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Sorafenib - Uses, Warnings, Side Effects, Dosage, and More

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Sorafenib is a targeted cancer cell inhibitor used to treat advanced renal cell carcinoma. Read this article to know about its pharmacological uses.

Written by

Dr. Preethi. R

Medically reviewed by

Dr. Rajesh Gulati

Published At January 19, 2023
Reviewed AtJune 1, 2023

Overview

Sorafenib is an oral receptor multikinase inhibitor recently used in targeted cancer cell therapy. Sorafenib is a synthetic compound that blocks growth signals in cancer cells. The Food and Drug Administration (FDA) approved Sorafenib on 20th December 2005 and has enlisted it in FDA Orange Book (Approved Drug Products with Therapeutic Equivalence Evaluations). Sorafenib belongs to the class of phenyl ureas (urea containing nitrogen substituted by the 4-chloro-3-trifluoro phenyl group). It is a pyridine carboxamide (a member of monochlorobenzenes) which is an aromatic ether. It acts as a potent antineoplastic agent and a tyrosine kinase inhibitor. Sorafenib induces ferroptosis and inhibits angiogenesis. It is also effective as an anti-coronaviral agent.

Indications

  • Advanced renal cell carcinoma.

  • In cases of untreatable end-stage renal cell carcinoma, such as failure or unresponsive to anticancer cytokines (interferon-alpha, interleukin-2) therapy.

  • In advanced renal cell carcinoma patients for whom surgeries or anticancer cytokine therapy is contraindicated.

  • Unresectable (surgery contraindicated) hepatocellular carcinoma (liver cancer).

  • In differentiated (follicular, papillary, Hurthle cell) thyroid carcinoma.

  • To treat various stages of thyroid carcinoma (progressive, locally invasive, and metastatic).

  • It is indicated in thyroid cancers which are refractory to radioactive iodine.

  • To treat colon, metastatic pancreatic, and lung cancers.

  • Ovarian tumors.

  • Malignant melanoma.

  • Prostate cancers that are refractory to steroids.

Contraindications

  • In known cases of severe hypersensitivity to sorafenib.

  • In combination, cancer therapy with Paclitaxel and Carboplatin to treat squamous cell lung carcinoma.

Dosage Forms and Strengths

  • Sorafenib is available as 200 mg tablets coated with film (thin uniform layer of polymer).

  • Tablet film coating is done to increase drug availability and achieve therapeutic efficacy.

Dosage and Administration

  • Route of Administration - oral intake.

  • Recommended Dose - 400 mg (2 x 200 mg tablet).

  • Two tablets of Sorafenib are taken twice daily on an empty stomach without food (one hour before the meal or two hours after it).

  • An interrupted treatment regime or dosage reduction is adopted to manage reported adverse drug side effects.

  • In dose reduction, 400 mg of Sorafenib is recommended once daily.

  • If an additional dose reduction is required, a single dose of 400 mg every other alternate day is advised.

  • Treatment with the prescribed dosage must continue until no clinical improvement in the patient’s condition from the therapy or until severe toxic side effects occur.

For Patients

What Is Advanced Renal Cell Carcinoma?

Advanced renal cell carcinoma (advanced RCC) is a rare kidney tumor that spreads to other body parts (secondary metastasis). Recent studies show that it is rapidly increasing and accounts for about 3 % of all cancers, particularly in the USA. Cancer cells invade the renal tubules and adjacent structures in the kidney. In advanced RCC, these cancer cells spread to other closely related body parts like kidneys, bones, liver, lungs, and pelvis (lower abdomen).

Affected individuals show clinical symptoms of a sudden decrease in body weight, localized loin (lower back) pain, and haematuria (blood in urine). Advanced renal cell carcinoma diagnosis is often confirmed by imaging techniques (ultrasound, CT scan). Surgical removal is recommended initially but shows a poor prognosis due to an increased relapse rate. Anemia, increased serum calcium, and metastases to multiple organs are parameters of poor prognosis in an advanced disease condition. The mean survival for patients with advanced renal cell carcinoma is estimated to be 12 months.

Advanced renal cell carcinoma is a rapidly progressive disease with a high degree of disease instability. Spontaneous relapse rates are reported even after treatment interventions like surgical removal, anticancer agents, and immunotherapy. Monotherapy with novel targeted cancer cell inhibitors such as Sorafenib shows significant recovery outcomes in advanced RCC patients.

What Is Sorafenib?

Sorafenib is a synthetic antineoplastic drug targeted to block cancer cell growth. It stops tumor cell growth and multiplication in two ways:

  • It blocks the signals needed for cancer cells to grow and multiply.

  • It stops the tumor cells from forming new blood vessels, thus preventing the oxygen and nutrient supply to growing cancer cells.

