Regorafenib

STIVARGA is a kinase inhibitor indicated for the treatment of adult patients with: • Metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy. • Locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. • Hepatocellular carcinoma (HCC) who have been previously treated with sorafenib

Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, metastasis and tumor immunity. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, Abl and CSF1R at concentrations of regorafenib that have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model and inhibition of tumor growth in several mouse xenograft models including some for human colorectal carcinoma, gastrointestinal stromal and hepatocellular carcinoma.

• Recommended dose: 160 mg orally, once daily for the first 21 days of each 28-day cycle. • Take STIVARGA after a low-fat meal.

None. None.

Boxed warning (hepatotoxicity •): Severe and sometimes fatal hepatotoxicity has occurred in clinical trials. • Monitor hepatic function prior to and during treatment. • Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence. • Hepatotoxicity: Monitor liver function tests. Withhold and then reduce or discontinue STIVARGA based on severity and duration. • Infections: Withhold STIVARGA in patients with worsening or severe infections. • Hemorrhage: Permanently discontinue STIVARGA for severe or life-threatening hemorrhage. • Gastrointestinal perforation or fistula: Discontinue STIVARGA. • Dermatologic toxicity: Withhold and then reduce or discontinue STIVARGA depending on severity and persistence of dermatologic toxicity.

The following serious adverse reactions are discussed elsewhere in the labeling: • Hepatotoxicity • Infections • Hemorrhage • Gastrointestinal Perforation or Fistula • Dermatological Toxicity • Hypertension • Cardiac Ischemia and Infarction • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) The most common adverse reactions (≥20%) are pain (including gastrointestinal and abdominal pain), HFSR, asthenia/fatigue, diarrhea, decreased appetite/food intake, hypertension, infection, dysphonia, hyperbilirubinemia, fever, mucositis, weight loss, rash, and nausea.

• Strong CYP3A4 inducers: Avoid strong CYP3A4 inducers. • Strong CYP3A4 inhibitors: Avoid strong CYP3A4 inhibitors. • BCRP substrates: Monitor patients closely for symptoms of increased exposure to BCRP substrates.

Store STIVARGA at 25°C (77°F), excursions are permitted from 15 to 30°C (59 to 86°F). Store tablets in the original bottle and do not remove the desiccant.