Usage
Sorafenib is prescribed for the treatment of:
- Hepatocellular carcinoma (HCC): The most common type of liver cancer.
- Advanced Renal Cell Carcinoma (RCC): Kidney cancer that has spread to other parts of the body.
- Differentiated Thyroid Carcinoma (DTC): Thyroid cancer that has spread and no longer responds to radioactive iodine treatment.
Pharmacological Classification: Sorafenib is a multi-kinase inhibitor, classified as an antineoplastic agent. It inhibits several tyrosine protein kinases implicated in tumor growth and angiogenesis (formation of new blood vessels that feed tumors).
Mechanism of Action: Sorafenib blocks tumor cell proliferation by inhibiting intracellular serine/threonine kinases (CRAF, BRAF, and mutant BRAF) and cell surface receptor tyrosine kinases (VEGFR-2, VEGFR-3, PDGFR-β, FLT-3, c-KIT, and RET). This dual action simultaneously targets tumor growth directly and disrupts the tumor’s blood supply.
Alternate Names
Sorafenib tosylate is the chemical name. It is marketed under the brand name Nexavar.
How It Works
Pharmacodynamics: Sorafenib exerts its anti-cancer effects through the inhibition of multiple kinases. By blocking these enzymes, it disrupts several key pathways involved in tumor growth, proliferation, and angiogenesis. The inhibition of RAF kinases directly targets tumor cell growth, while blocking VEGFR and PDGFR inhibits the formation of new blood vessels, cutting off the tumor’s blood supply.
Pharmacokinetics:
- Absorption: Sorafenib is absorbed orally, reaching peak plasma concentrations around 3 hours post-administration. High-fat meals can reduce its absorption by approximately 29%.
- Metabolism: Sorafenib is primarily metabolized in the liver by CYP3A4 and UGT1A9 enzymes.
- Elimination: Sorafenib is eliminated through both hepatic (feces) and renal (urine) routes. The half-life is 25-48 hours, resulting in accumulation with daily dosing.
Mode of Action: Sorafenib acts by binding to the ATP-binding pockets of the target kinases, preventing the phosphorylation of downstream signaling molecules essential for tumor growth and angiogenesis.
Elimination Pathways: Sorafenib is primarily eliminated via hepatic metabolism, with biliary excretion into feces being the main route. Renal excretion plays a minor role. CYP3A4 is the major enzyme involved in its metabolism.
Dosage
Standard Dosage
Adults:
The standard dose of Sorafenib for adults is 400 mg (two 200 mg tablets) twice daily, taken without food or with a low to moderate-fat meal. If a high-fat meal is anticipated, Sorafenib should be taken at least 1 hour before or 2 hours after the meal.
Children:
The safety and efficacy of Sorafenib have not been established in children and adolescents under 18 years old.
Special Cases:
- Elderly Patients: No dose adjustment is generally required for elderly patients. However, careful monitoring is advised due to potential age-related decline in organ function.
- Patients with Renal Impairment: No dose adjustment is necessary for patients with mild to moderate renal impairment. No data are available for patients with severe renal impairment or those requiring dialysis. Close monitoring of fluid and electrolyte balance is advised.
- Patients with Hepatic Dysfunction: No dose adjustment is needed for patients with Child-Pugh A or B (mild to moderate) hepatic impairment. No data are available for patients with Child-Pugh C (severe) hepatic impairment.
- Patients with Comorbid Conditions: Patients with pre-existing conditions like hypertension, cardiac disease, or bleeding disorders require close monitoring.
Clinical Use Cases
Sorafenib is not typically used in settings like intubation, surgical procedures, mechanical ventilation, ICU care, or emergency situations. Its use is primarily focused on the targeted treatment of specific cancer types as outlined in the “Usage” section.
Dosage Adjustments
Dose reductions may be necessary for managing adverse effects, particularly dermatological toxicities like hand-foot skin reaction and rash. Dose reductions may be to 400 mg once daily, further reduced to 400 mg every other day, or 200 mg once daily. If toxicity resolves, the dose may be carefully escalated.
Side Effects
Common Side Effects:
Diarrhea, fatigue, hair loss (alopecia), hand-foot skin reaction (palmar-plantar erythrodysesthesia), rash, weight loss, decreased appetite, nausea, abdominal pain, hypertension, and hemorrhage.
Rare but Serious Side Effects:
Myocardial infarction/ischemia, gastrointestinal perforation, drug-induced hepatitis, severe bleeding, Stevens-Johnson syndrome, QT prolongation, reversible posterior leukoencephalopathy syndrome (RPLS).
Long-Term Effects:
Chronic complications may include cardiac dysfunction, liver damage, renal impairment, and secondary malignancies.
Adverse Drug Reactions (ADR):
Severe hypersensitivity reactions, angioedema, severe hemorrhage, liver failure, RPLS, severe skin reactions.
Contraindications
- Hypersensitivity to sorafenib or any component of the formulation.
- Sorafenib is contraindicated in combination with carboplatin and paclitaxel in patients with squamous cell lung cancer.
