Sorafenib

Sorafenib is a multikinase inhibitor with both anti-proliferative and anti-angiogenic properties in vitro and in vivo. It acts on kinases inside the tumour cell and on receptor kinases in the tumour blood vessels, so it attacks tumour growth on two fronts.

Mechanism of Action

• Targets in the tumour cell: CRAF, BRAF (including V600E-mutant BRAF), c-KIT and FLT-3. The RAF kinases are serine/threonine kinases of the RAS/MAPK signalling pathway; c-KIT and FLT-3 are receptor tyrosine kinases.
• Targets in the tumour vasculature: CRAF, VEGFR-2, VEGFR-3 and PDGFR-β. Blocking them reduces tumour angiogenesis.
• Effects in models: sorafenib reduces tumour-cell proliferation in vitro and inhibits the growth of a broad range of human tumour xenografts in mice, with reduced angiogenesis.
• Active metabolite: the main circulating metabolite, the pyridine N-oxide, has an in vitro potency similar to that of sorafenib.
• Cardiac electrophysiology: sorafenib has been shown to prolong the QT/QTc interval.

Pharmacokinetics

• Absorption: mean relative bioavailability of the tablets is 38–49% compared with an oral solution (absolute bioavailability is not known). Peak plasma concentrations are reached in about 3 hours. A high-fat meal reduces absorption by about 30% compared with fasting. Above 400 mg twice daily, Cmax and AUC rise less than in proportion to the dose. Repeated dosing for 7 days gives 2.5- to 7-fold accumulation, with steady state reached within 7 days. Steady-state concentrations in thyroid carcinoma are about twice those in renal cell and hepatocellular carcinoma, for reasons that are unknown.
• Distribution: about 99.5% bound to human plasma proteins in vitro.
• Metabolism: mainly hepatic, by CYP3A4 (oxidation) and UGT1A9 (glucuronidation). Glucuronide conjugates can be cleaved by gut bacteria and reabsorbed; neomycin interferes with this and lowered mean bioavailability by 54%. The parent drug is about 70–85% of circulating analytes at steady state; the pyridine N-oxide metabolite is about 9–16%.
• Elimination: half-life about 25–48 hours. After an oral solution dose, 96% was recovered within 14 days: 77% in faeces and 19% in urine as glucuronidated metabolites. Unchanged drug (51% of the dose) was found in faeces but not in urine, suggesting that biliary excretion may contribute.
• Special populations: no relationship between exposure and age (up to 65 years), gender or body weight, and no clinically relevant difference between Caucasian and Asian subjects. Mild, moderate or severe renal impairment does not change exposure (no data for dialysis). Exposure in Child-Pugh A and B hepatic impairment is comparable with that in patients without it; there are no data for Child-Pugh C, where exposure may be higher because sorafenib is mainly eliminated by the liver. No paediatric studies have been done.

• Hepatocellular carcinoma: treatment of hepatocellular carcinoma.
• Renal cell carcinoma: patients with advanced renal cell carcinoma who have failed prior interferon-alpha or interleukin-2 based therapy or are considered unsuitable for such therapy.
• Differentiated thyroid carcinoma: patients with progressive, locally advanced or metastatic, differentiated (papillary, follicular or Hürthle cell) thyroid carcinoma that is refractory to radioactive iodine.

• Hypersensitivity to sorafenib or to any of the excipients.

The most common side effects are diarrhoea, fatigue, alopecia, infection, hand-foot skin reaction (palmar-plantar erythrodysaesthesia) and rash. The most important serious reactions are myocardial infarction or ischaemia, gastrointestinal perforation, drug-induced hepatitis, haemorrhage and hypertension or hypertensive crisis. The frequencies below come from the SmPC table, which combines clinical trials and post-marketing reports.

Very common (≥1/10): infection, lymphopenia, anorexia, hypophosphataemia, haemorrhage (including gastrointestinal, respiratory tract and cerebral haemorrhage), hypertension, diarrhoea, nausea, vomiting, constipation, dry skin, rash, alopecia, hand-foot skin reaction, erythema, pruritus, arthralgia, fatigue, pain (including mouth, abdominal, bone and tumour pain and headache), fever, weight loss, increased amylase and lipase.

