|Trade names||Nexavar, others|
|Drug class||Protein kinase inhibitor|
|Main uses||Renal cell carcinoma, hepatocellular carcinoma, thyroid cancer|
|Side effects||Diarrhea, rash, hair loss, infection, rash, tiredness|
|Defined daily dose||400 mg BID|
|Metabolism||Liver oxidation and glucuronidation (CYP3A4 & UGT1A9-mediated)|
|Elimination half-life||25–48 hours|
|Excretion||Faeces (77%) and urine (19%)|
|Chemical and physical data|
|Molar mass||464.83 g·mol−1|
|3D model (JSmol)|
Common side effects include diarrhea, rash, hair loss, infection, rash, and tiredness. Other side effects may include a heart attack, gastrointestinal perforation, liver problems, bleeding, and high blood pressure. Use in pregnancy or breastfeeding may harm the baby. It is a protein kinase inhibitor.
Sorafenib was approved for medical use in the United States in 2005 and Europe in 2006. In the United Kingdom 4 weeks of treatment costs the NHS about £3,600 as of 2021. This amount in the United States costs about 20,200 USD.
Clinical trial results, published January 2007, showed that, compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear cell renal cell carcinoma in whom previous therapy has failed. The median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio for disease progression in the sorafenib group, 0.44; 95% confidence interval [CI], 0.35 to 0.55; P<0.01).
At ASCO 2007, results from the SHARP trial were presented, which showed efficacy of sorafenib in hepatocellular carcinoma. The primary endpoint was median overall survival, which showed a 44% improvement in patients who received sorafenib compared to placebo (hazard ratio 0.69; 95% CI, 0.55 to 0.87; p=0.0001). Both median survival and time to progression showed 3-month improvements; however, there was no significant difference in median time to symptomatic progression (p=0.77). There was no difference in quality of life measures, possibly attributable to toxicity of sorafenib or symptoms related to underlying progression of liver disease. Of note, this trial only included patients with Child-Pugh Class A (i.e. mildest) cirrhosis. Because of this trial Sorafenib obtained FDA approval for the treatment of advanced hepatocellular carcinoma in November 2007.
In a randomized, double-blind, phase II trial combining sorafenib with doxorubicin, the median time to progression was not significantly delayed compared with doxorubicin alone in patients with advanced hepatocellular carcinoma. Median durations of overall survival and progression-free survival were significantly longer in patients receiving sorafenib plus doxorubicin than in those receiving doxorubicin alone.
A prospective single-centre phase II study which included the patients with unresectable hepatocellular carcinoma (HCC)concluding that the combination of sorafenib and DEB-TACE in patients with unresectable HCC is well tolerated and safe, with most toxicities related to sorafenib.
In Australia this is the only indication for which sorafenib is listed on the PBS and hence the only Government-subsidised indication for sorafenib. Along with renal cell carcinoma, hepatocellular carcinoma is one of the TGA-labelled indications for sorafenib.
On November 22, 2013, sorafenib was approved by the FDA for the treatment of locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment.
The Phase 3 DECISION trial showed significant improvement in progression-free survival but not in overall survival. However, as is known, the side effects were very frequent, specially hand and foot skin reaction.
It is generally taken at a dose of 400 mg twice per day.
Very common (>10% frequency)
- Hypophosphataemia[Note 1]
- Haemorrhage[Note 2]
- Hypertension[Note 3]
- Alopecia (hair loss; occurs in roughly 30% of patients receiving sorafenib)
- Hand-foot syndrome
- Pruritus (itchiness)
- Increased amylase
- Increased lipase
- Pain[Note 4]
- Vomiting[Note 5]
Common (1-10% frequency)
- Leucopenia[Note 6]
- Neutropoenia[Note 7]
- Anaemia[Note 8]
- Thrombocytopenia[Note 9]
- Anorexia (weight loss)
- Hypocalcaemia[Note 10]
- Hypokalaemia[Note 11]
- Peripheral sensory neuropathy
- Tinnitus[Note 12]
- Congestive heart failure
- Myocardial infarction[Note 13]
- Myocardial ischaemia[Note 14]
- Stomatitis[Note 15]
- Dyspepsia[Note 16]
- Dysphagia[Note 17]
- Dry skin
- Exfoliative dermatitis
- Skin desquamation
- Arthralgia[Note 18]
- Myalgia[Note 19]
- Kidney failure[Note 20]
- Proteinuria[Note 21]
- Erectile dysfunction
- Asthenia (weakness)
- Influenza-like illness
- Transient increase in transaminase
Uncommon (0.1-1% frequency)
- Hypersensitivity reactions[Note 22]
- Hypothyroidism[Note 23]
- Hyperthyroidism[Note 24]
- Hyponatraemia[Note 25]
- Reversible posterior leukoencephalopathy
- Hypertensive crisis
- Rhinorrhoea[Note 26]
- Interstitial lung disease-like events[Note 27]
- Gastro-oesophageal reflux disease (GORD)
- Pancreatitis[Note 28]
- Gastritis[Note 29]
- Gastrointestinal perforations[Note 30]
- Increase in bilirubin leading, potentially, to jaundice[Note 31]
- Cholecystitis[Note 32]
- Cholangitis[Note 33]
- Erythema multiforme[Note 34]
- Keratoacanthoma[Note 35]
- Squamous cell carcinoma
- Gynaecomastia (swelling of the breast tissue in men)
- Transient increase in blood alkaline phosphatase
- INR abnormal
- Prothrombin level abnormal
- bulbous skin reaction
Rare (0.01-0.1% frequency)
Mechanism of action
Sorafenib is a protein kinase inhibitor with activity against many protein kinases, including VEGFR, PDGFR and RAF kinases. Of the RAF kinases, Sorafenib is more selective for c-Raf than B-RAF. (See BRAF (gene)#Sorafenib for details the drug's interaction with B-Raf.)
Sorafenib treatment induces autophagy, which may suppress tumor growth. Based on its 1,3-disubstituted urea structure, Sorafenib is also a potent soluble epoxide hydrolase inhibitor and this activity likely reduces the severity of its adverse effects.
Sorafenib was approved by the U.S. Food and Drug Administration (FDA) in December 2005, and received European Commission marketing authorization in July 2006, both for use in the treatment of advanced renal cancer.
The European Commission granted marketing authorization to the drug for the treatment of patients with hepatocellular carcinoma(HCC), the most common form of liver cancer, in October 2007, and FDA approval for this indication followed in November 2007.
In November 2009, the UK's National Institute of Clinical Excellence declined to approve the drug for use within the NHS in England, Wales and Northern Ireland, stating that its effectiveness (increasing survival in primary liver cancer by 6 months) did not justify its high price, at up to £3000 per patient per month. In Scotland the drug had already been refused authorization by the Scottish Medicines Consortium for use within NHS Scotland, for the same reason.
In March 2012, the Indian Patent Office granted a domestic company, Natco Pharma, a license to manufacture generic Sorafenib, bringing its price down by 97%. Bayer sells a month's supply, 120 tablets, of Nexavar for₹280,000 (US$3,700). Natco Pharma will sell 120 tablets for ₹8,800 (US$120), while still paying a 6% royalty to Bayer. The royalty was later raised to 7% on appeal by Bayer. Under the Patents Act, 1970 and the World Trade Organisation TRIPS Agreement, the government can issue a compulsory license when a drug is not available at an affordable price.
Sorafenib has been studied as maintenance therapy after ovarian cancer treatment and in combination with chemotherapy for recurrent ovarian cancer but did not show results that led to approval of the drug for these indications.
A study performed in 2011 showed that sorafenib is active against aggressive fibromatosis. This study is being used as justification for using Sorafenib as an initial course of treatment in some patients with aggressive fibromatosis.
A phase 3 clinical trial is under way testing the effectiveness of Sorafenib to treat desmoid tumors (also known as aggressive fibromatosis), after positive results in the first two trial stages. Dosage is typically half of that applied for malignant cancers (400 mg vs 800 mg). NCI are sponsoring this trial.
In January 2014, Bayer's CEO Marijn Dekkers allegedly stated that Nexavar was developed for "Western Patients Who Can Afford it, not for Indians". However, Dekkers actually never said this. In fact, his words were misquoted and the context was omitted. A kidney cancer patient would pay $96,000 (£58,000) for a year's course of the Bayer-made drug, whereas the cost of the Indian version of the generic drug would be around $2,800 (£1,700).>
- Low blood phosphate levels
- Bleeding; including serious bleeds such as intracranial and intrapulmonary bleeds
- High blood pressure
- Including abdominal pain, headache, tumour pain, etc.
- Considered a low (~10-30%) risk chemotherapeutic agent for causing emesis)
- Low level of white blood cells in the blood
- Low level of neutrophils in the blood
- Low level of red blood cells in the blood
- Low level of plasma cells in the blood
- Low blood calcium
- Low blood potassium
- Hearing ringing in the ears
- Heart attack
- Lack of blood supply for the heart muscle
- Mouth swelling, also dry mouth and glossodynia
- Not being able to swallow
- Sore joints
- Muscle aches
- Kidney failure
- Excreting protein [usually plasma proteins] in the urine. Not dangerous in itself but it is indicative kidney damage
- Including skin reactions and urticaria (hives)
- Underactive thyroid
- Overactive thyroid
- Low blood sodium
- Runny nose
- Pneumonitis, radiation pneumonitis, acute respiratory distress, etc.
- Swelling of the pancreas
- Swelling of the stomach
- Formation of a hole in the gastrointestinal tract, leading to potentially fatal bleeds
- Yellowing of the skin and eyes due to a failure of the liver to adequately cope with the amount of bilirubin produced by the day-to-day actions of the body
- Swelling of the gallbladder
- Swelling of the bile duct
- A potentially fatal skin reaction
- A fairly benign form of skin cancer
- A potentially fatal abnormality in the electrical activity of the heart
- Swelling of the skin and mucous membranes
- A potentially fatal allergic reaction
- Swelling of the liver
- The rapid breakdown of muscle tissue leading to the build-up of myoglobin in the blood and resulting in damage to the kidneys
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