- Co-administration with drugs that prolong the QT interval (e.g., dronedarone, pimozide, thioridazine, ziprasidone).
- Co-administration with lefamulin.
Drug Interactions
Sorafenib has numerous potential drug interactions. Some important interactions include:
- CYP3A4 Inducers (e.g., rifampin, St. John’s Wort): Reduce sorafenib exposure.
- CYP3A4 Inhibitors (e.g., ketoconazole): Increase sorafenib exposure.
- Warfarin: Monitor INR closely.
- Docetaxel: Increased docetaxel exposure.
- Neomycin: Reduced sorafenib exposure.
- Irinotecan: Increased SN-38 (active metabolite) exposure.
- Drugs that prolong QT interval: Increased risk of cardiotoxicity.
Pregnancy and Breastfeeding
- Pregnancy: Sorafenib is contraindicated during pregnancy due to the risk of fetal harm, including malformations. Effective contraception is mandatory during treatment and for a period after the last dose (6 months for women, 3 months for men).
- Breastfeeding: Sorafenib is contraindicated during breastfeeding and for 2 weeks after the final dose due to potential harm to the infant.
Drug Profile Summary
- Mechanism of Action: Multi-kinase inhibitor targeting tumor growth and angiogenesis.
- Side Effects: Diarrhea, fatigue, hand-foot skin reaction, rash, hypertension, hemorrhage.
- Contraindications: Hypersensitivity, pregnancy, breastfeeding, specific drug combinations (e.g., carboplatin/paclitaxel in squamous cell lung cancer).
- Drug Interactions: Numerous; avoid CYP3A4 inducers, caution with warfarin, docetaxel, neomycin, irinotecan.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 400 mg twice daily (adults). Adjustments may be necessary for adverse reactions.
- Monitoring Parameters: Blood pressure, liver function tests, complete blood count, TSH (in DTC patients), renal function, electrolytes (especially potassium, magnesium, and calcium), ECG (for QT interval prolongation).
Popular Combinations
Sorafenib is generally used as a single agent. Combining it with other anticancer therapies requires careful consideration due to the potential for increased toxicity.
Precautions
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General Precautions: Assess for hypersensitivity, cardiac function, liver and kidney function, and bleeding disorders before initiating therapy.
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Specific Populations:
- Pregnant Women: Contraindicated.
- Breastfeeding Mothers: Contraindicated.
- Children & Elderly: Not established safety and effectiveness in children; caution advised in the elderly due to potential for reduced drug clearance and increased sensitivity.
- Menstruating Individuals: Potential for increased bleeding.
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Lifestyle Considerations: Limit alcohol intake, avoid smoking, and advise against driving or operating heavy machinery if experiencing side effects such as dizziness or fatigue.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Sorafenib?
A: The standard adult dosage is 400 mg twice daily, taken without food or with a low to moderate-fat meal. Dose adjustments are necessary for specific adverse reactions.
Q2: What are the most common side effects of Sorafenib?
A: Diarrhea, fatigue, hand-foot skin reaction, rash, alopecia, decreased appetite, nausea, and hypertension are among the most common side effects.
A: Severe bleeding, myocardial infarction/ischemia, signs of liver damage (e.g., jaundice, dark urine), gastrointestinal perforation, signs of infection (e.g., persistent fever), or severe allergic reactions require immediate medical intervention.
Q4: Can Sorafenib be used during pregnancy or breastfeeding?
A: No, Sorafenib is contraindicated in both pregnancy and breastfeeding due to its potential to cause fetal harm and transfer into breast milk.
Q5: How does Sorafenib interact with other medications?
A: Sorafenib can interact with numerous medications, including CYP3A4 inducers and inhibitors, warfarin, docetaxel, and neomycin. A comprehensive medication review is essential before initiating Sorafenib therapy.
Q6: What should be monitored during Sorafenib treatment?
A: Blood pressure, complete blood count, liver and kidney function tests, and ECG (for QT prolongation) should be regularly monitored during treatment. TSH levels should be monitored in patients with DTC.
Q7: What are the dose adjustments for dermatological toxicity?
A: The dose may be reduced to 400 mg daily, then potentially further to 400 mg every other day, or 200 mg daily. If the toxicity resolves, the dose may be carefully increased.
Q8: What should patients be counseled about regarding lifestyle modifications?
A: Patients should be advised to limit alcohol consumption, avoid smoking, and use appropriate sun protection due to increased photosensitivity. Driving or operating machinery should be avoided if experiencing side effects like dizziness or fatigue.
A: Sorafenib is primarily metabolized by the liver enzyme CYP3A4, making drug interactions with CYP3A4 inducers or inhibitors a significant concern.
Q10: What is the mechanism of action of Sorafenib?
A: Sorafenib is a multi-kinase inhibitor, which means it blocks the activity of several enzymes that are involved in tumor growth and spread, including those that promote the development of new blood vessels to nourish the tumor. It inhibits both intracellular (RAF kinases) and cell surface receptor tyrosine kinases (VEGFR, PDGFR, etc.).
