Regorafenib

Based on its mechanism of action, can cause fetal harm

There are no adequate and well-controlled studies in pregnant women; embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations

Lactation: Unknown whether distributed in breast milk; decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Mechanism of Action

Tyrosine kinase inhibitor; shown to inhibit activity of membrane-bound and intracellular kinases involved in normal cellular functions and in pathological processes (eg, oncogenesis, tumor angiogenesis) RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl

Absorption

Bioavailability: 69-83% (with low fat meal)

Peak Plasma Time: 4 hr

Peak Plasma Concentration: 2.5 mcg/mL (single dose); 3.9 mcg/mL (steady-state)

AUC: 70.4 mcg•h/mL (single dose); 58.3 mcg•h/mL (steady-state)

Distribution

Protein Bound: 99.5% (regorafenib); 99.8% (M-2 active metabolite); 99.95% (M-5 active metabolite)

Undergoes enterohepatic circulation with multiple plasma concentration peaks observed during 24-hr interval

Metabolism

Metabolized by CYP3A4 and UGT1A9

Metabolites (active): M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), both of them having similar in vitro pharmacological activity and steady-state concentrations as regorafenib

Elimination

Half-life: 28 hr (regorafenib); 25 hr (M-2 active metabolite); 51 hr (M-5 active metabolite)

Excretion: 71% feces; 19% urine (within 12 days of single dose)

Regorafenib is a cancer medication that interferes with the growth and spread of cancer cells in the body.

Regorafenib is used to treat colorectal cancer. It is also used to treat a rare type of tumor that can affect the esophagus, stomach, or intestines.

Regorafenib is usually given after other cancer medications have been tried without success.

Regorafenib may also be used for purposes not listed in this medication guide.

You should not use regorafenib if past use has caused severe bleeding or severe liver problems.

Regorafenib can harm your liver. Stop taking this medicine and call your doctor at once if you have nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

You should not use regorafenib if past use has caused severe bleeding or severe liver problems.

To make sure regorafenib is safe for you, tell your doctor if you have:

• liver disease;
• heart disease, high blood pressure;
• bleeding or blood clotting disorder such as hemophilia;
• a history of recent heart attack or stroke (including "mini-stroke"); or
• if you have recently had surgery.

Do not use regorafenib if you are pregnant. It could harm the unborn baby.

Use birth control to prevent pregnancy while you are receiving regorafenib, whether you are a man or a woman. Tell your doctor right away if a pregnancy occurs while either parent is taking regorafenib. Keep using birth control for at least 2 months after your treatment ends.

It is not known whether regorafenib passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Regorafenib is a prescription medication used to treat colon or rectal cancer that has spread (metastasized) in adults. It is also used to treat a type of tumor that occurs in the stomach or small intestine and is approved to treat a type of liver cancer called hepatocellular carcinoma (HCC). 

Regorafenib belongs to a group of drugs called kinase inhibitors, which prevent the growth and spread of cancer cells by blocking certain enzymes.

This medication comes in tablet form and is taken once a day for 3 weeks, then stopped for 1 week.  This cycle is then repeated throughout treatment. Regorafenib should be taken with a low-fat breakfast.

Common side effects include tiredness, weakness, loss of appetite, and diarrhea. 

Regorafenib is a prescription medicine used to treat people with colon or rectal cancer that has spread to other parts of the body and for which they have received previous treatment with certain chemotherapy medicines.

Regorafenib is also used to treat advanced gastrointestinal stromal tumors (GIST) that cannot be surgically removed, or has spread to other parts of the body, and no longer respond to other treatments.

This medication is also approved to treat a type of liver cancer called hepatocellular carcinoma (HCC) in adults who have been previously treated with sorafenib. 

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Regorafenib falls into category D. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Females and males should use effective birth control during treatment with regorafenib and for 2 months after your last dose of regorafenib. Tell your healthcare provider right away if you or your partner becomes pregnant either while taking regorafenib or within 2 months after your last dose of regorafenib.

If you take too much regorafenib call your healthcare provider or go to the nearest emergency room right away.

Store regorafenib tablets at room temperature between 68° F to 77° F (20° C to 25° C).

• Keep regorafenib in the bottle that it comes in. Do not put regorafenib tablets in a daily or weekly pill box.
• The regorafenib bottle contains a desiccant to help keep your medicine dry. Keep the desiccant in the bottle. 
• Keep the bottle of regorafenib tightly closed.
• Safely throw away (discard) any unused regorafenib tablets after 28 days of opening the bottle.

You should not use regorafenib if past use has caused severe bleeding or severe liver problems.

To make sure regorafenib is safe for you, tell your doctor if you have ever had:

• liver disease;

• high blood pressure;

• a bleeding or blood clotting disorder;

• heart disease, chest pain; or

• if you recently had surgery or plan to have surgery.

Do not use regorafenib if you are pregnant. It could harm the unborn baby.

Use birth control to prevent pregnancy while you are receiving regorafenib, whether you are a man or a woman. Tell your doctor right away if a pregnancy occurs while either parent is taking regorafenib. Keep using birth control for at least 2 months after your treatment ends.

It is not known whether regorafenib passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Usual Adult Dose for Colorectal Cancer:

160 mg orally once a day for the first 21 days of each 28-day cycle
-Lowest Dose: 80 mg per day
-Duration of Therapy: Until disease progression or unacceptable toxicity

Uses: Treatment of:
-Metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and an anti-EGFR therapy if RAS wild-type.
-Locally advanced, unresectable or metastatic gastrointestinal stromal tumor previously treated with imatinib mesylate and sunitinib malate.
-Hepatocellular carcinoma previously treated with sorafenib.

Usual Adult Dose for Gastrointestinal Stromal Tumor:

160 mg orally once a day for the first 21 days of each 28-day cycle
-Lowest Dose: 80 mg per day
-Duration of Therapy: Until disease progression or unacceptable toxicity

Uses: Treatment of:
-Metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and an anti-EGFR therapy if RAS wild-type.
-Locally advanced, unresectable or metastatic gastrointestinal stromal tumor previously treated with imatinib mesylate and sunitinib malate.
-Hepatocellular carcinoma previously treated with sorafenib.

Usual Adult Dose for Hepatocellular Carcinoma:

160 mg orally once a day for the first 21 days of each 28-day cycle
-Lowest Dose: 80 mg per day
-Duration of Therapy: Until disease progression or unacceptable toxicity

Uses: Treatment of:
-Metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and an anti-EGFR therapy if RAS wild-type.
-Locally advanced, unresectable or metastatic gastrointestinal stromal tumor previously treated with imatinib mesylate and sunitinib malate.
-Hepatocellular carcinoma previously treated with sorafenib.

Sometimes it is not safe to use certain medications at the same time. Some drugs can affect your blood levels of other drugs you take, which may increase side effects or make the medications less effective.

Many drugs can interact with regorafenib. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Tell your doctor about all your current medicines and any you start or stop using.

Contraindications

• Manufacturer states none known.1

Warnings/Precautions

Warnings

Fatal hepatotoxicity, with biopsy findings of hepatocyte necrosis and lymphocyte infiltration, reported.1 2

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

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.)

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

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.)

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 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

RPLS reported in 1 of 1200 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

GI perforation and fistula formation (including 4 deaths) reported in 0.6% of 1200 regorafenib-treated patients in clinical trials.1

Discontinue therapy if GI perforation or fistula formation occurs.1

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

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.)

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

Specific Populations

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or drug.1

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

No overall differences in safety and efficacy relative to younger adults.1

Systemic exposure not affected by mild or moderate hepatic impairment (Child-Pugh class A or B); however, monitor closely for adverse effects.1

Not studied and not recommended in patients with severe hepatic impairment (Child-Pugh class C).1

Systemic exposure not affected by mild renal impairment (Clcr 60–89 mL/minute).1

Limited data in patients with moderate renal impairment (Clcr 30–59 mL/minute).1

Not studied in patients with severe renal impairment or end-stage renal disease.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 fever,1 2 decreased appetite,1 2 6 nausea,2 palmar-plantar erythrodysesthesia (hand-foot syndrome),1 2 6 rash,1 2 6 diarrhea,1 2 6 mucositis,1 2 6 weight loss,1 2 6 infection,1 hypertension,1 2 6 hemorrhage,1 dysphonia,1 2 6 headache,1 anemia,1 thrombocytopenia,1 2 6 lymphopenia,1 hypocalcemia,1 hypokalemia,1 hyponatremia,1 hypophosphatemia,1 elevated concentrations of pancreatic enzymes (e.g., amylase, lipase),1 proteinuria,1 hyperbilirubinemia,1 elevated concentrations of hepatic enzymes (e.g., AST, ALT),1 increased INR.1

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

• 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).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

In the U.S.

• Stivarga

Available Dosage Forms:

• Tablet

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Stivarga: 40 mg [contains soybean lecithin]

If dose reduction is necessary, reduce in 40 mg increments; the lowest recommended dose is 80 mg/day.

Dermatologic:

Grade 2 hand-foot skin reaction (HFSR; palmar-plantar erythrodysesthesia syndrome [PPES]) of any duration: Reduce dose to 120 mg once daily for first occurrence. If grade 2 HFSR recurs at this dose, further reduce the dose to 80 mg once daily. Interrupt therapy for grade 2 HFSR that is recurrent or fails to improve within 7 days in spite of dosage reduction.

Grade 3 HFSR: Interrupt therapy for a minimum of 7 days. Upon recovery, reduce dose to 120 mg once daily. If grade 2 to 3 toxicity recurs at this dose, further reduce dose to 80 mg once daily upon recovery. Interrupt therapy for grade 2 to 3 HFSR that is recurrent or fails to improve within 7 days in spite of dosage reduction.

Recurrent or persistent HFSR at 80 mg once daily: Discontinue treatment.

Other dermatologic toxicity: Withhold treatment, reduce dose or permanently discontinue treatment depending on the severity and persistence of the dermatologic toxicity. Symptomatic relief may be managed with supportive measures.

Hypertension: Grade 2 (symptomatic): Interrupt therapy.

Infection: Grade 3 or 4 (or worsening infection of any grade): Interrupt therapy; resume regorafenib at the same dose following infection resolution.

Other toxicity: Any grade 3 or 4 adverse reaction (other than hepatotoxicity or infection): Interrupt therapy; upon recovery, reduce dose to 120 mg once daily (except infection). If any grade 3 or 4 adverse reaction occurs (other than hepatotoxicity or infection) while on this reduced dose, may further reduce dose to 80 mg once daily upon recovery. For any grade 4 adverse reaction, only resume therapy if the benefit outweighs the risk. Permanently discontinue therapy if unable to tolerate 80 mg once daily.

Gastrointestinal perforation/fistula: Discontinue permanently.

Hemorrhage (severe or life-threatening): Discontinue permanently.

Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue.

Wound dehiscence: Discontinue.

Oral: Take at the same time each day. Swallow tablet whole with water after a low-fat meal (containing <600 calories and <30% fat).

Avoid grapefruit juice.

Obtain liver function tests at baseline, every 2 weeks during the first 2 months of treatment, then monthly or more frequently if clinically necessary (weekly until improvement if liver function tests are elevated). CBC with differential and platelets and serum electrolytes (baseline and periodic). Monitor INR more frequently if receiving warfarin. Monitor blood pressure weekly for the first 6 weeks of therapy and with every subsequent cycle, or more frequently if indicated. Monitor for hand-foot skin reaction (HFSR)/palmar-plantar erythrodysesthesia syndrome (PPES); it is recommended to monitor for signs of HFSR during the first weeks of treatment, then every 1 to 2 weeks for 2 cycles, then every 4 to 6 weeks thereafter (McLellan 2015). Monitor for signs/symptoms of cardiac ischemia or infarction, bleeding, GI perforation or fistula, infection, and reversible posterior leukoencephalopathy syndrome (severe headaches, seizure, confusion, or change in vision). Monitor for impaired wound healing.

160 mg orally once a day for the first 21 days of each 28-day cycle
-Lowest Dose: 80 mg per day
-Duration of Therapy: Until disease progression or unacceptable toxicity

Uses: Treatment of:
-Metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and an anti-EGFR therapy if RAS wild-type.
-Locally advanced, unresectable or metastatic gastrointestinal stromal tumor previously treated with imatinib mesylate and sunitinib malate.
-Hepatocellular carcinoma previously treated with sorafenib.