Dermatological Toxicities: Hand-foot skin reaction (palmar-plantar erythrodysaesthesia) and rash represent the most common adverse drug reactions with sorafenib. Rash and hand-foot skin reaction are usually National Cancer Institute Common Toxicity Criteria (CTC) grade 1 and 2 and generally appear during the 1st 6 weeks of treatment with sorafenib. Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of sorafenib or in severe or persistent cases, permanent discontinuation of sorafenib (see Adverse Reactions).
Hypertension: An increased incidence of hypertension was observed in sorafenib-treated patients. Hypertension was usually mild to moderate, occurred early in the course of treatment and was amenable to management with standard antihypertensive therapy. Blood pressure should be monitored regularly and treated, if required, in accordance with standard medical practice. In cases of severe or persistent hypertension or hypertensive crisis despite adequate antihypertensive therapy, permanent discontinuation of sorafenib should be considered (see Adverse Reactions).
Hemorrhage: An increase in the risk of bleeding may occur following sorafenib administration. If any bleeding event necessitates medical intervention, it is recommended that permanent discontinuation of sorafenib should be considered (see Adverse Reactions).
Cardiac Ischemia and/or Infarction: In a randomised, placebo-controlled, double-blind study (study 1, see Pharmacology: Pharmacodynamics under Actions), the incidence of treatment-emergent cardiac ischemia/infarction events was higher in the sorafenib group (4.9%) compared with the placebo group (0.4%). In study 3 (see Pharmacology: Pharmacodynamics under Actions), the incidence of treatment-emergent cardiac ischemia/infarction events was 2.7% in sorafenib patients compared with 1.3% in the placebo group. Patients with unstable coronary artery disease or recent myocardial infarction were excluded from these studies. Temporary or permanent discontinuation of sorafenib should be considered in patients who develop cardiac ischemia and/or infarction (see Adverse Reactions).
QT Interval Prolongation: Sorafenib has been shown to prolong the QT/QTc interval (see Pharmacology: Pharmacodynamics under Actions), which may lead to an increased risk for ventricular arrhythmias. Use sorafenib with caution in patients who have, or may develop prolongation of QTc eg, patients with a congenital long QT syndrome, patients treated with a high cumulative dose of anthracycline therapy, patients taking certain antiarrhythmic medicines or other medicinal products that lead to QT prolongation and those with electrolyte disturbances eg, hypokalemia, hypocalcemia or hypomagnesemia. When using sorafenib in these patients, periodic monitoring with on-treatment electrocardiograms and electrolytes (magnesium, potassium, calcium) should be considered.
Gastrointestinal Perforation: Gastrointestinal perforation is an uncommon event and has been reported in <1% of patients taking sorafenib. In some cases, this was not associated with apparent intra-abdominal tumor. Sorafenib therapy should be discontinued (see Adverse Reactions).
Hepatic Impairment: No data is available on patients with Child-Pugh C (severe) hepatic impairment. Since sorafenib is mainly eliminated via the hepatic route, exposure might be increased in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Warfarin Co-Administration: Infrequent bleeding events or elevations in the international normalised ratio (INR) have been reported in some patients taking warfarin while on sorafenib therapy. Patients taking concomitant warfarin or phenprocoumon should be monitored regularly for changes in prothrombin time, INR or clinical bleeding episodes (see Adverse Reactions and Interactions).
Wound Healing Complications: No formal studies of the effect of sorafenib on wound healing have been conducted.
Temporary interruption of sorafenib therapy is recommended for precautionary reasons in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume sorafenib therapy following a major surgical intervention should be based on clinical judgment of adequate wound healing.
Drug-Drug Interactions: Caution is recommended when administering sorafenib with compounds that are metabolized/eliminated predominantly by the UGT1A1 (eg, irinotecan) or UGT1A9 pathways (see Interactions).
Caution is recommended when sorafenib is co-administered with docetaxel (see Interactions).
