Sorafenib (Nexavar) is a multikinase inhibitor that is used as a targeted therapy in patients with liver cancer, kidneys and thyroid cancers.

Sorafenib (Nexavar) Uses:

• Hepatocellular cancer:

  • Unresectable hepatocellular cancer (HCC) treatment

• Advanced Renal cell cancer:

  • Advanced renal cell cancer (RCC) treatment

• Differentiated Thyroid cancer:

  • Locally recurrent or metastatic, progressive, differentiated thyroid cancer treatment (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):

• P/O:
  • 400 mg twice daily.
  • Continue until no longer clinically benefiting or until unacceptable toxicity occurs (Llovet 2008).

• Off-label dosing:

  • In patients with hepatocellular carcinoma, a large retrospective analysis determined that a reduced initial dose (<800 mg/day) was associated with a reduced pill burden, reduced cost, and a trend toward reduced discontinuation rates while not associated with inferior overall survival rates.
  • Most patients had Child-Pugh class A or B impairment.
  • the average sorafenib starting dose was 367 mg/day.
  • Within 2 months of initiation, doses were escalated in less than half of the patients (Reiss 2017).

Sorafenib (Nexavar) Dose in the treatment of advanced Renal cell cancer (RCC):

• P/O:
  • 400 mg twice daily.
  • Continue until no longer clinically benefiting or until unacceptable toxicity occurs (Escudier 2007; Escudier 2009)

Sorafenib (Nexavar) Dose in the treatment of differentiated Thyroid cancer:

• P/O:
  • 400 mg twice daily.
  • Continue until disease progression or until unacceptable toxicity (Brose 2014).

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

• P/O:
  • 400 mg twice daily (Maki 2009)

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

• P/O:
  • Until disease progression or unacceptable toxicity, 400 mg twice daily (Kindler 2011; Montemurro 2013; Park 2012)

Pregnancy Risk Category:

• Based on animal reproduction studies and the mechanism of action, adverse effects on pregnancy could be expected.
• Sorafenib blocks angiogenesis, which is crucial for fetal development.
• Before you start sorafenib therapy, assess the pregnancy status of females with reproductive potential.
• Females with reproductive potential should use a non-hormonal contraceptive method for six months following treatment.
• Effective contraception should be used by males who have female partners with reproductive potential during treatment and for three months following the last sorafenib dosage.
• Based on animal data, Sorafenib could impair male fertility

Use Sorafenib while you breastfeed

• It is unknown if sorafenib can be found in breast milk.
• Manufacturers recommend that breastfeeding be stopped during sorafenib treatment. This is in addition to stopping breastfeeding for at least 2 weeks after the last sorafenib dose.

Sorafenib (Nexavar) Dose in Kidney Disease:

• Manufacturer’s labeling:
  • No dosage adjustment is necessary for mild, moderate, or severe impairment (not dependent on dialysis).
  • Has not been studied in dialysis patients.
• In patients with varying degrees of renal dysfunction, a pharmacokinetic study evaluated sorafenib dosing to determine an initial tolerable dose.
• The following empiric starting doses were identified based on patient tolerance (Miller 2009):
  • • CrCl 40-59 mL/min:
      • 400 mg twice daily
    • CrCl 20-39 mL/min:
      • 200 mg twice daily
    • CrCl <20 mL/min:
      • Data inadequate to define dose
    • Hemodialysis (any CrCl):
      • 200 mg once daily

Sorafenib (Nexavar) Dose in Liver disease:

Hepatic impairment at baseline:

• Manufacturer's labeling:

  • Mild to moderate (Child-Pugh class A and B) impairment:
    • No dosage adjustment is necessary.
  • Severe impairment (Child-Pugh class C):
    • In the manufacturer's labeling, there are no dosage adjustments provided (has not been studied).
• A pharmacokinetic study evaluated sorafenib dosing to determine an initial tolerable dose in patients with varying degrees of hepatic dysfunction. The following empiric starting doses were identified based on patient tolerance (Miller 2009):
  • Mild hepatic dysfunction (bilirubin >1 to ≤1.5 times ULN and/or AST >ULN):
    • 400 mg twice daily
  • Moderate hepatic dysfunction (bilirubin >1.5 to ≤3 times ULN; any AST):
    • 200 mg twice daily
  • Severe hepatic dysfunction:
    • Albumin <2.5 g/dL (any bilirubin and any AST):
      • 200 mg once daily
    • Bilirubin >3 to 10 x ULN (any AST):
      • A dose of 200 mg every 3 days was not tolerated, therefore no dosage was identified in this pharmacokinetic study for patients meeting these parameters.
  • Drug-induced liver injury during treatment (severe):
    • ALT elevation, grade 3 or higher (in the absence of another cause):
      • Permanently discontinue (do not resume).
    • ALT, AST >3 times ULN with bilirubin >2 times ULN (in the absence of another cause):
      • Permanently discontinue (do not resume).
    • Alkaline phosphatase increase (any grade) in the absence of known bone pathology:
      • Permanently discontinue (do not resume).
    • Bilirubin increase (grade 2 or higher):
      • Permanently discontinue (do not resume).
    • INR ≥1.5 considered to be due to drug-induced liver injury:
      • Permanently discontinue (do not resume).
    • Ascites and/or encephalopathy (in the absence of underlying cirrhosis or other organ failure) considered to be due to drug-induced liver injury:
      • Permanently discontinue (do not resume).

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):

• Hypersensitivity to sorafenib and any component of the formulation.
• Use in combination with paclitaxel and carboplatin for patients with squamous-cell lung cancer.

Warnings and precautions

• Bleeding

  • An increase in bleeding risk may be possible
  • If you experience severe bleeding (eg, needs medical intervention), consider stopping your use permanently
  • There have been reports of fatal bleeding.
  • Patients with thyroid cancer who have esophageal, tracheal or bronchial infiltration must be treated locally before sorafenib can be administered.

• Cardiovascular events

  • Could cause infarction or cardiac ischemia.
  • Consider discontinuing treatment for patients with these conditions.
  • Patients with unstable coronary disease or myocardial injury have not been tested.
  • Multiple clinical studies have shown that heart failure is a common complication.
  • In a scientific statement by the American Heart Association, Sorafenib was found to be an agent that can exacerbate myocardial dysfunction. (magnitude: Minor).

• Dermatologic toxicities:

  • The most common adverse drug-related events are hand-foot skin reactions & rash (generally grade 1 or 2), which usually appear within 6 weeks of starting treatment.
  • Most cases can be managed by topical treatment, dose reductions and delay.
  • In cases of persistent or severe dermatological toxicities, consider discontinuing treatment.
  • The risk of hand-foot reactions to sorafenib increased with increasing cumulative doses
  • There have been reports of severe dermatologic toxicities including Stevens-Johnson syndrome and toxic epidermal necrolysis that could be life-threatening.
  • For SJS or TEN suspected, discontinue sorafenib.

  • These treatments can be used in conjunction with the recommended dosage modifications to treat hand-foot skin reactions.

    • Before starting treatment, a pedicure is recommended. This will remove any hyperkeratotic calluses or areas that may be predisposed to HFSR.
    • Avoid strenuous exercise/activities that may cause stress to your feet or hands.
    • Patients should avoid hot water exposure during therapy as it can worsen hand-foot symptoms.
    • Avoid wearing constrictive shoes and excessive skin friction.
    • Patients can also wear thick cotton socks or gloves and should wear shoes with padded soles.
    • Grade 1 HFSR can be treated with moisturizing creams and cotton gloves (at night), and keratolytic creams like urea (20%-40%) or salicylic Acid (6%).
    • To control pain, apply a topical steroid (eg clobetasol cream ointment), twice daily to the erythematous zones of grade 2 HFSR.
    • Keratotic areas may develop from acute erythema. These can be treated with keratolytic drugs.

• Perforation of the GI:

  • Rarely, GI perforation has been reported.
  • Check for symptoms (abdominal pain or constipation) in patients.
  • Stop treatment if gastrointestinal perforation is observed

• Hepatotoxicity

  • Hepatitis caused by Sorafenib (characterized as a hepatocellular pattern liver damage with significant rises in transaminases), which can lead to hepatic failure and death has been reported.
  • There may be bilirubin increases and bilirubin elevations.
  • Rarely did we see severe drug-induced liver injury (transaminase elevations greater than 20 times the ULN or significant clinical sequelae [eg elevated INR, ascites or transplantation or death]).
  • Regularly test your liver function.
  • Stop taking sorafenib if transaminases are significantly elevated without any other explanation.

• Hypertension

  • It may cause hypertension, especially in the first six weeks of treatment.
  • Pay attention.
  • Patients with hypertension that is not controlled or underlying should be cautious.
  • Patients with persistent or severe hypertension should be considered discontinuing antihypertensive therapy.

• Extension of QT

  • It has been shown that QT can be prolonged.
  • May increase the chance of ventricular arrhythmia.
  • Patients with congenital long QT syndrome should be avoided.
  • Patients with heart failure, bradyarrhythmias and patients taking concurrent medications that can prolong the QT interval should monitor electrolytes and ECG.
  • Correct electrolyte imbalances (calcium-magnesium-potassium).
  • Interrupt treatment for QTc intervals >500 msec, or for >=60msec increase in baseline.

• Thyroid impairment

  • Exogenous thyroid suppression is impaired by Sorafenib.
  • TSH levels were frequently elevated in the thyroid cancer study.
  • TSH levels should be checked monthly. If necessary, adjust the thyroid replacement as required.

• Wound healing complications

  • This can complicate wound healing.
  • Patients undergoing major surgery may be temporarily withheld from receiving treatment.
  • It is not known when it is appropriate to resume sorafenib following major surgery.

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:

• CBC with differential, electrolytes (magnesium, potassium, calcium), phosphorus, lipase & amylase levels.
• Liver function tests.
• Pregnancy test (females of reproductive potential prior to initiating sorafenib treatment).
• Blood pressure (baseline, weekly for the first 6 weeks, then periodic).
• Examine for a hand-foot skin reaction and other dermatologic toxicities.
• Examine ECG in patients at risk for extended QT interval.
• signs/symptoms of bleeding, GI perforation, and heart failure.
• Monitor adherence.

Thyroid function testing:

• Patients with differentiated thyroid cancer:

  • Monitor TSH monthly.

• Patients with RCC and HCC:

  • Preexisting levothyroxine therapy:

    • Obtain baseline TSH levels, then monitor every 4 weeks until levels & levothyroxine dose are stable, then examine every 2 months

  • Without preexisting thyroid hormone replacement:

    • TSH at baseline, then every 4 weeks for 4 months, then every 2-3 months

How to administer Sorafenib (Nexavar)?

• Administer on an empty stomach (1 hour before or 2 hours after eating).

Mechanism of action of Sorafenib (Nexavar):

• Sorafenib is a multikinase inhibitor that inhibits tumor growth and angiogenesis by inhibiting intracellular Raf kinases (CRAF, BRAF, and mutant BRAF), and cell surface kinase receptors (VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-beta, cKIT, FLT-3, RET, and RET/PTC)

Protein binding:

• 99.5%

Metabolism:

• Hepatic, via CYP3A4 (primarily oxidated to the pyridine N-oxide; active, minor) & UGT1A9 (glucuronidation)

Bioavailability:

• 38%-49%.
• Reduced by 29% when administered with a high-fat meal

Half-life elimination:

• 25-48 hours

Time to peak, plasma:

• ~3 hours

Excretion:

• Feces (77%, 51% of dose as unchanged drug).
• Urine (19%, as metabolites)

International Brands of Sorafenib:

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

Sorafenib Brand Names in Pakistan: