib) tablets prescribing information. Whippany, NJ; 2017 Apr.

2. Grothey A, Van Cutsem E, Sobrero A et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013; 381:303-12. http://www.ncbi.nlm.nih.gov/pubmed/23177514?dopt=AbstractPlus

3. Demetri GD, Reichardt P, Kang YK et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013; 381:295-302. http://www.ncbi.nlm.nih.gov/pubmed/23177515?dopt=AbstractPlus

4. George S, Wang Q, Heinrich MC et al. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. J Clin Oncol. 2012; 30:2401-7. http://www.ncbi.nlm.nih.gov/pubmed/22614970?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3675695&blobtype=pdf

5. Mross K, Frost A, Steinbild S et al. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res. 2012; 18:2658-67. http://www.ncbi.nlm.nih.gov/pubmed/22421192?dopt=AbstractPlus

6. Strumberg D, Scheulen ME, Schultheis B et al. Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study. Br J Cancer. 2012; 106:1722-7. http://www.ncbi.nlm.nih.gov/pubmed/22568966?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3364125&blobtype=pdf

7. Schultheis B, Folprecht G, Kuhlmann J et al. Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study. Ann Oncol. 2013; :. http://www.ncbi.nlm.nih.gov/pubmed/23493136?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3660081&blobtype=pdf

8. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2017 Jul 7. http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

9. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 203085Orig1s000: Summary review. From FDA website. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203085Orig1s000SumR.pdf

10. Wilhelm SM, Dumas J, Adnane L et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011; 129:245-55. http://www.ncbi.nlm.nih.gov/pubmed/21170960?dopt=AbstractPlus

11. Sunakawa Y, Furuse J, Okusaka T et al. Regorafenib in Japanese patients with solid tumors: phase I study of safety, efficacy, and pharmacokinetics. Invest New Drugs. 2013; :.

12. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 203085Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203085Orig1s000ClinPharmR.pdf

13. Bayer Healthcare. Stivarga (regorafenib) for professionals: Dosage and administration: Dose modifications. 2013 May. From Stivarga website. http://www.stivarga-us.com/hcp/mcrc/dosing_modifications.html

14. Bruix J, Qin S, Merle P et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017; 389:56-66. http://www.ncbi.nlm.nih.gov/pubmed/27932229?dopt=AbstractPlus

15. Bayer Healthcare. Clinical Study Synopsis. 2015 Mar 18. From Bayer AG website. http://trialfinder.bayerscheringpharma.de/html/pdf/16675_Study_Synopsis_CTP.pdf

16. Bayer PLC. Stivarga 40 mg film-coated tablets summary of product characteristics. Reading, England; 2017 Aug.

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