Colorectal Cancer (CRC): Regorafenib is indicated for patients with metastatic colorectal cancer who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and, in RAS wild-type cases, anti-EGFR therapy.

Gastrointestinal Stromal Tumor (GIST): Indicated for patients with locally advanced, unresectable, or metastatic GIST who have been previously treated with imatinib mesylate and sunitinib malate.

Hepatocellular Carcinoma (HCC): Indicated for the treatment of hepatocellular carcinoma in patients who have previously been treated with sorafenib

Regorafenib is an oral multi-kinase inhibitor targeting multiple membrane-bound and intracellular kinases involved in tumor growth, angiogenesis, metastasis, and immune regulation. It inhibits several kinases including VEGFR1–3, KIT, PDGFR-α/β, FGFR1/2, TIE2, RAF-1, BRAF (including BRAF V600E), RET, and others at clinically relevant concentrations. In preclinical studies, regorafenib demonstrated anti-angiogenic, anti-proliferative, and anti-metastatic activity in various tumor models including colorectal, gastrointestinal stromal, and hepatocellular carcinoma xenografts. A clinical QT study showed no clinically significant prolongation of the QTc interval (>20 msec). Pharmacokinetics

Absorption: After a single 160 mg dose, regorafenib reaches peak plasma concentration (Cmax) of 2.5 µg/mL at about 4 hours, with an AUC of 70.4 µg·h/mL. At steady state, exposure increases less than dose proportionally above 60 mg.

Distribution: Regorafenib undergoes enterohepatic circulation and is highly protein bound (99.5%).

Elimination: Half-life is approximately 28 hours for regorafenib, 25 hours for M-2, and 51 hours for M-5 metabolite.

Metabolism: Metabolized mainly by CYP3A4 and UGT1A9. Active metabolites M-2 and M-5 show similar pharmacological activity and are highly protein bound.

Excretion: Approximately 71% is excreted in feces and 19% in urine over 12 days, mainly as metabolites.

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. Treatment should be continued until disease progression or unacceptable toxicity. Regorafenib should be taken at the same time each day and swallowed tablet whole with water after a low-fat meal that contains less than 600 calories and less than 30% fat. Two doses of Regorafenib should not be taken on the same day to make up for a missed dose from the previous day.

Dose Modifications: If dose modifications are required, the dose should be reduced in 40 mg (one tablet) increments; the lowest recommended daily dose of Regorafenib is 80 mg daily. Or, as directed by the registered physicians.

Pediatric Use: The safety and efficacy of Regorafenib in pediatric patients less than 18 years of age have not been established.

Effect of strong CYP3A4 inducers on Regorafenib: Co-administration with strong CYP3A4 inducers decreases plasma levels of regorafenib, increases levels of metabolite M-5, and does not significantly affect M-2. This may reduce therapeutic efficacy. Concomitant use with strong CYP3A4 inducers (e.g. Rifampin, Phenytoin, Carbamazepine, Phenobarbital, St. John’s Wort) should be avoided.

Effect of strong CYP3A4 inhibitors on Regorafenib: Co-administration with strong CYP3A4 inhibitors increases regorafenib plasma concentration while reducing active metabolites M-2 and M-5, which may increase toxicity. Concomitant use with strong inhibitors (e.g. Clarithromycin, Ketoconazole, Itraconazole, Voriconazole, Posaconazole, Nefazodone, Telithromycin, Grapefruit juice) should be avoided.

Effect on BCRP substrates: Regorafenib may increase plasma levels of BCRP substrates, potentially increasing toxicity. Patients should be closely monitored when used with drugs such as Methotrexate, Fluvastatin, or Atorvastatin.

Regorafenib is contraindicated in patients with known hypersensitivity to regorafenib or any of its components.

• Hepatotoxicity
• Infections
• Hemorrhage
• Gastrointestinal perforation or fistula
• Dermatologic toxicity
• Hypertension
• Cardiac ischemia and infarction
• Reversible posterior leukoencephalopathy syndrome (RPLS)

No adequate data are available in pregnant women. Regorafenib may cause fetal harm. It should be avoided during pregnancy.

It is unknown whether regorafenib is excreted in human milk. Due to potential serious adverse effects in infants, breastfeeding should be discontinued during treatment and for 2 weeks after the last dose.

Female reproductive potential: Effective contraception is required during treatment and for 2 months after therapy.
Male patients: Effective contraception should be used during treatment and for 2 months after the last dose.
Fertility: No data available on effects on human fertility.

Hepatotoxicity: Severe and sometimes fatal liver injury has been reported. Liver function tests (ALT, AST, bilirubin) should be monitored before and every 2 weeks during the first 2 months. Dose modification or discontinuation may be required.

Infections: Increased risk of infections including urinary tract infection, pneumonia, and fungal infections. Severe infections may require treatment interruption.

Hemorrhage: Serious and fatal bleeding events may occur. Regorafenib should be permanently discontinued in severe hemorrhage. INR should be monitored in patients on warfarin.

Gastrointestinal perforation/fistula: May occur and requires permanent discontinuation.

Dermatologic toxicity: Hand-foot skin reaction is common. Dose interruption or reduction may be required.

Hypertension: May occur early in treatment. Blood pressure must be controlled before starting therapy and monitored regularly.

Cardiac ischemia/infarction: Treatment should be interrupted in acute events and resumed only after risk-benefit evaluation.

RPLS: Discontinue if symptoms such as seizures, headache, or confusion occur.

Wound healing: Should be stopped at least 2 weeks before surgery. Restart only after proper wound healing.

Embryo-fetal toxicity: Effective contraception is required for both males and females during and after treatment.

No specific antidote is available. Overdose may cause dermatologic reactions, hypertension, diarrhea, fatigue, and other known adverse effects. Treatment is supportive and symptomatic with discontinuation of therapy.

Targeted cancer therapy

Store below 30°C in a cool, dry place, protected from light. Keep out of reach of children.