ALIREGFENIB Regorafenib

I. Basic Drug Information

Trade Name: Baiwango, ALIREGFENIB

Generic Name: Regorafenib Tablets

English Name: Regorafenib

Dosage Form: Film-coated tablets

Common Specifications: 40 mg/tablet; 28 tablets/bottle

Manufacturer: Lao Pharmaceutical Group Co., Ltd.

II. Pharmacological Actions and Mechanism of Action

Regorafenib is a multi-targeted tyrosine kinase inhibitor capable of blocking various enzymes that promote tumor growth and angiogenesis.

Mechanism of Action:

1.  Inhibition of Tumor Angiogenesis: By targeting receptors such as VEGFR-1, -2, -3, and TIE2, it blocks the tumor's blood supply, thereby preventing its growth. 

2.  Inhibition of Tumor Cell Proliferation: By targeting kinases such as RAF, KIT, and RET, it directly inhibits the growth and survival of tumor cells. 

3.  Modulation of the Tumor Microenvironment: By targeting receptors such as CSF1R, it influences tumor-associated macrophages and alters the immune environment surrounding the tumor.

III. Indications

Regorafenib is indicated for the treatment of the following patients:

1.  Metastatic Colorectal Cancer (mCRC): For patients whose disease has progressed following prior therapies including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, as well as anti-VEGF therapy and (if RAS wild-type) anti-EGFR therapy.

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

3.  Hepatocellular Carcinoma (HCC): For patients with HCC who have previously been treated with sorafenib.

IV. Dosage and Administration

Route of Administration: Oral.

Recommended Dose: 160 mg (i.e., four 40 mg tablets), taken once daily.

Treatment Cycle: Each treatment cycle consists of 28 days; the medication is taken for the first 21 days of each cycle, followed by a 7-day drug-free interval (i.e., a "3 weeks on, 1 week off" regimen).

Administration Method:

Take at the same time each day. 

Take with a low-fat meal. A low-fat meal is defined as a meal containing fewer than 600 calories and less than 30% fat. Examples include: one slice of toast, one egg, 240 mL of skim milk, and one slice of apple. 

Swallow the tablets whole; do not crush or chew them.

Dosage Adjustment:

The physician will adjust the dosage, temporarily suspend administration, or permanently discontinue the medication based on the severity of any toxic or adverse reactions experienced by the patient (particularly hand-foot skin reactions, hypertension, abnormal liver function, etc.). 

The standard dosage adjustment steps are as follows: 160 mg → 120 mg → 80 mg → Permanent Discontinuation.

Never adjust the dosage or stop taking the medication on your own.

V. Contraindications

This medication is contraindicated in patients with a history of severe allergic reactions to regorafenib or any of its excipients.

VI. Warnings and Precautions

1.  Hepatotoxicity: May cause severe, or even fatal, liver injury. Liver function (transaminases, bilirubin, etc.) must be monitored regularly prior to the initiation of treatment and throughout the treatment period.

2.  Infection: May increase the risk of infection, including severe or even fatal infections. Patients should seek immediate medical attention if fever or other signs of infection occur.

3.  Hemorrhage: May cause severe or even fatal major bleeding. This medication is contraindicated in patients with active bleeding. If severe bleeding occurs, the medication must be immediately discontinued, and the patient should seek medical attention.

4.  Gastrointestinal Perforation or Fistula: There is a risk of gastrointestinal perforation or fistula formation; if this occurs, the medication must be permanently discontinued.

5.  Dermatologic Toxicity:

Hand-foot skin reactions and rashes are very common side effects. In severe cases, dosage adjustment and symptomatic treatment (e.g., using urea-based ointments, moisturizers, etc.) may be required.

There have also been reports of severe dermatologic reactions, such as Stevens-Johnson syndrome; if such a reaction is suspected, the medication must be immediately discontinued.

6.  Hypertension: May cause or exacerbate hypertension. Blood pressure should be well-controlled prior to treatment and monitored regularly throughout the treatment period. If severe or persistent hypertension develops, temporary suspension of the medication and initiation of antihypertensive therapy may be necessary.

7.  Cardiac Ischemia and Infarction: May increase the risk of myocardial ischemia and infarction. Use with caution in patients with unstable angina or recent myocardial infarction.

8.  Impaired Wound Healing: May impair wound healing. Treatment should be suspended at least 2 weeks prior to major surgery. The decision to resume therapy after surgery should be based on the status of wound healing.

9.  Reversible Posterior Leukoencephalopathy Syndrome (RPLS): A rare neurological disorder characterized by symptoms such as headache, seizures, lethargy, and confusion. If it occurs, the drug must be permanently discontinued.

10. Embryo-Fetal Toxicity: May cause harm to the fetus. Women of reproductive potential and their partners must use effective contraception during treatment and for 2 months after the last dose.

VII. Adverse Reactions

Adverse reactions to regorafenib are very common and occur in the majority of patients.

Very Common (≥ 1/10) Adverse Reactions:

Metabolism and Nutrition: Decreased appetite, weight loss, hypocalcemia, hyponatremia. 

Nervous System: Headache, dysgeusia, hoarseness. 

Gastrointestinal: Diarrhea, nausea, vomiting, abdominal pain, oral mucositis, constipation. 

Skin and Subcutaneous Tissue: Hand-foot skin reaction, rash, alopecia, pruritus. 

Musculoskeletal: Musculoskeletal pain, asthenia. 

General Disorders: Asthenia/fatigue, fever, pain. 

Laboratory Abnormalities: Thrombocytopenia, lymphopenia, neutropenia, anemia, elevated ALT/AST, elevated bilirubin, elevated amylase/lipase, hypophosphatemia, proteinuria.

Common (≥ 1/100 to < 1/10) Adverse Reactions:

Infections: Oral candidiasis, respiratory tract infection, urinary tract infection. 

Cardiovascular: Hypertension, flushing. 

Respiratory System: Dyspnea. 

Skin: Dry skin, erythema multiforme. 

Nervous System: RPLS, tremor. 

Gastrointestinal: Pancreatitis, gastrointestinal perforation, gastrointestinal fistula. VIII. Drug Interactions

1.  Strong CYP3A4 Inducers (e.g., rifampin, phenytoin, carbamazepine, St. John's wort): May decrease plasma concentrations of regorafenib, thereby compromising efficacy. Concomitant use should be avoided.

2.  Strong CYP3A4 Inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, ritonavir): May increase plasma concentrations of regorafenib, thereby increasing the risk of adverse reactions. If co-administration is necessary, close monitoring is required.

3.  Transporter Substrates (e.g., digoxin, repaglinide): Regorafenib may increase plasma concentrations of these drugs; caution is advised during co-administration, and concentrations or effects of the relevant drugs should be monitored.

IX. Use in Specific Populations

Pregnant Women: Based on its mechanism of action and observed embryo-fetal toxicity in animals, regorafenib is contraindicated in pregnant women.

Lactating Women: It is recommended to discontinue breastfeeding during treatment and for 2 months following the last dose.

Children and Adolescents: Safety and efficacy have not been established.

Elderly Patients (≥65 years): No overall differences in safety were observed compared to younger patients; however, the incidence of certain adverse reactions (e.g., fatigue, decreased appetite) may be higher in this population.

Hepatic Impairment: Use with caution in patients with mild or moderate hepatic impairment. Regorafenib is contraindicated in patients with severe hepatic impairment.

Renal Impairment: No dose adjustment is required for patients with mild or moderate renal impairment. Data are limited for patients with severe renal impairment; use with caution.

X. Overdosage

There is currently no specific antidote. In the event of an overdose, treatment should be immediately discontinued, and supportive measures—including close monitoring of vital signs and adverse reactions—should be initiated.

XI. Storage

Store below 30°C.

Keep out of the reach of children.

Important Reminder:

All treatment decisions must be made by a qualified oncologist following a comprehensive assessment of the patient's specific condition. Patients should strictly adhere to their physician's instructions, attend regular follow-up appointments, and promptly report any discomfort or adverse reactions to their doctor.