Sorafenib is used to treat advanced renal cell carcinoma, especially in cases that do not respond to other anticancer drugs or recurrence after surgery. In advanced RCC patients receiving Sorafenib, progression-free survival (PFS) has considerably improved (with a median duration of 5.5 months). Administration of Sorafenib in advanced RCC strictly follows authorized prescription and is regularly monitored since its use is related to certain side effects.

How to Use Sorafenib?

  • Sorafenib is taken exactly as prescribed and advised by the doctor.

  • The usual dose is two tablets taken orally twice daily (four tablets per day).

  • The dosage could vary depending on responsiveness to treatment and severity of side effects.

  • Sorafenib is swallowed with water, preferably on an empty stomach, with a minimum interval of one hour before a meal or two hours after it.

  • In case of a missed dose, the next dose should be taken at the regular time as a prescribed dose and should not be doubled.

  • Overdosage should be immediately reported to the doctor.

How to Store Sorafenib?

  • Sorafenib should be stored at room temperature between 15 to 30 degrees centigrades.

  • It should be kept out of reach of children.

  • Sorafenib tablets should be kept in a cool, dry place away from direct sunlight.

What Are the Adverse Side Effects of Sorafenib?

The side effects of the administration of Sorafenib differ from person to person. The clinical manifestations of side effects also depend on interactions with other treatments, such as radiotherapy. The most commonly reported adverse effects are skin reactions. Some of the adverse side effects of Sorafenib are as follows:

  • Hand-foot syndrome is characterized by soreness, rashes, and peeling of skin in the soles of feet and palms.

  • Rash.

  • Diarrhea.

  • Fatigue.

  • Weight loss.

  • Increased risk susceptibility to getting an infection.

  • Frequent sickness (tiredness and feeling weak).

  • Loss of appetite.

  • High temperature with fever and chills.

  • High blood pressure.

  • Bleeding (nose bleeds).

  • Gastrointestinal disturbances (diarrhea or constipation).

  • Skin changes such as dryness and itching.

  • Hair thinning.

  • Pain (joints, abdomen).

  • Headaches.

  • Low plasma phosphate levels.

  • Elevated levels of pancreatic enzymes.

  • Cardoiovascular complications.

What Are the Precautions to Be Followed for Using Sorafenib?

  • Sorafenib should be taken on an empty stomach. If taken along with food or other drugs, It could interact with other drugs or food, reducing its efficiency.

  • In case of hypersensitivity reactions, the doctor should be consulted immediately.

  • Pregnant and lactating mothers should avoid its usage due to its toxic effects on the fetus and newborns.

  • Women who suspect pregnancy should report the condition to the doctor.

  • Patients should inform the doctor before any surgical procedure or dental extractions since Sorafenib causes mild bleeding.

  • Vitamin supplements and herbal medications should not be taken during Sorafenib therapy.

  • Immunizations with live vaccines are to be avoided.

  • Patients with liver problems should report it to the doctor before starting sorafenib therapy.

  • Any signs of adverse reaction must be reported, and Sorafenib should not be discontinued upon self-decision.

  • Excessive dosage should be reported immediately.

For Doctors

Pharmacodynamics

Sorafenib is a protein kinase inhibitor that inhibits and prevents the proliferation of neoplasms. It blocks the tyrosine kinase enzyme that helps in tumor cell proliferation. Sorafenib inhibits tumor growth and angiogenesis by blocking the pathway of growth signaling and angiogenesis (formation of new blood vessels) in cancer cells. It inhibits the enzyme RAF (rapidly accelerated fibrosarcoma) kinase that controls cancer cell division and proliferation. Sorafenib also inhibits the vascular Endothelial Growth Factor 2 (VEGFR-2), and beta-platelet derived growth factor (beta-PDGFR) signaling cascades, eventually blocking angiogenesis in tumor cells. Targeting both the RAF pathway and receptor for tyrosine kinases, Sorafenib acts as a potent antineoplastic agent.

Chemical Taxonomy of Sorafenib

Chemical Taxonomy of Sorafenib

Pharmacokinetics

Bioavailability

  • On oral administration, Sorafenib achieves an average bioavailability ranging from 38 % to 49 % and its mean half-life is 25 to 48 hours.

  • Continuous dosing of Sorafenib for seven consecutive days results in a 2.5 to seven-fold accumulation in plasma when compared to administration of a single dose.

  • Steady-state serum Sorafenib concentrations are reached within seven days.

Absorption and Distribution

  • Following oral administration in a fasting state, Sorafenib is readily absorbed and reaches peak plasma levels within 3 hours.

  • The bioavailability of Sorafenib is reduced by 29 % if taken along with a high-fat meal.

