Sorafenib (Nexavar) is classified as a multikinase inhibitor, which means it works by blocking the action of several different enzymes and proteins that are involved in the growth and spread of cancer cells.

Sorafenib (Nexavar) Uses:

• Unresectable Hepatocellular cancer:
• Advanced Renal cell cancer:
• Differentiated Thyroid Cancer (locally recurrent, metastatic, progressive and refractory to radioactive iodine treatment)
• Off-Label Use of Sorafenib in Adults:
  • Recurrent or metastatic Angiosarcoma
  • Resistant or refractory gastrointestinal stromal tumor

Sorafenib (Nexavar) Dose in Adults

Note: In patients undergoing major surgical procedures, interrupt treatment (temporarily).

Sorafenib (Nexavar) Dose in the Treatment of Hepatocellular Cancer (HCC):

• Take 400 mg of sorafenib orally two times a day until it no longer benefits you or causes harmful effects.
• According to a study, a lower initial dose of sorafenib (less than 800 mg/day) was associated with lower pill burden, reduced cost, and less chance of discontinuation without affecting overall survival rates.
• This is especially true for patients with Child-Pugh class A or B impairment.
• The average starting dose of sorafenib in the study was 367 mg/day, and less than half of the patients had their doses increased within two months of starting the treatment.

Sorafenib (Nexavar) Dose in the Treatment of Advanced Renal Cell Cancer (RCC):

• Take 400 mg twice a day.
• Keep taking it until it no longer helps or it causes harmful effects that cannot be tolerated.

Sorafenib (Nexavar) Dose in the Treatment of Differentiated Thyroid Cancer:

• Take 400 mg twice a day.
• Keep taking it until the disease gets worse or it causes harmful effects that cannot be tolerated.

Sorafenib (Nexavar) Dose in the treatment of Angiosarcoma (off-label):

• Take 400 mg twice daily.

Sorafenib (Nexavar) Dose in the treatment of Gastrointestinal stromal tumor (GIST) (off-label):

• Take 400 mg two times a day.
• Keep taking it until the disease gets worse or it causes harmful effects that cannot be tolerated.

Pregnancy Risk Category:

• Sorafenib may have harmful effects on pregnancy based on its mechanism of action and studies on animals.
• It can interfere with the formation of blood vessels, which is an important process for the growth and development of the fetus.
• Therefore, before starting sorafenib treatment, it's important to check if a woman of reproductive age is pregnant or planning to become pregnant.
• Women of reproductive age who are receiving sorafenib treatment should use effective non-hormonal birth control methods during the treatment and for six months after the final dose.
• Men who have female partners who can become pregnant should use effective birth control methods during the treatment and for three months after the last dose.
• Sorafenib may also reduce male fertility according to animal studies.

Use Sorafenib while you breastfeed

• It's unclear whether sorafenib is present in breast milk.
• To avoid any potential risks to the nursing infant, the manufacturer advises women to stop breastfeeding while receiving sorafenib treatment and for two weeks after the last dose.
• This is because sorafenib can have severe side effects in infants who are breastfed.

Sorafenib (Nexavar) Dose in Kidney Disease:

• Manufacturer’s labeling:
  • According to the manufacturer's labeling, sorafenib does not require a dosage adjustment for people with mild, moderate, or severe impairment of kidney function that is not dependent on dialysis. However, there are no studies available to determine the appropriate dosage for people who are undergoing dialysis treatment.

To determine a safe initial dose of sorafenib for patients with different levels of kidney function, a pharmacokinetic study was conducted. The study identified the following starting doses based on the patient's tolerance levels:

• For patients with a creatinine clearance (CrCl) of 40 to 59 mL/minute: 400 mg twice daily
• For patients with a CrCl of 20 to 39 mL/minute: 200 mg twice daily
• There is not enough data available to determine a dose for patients with a CrCl less than 20 mL/minute.
• For patients undergoing hemodialysis (with any CrCl): 200 mg once daily.

Sorafenib (Nexavar) Dose in Liver Disease:

Hepatic impairment at baseline:

According to the manufacturer's labeling:

For patients with mild to moderate liver impairment (Child-Pugh class A and B):

• No dosage adjustment is needed.
• Follow the recommended dosage as directed.

For patients with severe liver impairment (Child-Pugh class C):

• The manufacturer's labeling does not provide specific dosage adjustment instructions.
• However, caution should be exercised when using sorafenib in patients with severe liver impairment.
• Close monitoring of liver function is advised.

