Usage
Regorafenib is prescribed for the treatment of:
- Metastatic colorectal cancer (mCRC): In patients 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 (GIST): In patients who have been previously treated with imatinib and sunitinib.
- Hepatocellular carcinoma (HCC): In patients who have been previously treated with sorafenib.
Pharmacological Classification: Regorafenib is a multi-kinase inhibitor.
Mechanism of Action: Regorafenib inhibits multiple protein kinases involved in tumor angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E), metastasis (VEGFR3, PDGFR, FGFR), and tumor immunity (CSF1R). This broad kinase inhibition disrupts several pathways crucial for tumor growth, proliferation, and spread.
Alternate Names
Stivarga is the most common brand name for regorafenib. There are no widely used alternate generic names or regional variations.
How It Works
Pharmacodynamics: Regorafenib exerts its anti-tumor effects by blocking key signaling pathways responsible for tumor growth and progression. It disrupts angiogenesis (formation of new blood vessels), inhibits cellular proliferation, and modulates tumor immunity.
Pharmacokinetics:
- Absorption: Regorafenib is administered orally and is absorbed with peak plasma concentrations reached approximately 3-4 hours after administration with a low-fat meal. Taking it with a high-fat meal reduces its absorption.
- Metabolism: It is primarily metabolized in the liver by CYP3A4 and UGT1A9 enzymes, producing active metabolites (M-2 and M-5).
- Elimination: Excreted primarily in feces (71%), with a smaller portion eliminated in urine (19%). The terminal half-life is 20-30 hours for regorafenib and M-2, and 40-100 hours for M-5.
Mode of Action: Regorafenib binds to and inhibits the activity of multiple tyrosine kinases. These kinases play essential roles in cellular signaling pathways that regulate tumor growth, angiogenesis, and metastasis. The primary mechanism of action is thought to be related to the inhibition of angiogenesis and oncogenesis, ultimately leading to tumor growth inhibition.
Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Primarily enzyme inhibition (kinase inhibition) specifically targeting tyrosine kinases.
Elimination Pathways: Predominantly hepatic metabolism and fecal excretion.
Dosage
Standard Dosage
Adults:
The standard dose is 160 mg (four 40 mg tablets) taken orally once daily for 21 days, followed by a 7-day break. This 28-day cycle is repeated until disease progression or unacceptable toxicity. The tablets should be taken with water after a low-fat meal (less than 30% fat).
Children:
Regorafenib is not recommended for use in children. Safety and efficacy have not been established in pediatric patients.
Special Cases:
- Elderly Patients: No dose adjustments are generally required. Close monitoring is recommended due to potential age-related decline in organ function.
- Patients with Renal Impairment: No dose adjustment is generally needed for mild to moderate renal impairment. Data is limited in patients with severe renal impairment or end-stage renal disease.
- Patients with Hepatic Dysfunction: Close monitoring and dose adjustments may be necessary. Avoid use in severe hepatic impairment (Child-Pugh C).
- Patients with Comorbid Conditions: Close monitoring is recommended for patients with cardiovascular disease, hypertension, bleeding disorders, or those taking medications that affect blood clotting.
Clinical Use Cases
Regorafenib is not typically used in clinical settings like intubation, surgical procedures, mechanical ventilation, or emergency situations such as status epilepticus or cardiac arrest. Its use is limited to the treatment of specific cancer types as mentioned in the “Usage” section.
Dosage Adjustments
Dose reductions may be necessary based on individual tolerability and adverse effects. Dosage modifications are made in 40 mg steps. The lowest recommended daily dose is 80 mg, and the maximum daily dose is 160 mg. Specific dose adjustments should be made in consultation with an oncologist and based on the severity and type of adverse events experienced.
Side Effects
Common Side Effects:
Hand-foot syndrome (palmar-plantar erythrodysesthesia), fatigue, diarrhea, hypertension, decreased appetite, mucositis, dysphonia, rash, alopecia, infection, pain, elevated liver enzymes, proteinuria, bleeding.
Rare but Serious Side Effects:
Severe liver injury (hepatotoxicity), gastrointestinal perforation, severe hemorrhage, reversible posterior leukoencephalopathy syndrome (RPLS), cardiac ischemia/infarction, wound dehiscence, severe hypertension, serious infections.
Long-Term Effects:
Potential long-term effects are not fully characterized but may include chronic liver dysfunction, cardiovascular complications, secondary malignancies, and impaired wound healing.
Adverse Drug Reactions (ADR):
Clinically significant ADRs include severe hepatotoxicity, gastrointestinal perforation, hemorrhage, RPLS, and severe hypertension. These ADRs require immediate intervention and possible discontinuation of the drug.
