• Metastatic colorectal cancer 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 in patients who have previously been treated with imatinib and sunitinib.
• Hepatocellular carcinoma in patients who have previously been treated with sorafenib.

Contraindicated in:

• Severe hepatic impairment
• OB: Pregnancy
• Lactation: Lactation.

Use Cautiously in:

• History of hypertension or 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)
• Women of reproductive potential and men with female partners of reproductive potential
• Pedi: Safety and effectiveness not established in children.

CV: hypertension, MYOCARDIAL ISCHEMIA/INFARCTION.

Derm: alopecia, ERYTHEMA MULTIFORME, impaired wound healing, PALMAR-PLANTAR ERYTHRODYSESTHESIA, rash, STEVENS-JOHNSON SYNDROME (SJS), TOXIC EPIDERMAL NECROLYSIS (TEN).

EENT: dysphonia.

Endo: hypothyroidism.

F and E: hypocalcemia, hypokalemia, hypophosphatemia, hyponatremia.

GI: ↓appetite, ↓weight, ↑lipase, diarrhea, mucositis, ↑ amylase, ↑ liver enzymes, dry mouth, GI FISTULA/PERFORATION, HEPATOTOXICITY, reflux.

GU: proteinuria, ↓ fertility.

Hemat: anemia, bleeding, lymphopenia, thrombocytopenia.

MS: pain, musculoskeletal stiffness.

Neuro: fatigue, dysgeusia, headache, POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES), tremor.
Misc: fever, infection.

Drug-Drug:

• Strong CYP3A4 inhibitors, including clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole, ↑ levels and the risk of toxicity, avoid concurrent use.
• Strong CYP3A4 inducers, 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.

Drug-Natural Products:

• St. John's wort↓ levels and effectiveness; avoid concurrent use.

Drug-Food:

• Grapefruit juice↑ levels and the risk of toxicity; avoid concurrent use.

• Tablets: 40 mg;

• PO (Adults): 160 mg daily on days 1–21 of a 28-day cycle. Continue until disease progression or unacceptable toxicity.

Stivarga

• Inhibits kinases, which are responsible for many phases of cell function and proliferation.

• Decreased progression of hepatocellular carcinoma and metastatic colorectal cancer with improved survival.
• Decreased progression of gastrointestinal stromal tumor.

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

Absorption: Well absorbed following oral administration (69–83%).

Distribution: Unknown.

Protein Binding: Regorafenib: >99.5%, M-2 metabolite: 99.8%, M-5 metabolite: 99.95%.

Metabolism/Excretion: Primarily metabolized by the liver via the CYP3A4 isoenzyme and UGT1A9; 2 metabolites (M-2 and M-5) have antineoplastic activity. Undergoes enterohepatic circulation. 47% excreted in feces as parent compound, 24% as metabolites; 19% excreted in urine (mostly as inactive metabolites).

Half-life: Regorafenib: 28 hr, M-2 metabolite: 25 hr, M-5 metabolite: 51 hr.

(improved survival)

• 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 read Patient Information before starting therapy and with each Rx refill in case of changes.
• 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 PRES (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.
• May cause fetal harm. Advise women of 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 breastfeeding during therapy.
• Emphasize importance of monitoring lab values to monitor for adverse reactions.

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