Common (≥1/100 to <1/10): folliculitis, leucopenia, neutropenia, anaemia, thrombocytopenia, hypothyroidism, hypocalcaemia, hypokalaemia, hyponatraemia, hypoglycaemia, depression, peripheral sensory neuropathy, dysgeusia, tinnitus, congestive heart failure, myocardial ischaemia and infarction, flushing, rhinorrhoea, dysphonia, stomatitis (including dry mouth and glossodynia), dyspepsia, dysphagia, gastro-oesophageal reflux disease, keratoacanthoma or squamous cell carcinoma of the skin, exfoliative dermatitis, acne, skin desquamation, hyperkeratosis, myalgia, muscle spasms, renal failure, proteinuria, erectile dysfunction, asthenia, influenza-like illness, mucosal inflammation, transient increase in transaminases.

Uncommon (≥1/1,000 to <1/100): hypersensitivity reactions (including skin reactions and urticaria), anaphylactic reaction, hyperthyroidism, dehydration, reversible posterior leukoencephalopathy, hypertensive crisis, interstitial lung disease-like events (pneumonitis, radiation pneumonitis, acute respiratory distress syndrome and others), pancreatitis, gastritis, gastrointestinal perforation, raised bilirubin and jaundice, cholecystitis, cholangitis, eczema, erythema multiforme, gynaecomastia, transient increase in alkaline phosphatase, abnormal INR, abnormal prothrombin level.

Rare (≥1/10,000 to <1/1,000): angioedema, QT prolongation, drug-induced hepatitis, radiation recall dermatitis, Stevens-Johnson syndrome, leukocytoclastic vasculitis, toxic epidermal necrolysis, rhabdomyolysis, nephrotic syndrome.

Not known: tumour lysis syndrome, encephalopathy (reported after marketing), aneurysms and artery dissections.

The SmPC marks the following as potentially life-threatening or fatal (these are uncommon or less frequent): gastrointestinal, respiratory tract and cerebral haemorrhage, congestive heart failure, myocardial ischaemia and infarction, reversible posterior leukoencephalopathy, hypertensive crisis, interstitial lung disease-like events, gastrointestinal perforation, drug-induced hepatitis and toxic epidermal necrolysis. Hand-foot skin reaction, diarrhoea, alopecia, weight loss, hypertension, hypocalcaemia and keratoacanthoma or squamous cell carcinoma of the skin were notably more frequent in thyroid carcinoma than in the renal cell and hepatocellular carcinoma studies.

• CYP3A4 and glucuronidation inducers: rifampicin given for 5 days before a single dose reduced sorafenib exposure (AUC) by an average of 37%. Other inducers (St John’s wort, phenytoin, carbamazepine, phenobarbital, dexamethasone) may also lower sorafenib concentrations.
• CYP3A4 inhibitors: the strong inhibitor ketoconazole did not change the AUC of a single sorafenib dose, so clinical interactions with CYP3A4 inhibitors are unlikely. DrugBank nevertheless advises caution with grapefruit products, which inhibit CYP3A4.
• Warfarin and phenprocoumon: sorafenib did not change mean PT-INR compared with placebo in a study with warfarin, but bleeding events and INR elevations have been reported in some patients. INR should be checked regularly.
• Other CYP enzymes: sorafenib inhibited CYP2B6, CYP2C8 and CYP2C9 in vitro, but no clinically meaningful inhibition was seen with cyclophosphamide (CYP2B6) or paclitaxel (CYP2C8). Probe substrates of CYP3A4, CYP2D6 and CYP2C19 were unaffected, so interactions with substrates of these enzymes are unlikely.
• UGT1A1 and UGT1A9 substrates: sorafenib inhibits this glucuronidation in vitro (clinical relevance unknown). Caution is advised with medicines cleared mainly by UGT1A1, such as irinotecan, or by UGT1A9.
• P-glycoprotein substrates: sorafenib inhibits P-glycoprotein in vitro, so higher concentrations of substrates such as digoxin cannot be excluded.
• Gemcitabine, cisplatin, oxaliplatin, carboplatin, cyclophosphamide: no clinically relevant effect of sorafenib on their pharmacokinetics.
• Paclitaxel with carboplatin: with a 3-day break in sorafenib (the two days before and the day of chemotherapy) paclitaxel exposure was not significantly affected and no dose adjustment is needed. Without a break, sorafenib exposure rose by 47%, paclitaxel by 29% and 6-OH paclitaxel by 50%; the clinical significance is unknown.
• Capecitabine: capecitabine exposure rose by 15–50% and 5-FU exposure by 0–52%; clinical significance unknown.
• Doxorubicin and irinotecan: doxorubicin AUC rose by 21%. With irinotecan, the AUC of its active metabolite SN-38 rose by 67–120% and that of irinotecan by 26–42%; clinical significance unknown.
• Docetaxel: docetaxel AUC rose by 36–80% and Cmax by 16–32%. Caution is recommended.
• Neomycin and other antibiotics: a 5-day neomycin course lowered average sorafenib exposure by 54%. Other antibiotics have not been studied, but antibiotics that cause major disturbance of the gut flora may reduce sorafenib bioavailability; this risk should be considered before starting an antibiotic course.
• QT-prolonging medicines: caution with anti-arrhythmic medicines or other medicines that prolong the QT interval.
• Food: a high-fat meal lowers absorption. Take sorafenib without food, or with a low- or moderate-fat meal.