Contraindications
- Hypersensitivity to regorafenib or any of its components.
- Pregnancy.
- Concurrent use with strong CYP3A4 inducers.
Drug Interactions
Regorafenib interacts with numerous medications, including:
- Strong CYP3A4 inhibitors: Increase regorafenib exposure.
- Strong CYP3A4 inducers: Decrease regorafenib exposure.
- Warfarin and other anticoagulants: Increased risk of bleeding.
- Grapefruit juice: Increased regorafenib exposure.
- St. John’s wort: Decreased regorafenib exposure.
Pregnancy and Breastfeeding
Pregnancy Safety Category: Regorafenib is contraindicated in pregnancy. It can cause fetal harm. Effective contraception is required during treatment and for 8 weeks after discontinuation.
Breastfeeding: Regorafenib and/or its metabolites may be excreted in human milk. Breastfeeding should be avoided during treatment and for 2 weeks after discontinuation.
Drug Profile Summary
- Mechanism of Action: Multi-kinase inhibitor targeting tumor angiogenesis, oncogenesis, and metastasis.
- Side Effects: Hand-foot syndrome, fatigue, diarrhea, hypertension, decreased appetite, mucositis, dysphonia, rash, alopecia, infection, pain, elevated liver enzymes, proteinuria, bleeding. Severe side effects include hepatotoxicity, GI perforation, and hemorrhage.
- Contraindications: Hypersensitivity, pregnancy, strong CYP3A4 inducers.
- Drug Interactions: Numerous drug interactions, including CYP3A4 inhibitors and inducers, anticoagulants, and grapefruit juice.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy and breastfeeding.
- Dosage: 160 mg daily for 21 days of a 28-day cycle, taken with a low-fat meal. Dose modifications may be necessary.
- Monitoring Parameters: Liver function tests (LFTs), blood pressure, complete blood counts (CBCs), electrolytes, and signs and symptoms of adverse events.
Popular Combinations
Regorafenib is usually used as a single agent. There are currently no established, frequently used drug combinations. Research is ongoing to explore potential combination therapies.
Precautions
- General Precautions: Monitor liver function, blood pressure, and complete blood counts.
- Pregnant Women: Contraindicated.
- Breastfeeding Mothers: Contraindicated.
- Children & Elderly: Not recommended in children. Caution in elderly due to potential age-related decline in organ function.
- Lifestyle Considerations: Avoid grapefruit and its juice. Counsel patients about managing side effects like fatigue and hand-foot syndrome.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Regorafenib?
A: The standard adult dose is 160 mg (four 40-mg tablets) orally once a day, taken with water after a low-fat meal for 21 days, followed by a 7-day break. This cycle is repeated. Dose adjustments may be needed based on tolerability and side effects. Not recommended for pediatric use.
Q2: What are the most common side effects of Regorafenib?
A: Hand-foot syndrome, fatigue, diarrhea, and hypertension are among the most frequently reported side effects.
Q3: How should Regorafenib be administered?
A: Orally, with water, after a low-fat meal (less than 30% fat and about 300-550 calories). Taking the dose at the same time each day is recommended.
A: Signs of liver damage (jaundice, dark urine, right upper quadrant pain), severe bleeding, severe hypertension, gastrointestinal perforation (severe abdominal pain, fever), signs of infection, and any signs of an allergic reaction (rash, swelling, difficulty breathing).
Q5: Is Regorafenib safe to use during pregnancy or breastfeeding?
A: No, Regorafenib is contraindicated in pregnancy and breastfeeding as it can cause harm to the fetus or baby.
Q6: What should patients avoid while taking Regorafenib?
A: Patients should avoid grapefruit and its juice as they can increase the concentration of regorafenib in the blood, leading to an increased risk of side effects. Strong CYP3A4 inducers like St. John’s wort should also be avoided as they can decrease the effectiveness of Regorafenib. Patients should talk to their doctor about all other medications and supplements they take.
Q7: How does hepatic or renal impairment affect Regorafenib dosing?
A: Close monitoring is necessary for patients with mild to moderate hepatic impairment, and dose adjustments may be required. It should be avoided in patients with severe hepatic impairment (Child-Pugh C). For renal impairment, no dose adjustment is generally needed for mild to moderate renal dysfunction. Data is limited for severe renal impairment.
Q8: What if a patient misses a dose of Regorafenib?
A: If a dose is missed, it should be taken as soon as remembered on the same day. Do not double the dose. If it’s almost time for the next dose, skip the missed dose and resume the normal schedule. Do not take two doses on the same day.
Q9: How should Regorafenib be stored?
A: Store at room temperature in the original container. Protect from light and moisture. Do not remove the desiccant. Discard any unused tablets 7 weeks after the bottle is first opened.