To determine a safe initial dose of sorafenib for patients with different levels of kidney function, a pharmacokinetic study was conducted. The study identified the following starting doses based on the patient's tolerance levels:

• For individuals with mild hepatic dysfunction (bilirubin levels greater than 1 but less than or equal to 1.5 times the upper limit of normal [ULN] and/or AST levels higher than the ULN):
  • The recommended dose is 400 mg taken twice daily.

• For individuals with moderate hepatic dysfunction (bilirubin levels greater than 1.5 but less than or equal to 3 times the upper limit of normal [ULN] and any AST levels):
  • The recommended dose is 200 mg taken twice daily.

• For individuals with severe hepatic dysfunction:
  • If the albumin level is less than 2.5 g/dL (regardless of bilirubin and AST levels), the recommended dose is 200 mg taken once daily.
  • If the bilirubin levels are greater than 3 to 10 times the upper limit of normal (ULN) and any AST levels, a dosage of 200 mg every 3 days was not tolerated in the study. Therefore, no specific dosage recommendation was identified for patients with these parameters in the pharmacokinetic study.

In cases of severe drug-induced liver injury during treatment, the following actions should be taken:

• If ALT (alanine aminotransferase) elevation is grade 3 or higher (in the absence of another cause), sorafenib should be permanently discontinued without resuming treatment.
• If ALT and AST (aspartate aminotransferase) levels are greater than 3 times the upper limit of normal (ULN) along with bilirubin levels greater than 2 times the ULN (in the absence of another cause), sorafenib should be permanently discontinued without resuming treatment.
• If there is an increase in alkaline phosphatase (any grade) in the absence of known bone pathology, sorafenib should be permanently discontinued without resuming treatment.
• If there is an increase in bilirubin levels of grade 2 or higher, sorafenib should be permanently discontinued without resuming treatment.
• If INR (international normalized ratio) is equal to or greater than 1.5 and considered to be due to drug-induced liver injury, sorafenib should be permanently discontinued without resuming treatment.
• If there is the presence of ascites and/or encephalopathy (in the absence of underlying cirrhosis or other organ failures) considered to be due to drug-induced liver injury, sorafenib should be permanently discontinued without resuming treatment.

Common Side Effects of Sorafenib (Nexavar):

• Cardiovascular:
  • Hypertension
• Central Nervous System:
  • Fatigue
  • Headache
  • Mouth Pain
  • Voice Disorder
  • Peripheral Sensory Neuropathy
  • Pain
• Dermatologic:
  • Palmar-Plantar Erythrodysesthesia
  • Alopecia
  • Skin Rash
  • Pruritus
  • Xeroderma
  • Erythema
• Endocrine & Metabolic:
  • Hypoalbuminemia
  • Weight Loss
  • Hypophosphatemia
  • Increased Thyroid Stimulating Hormone Level
  • Hypocalcemia
  • Increased Amylase
• Gastrointestinal:
  • Diarrhea
  • Increased Serum Lipase
  • Abdominal Pain
  • Decreased Appetite
  • Anorexia
  • Stomatitis
  • Nausea
  • Constipation
  • Vomiting
• Hematologic & Oncologic:
  • Lymphocytopenia
  • Thrombocytopenia
  • Increased INR
  • Neutropenia
  • Hemorrhage
  • Leukopenia
• Hepatic:
  • Increased Serum ALT
  • Increased Serum AST
  • Hepatic Insufficiency
• Infection:
  • Infection
• Neuromuscular & Skeletal:
  • Limb Pain
  • Weakness
  • Myalgia
• Respiratory:
  • Dyspnea
  • Cough
• Miscellaneous:
  • Fever

Less Common Side Effects Of Sorafenib (Nexavar):

• Cardiovascular:
  • Ischemic Heart Disease
  • Cardiac Failure
  • Flushing
• Central Nervous System:
  • Depression
  • Glossalgia
• Dermatologic:
  • Hyperkeratosis
  • Acne Vulgaris
  • Exfoliative Dermatitis
  • Folliculitis
• Endocrine & Metabolic:
  • Hypokalemia
  • Hyponatremia
  • Hypothyroidism
• Gastrointestinal:
  • Dysgeusia
  • Dyspepsia
  • Dysphagia
  • Gastroesophageal Reflux Disease
  • Mucositis
  • Xerostomia
• Genitourinary:
  • Erectile Dysfunction
  • Proteinuria
• Hematologic & Oncologic:
  • Squamous Cell Carcinoma Of Skin
  • Anemia
• Hepatic:
  • Increased Serum Transaminases
• Neuromuscular & Skeletal:
  • Muscle Spasm
  • Arthralgia
  • Myalgia
• Renal:
  • Renal Failure
• Respiratory:
  • Epistaxis
  • Flu-Like Symptoms
  • Hoarseness
  • Rhinorrhea

Contraindications to Sorafenib (Nexavar):

Sorafenib should not be used in the following situations:

• If there is known severe hypersensitivity reactions to sorafenib or any component of the formulation.
• This means that individuals who have experienced a serious allergic reaction to sorafenib or any of its ingredients should not take this medication.
• In combination with carboplatin and paclitaxel for the treatment of squamous cell lung cancer.
• This specific combination therapy should be avoided in patients with squamous cell lung cancer.