  • It is recommended that Sorafexib is administered without food to increase its absorption.

  • 99.5 % of Sorafenib binds with plasma proteins in humans.

Metabolism and Elimination

  • Metabolism of Sorafenib primarily occurs in the liver, where it undergoes oxidation mediated by cytochrome P450 3A4 (CYP3A4) enzyme and followed by UDP-glucuronosyltransferase (UGT1A9) enzyme-mediated glucuronidation.

  • There are about eight Sorafenib metabolites, accounting for about 70 % to 85 % of circulating metabolites in plasma.

  • Pyridine N-oxide is sorafenib's main circulating plasma metabolite, which comprises 9 % to 16 % of circulating metabolites at steady state.

  • For every 100 mg of the administered oral dose, 96% of the dosage is recovered within 14 days.

  • Route of Elimination - 77 % in feces and 19 % in urine in glucuronidated metabolites.

  • Unchanged Sorafenib is also eliminated through feces but is not found in urine.

Toxicity in Sorafenib Therapy

Despite the effective outcome of Sorafenib therapy in advanced renal cell carcinoma, its use is associated with various toxic effects. Its use is associated with several toxic effects, such as cardiovascular, gastrointestinal, and dermatologic complications. The following are the toxicities related to Sorafenib.

  • Cardiac ischemia and myocardial infarction.

  • Congestive heart failure.

  • Higher risk for bleeding and hemorrhage.

  • Esophageal varices.

  • Severe hypertension.

  • Dermatologic toxicities causing desquamation of hand-foot skin (Palmar-plantar erythrodysesthesia).

  • Gastrointestinal Perforation.

  • Delayed or impaired wound healing, particularly after major surgeries.

  • Liver injury.

  • Arthralgia and myalgia.

  • Transient ischemic attack.

  • Arrhythmia.

  • Thromboembolism.

  • Hypersensitivity reactions and urticaria.

  • Dyspnea.

  • Leukopenia and lymphopenia.

  • Erectile dysfunction.

  • Birth defects and fetal loss is reported when administered during pregnancy.

Dose Modifications According to the Severity of Skin Toxicity

  • In Grade 1 Toxicity - Numbness, paresthesia, tingling, erythema, and tolerable discomfort in hands and feet, no change in Sorafenib dosage. Topical symptomatic relief therapy is recommended.

  • In Grade 2 toxicity - Painful erythema and swelling of the hands or feet, Sorafenib dosage is decreased by a single dose level (400 mg per day or 400 mg every alternate day).

  • In Grade 3 toxicity - Wet desquamation along with ulceration and blistering of the hands or feet, the dosage is reduced below 400 mg per or 400 mg every alternate day. If the condition worsens, the use of Sorafenib is discontinued.

Drug Interactions

  • Increased bleeding tendencies with Warfarin co-administration.

  • Increased mortality rate when used with Carboplatin and Paclitaxel.

  • Sorafenib increases the drug bioavailability of Docetaxel and Doxorubicin.

  • Sorafenib inhibits the metabolism of Irinotecan (blocks glucuronidation).

  • Concomitant use of Sorafenib and Rifampicin reduces the bioavailability of Sorafenib.

  • Anti-epileptic drugs such as Phenytoin, Phenobarbital, and Carbamazepine increase the metabolism of Sorafenib.

  • Neomycin decreases the plasma levels of Sorafenib.

  • Sorafenib interferes with antibody production when live vaccines are administered.

Use of Sorafenib in Special Considerations

  • Pregnancy - Toxic effects on the fetus occur when administered to pregnant mothers. The reduction in dose below 400 mg twice daily could prevent toxicity in the fetus.

  • Nursing Mothers - No documented evidence on the excretion of Sorafenib in milk. Due to the potential toxicity of Sorafenib, the drug can be discontinued during nursing, or the drug is usually recommended.

  • Pediatric Use - The safety of Sorafenib in the pediatric population is not yet studied. Hypocellularity in bone marrow is observed in animal models.

  • Patients With Hepatic Dysfunction - Since Sorafenib is metabolized in the liver, dosage should be reduced in mild to moderate liver impairment.

  • Geriatric Use - No significant dose change related to adverse reactions is reported.

  • Patients With Renal Dysfunction - Fluid and electrolyte balance should be monitored in individuals susceptible to renal impairment.

Frequently Asked Questions

1.

What Is the Level of Effectiveness of Sorafenib?

Advanced kidney and liver cancer are two forms of cancer that can be treated with Sorafenib, a targeted therapy. It has demonstrated efficacy in reducing the progression of tumors and extending survival in people with these illnesses.

2.

What Conditions Does the Drug Sorafenib Treat?

Advanced liver (hepatocellular carcinoma) and kidney (renal cell carcinoma) cancers are the main conditions that Sorafenib is used to treat. It is a targeted therapy that prevents angiogenesis and tumor growth in these particular cancer types.

3.

Do Doctors Really Need to Use Gloves When Giving Sorafenib?

Yes, medical professionals should wear gloves when handling and administering Sorafenib or any other chemotherapeutic medications to guard against any skin contact and potentially hazardous drug absorption. To guarantee the security of medical workers during the delivery of drugs, appropriate protective measures are crucial.

4.

What Is Sorafenib’s Primary Target Communication Pathway?

Inhibiting many kinases, such as Raf kinase, VEGFR (vascular endothelial growth factor receptor), and PDGFR (platelet-derived growth factor receptor), which are essential for tumor cell proliferation and angiogenesis, is the main target communication pathway of Sorafenib. Particularly in cases with advanced kidney and liver tumors, this targeted activity prevents the growth and proliferation of cancer cells.

5.

Why Is Sorafenib a Prohibited Drug?

Sorafenib is not an illegal substance as of my most recent update in September 2021. It is a drug that has been FDA(Food and Drug Administration)-approved for the treatment of advanced liver and kidney cancer, and qualified patients may lawfully be prescribed it by medical experts. It is important to refer to the exact rules and legislation of the applicable jurisdiction because regulations and drug classifications may differ by region or nation.

6.

How Is Sorafenib Used for Liver Cancer Treatment?

In order to treat liver cancer, Sorafenib is commonly taken orally in the form of pills. It is administered every day as a targeted therapy to patients with advanced hepatocellular carcinoma to reduce tumor development and lengthen survival.

7.

How Well Does Sorafenib Work to Treat Hepatocellular Carcinoma?

By reducing tumor development and extending survival in patients with advanced liver cancer, Sorafenib has proven to be beneficial in the treatment of hepatocellular carcinoma. However, according to the characteristics of each patient and the stage of the disease, its overall effectiveness may vary.

8.

Why Are Patients More Likely to Bleed When Taking Kinase Inhibitors Like Sorafenib?

Because of the way kinase inhibitors like Sorafenib work, patients taking them are more likely to hemorrhage. These inhibitors work to stop the activity of kinases that are involved in blood clotting and platelet aggregation in addition to cancer cells. This disruption of regular blood clotting mechanisms may make some people more prone to bleeding and can result in bleeding problems.

9.

How Does Sorafenib Attach to a Receptor?

Sorafenib binds to particular locations on the kinase domain of its target receptors, including VEGFR and PDGFR. In malignancies like hepatocellular carcinoma and renal cell carcinoma, this binding relationship impairs the receptor's typical signaling pathway, preventing the development of tumor cells and angiogenesis.

10.

How Long Does a Typical Sorafenib Course Last?

Depending on the type of cancer being treated and how each patient reacts, the normal Sorafenib course may change. For some patients with advanced kidney or liver cancer, the treatment course frequently lasts until the illness worsens or unmanageable side effects appear, making it a long-term therapy option.

11.

How Long Should Sorafenib Be Used to Treat RAI-Refractory Thyroid Cancer?

The response of the patient to the drug and the rate of disease progression determine how long the patient will get Sorafenib treatment for RAI-refractory thyroid cancer. It is a flexible and individualized therapeutic technique where the patient receives treatment till the disease progresses or until the patient encounters severe adverse effects.

12.

How Long Does Sorafenib Provide in Terms of Months?

Depending on the precise type and stage of the cancer being treated, Sorafenib's effectiveness can vary greatly in terms of months. Sorafenib has been shown to offer a median overall survival of about 10 to 12 months in clinical studies for advanced kidney and liver cancer, but individual responses may range from a few months to several years.

13.

How Common Is Sorafenib Hair Loss?

Alopecia (hair loss caused by Sorafenib) occurs in a small percentage of patients (less than 10 %) and is relatively infrequent. The majority of the medication's adverse effects are gastrointestinal problems, weariness, and skin reactions, including hand-foot reactions.

14.

How Does Sorafenib Prevent Kinases from Acting?

Sorafenib inhibits the activity of kinases by attaching to the ATP (adenosine triphosphate ) -binding site in their kinase domains and preventing the enzymes from functioning. When kinase signaling pathways are disrupted, malignancies, including hepatocellular carcinoma and renal cell carcinoma, experience problems with tumor cell development, angiogenesis, and proliferation.

15.

When Does Sorafenib Stop Functioning?

When cancer cells acquire medication resistance or when the condition worsens in spite of therapy, Sorafenib may stop working. In certain situations, various treatment methods might be taken into account to properly manage the malignancy.
Dr. Rajesh Gulati
Dr. Rajesh Gulati

Family Physician

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