- Metastatic colorectal cancer (CRC) that has failed previous treatment that included a fluoropyrimidine, oxaliplatin, irinotecan, an anti-VEGF therapy, and additional anti-EGFR therapy if tumor is of the RAS wild type.
- Locally advanced, unresectable, or metastatic gastrointestinal stromal tumor (GIST) in patients who have previously been treated with imatinib and sunitinib.
- Hepatocellular carcinoma (HCC) in patients who have previously been treated with sorafenib.
Inhibits kinases, which are responsible for many phases of cell function and proliferation.
- Decreased progression of HCC and metastatic CRC with improved survival.
- Decreased progression of GIST
Absorption: Well absorbed following oral administration (69–83%).
Protein Binding: Regorafenib–>99.5%, M-2 metabolite–99.8%, M-5 metabolite–99.95%.
Metabolism and Excretion: Highly metabolized (by CYP3A4 and UGT1A9), 2 metabolites (M-2 and M-5) have antineoplastic activity. Undergoes enterohepatic circulation.
Half-life: Regorafenib–28 hr (range 14–58 hr), M-2 metabolite–25 hr (range 14–32 hr), M-5 metabolite–51 hr (range 32–70 hr). 47% excreted in feces as parent compound, 24% as metabolites; 19% excreted in urine (mostly as inactive metabolites).
TIME/ACTION PROFILE (improved survival)
|PO||3 mo||3 mo||up to 10 mo|
- Avoid strong inducers/inhibitors of CYP3A4;
- OB: May cause fetal harm;
- Lactation: Breast feeding should be avoided;
- Severe hepatic impairment (Child-Pugh Class C).
Use Cautiously in:
- History of hypertension/cardiovascular disease (BP should be controlled prior to treatment);
- Elective surgical procedures (discontinue 2 wk prior to surgery);
- Asian patients (↑ risk of palmar-plantar erythrodysesthesia);
- Rep: Women of reproductive potential and men with female partners or reproductive potential;
- Pedi: Safety and effectiveness not established.
Adverse Reactions/Side Effects
CNS: REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY, fatigue, headache
CV: HYPERTENSION, MYOCARDIAL ISCHEMIA/INFARCTION
GI: GASTROINTESTINAL FISTULA/PERFORATION, HEPATOTOXICITY, ↓ appetite, diarrhea, mucositis, altered taste, dry mouth, gastrointestinal reflux, ↑ transaminases
Derm: ERYTHEMA MULTIFORME, PALMAR-PLANTAR ERYTHRODYSESTHESIA, STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, alopecia, impaired wound healing, rash
F and E: hypocalcemia, hypokalemia, hypophosphatemia, hyponatremia
GU: proteinuria, ↓ fertility
Hemat: BLEEDING, THROMBOCYTOPENIA, anemia, lymphopenia
Metabolic: weight loss, ↑ lipase, ↑ amylase
MS: pain, musculoskeletal stiffness
Misc: HYPERSENSITIVITY REACTIONS, INFECTION, fever
* CAPITALS indicate life-threatening.
Underline indicate most frequent.
- Strong inhibitors of CYP3A4 including clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole ↑ levels and the risk of toxicity, avoid concurrent use.
- Strong inducers of CYP3A4 including carbamazepine, phenobarbital, phenytoin, and rifampin ↓ levels and effectiveness, avoid concurrent use.
- May ↑ risk of bleeding with warfarin.
- May ↑ levels and risk of toxicity of breast cancer resistance protein (BCRP) substrates, including methotrexate, fluvastatin, or atorvastatin.
St. John's wort ↓ blood levels and effectiveness, avoid concurrent use.
Grapefruit juice ↑ blood levels and the risk of toxicity, avoid concurrent use.
PO: (Adults) 160 mg daily on days 1–21 of a 28-day cycle. Continue treatment until disease progression or unacceptable toxicity.
Tablets: 40 mg
- Monitor BP prior to and weekly during the first 6 wk, then every cycle of therapy. Do not initiate regorafenib until BP is well controlled.
- Assess for cardiac ischemia or infarction during therapy.
- Assess for bleeding during therapy. Interrupt therapy if severe hemorrhage occurs.
- Assess for rash periodically during therapy. May cause Stevens-Johnson syndrome or Toxic Epidermal Necrolysis. Discontinue therapy if severe or if accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.
Lab Test Considerations:
Obtain liver function test (ALT, AST, bilirubin) before starting, at least every 2 wk during first 2 mo of therapy, and monthly thereafter. Monitor liver function tests weekly in patients with ↑ liver function tests until improvement to <3 × the upper limit of normal or baseline.
- May cause anemia, thrombocytopenia, neutropenia, and lymphopenia.
- May cause hypocalcemia, hypokalemia, hyponatremia, and hypophosphatemia.
- May cause proteinuria, ↑ serum lipase, and ↑ serum amylase.
- May cause ↑ INR. Monitor INR levels more frequently in patients receiving warfarin.
- Risk for impaired skin integrity
- Deficient knowledge, related to medication regimen (Patient/Family/Teaching)
- High Alert: Fatalities have occurred with incorrect administration of chemotherapeutic agents. Before administering, clarify all ambiguous orders; double check single, daily, and course-of-therapy dose limits; have second practitioner independently double check original order and dose calculations. Therapy should be initiated by physician experienced in the treatment of patients with colorectal cancer.
- PO: Administer four 40 mg tablets once daily at same time of day with a whole glass of water for the first 21 days of the of each 28-day cycle. Swallow tablets whole with a low-fat meal that contains <30% fat and <600 calories.
- Interrupt therapy for Grade 2 hand-foot skin reaction (HFSR) that is recurrent or does not improve in 7 days despite dose reduction; interrupt therapy for a minimum of 7 days for Grade 3 (HFSR), symptomatic Grade 2 hypertension, any Grade 3 or 4 adverse reactions.
- Reduce dose to 120 mg daily for first occurrence of Grade 2 HFSR of any duration, after first recovery of any Grade 3 or 4 adverse reaction, for Grade 3 ↑ AST or ALT; only resume if potential benefit outweighs risk of hepatotoxicity.
- Reduce dose to 80 mg daily for re-occurrence of Grade 2 HFSR at 120 mg dose, after recovery of any Grade 3 or 4 adverse reaction at 120 mg dose (except hepatotoxicity).
- Discontinue regorafenib permanently for failure to tolerate 80 mg dose, any occurrence of ↑ AST or ALT >20 × upper limit of normal, any occurrence of ↑ AST or ALT >3 × upper limit of normal with concurrent bilirubin >2 × upper limit of normal, re-occurrence of ↑ AST or ALT >5 × upper limit of normal despite reduction to 120 mg dose, any Grade 4 adverse reaction; only resume if the potential benefits outweigh the risks.
- Instruct patient to take tablets at the same time each day with a low-fat meal. Take missed doses on the same day as soon as remembered; do not take 2 doses on the same day to make up for a missed dose. Store medicine in original container; do not place in daily or weekly pill boxes. Discard remaining tablets 28 days after opening bottle. Tightly close bottle after each opening and keep desiccant in bottle.
- Advise patient to avoid drinking grapefruit juice or eating grapefruit during regorafenib therapy.
- Advise patient to notify health care professional immediately if signs and symptoms of liver problems (yellowing of skin or white part of eyes, nausea, vomiting, dark tea-colored urine, change in sleep pattern), bleeding, skin changes (redness, pain, blisters, bleeding, swelling), hypertension (severe headache, lightheadedness, neurologic symptoms), myocardial ischemia or infarction (chest pain, shortness of breath, dizziness, fainting), or GI perforation or fistula (severe abdominal pain, persistent swelling of abdomen, high fever, chills, nausea, vomiting, severe diarrhea, dehydration) occur.
- Advise patient to notify health care provider of therapy prior to surgery or if had recent surgery.
- Advise patient to maintain adequate hydration to minimize risk and to notify health care professional promptly if signs and symptoms of reversible posterior leukoencephalopathy syndrome (RPLS) (headache, seizures, weakness, confusion, high BP, blindness or change in vision, problems thinking) occur.
- Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's wort.
- Rep: Inform female patient that regorafenib can cause fetal harm. Advise women with reproductive potential and men of the need for effective contraception during and for at least 2 mo after completion of therapy. Notify health care provider immediately if pregnancy is planned or suspected and to avoid breast feeding during and for at least 2 wks after final dose.
- Emphasize importance of monitoring lab values to monitor for adverse reactions.
- Decreased progression of HCC and metastatic CRC.
- Decreased progression of GIST
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