Comprehensive Guide to Regorafenib: Uses, Dosage, Side Effects, and More

1. What is Regorafenib?

2. Overview of Regorafenib

Generic Name

Regorafenib

Brand Name

Stivarga, generics

Drug Group

Multi-kinase inhibitor (antineoplastic)

Commonly Used For

This medication is used to:

• Treat metastatic colorectal cancer (mCRC).
• Manage hepatocellular carcinoma (HCC).
• Control gastrointestinal stromal tumors (GIST).

Key Characteristics

• Form: Oral tablets (40 mg) (detailed in Dosage section).
• Mechanism: Inhibits tumor angiogenesis, proliferation, and metastasis via multiple kinase pathways.
• Approval: FDA-approved (2012 for Stivarga) and EMA-approved for mCRC, HCC, and GIST.

3. Indications and Uses of Regorafenib

Regorafenib is indicated for advanced cancers, leveraging its multi-targeted action to inhibit tumor growth:

• Metastatic Colorectal Cancer (mCRC): Treats mCRC in patients previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and anti-EGFR therapy (if RAS wild-type), improving progression-free survival, per oncology guidelines.
• Hepatocellular Carcinoma (HCC): Manages HCC in patients with Barcelona Clinic Liver Cancer (BCLC) Stage B or C disease who have progressed on sorafenib, enhancing overall survival, supported by the RESORCE trial.
• Gastrointestinal Stromal Tumors (GIST): Controls advanced GIST after imatinib and sunitinib failure, reducing tumor burden, per sarcoma management protocols.
• Metastatic Gastric Cancer: Investigated off-label for metastatic gastric cancer resistant to standard therapies, improving outcomes in select patients, with emerging data from gastrointestinal oncology.
• Cholangiocarcinoma: Explored off-label for advanced cholangiocarcinoma, slowing disease progression when combined with other agents, supported by hepatobiliary research.
• Soft Tissue Sarcoma: Used off-label in advanced soft tissue sarcoma, particularly leiomyosarcoma, enhancing response rates, with evidence from sarcoma studies.
• Non-Small Cell Lung Cancer (NSCLC): Investigated off-label for NSCLC with EGFR mutations post-tyrosine kinase inhibitor failure, improving survival in trials, noted in pulmonary oncology.
• Renal Cell Carcinoma (RCC): Employed off-label in RCC after anti-angiogenic therapy failure, reducing metastatic spread, with urologic oncology data.
• Pancreatic Neuroendocrine Tumors (pNET): Explored off-label for pNET, stabilizing disease in advanced cases, supported by neuroendocrine tumor research.
• Thyroid Cancer: Managed off-label in progressive radioactive iodine-refractory thyroid cancer, improving progression-free survival, with endocrinology evidence.

Note: This drug requires careful monitoring for toxicity and resistance; consult a healthcare provider for tailored therapy and supportive care.

4. Dosage of Regorafenib

Important Note: The dosage of this kinase inhibitor must be prescribed by a healthcare provider. Dosing varies by indication and patient tolerance, with adjustments based on clinical evaluation.

Dosage for Adults

• Metastatic Colorectal Cancer (mCRC):
  • 160 mg orally once daily for the first 21 days of a 28-day cycle, taken with a low-fat meal.
• Hepatocellular Carcinoma (HCC):
  • 160 mg orally once daily for the first 21 days of a 28-day cycle, with a low-fat meal.
• Gastrointestinal Stromal Tumors (GIST):
  • 160 mg orally once daily for the first 21 days of a 28-day cycle, with a low-fat meal.

Dosage for Children

• Not recommended for pediatric use due to insufficient safety and efficacy data; consult a pediatric oncologist for alternative therapies.

Dosage for Pregnant Women

• Pregnancy Category D: Avoid unless benefits outweigh risks (e.g., life-threatening cancer). Consult an obstetrician, with fetal monitoring.

Dosage Adjustments

• Renal Impairment: No adjustment needed; monitor in severe cases (CrCl <30 mL/min).
• Hepatic Impairment:
  • Mild (Child-Pugh A): No adjustment; moderate (Child-Pugh B): Reduce to 120 mg/day; severe (Child-Pugh C): Avoid.
• Elderly: Start with 120 mg/day; increase to 160 mg if tolerated.
• Concomitant Medications: Adjust if combined with CYP3A4 inducers/inhibitors (e.g., rifampin, ketoconazole), altering levels.

Additional Considerations

• Take this active ingredient with a low-fat meal (e.g., <600 calories, <30% fat) at the same time daily.
• Use a pill organizer to maintain the 21-day-on/7-day-off cycle.

5. How to Use Regorafenib

• Administration:
  • Swallow tablets whole with a low-fat meal and water; avoid high-fat meals to minimize absorption variability.
  • Take consistently at the same time each day for the first 21 days of a 28-day cycle.
• Timing: Use once daily, with a 7-day rest period each cycle, as directed.
• Monitoring: Watch for hand-foot skin reaction, fatigue, or signs of liver issues (e.g., yellowing skin).
• Additional Tips:
  • Store at 20–25°C (68–77°F), protecting from moisture and heat.
  • Keep out of reach of children due to toxicity risk.
  • Report severe abdominal pain, bleeding, or signs of infection immediately.

6. Contraindications for Regorafenib

This drug is contraindicated in:

• Hypersensitivity: Patients with a known allergy to Regorafenib or its components.
• Severe Hepatic Impairment: Contraindicated in Child-Pugh Class C due to toxicity risk.
• Severe Uncontrolled Hypertension: Avoid due to cardiovascular risk.

7. Warnings & Precautions for Regorafenib

General Warnings

• Hepatotoxicity: Risk of severe liver injury or failure; monitor liver function every 2 weeks during the first 2 months.
• Hemorrhage: Risk of gastrointestinal bleeding or intracranial hemorrhage; discontinue if severe.
• Hand-Foot Skin Reaction (HFSR): Common painful skin reaction on palms and soles; manage with dose reduction.
• Gastrointestinal Perforation: Rare but life-threatening; monitor for abdominal pain.
• Cardiovascular Events: Risk of myocardial infarction or hypertension; check blood pressure regularly.

Additional Warnings

• Wound Healing Complications: Delay surgery for at least 2 weeks before and after treatment; assess healing.
• Infections: Increased risk due to immunosuppression; prophylaxis may be needed.
• Thyroid Dysfunction: Risk of hypothyroidism; monitor thyroid function.
• Osteonecrosis: Rare jaw bone damage; assess dental health.
• Hypersensitivity Reactions: Rare anaphylaxis; discontinue if swelling occurs.

Use in Specific Populations

• Pregnancy: Category D; avoid unless critical; use contraception.
• Breastfeeding: Avoid due to potential toxicity; monitor infant.
• Elderly: Higher risk of toxicity; start with lower doses.
• Children: Not recommended; explore alternatives.
• Renal/Hepatic Impairment: Adjust dose; avoid in severe cases.

Additional Precautions

• Inform your doctor about liver disease, bleeding disorders, or recent surgery before starting this medication.
• Avoid over-the-counter NSAIDs unless approved, due to bleeding risk.

8. Overdose and Management of Regorafenib

Overdose Symptoms

Overdose may cause:

• Nausea, diarrhea, or hypertension.
• Severe cases: Liver failure, gastrointestinal perforation, or cardiac arrest.
• Fatigue, rash, or bleeding as early signs.
• Seizures with extremely high doses.

Immediate Actions

• Contact the Medical Team: Seek immediate medical help.
• Supportive Care: Administer IV fluids, monitor vital signs, and manage bleeding or hypertension.
• Specific Treatment: No antidote; support liver and cardiovascular function.
• Monitor: Check liver enzymes, blood pressure, and coagulation for 24–72 hours.

Additional Notes

• Overdose risk is moderate; store securely.
• Report persistent symptoms (e.g., jaundice, severe weakness) promptly.

9. Side Effects of Regorafenib

Common Side Effects

• Hand-Foot Skin Reaction (40–50%, manageable with moisturizers)
• Diarrhea (30–45%, reduced with loperamide)
• Fatigue (25–40%, decreases with rest)
• Hypertension (20–35%, controlled with antihypertensives)
• Nausea (15–30%, relieved with antiemetics)
  These effects may subside with dose adjustment or cycle breaks.

Serious Side Effects

Seek immediate medical attention for:

• Hepatic: Jaundice, hepatitis, or liver failure.
• Gastrointestinal: Perforation, bleeding, or severe diarrhea.
• Cardiovascular: Myocardial infarction, hypertension crisis, or arrhythmia.
• Dermatologic: Severe HFSR or rash.
• Allergic: Rash, angioedema, or anaphylaxis.

Additional Notes

• Regular monitoring for liver function, blood pressure, and skin health is advised.
• Report any unusual symptoms (e.g., severe abdominal pain, chest pain) immediately to a healthcare provider.

10. Drug Interactions with Regorafenib

This active ingredient may interact with:

• CYP3A4 Inhibitors/Inducers: Alters levels (e.g., ketoconazole, rifampin); adjust dose.
• Warfarin: Increases bleeding risk; monitor INR.
• Antihypertensives: Potentiates hypotension; adjust dose.
• Statins: Increases myopathy risk (e.g., atorvastatin); use alternatives.
• Grapefruit Juice: Inhibits metabolism; avoid consumption.

Action: Provide your healthcare provider with a complete list of medications.

11. Patient Education or Lifestyle

• Medication Adherence: Take this kinase inhibitor as prescribed in 28-day cycles, following the exact schedule.
• Monitoring: Report hand-foot reaction, bleeding, or fatigue immediately.
• Lifestyle: Avoid sun exposure; use sunscreen and protective clothing.
• Diet: Take with a low-fat meal; avoid grapefruit or high-fat foods.
• Emergency Awareness: Know signs of liver failure or gastrointestinal perforation; seek care if present.
• Follow-Up: Schedule regular check-ups every 2–4 weeks during therapy to monitor liver, blood pressure, and tumor markers.

12. Pharmacokinetics of Regorafenib

• Absorption: Well-absorbed orally (peak at 3–4 hours); enhanced with a low-fat meal, reduced with high-fat meals.
• Distribution: Volume of distribution ~166 L; 99.5% protein-bound.
• Metabolism: Hepatic via CYP3A4 and UGT1A9 to active metabolites (e.g., M-2, M-5).
• Excretion: Primarily fecal (71%) as metabolites; renal (19%); half-life 28 hours.
• Half-Life: 28 hours, with sustained anti-angiogenic effect.

13. Pharmacodynamics of Regorafenib

This drug exerts its effects by:

• Inhibiting VEGFR1-3, PDGFR, and FGFR, blocking tumor angiogenesis and growth.
• Inducing apoptosis in cancer cells via RAF/MEK/ERK pathway inhibition.
• Reducing metastatic potential in advanced cancers.
• Exhibiting dose-dependent liver, skin, and cardiovascular toxicity risks.

14. Storage of Regorafenib

• Temperature: Store at 20–25°C (68–77°F); protect from moisture.
• Protection: Keep in original container, away from light.
• Safety: Store in a locked container out of reach of children due to toxicity risk.
• Disposal: Dispose of unused tablets per local regulations or consult a pharmacist.

15. Frequently Asked Questions (FAQs) About Regorafenib

Q: What does Regorafenib treat?
A: This medication treats colorectal cancer, HCC, and GIST.

Q: Can this active ingredient cause hand-foot reaction?
A: Yes, hand-foot skin reaction may occur; use moisturizers.

Q: Is Regorafenib safe for children?
A: No, it’s not recommended for pediatric use.

Q: How is this drug taken?
A: Orally as tablets once daily with a low-fat meal, as directed.

Q: How long is Regorafenib treatment?
A: Long-term in cycles, depending on cancer response.

Q: Can I use Regorafenib if pregnant?
A: No, avoid unless life-saving; consult a doctor.

16. Regulatory Information for Regorafenib

This medication is approved by:

• U.S. Food and Drug Administration (FDA): Approved in 2012 (Stivarga) for mCRC, expanded to HCC (2017) and GIST (2013).
• European Medicines Agency (EMA): Approved for mCRC, HCC, and GIST.
• Other Agencies: Approved globally for oncology; consult local guidelines.

17. References

1. U.S. Food and Drug Administration (FDA). (2023). Stivarga (Regorafenib) Prescribing Information.
   • Official FDA documentation detailing the drug’s approved uses, dosage, and safety.
2. European Medicines Agency (EMA). (2023). Regorafenib Summary of Product Characteristics.
   • EMA’s comprehensive information on the medication’s indications and precautions in Europe.
3. National Institutes of Health (NIH). (2023). Regorafenib: MedlinePlus Drug Information.
   • NIH resource providing detailed information on the drug’s uses, side effects, and precautions.
4. World Health Organization (WHO). (2023). WHO Model List of Essential Medicines: Regorafenib.
   • WHO’s consideration of Regorafenib for cancer therapy.
5. Journal of Clinical Oncology. (2022). Regorafenib in Hepatocellular Carcinoma.
   • Peer-reviewed article on Regorafenib efficacy (note: access may require a subscription).