Regorafenib

Regorafenib is used for: Colorectal cancer, Gastrointestinal stromal tumours, Hepatocellular Carcinoma Regorafenib is indicated as monotherapy for the treatment of adult patients with 1. Metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy 2. Unresectable or metastatic gastrointestinal stromal tumours (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib 3.Hepatocellular carcinoma (HCC) who have been previously treated with sorafenib

Oral Metastatic colorectal cancer, Unresectable, metastatic malignant gastrointestinal stromal tumours, hepatocellular Carcinoma Adult: In patients who have been previously treated w/ or are not candidates for available therapies: 160 mg once daily for 21 days of each 28-day cycle. Continue treatment until disease progression or if unacceptable toxicity occurs. Hepatic Impairment Mild (total bilirubin ?ULN and AST>ULN, or total bilirubin >ULN to ?1.5x ULN) or moderate (total bilirubin >1.5 to ?3x ULN and any AST): No dosage adjustment necessary Severe (total bilirubin >3x ULN): Not recommended; not studied

Renal Impairment Mild-to-severe: No dosage adjustment necessary Patients on dialysis: Not studied

Should be taken with food. Take at the same time each day w/ a low-fat meal (<30% fat).

Hypersensitivity to the active substance or to any of the excipients used

Hepatotoxicity Severe and sometimes fatal hepatotoxicity observed in clinical trials Monitor hepatic function prior to and during treatment Interrupt and then reduce or discontinue for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence Increases risk for hemorrhage; discontinue therapy for severe or life-threatening hemorrhage Increased risk of infections reported; most common infections include urinary tract infections, nasopharyngitis, mucocutaneous and systemic fungal infections and pneumonia Increases risk for HFSR/PPES and rash; a higher incidence of HFSR reported in Asian patients; interrupt and then reduce or discontinue regorafenib depending on severity and persistence of dermatologic toxicity Hypertension may occur, typically during the first treatment cycle; do not initiate therapy unless blood pressure is adequately controlled; monitor blood pressure weekly for first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated; temporarily or permanently withhold therapy for severe or uncontrolled hypertension Myocardial ischemia and infarction observed in clinical trials; withhold regorafenib for new or acute cardiac ischemia/infarction and resume only after resolution of acute ischemic events

Pregnancy Based on animal studies and mechanism of action, fetal harm may occur when administered to a pregnant woman There are no available data on use in pregnant women Advise pregnant women of the potential hazard to a fetus Animal data Administration of regorafenib was 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 Contraception Females: Use effective contraception during treatment and for 2 months following the final dose Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 2 months following final dose Infertility There are no data on the effect on human fertility Results from animal studies indicate that regorafenib can impair male and female fertility Lactation There are no data on the presence of regorafenib or its metabolites in human milk, the effects of regorafenib on the breastfed infant, or on milk production In rats, regorafenib and its metabolites are excreted in milk Because of the potential for serious adverse reactions in breastfed infants from regorafenib, do not breastfeed during treatment and for 2 weeks after the final dose

Strong CYP3A4 inhibitors Coadministration with strong CYP3A4 inhibitors increases regorafenib plasma concentrations, decreased active metabolite (M-2 and M-5) plasma concentrations, and may increase toxicity Avoid concomitant use of regorafenib with strong CYP3A4 inhibitors (eg, clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole) Breast cancer resistance protein (BCRP) substrates Coadministration with a BCRP substrate increases the BCRP substrate plasma concentrations Closely monitor for signs and symptoms of exposure-related toxicity of the BCRP substrate (eg, methotrexate, fluvastatin, atorvastatin) Consult the concomitant BCRP substrate product information when considering administration of regorafenib UGT substrates Regorafenib competitively inhibits UGT1A9 and UGT1A1 substrates