Warnings and precautions

Bleeding

• Taking sorafenib may increase the risk of bleeding.
• If there are serious bleeding events that require medical attention, the drug may need to be stopped permanently.
• Some people have died due to bleeding caused by sorafenib.
• If you have thyroid cancer with infiltration in your trachea, bronchi, or esophagus, you should get local treatment before taking sorafenib to avoid bleeding risk.

Cardiovascular events

• Sorafenib may lead to problems with the heart, such as cardiac ischemia (reduced blood flow to the heart) or heart attack.
• If patients develop these conditions, it may be necessary to temporarily or permanently stop taking sorafenib.
• The use of sorafenib in patients with unstable coronary artery disease or recent heart attack has not been studied.
• Heart failure (a condition where the heart cannot pump blood effectively) has been reported in several clinical studies.
• According to a statement from the American Heart Association, sorafenib is considered a drug that could worsen pre-existing heart problems, although the impact is considered minor.

Dermatologic toxicities:

• The most common side effects related to sorafenib are hand-foot skin reaction (HFSR) and rash, usually of mild to moderate severity (grades 1 or 2). These side effects typically occur within the first 6 weeks of treatment. They can be managed with topical treatments, treatment delays, or reducing the dose of sorafenib. In cases of severe or persistent dermatologic toxicities, it may be necessary to permanently stop taking sorafenib. The risk of HFSR increases with higher cumulative doses of sorafenib.
• Severe dermatologic toxicities, such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported and can be life-threatening. If SJS or TEN is suspected, sorafenib should be discontinued immediately.
• In addition to the recommended dosage adjustments, the following treatments can be used to manage HFSR, as suggested by Lacouture in 2008:
  • Before starting treatment, it is recommended to have a pedicure to remove areas of thickened skin (calluses) that could increase the risk of HFSR. It is also advised to avoid activities that stress the hands or feet.
  • During therapy, patients should minimize exposure to hot water, as it can worsen HFSR symptoms. It is important to avoid wearing tight shoes and to reduce friction on the skin.
  • Patients may find relief by wearing thick cotton gloves or socks and using shoes with padded insoles.
  • Grade 1 HFSR can be relieved with moisturizing creams, cotton gloves and socks at night, and keratolytic creams containing urea (20% to 40%) or salicylic acid (6%).
  • For grade 2 HFSR, a topical steroid such as clobetasol ointment can be applied twice daily to areas with redness. Topical anesthetics like lidocaine (2%) and systemic analgesics (if appropriate) can be used for pain control.
  • As acute redness subsides, the affected areas may become thickened. Keratolytic agents can be used to soften these areas.

Perforation of the GI:

• Although rare, cases of gastrointestinal (GI) perforation have been reported with the use of sorafenib.
• It is important to closely monitor patients for any signs or symptoms that may indicate GI perforation, such as abdominal pain, constipation, or vomiting.
• If GI perforation is suspected, treatment with sorafenib should be discontinued immediately.

Hepatotoxicity

• The use of sorafenib can lead to a condition known as sorafenib-induced hepatitis, which is characterized by liver damage with elevated levels of liver enzymes (transaminases).
• This can potentially progress to hepatic failure and even death.
• There may also be increases in bilirubin levels and changes in INR (a measure of blood clotting).
• Although rare, severe drug-induced liver injury with transaminase elevations greater than 20 times the upper limit of normal (ULN) or with significant clinical consequences, such as elevated INR, ascites, or the need for liver transplantation or resulting in fatality, has been reported.
• Regular monitoring of liver function tests is important while on sorafenib treatment.
• If there is a significant increase in transaminase levels without an alternative explanation (such as viral hepatitis or disease progression), sorafenib should be discontinued.

Hypertension

• Sorafenib can cause an increase in blood pressure, typically in the mild-to-moderate range, especially during the first 6 weeks of treatment.
• It is important to monitor blood pressure regularly.
• Caution should be exercised in patients with pre-existing hypertension or poorly controlled blood pressure.
• If a patient develops severe or persistent hypertension despite receiving appropriate antihypertensive therapy, consideration should be given to temporary or permanent discontinuation of sorafenib.
• Close monitoring and appropriate management of blood pressure are essential during treatment with sorafenib.

Extension of QT

• Sorafenib use has been associated with QT prolongation, which may increase the risk of ventricular arrhythmias.
• It is important to avoid the use of sorafenib in patients with congenital long QT syndrome.
• Electrolyte levels and electrocardiograms (ECGs) should be monitored in patients with heart failure, bradyarrhythmias, and those taking medications known to prolong the QT interval.
• Any electrolyte imbalances, such as low levels of calcium, magnesium, or potassium, should be corrected. Treatment with sorafenib should be interrupted if the QTc interval (corrected QT interval) exceeds 500 msec or shows an increase of 60 msec or more from the baseline.
• Monitoring and appropriate management of QT interval and electrolyte levels are necessary to minimize the risk of serious cardiac events.

Thyroid impairment

• Sorafenib can interfere with the suppression of thyroid function.
• In studies involving patients with thyroid cancer, elevations in thyroid-stimulating hormone (TSH) levels were frequently observed.
• It is important to monitor TSH levels on a monthly basis and as clinically necessary.
• Thyroid replacement therapy may need to be adjusted based on the TSH levels to maintain optimal thyroid function.
• Regular monitoring and appropriate management of thyroid function are essential during sorafenib treatment.

Wound healing complications

• Sorafenib treatment may interfere with the normal process of wound healing.
• Therefore, it is recommended to temporarily stop treatment in patients who are undergoing major surgical procedures.
• The optimal timing for resuming sorafenib after major surgery has not been established and should be determined on a case-by-case basis in consultation with the healthcare provider.
• Close monitoring and appropriate management of wound healing are important to minimize the risk of complications.

Sorafenib: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Complete blood count (CBC) with differential: To assess for any abnormalities in blood cell counts.
• Electrolytes (magnesium, potassium, calcium) and phosphorus: To monitor electrolyte levels, as imbalances can occur with sorafenib treatment.
• Lipase and amylase levels: To evaluate pancreatic function and monitor for potential pancreatitis.
• Liver function tests: Including transaminases (ALT, AST), bilirubin, and INR to assess hepatic function and monitor for hepatotoxicity.
• Pregnancy test: It is recommended to perform a pregnancy test in females of reproductive potential prior to initiating sorafenib treatment, as it can cause adverse effects on pregnancy.
• Blood pressure: Baseline measurement should be obtained, followed by weekly monitoring for the first 6 weeks of treatment, and periodic monitoring thereafter.
• Monitoring for hand-foot skin reaction and other dermatologic toxicities: Regular evaluation of the skin for any signs of skin reactions, such as redness, blistering, or peeling.
• Electrocardiogram (ECG) in patients at risk for prolonged QT interval: To assess for any QT prolongation, which can increase the risk of ventricular arrhythmias.
• Monitoring for signs/symptoms of bleeding, GI perforation, and heart failure: Close observation for any signs such as abdominal pain, vomiting, or cardiac symptoms.

Thyroid function testing:

• Depending on the indication, monitoring of thyroid-stimulating hormone (TSH) levels may be required.
• For differentiated thyroid cancer, monthly TSH monitoring is recommended. In patients with renal cell carcinoma (RCC) or hepatocellular carcinoma (HCC), the monitoring frequency may vary based on preexisting levothyroxine therapy or the absence of thyroid hormone replacement.

Additionally, it is important to monitor patient adherence to the prescribed treatment regimen to ensure optimal therapeutic outcomes. Regular communication and follow-up with the healthcare provider are essential to address any concerns or side effects that may arise during sorafenib treatment.

How to administer Sorafenib (Nexavar)?

• Sorafenib should be administered on an empty stomach. It is recommended to take it either 1 hour before or 2 hours after eating.
• This allows for better absorption of the medication and helps maintain consistent blood levels for optimal effectiveness.
• Following the specific instructions regarding the timing of administration in relation to meals is important to ensure the desired therapeutic effect of sorafenib.

Mechanism of action of Sorafenib (Nexavar MOA):

Sorafenib is a multikinase inhibitor that exerts its therapeutic effects by inhibiting tumor growth and angiogenesis. It achieves this by targeting various intracellular Raf kinases, including CRAF, BRAF, and mutant BRAF, as well as several cell surface kinase receptors such as VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-beta, cKIT, FLT-3, RET, and RET/PTC.

International Brands of Sorafenib:

• NexAVAR
• Nexavar
• Sofenib
• Sorafen
• Soranib
• Soranix

Sorafenib Brand Names in Pakistan: