Regorafenib instructions

1. Common name:Regofenib

Product name:Stivarga

All names: Regorafenib, Regorafenib, Stivarga, Stivarga

2. Indications:

1, Colorectal cancer (CRC): Regofenib (Reg orafenib) is indicated for the treatment of patients with metastatic colorectal cancer who have received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and anti-EGFR therapy (if RAS wild-type).

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

3. Hepatocellular carcinoma (HCC): Regofenib is suitable for patients with hepatocellular carcinoma who have previously received sorafenib treatment.

3. Usage and dosage:

1. Recommended dose:The recommended dose of regorafenib is 160mg (four 40mg tablets), taken orally once a day during the first 21 days of each 28-day cycle. Continue treatment until disease progression or unacceptable toxicity occurs. Tablets may be swallowed whole with water after a low-fat meal containing 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 the day before.

2. Dose adjustment: If the patient needs to adjust the dose, reduce the dose in increments of 40 mg (one tablet). The lowest recommended daily dose of regorafenib is 80 mg.

（1) Dose interruption: Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar dysesthesia syndrome (PPES)], recurrence or dose reduction without improvement within 7 days; Grade 3 HFSR discontinuation of treatment for at least 7 days; symptomatic grade 2 hypertension; any grade 3 or 4 adverse reaction; worsening infection of any grade.

(2) Dose reduction to 120 mg: for the first onset of Grade 2 HFSR of any duration; after resolution of any Grade 3 or 4 adverse reaction other than infection; for Grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevations, resume only when the potential benefit outweighs the risk of hepatotoxicity.

(3) Dose reduction to 80 mg: for recurrence 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).

(4) Permanent discontinuation of dose: patients unable to tolerate the 80 mg dose; any event of AST or ALT exceeding 20 times the upper limit of normal (ULN); any occurrence of AST or ALT exceeding 3 times the ULN and simultaneous bilirubin exceeding 2 times the ULN; recurrence of AST or ALT exceeding 5 times the ULN despite dose reduction to 120 mg; any Grade 4 adverse reaction, which may be reinstated only if the potential benefit outweighs the risk.

4. Adverse reactions:

In randomized placebo-controlled trials, the most commonly observed adverse drug reactions (≥20%) in patients receiving regorafenib (≥20%) were pain (including gastrointestinal and abdominal pain), HFSR, asthenia/fatigue, diarrhea, decreased appetite/food intake, hypertension, infection, dysphonia, hyperbilirubinemia, pyrexia, mucositis, weight loss, rash, and nausea. Adverse reactions found during post-approval use of regorafenib include allergic reactions, nephrotic syndrome, heart failure, arterial (including aorta) aneurysms, dissections and ruptures.

5. Storage:

RegofenibUsuallystored at25°C (77°F), allowed excursions in the range of 15 to 30°C (59 to 86°F). Store tablets in their original bottles without removing the desiccant. After opening for the first time, keep the bottle tightly closed. Discard any unused tablets after 7 weeks of opening. Dispose of unused tablets according to local requirements.

Six, Special groups:

1. Women:According to animal studies and its mechanism of action, regorafenib taken by pregnant women can cause harm to the fetus. In rats, regorafenib and its metabolites are excreted in milk. Therefore, use effective contraceptive measures during treatment and for 2 months after the end of treatment. Do not breastfeed during treatment with regorafenib and for 2 weeks after the last dose.

2. Men: It is recommended that male patients with a female partner of reproductive potential use effective contraceptive measures during treatment and within 2 months after the last dose of regorafenib.

7. Mechanism of action:

Regofenib is a small molecule inhibitor of a variety of membrane-bound and intracellular kinases involved in normal cell functions and pathological processes, such as tumorigenesis, tumor angiogenesis, metastasis and tumor immunity. Regrafenib or its major active human metabolite M-2 and M-5 inhibit RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-α, PDGFR-β, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAF in in vitro biochemical or cellular assays at clinically achieved regorafenib concentrations. Activities of V600E, SAPK2, PTK5, Abl and CSF1R. In in vivo models, regorafenib exhibits anti-angiogenic activity in rat tumor models and tumor growth inhibition in several mouse xenograft models, including some human colorectal cancers, gastrointestinal stromal tumors, and hepatocellular carcinoma. Regorafenib also showed antimetastatic activity in a mouse xenograft model of human colorectal cancer and in two mouse orthotopic models.

8. Precautions: During treatment with regorafenib, patients should pay attention to the occurrence of hepatotoxicity, infection, bleeding, gastrointestinal perforation or fistula, skin toxicity, hypertension, cardiac ischemia and infarction, reversible posterior leukoencephalopathy syndrome, impaired wound healing and other events.

RegofenibThe original drug has been launched in China and has entered the scope of Class B medical insurance. Reimbursement is limited to patients who meet the indications. SpecificationThe price of each box of 40mg*28 tablets is around RMB 5,000. The reimbursement ratio is different in different regions, and the price after reimbursement is different. The Turkish version of regorafeniboriginal drug specifications 40mg*28 tablets sold overseas is priced around RMB 6,400 per box (the price may fluctuate due to exchange rates). There are also generic regorafenib drugs produced in other countries, and their drug ingredients are basically the same as those of the original drug. The price of a box of 40mg*90 tablets produced by a Bangladesh pharmaceutical factory is around 2,900 yuan (the price may fluctuate due to exchange rates).