Treatment should be supervised by a physician experienced in anticancer therapy. The tablets are swallowed with a glass of water, without food or with a low- or moderate-fat meal. If the patient plans a high-fat meal, the tablets should be taken at least 1 hour before or 2 hours after it.

Recommended Dose

The recommended dose is 400 mg (two 200 mg tablets) twice daily, a total of 800 mg a day, for as long as clinical benefit is seen or until unacceptable toxicity occurs. Dose reductions differ by indication:

• Hepatocellular carcinoma: 400 mg twice daily. If a reduction is needed, two 200 mg tablets once daily.
• Advanced renal cell carcinoma: 400 mg twice daily. If a reduction is needed, two 200 mg tablets once daily.
• Differentiated thyroid carcinoma: 400 mg twice daily. First reduction to 600 mg daily in divided doses (two tablets and one tablet twelve hours apart); if needed, 400 mg daily in divided doses (two tablets twelve hours apart) and then one 200 mg tablet once daily. After non-haematological adverse reactions improve, the dose may be increased again.

Dose Adjustments

Suspected adverse reactions may require temporary interruption or dose reduction. For skin reactions, hypertension, bleeding, cardiac ischaemia, gastrointestinal perforation and symptomatic hypoglycaemia the SmPC gives specific interruption or discontinuation advice (see Special Instructions).

Special Populations

• Elderly (above 65 years): no dose adjustment.
• Renal impairment: no dose adjustment in mild, moderate or severe impairment; no data in patients on dialysis. Fluid balance and electrolytes should be monitored in patients at risk of renal dysfunction.
• Hepatic impairment: no dose adjustment in Child-Pugh A or B (mild to moderate) impairment; no data in Child-Pugh C (severe).
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Skin Reactions

Hand-foot skin reaction and rash are the most common reactions. They are usually grade 1 or 2 and generally appear in the first six weeks. Management can include topical treatment for symptoms, temporary interruption or dose modification, and permanent discontinuation in severe or persistent cases.

Hypertension

Arterial hypertension is more frequent with sorafenib. It is usually mild to moderate, appears early and responds to standard antihypertensive treatment. Blood pressure should be monitored regularly. Permanent discontinuation should be considered for severe or persistent hypertension, or hypertensive crisis, despite treatment.

Aneurysms and Artery Dissections

Medicines that inhibit the VEGF pathway may promote aneurysms and artery dissections, with or without hypertension. This risk should be weighed before starting in patients with risk factors such as hypertension or a history of aneurysm.

Bleeding

Sorafenib can increase the risk of bleeding. If a bleeding event needs medical intervention, permanent discontinuation should be considered. Patients taking warfarin or phenprocoumon need regular checks of prothrombin time, INR and clinical bleeding. In differentiated thyroid carcinoma, tracheal, bronchial or oesophageal infiltration should be treated locally before sorafenib is started.

