Sorafenib

Oral
Advanced renal cell carcinoma
Adult: In patients who have failed previous interferon-alfa or interleukin-2-based therapy, or those considered unsuitable for such treatment: 400 mg bid. Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs. Dose reduction, dosing interruption and discontinuation may be required according to individual safety or tolerability (refer to detailed product guidelines).

Oral
Hepatocellular carcinoma
Adult: 400 mg bid. Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs. Dose reduction, dosing interruption and discontinuation may be required according to individual safety or tolerability (refer to detailed product guidelines).

Oral
Locally advanced differentiated thyroid cancer
Adult: For the treatment of cases refractory to radioactive iodine therapy: 400 mg bid. Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs. Dose reduction, dosing interruption and discontinuation may be required according to individual safety or tolerability (refer to detailed product guidelines).

Oral
Metastatic differentiated thyroid cancer
Adult: For the treatment of cases refractory to radioactive iodine therapy: 400 mg bid. Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs. Dose reduction, dosing interruption and discontinuation may be required according to individual safety or tolerability (refer to detailed product guidelines).

Oral
Progressive differentiated thyroid cancer
Adult: For the treatment of cases refractory to radioactive iodine therapy: 400 mg bid. Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs. Dose reduction, dosing interruption and discontinuation may be required according to individual safety or tolerability (refer to detailed product guidelines).

Should be taken on an empty stomach. Take on an empty stomach or w/ a low or moderate fat meal. If the patient intends to have a high fat meal, sorafenib should be taken on an empty stomach at least 1 hr before or 2 hr after meals. Swallow whole, do not chew/crush.

Coadministration with carboplatin and paclitaxel in patients with squamous cell lung cancer. Pregnancy and lactation.

Patient with risk factors for aneurysms and/or artery dissections (e.g. hypertension, history of aneurysm), congenital long QT syndrome, predisposing factors for QTc interval prolongation (e.g. hypokalaemia, hypocalcaemia, hypomagnesaemia, receiving a high cumulative dose of anthracycline therapy, taking QT-prolonging antiarrhythmic agents), risk factors for tumour lysis syndrome (TLS) (e.g. high tumour burden, hypotension, dehydration, oliguria, acidic urine, chronic renal insufficiency). Patients undergoing major surgery. Patients with differentiated thyroid carcinoma (DTC) who have tracheal, bronchial, or oesophageal infiltration must be treated with localised therapy before the administration of sorafenib due to bleeding risk. Patient Counselling Women of childbearing potential must use proven birth control methods during therapy and for 6 months after stopping the treatment. Monitoring Parameters Confirm pregnancy status before therapy initiation in females of reproductive potential. Monitor CBC with differential, LFTs, lipase, amylase and phosphorus levels; TSH levels monthly and adjust thyroid replacement treatment as necessary in patients with DTC; blood glucose levels in diabetic patients; electrolytes (particularly serum Mg, K, and Ca levels) and ECG in patients at risk of QT interval prolongation. Obtain blood pressure at baseline, every week for the 1st 6 weeks, then as clinically indicated. Assess for signs and symptoms of heart failure, hypothyroidism, TLS, gastrointestinal perforation, bleeding, impaired wound healing, and dermatologic reactions.

Significant: Mild to moderate hypertension, QT/QTc interval prolongation which may result in an increased risk of ventricular arrhythmias; renal failure (especially in the elderly), hypoglycaemia, hypocalcaemia, thyroid impairment (e.g. hypothyroidism), impaired wound healing, dermatological toxicity (e.g. palmar-plantar erythrodysaesthesia, rash). Blood and lymphatic system disorders: Lymphopenia, leucopenia, anaemia, neutropenia, thrombocytopenia. Ear and labyrinth disorders: Tinnitus. Gastrointestinal disorders: Nausea, vomiting, diarrhoea, constipation, abdominal or mouth pain, stomatitis, dry mouth, glossodynia, dyspepsia, dysphagia, GERD, dysgeusia. General disorders and administration site conditions: Fatigue, fever, asthenia, mucosal inflammation, influenza-like illness. Infections and infestations: Infection, folliculitis. Investigations: Increased lipase and amylase, decreased weight, transient increase in transaminases. Metabolism and nutrition disorders: Anorexia, hypophosphataemia, hypokalaemia, hyponatraemia, dehydration. Musculoskeletal and connective tissue disorders: Arthralgia, myalgia, muscle spasms, bone pain, pain in extremity. Neoplasms benign, malignant and unspecified: Tumour pain. Nervous system disorders: Headache, peripheral sensory neuropathy. Psychiatric disorders: Depression. Renal and urinary disorders: Proteinuria. Reproductive system and breast disorders: Erectile dysfunction. Respiratory, thoracic and mediastinal disorders: Dysphonia, hoarseness, rhinorrhoea. Skin and subcutaneous tissue disorders: Dry skin, pruritus, erythema, alopecia, keratoacanthoma, exfoliative dermatitis, acne, skin desquamation, hyperkeratosis. Vascular disorders: Flushing.
Potentially Fatal: Severe bleeding, including gastrointestinal, respiratory tract and cerebral haemorrhage; CV events (e.g. CHF, cardiac ischaemia, MI), aortic aneurysm, aortic dissection, TLS, hepatotoxicity (e.g. drug-induced hepatitis, hepatic failure); severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Rarely, gastrointestinal perforation.

Symptoms: Diarrhoea and dermatologic reactions. Management: Supportive treatment.

Increased risk of infrequent bleeding and elevated INR when given with warfarin or phenprocoumon. Sorafenib plasma concentration may be decreased by CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, dexamethasone). May increase the exposure to doxorubicin, irinotecan, and docetaxel. Neomycin may reduce the serum levels of sorafenib. May increase risk of QT prolongation when given with agents known to prolong QT/QTc interval (e.g. class I or III antiarrhythmic agents).
Potentially Fatal: Increased risk of respiratory failure, infectious events, and haemorrhage when coadministered with platinum-based chemotherapy (e.g. paclitaxel carboplatin), particularly in patients with squamous cell lung cancer.

Reduced absorption (by aprox 30%) with high-fat meals. May decrease plasma concentration with St. John's wort.

Sorafenib is a multikinase inhibitor antineoplastic agent. It blocks tumour growth and angiogenesis by inhibiting the activities of intracellular Raf kinases and cell surface kinase receptors, including vascular endothelial growth factor (VEGF) receptors (VEGFR-1, VEGFR-2, VEGFR-3), platelet-derived growth factor receptor β (PDGFR-β).
Absorption: Reduced absorption (by aprox 30%) with high-fat meals. Bioavailability: 38-49%. Time to peak plasma concentration: Approx 3 hours.
Distribution: Plasma protein binding: 99.5%.
Metabolism: Metabolised mainly in the liver via oxidation by CYP3A4 isoenzyme and to a smaller extent via glucuronidation mediated by UGT1A9.
Excretion: Via faeces (77%; 51% as unchanged drug); urine (19% as glucuronidated metabolites). Elimination half-life: 25-48 hours.

Targeted Cancer Therapy

L01EX02 - sorafenib