Side effects of Regorafenib : >10% (Colorectal Cancer) Anemia (79%) Increased AST (65%) Asthenia (64%) Proteinuria (60%) Hypocalcemia (59%) Hypophosphatemia (57%) Lymphopenia (54%) Decreased appetite and food intake (47%) Increased lipase (46%) HFSR/PPES (45%) Hyperbilirubinemia (45%) Increased ALT (45%) Diarrhea (43%) Thrombocytopenia (41%) Mucositis (33%) Weight loss (32%) Infection (31%) Hypophosphatemia, Grade 3 or 4 (31%) Hypertension (30%) Dysphonia (30%) Hyponatremia (30%) Pain (29%) Fever (28%) Rash (26%) Hypokalemia (26%) Increased amylase (26%) Increased INR (24%) Hemorrhage (21%) Nausea (20%) HFSR/PPES, Grade 3 or 4 (17%) Asthenia/fatigue, Grade 3 or 4 (15%) >10% (GIST) HFSR/PPES (67%) Pain (60%) Hypertension (59%) Proteinuria (59%) Increased AST (58%) Hypophosphatemia (55%) Asthenia (52%) Diarrhea (47%) Mucositis (40%) Dysphonia (39%) Increased ALT (39%) Hyperbilirubinemia (33%) Infection (32%) Decreased appetite and food intake (31%) Rash (30%) Lymphopenia (30%) Alopecia (24%) ever (21%) HFSR/PPES, Grade 3 or 4 (22%) Hypokalemia (21%) Nausea (20%) Hypophosphatemia, Grade 3 or 4 (20%) Hypothyroidism (18%) Vomiting (17%) Hypocalcemia (17%) Headache (16%) Neutropenia (16%) Weight loss (14%) Increased lipase (14%) Muscle spasms (14%) Thrombocytopenia (13%) Hemorrhage (11%) >10% (HCC) Increased AST (93%) Hyperbilirubinemia (78%) Hypophosphatemia (70%) Increased ALT (70%) Lymphopenia (68%) Thrombocytopenia (63%) Pain (55%) Proteinuria (51%) HFSR/PPES (51%) Increased INR (44%) Asthenia/fatigue (42%) Diarrhea (41%) Increased lipase (41%) Hypophosphatemia, Grade 3 or 4 (31%) Hypertension (31%) Infection (31%) Hypokalemia (31%) Decreased appetite and food intake (31%) Hypocalcemia (23%) Increased amylase (23%) Fever (20%) Hypothyroidism (18%) Hemorrhage (18%) Dysphonia (18%) Nausea (17%) Hypocalcemia (17%) Proteinuria, Grade 3 or 4 (17%) Headache (16%) Hypertension, Grade 3 or 4 (15%) Neutropenia (14%) Mucositis (13%) Vomiting (13%) Weight loss (13%) Hyperbilirubinemia, Grade 3 or 4 (13%) HFSR/PPES, Grade 3 or 4 (12%) Increased lipase, Grade 3 or 4 (11%) 1-10% (Colorectal Cancer) Headache (10%) Hyperbilirubinemia, Grade 3 or 4 (10%) Pain, Grade 3 or 4 (9%) Infection, Grade 3 or 4 (9%) Increased lipase, Grade 3 or 4 (9%) Lymphopenia, Grade 3 or 4 (9%) Hypertension, Grade 3 or 4 (8%) Diarrhea, Grade 3 or 4 (8%) Hypokalemia, Grade 3 or 4 (7%) Musculoskeletal stiffness (6%) Rash, Grade 3 or 4 (6%) Decreased appetite and food intake, Grade 3 or 4 (5%) Anemia, Grade 3 or 4 (5%) Increased AST/ALT, Grade 3 or 4 (6%) Mucositis, Grade 3 or 4 (4%) Hypokalemia, Grade 3 or 4 (4%) Neutropenia (3%) Tremor (2%) Hemorrhage, Grade 3 or 4 (2%) Fever, Grade 3 or 4 (2%) Proteinuria, Grade 3 or 4 (2%) Increased amylase, Grade 3 or 4 (2%) Neutropenia, Grade 3 or 4 (1%) Hypocalcemia, Grade 3 or 4 (1%) 1-10% (GIST) Lymphopenia, Grade 3 or 4 (8%) Pain, Grade 3 or 4 (8%) Diarrhea, Grade 3 or 4 (8%) Rash, Grade 3 or 4 (8%) Infection, Grade 3 or 4 (5%) Asthenia/fatigue, Grade 3 or 4 (4%) Hemorrhage, Grade 3 or 4 (4%) Increased AST/ALT, Grade 3 or 4 (3-4%) Hyperbilirubinemia, Grade 3 or 4 (3%) Proteinuria, Grade 3 or 4 (3%) Hypokalemia, Grade 3 or 4 (3%) Neutropenia, Grade 3 or 4 (2%) Mucositis, Grade 3 or 4 (2%) Nausea, Grade 3 or 4 (2%) Hypocalcemia, Grade 3 or 4 (2%) Thrombocytopenia, Grade 3 or 4 (1%) 1-10% (HCC) Muscle spasms (10%) Asthenia/fatigue, Grade 3 or 4 (10%) Infection, Grade 3 or 4 (8%) Increased ALT, Grade 3 or 4 (6%) Hemorrhage, Grade 3 or 4 (5%) Thrombocytopenia, Grade 3 or 4 (5%) Neutropenia, Grade 3 or 4 (4%) Diarrhea, Grade 3 or 4 (3%) Diarrhea, Grade 3 or 4 (3%) Decreased appetite or food intake (3%) Weight loss (2%) Mucositis, Grade 3 or 4 (1%) Potentially Fatal: Hepatotoxicity, haemorrhage, GI perforation or fistula.

Regorafenib, a tyrosine kinase inhibitor, potently blocks multiple protein kinase, including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E), and maintenance of the tumour microenvironment (PDGFR, FGFR).