Heart: Ischaemia and QT Prolongation

Cardiac ischaemia or infarction was more frequent with sorafenib than with placebo (4.9% versus 0.4% in the renal cell carcinoma study and 2.7% versus 1.3% in the hepatocellular carcinoma study); patients with unstable coronary artery disease or a recent myocardial infarction were excluded. Temporary or permanent discontinuation should be considered in patients who develop cardiac ischaemia or infarction. Because sorafenib prolongs the QT/QTc interval, caution is needed in patients with congenital long QT syndrome, a high cumulative anthracycline dose, anti-arrhythmic or other QT-prolonging medicines, or electrolyte disturbances (low potassium, calcium or magnesium). Periodic ECGs and electrolyte checks should be considered.

Hypoglycaemia

Blood glucose can fall, in some cases with symptoms and hospitalisation after loss of consciousness. Sorafenib should be interrupted temporarily in symptomatic hypoglycaemia. Glucose should be checked regularly in diabetic patients to see whether antidiabetic doses need adjusting.

Gastrointestinal Perforation

This is uncommon (below 1% of patients) and in some cases occurred without an apparent intra-abdominal tumour. Sorafenib should be discontinued.

Tumour Lysis Syndrome

Cases, some fatal, have been reported after marketing. Risk factors are high tumour burden, chronic renal insufficiency, oliguria, dehydration, hypotension and acidic urine. These patients should be monitored closely and treated promptly, and prophylactic hydration considered.

Liver, Kidney and Elderly Patients

No data exist for Child-Pugh C hepatic impairment, and exposure may be higher there. Renal failure has been reported in elderly patients, so monitoring of renal function should be considered.

Surgery and Wound Healing

Wound healing has not been studied formally. As a precaution, sorafenib should be interrupted temporarily around major surgery and restarted once adequate wound healing is judged clinically.

Lung Cancer with Platinum Chemotherapy

Higher mortality was reported in squamous cell carcinoma of the lung when sorafenib was added to platinum-based chemotherapy, with more respiratory failure, haemorrhage and infections. This comes from lung cancer trials; lung cancer is not an authorised use.

Differentiated Thyroid Carcinoma

Before starting, the prognosis should be assessed from lesion size, disease symptoms and rate of progression. Dose reductions only partly relieved adverse reactions in the pivotal study, so benefit and risk should be re-evaluated repeatedly. Blood calcium should be monitored closely: hypocalcaemia was more frequent and severe than in other tumour types, especially with a history of hypoparathyroidism (grade 3 and 4 in 6.8% and 3.4% of patients). Severe hypocalcaemia should be corrected to prevent QT prolongation or torsade de pointes. TSH should also be monitored, as levels above 0.5 mU/L were seen.

Renal Cell Carcinoma

Patients in the high-risk group of the MSKCC prognostic scoring were not included in the phase III study, and the benefit-risk balance in them has not been evaluated.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no data in pregnant women. Animal studies showed reproductive toxicity including malformations, and sorafenib crosses the placenta in rats. It should not be used in pregnancy unless clearly necessary, after weighing the needs of the mother against the risk to the foetus.
• Contraception: women of childbearing potential must use effective contraception during treatment.
• Breastfeeding: it is not known whether sorafenib passes into human milk; in animals it does. Women must not breastfeed during treatment.
• Fertility: animal studies indicate that sorafenib can impair male and female fertility.

Sodium

Each dose contains less than 1 mmol (23 mg) sodium, so the medicine is essentially sodium-free.

Effect on Driving

No studies have been done, but there is no evidence that sorafenib affects the ability to drive or use machines.

Nexavar tablets must not be stored above 25 °C. They are supplied as 112 film-coated tablets (4 × 28) in transparent PP/aluminium blister packs.

4 years. Do not use after the expiry date on the pack.

Prescription only (Rx), subject to restricted medical prescription (Annex II B); treatment is supervised by a physician experienced in anticancer therapy. Sorafenib tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription.