Regorafenib

Colorectal Cancer: Regorafenib is indicated for the treatment of 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.

Gastrointestinal Stromal Tumors: Regorafenib is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.

Hepatocellular Carcinoma: Regorafenib is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

Targeted Cancer Therapy

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. Regorafenib also demonstrated anti-metastatic activity in a mouse xenograft model and two mouse orthotopic models of human colorectal carcinoma.

Recommended Dose: The recommended dose is 160 mg Regorafenib (four 40 mg tablets) taken orally once daily for the first 21 days of each 28-day cycle. Continue treatment until disease progression or unacceptable toxicity.

Take Regorafenib at the same time each day. Swallow tablet whole with water after a low-fat meal that contains less than 600 calories and less than 30% fat. Do not take two doses of Regorafenib on the same day to make up for a missed dose from the previous day.

Dose Modifications: If dose modifications are required, reduce the dose in 40 mg (one tablet) increments; the lowest recommended daily dose of Regorafenib is 80 mg daily.

Interrupt Regorafenib for the following:

Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia syndrome (PPES)] that is recurrent or does not improve within 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 reaction

Worsening infection of any grade

Reduce the dose of Regorafenib to 120 mg:

• For the first occurrence of Grade 2 HFSR of any duration
• After recovery of any Grade 3 or 4 adverse reaction except infection
• For Grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation, only resume if the potential benefit outweighs the risk of hepatotoxicity

Reduce the dose of Regorafenib to 80 mg:

• For re-occurrence of Grade 2 HFSR at the 120 mg dose
• After recovery of any Grade 3 or 4 adverse reaction at the 120 mg dose (except hepatotoxicity or infection)

Discontinue Regorafenib permanently for the following:

• Failure to tolerate 80 mg dose
• Any occurrence of AST or ALT more than 20 times the upper limit of normal (ULN)
• Any occurrence of AST or ALT more than 3 times ULN with concurrent bilirubin more than 2 times ULN
• Re-occurrence of AST or ALT more than 5 times ULN despite dose reduction to 120 mg
• For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks

Administration:

Advise patients to swallow the Regorafenib tablet whole with water at the same time each day following a low-fat meal. Inform patients that the low-fat meal should contain less than 600 calories and less than 30% fat

Advise patients to store medicine in the original container. Do not place medication in daily or weekly pill boxes. Discard any remaining tablets 7 weeks after opening the bottle. Tightly close bottle after each opening and keep the desiccant in the bottle

Effect Of Strong CYP3A4 Inducers On Regorafenib: Co-administration of a strong CYP3A4 inducer with Regorafenib decreased the plasma concentrations of regorafenib, increased the plasma concentrations of the active metabolite M-5, and resulted in no change in the plasma concentrations of the active metabolite M-2, and may lead to decreased efficacy. Avoid concomitant use of Regorafenib with strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's Wort).

Effect Of Strong CYP3A4 Inhibitors On Regorafenib: Co-administration of a strong CYP3A4 inhibitor with Regorafenib increased the plasma concentrations of regorafenib and decreased the plasma concentrations of the active metabolites M-2 and M-5, and may lead to increased toxicity. Avoid concomitant use of Regorafenib with strong CYP3A4 inhibitors (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole).

Effect Of Regorafenib On Breast Cancer Resistance Protein (BCRP) Substrates: Co-administration of Regorafenib with a BCRP substrate increased the plasma concentrations of the BCRP substrate. Monitor patients closely for signs and symptoms of exposure related toxicity to the BCRP substrate (e.g. methotrexate, fluvastatin, atorvastatin). Consult the concomitant BCRP substrate product information when considering administration of such products together with Regorafenib.

None

Common side effects are Hepatotoxicity, Infections, Hemorrhage, Gastrointestinal Perforation or Fistula, Dermatological Toxicity, Hypertension, Cardiac Ischemia and Infarction, Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Pregnancy: Based on animal studies and its mechanism of action, Regorafenib can cause fetal harm when administered to a pregnant woman. There are no available data on Regorafenib use in pregnant women. 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. Advise pregnant women of the potential hazard to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 % and 15 to 20%, respectively.

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 with Regorafenib and for 2 weeks after the final dose.

The highest dose of Regorafenib studied clinically is 220 mg per day. The most frequently observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue. There is no known antidote for Regorafenib overdose. In the event of suspected overdose, interrupt Regorafenib, institute supportive care, and observe until clinical stabilization.

Store Regorafenib at 25°C; excursions are permitted from 15 to 30°C. Store tablets in the original bottle and do not remove the desiccant. Keep the bottle tightly closed after first opening. Discard any unused tablets 7 weeks after opening the bottle. Dispose of unused tablets in accordance with local requirements.

Safe

Regorafenib 40mg