Co-administration of neomycin or other antibiotics that cause major ecological disturbances of the gastrointestinal microflora may lead to a decrease in sorafenib bioavailability (see Interactions). The risk of reduced plasma concentrations of sorafenib should be considered before starting a treatment course with antibiotics.
Higher mortality has been reported in patients with squamous cell carcinoma of the lung treated with sorafenib in combination with platinum-based chemotherapies. In 2 randomised trials investigating patients with non-small cell lung cancer in the subgroup of patients with squamous cell carcinoma treated with sorafenib as add-on to paclitaxel/carboplatin, the HR for overall survival was found to be 1.81 (95% CI 1.19; 2.74) and as add-on to gemcitabine/cisplatin 1.22 (95% CI 0.82; 1.8). No single cause of death dominated, but higher incidence of respiratory failure, hemorrhages and infectious adverse events were observed in patients treated with sorafenib as add-on to platinum-based chemotherapies.
Disease Specific Warnings: Differentiated Thyroid Cancer (DTC): Before initiating treatment, physicians are recommended to carefully evaluate the prognosis in the individual patient considering maximum lesion size (see Pharmacology: Pharmacodynamics under Actions), symptoms related to the disease (see Pharmacology: Pharmacodynamics under Actions) and progression rate.
Management of suspected adverse drug reactions may require temporary interruption or dose reduction of sorafenib therapy. In study 5 (see Pharmacology: Pharmacodynamics under Actions), 37% of subjects had dose interruption and 35% had dose reduction already in cycle 1 of sorafenib treatment.
Dose reductions were only partially successful in alleviating adverse reactions. Therefore repeat evaluations of benefit and risk is recommended taking anti-tumour activity and tolerability into account.
Haemorrhage in DTC: Due to the potential risk of bleeding, tracheal, bronchial and oesophageal infiltration should be treated with localized therapy prior to administering sorafenib in patients with DTC.
Hypocalcaemia in DTC: When using sorafenib in patients with DTC, close monitoring of blood calcium level is recommended.
In clinical trials, hypocalcaemia was more frequent and more severe in patients with DTC, especially with a history of hypoparathyroidism, compared to patients with renal cell or hepatocellular carcinoma. Hypocalcaemia grade 3 and 4 occurred in 6.8% and 3.4% of sorafenib-treated patients with DTC (see Adverse Reactions). Severe hypocalcaemia should be corrected to prevent complications eg, QT-prolongation or Torsade de pointes (see QT Interval Prolongation previously mentioned).
Thyroid-Stimulating Hormone (TSH) Suppression in DTC: In study 5 (see Pharmacology: Pharmacodynamics under Actions), increases in TSH levels above 0.5 mU/L were observed in sorafenib-treated patients. When using sorafenib in DTC patients, close monitoring of TSH level is recommended.
Renal Cell Carcinoma: High risk patients, according to MSKCC prognostic group, were not included in the phase III clinical study in renal cell carcinoma (see study 1 in Pharmacology: Pharmacodynamics under Actions) and benefit-risk in these patients has not been evaluated.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed. There is no evidence that sorafenib affects the ability to drive or to operate machinery.
Impairment of Fertility: Results from animal studies indicate that sorafenib can impair male and female fertility (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Use in pregnancy: There are no data on the use of sorafenib in pregnant women. Studies in animals have shown reproductive toxicity including malformations (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). In rats, sorafenib and its metabolites were demonstrated to cross the placenta and sorafenib is anticipated to cause harmful effects on the fetus. Sorafenib should not be used during pregnancy unless clearly necessary, after careful consideration of the needs of the mother and the risk to the foetus.
Women of childbearing potential must use effective contraception during treatment.
Use in lactation: It is not known whether sorafenib is excreted in human milk. In animals, sorafenib and/or its metabolites were excreted in milk. Because sorafenib could harm infant growth and development (see Pharmacology: Toxicology: Preclinical Safety Data under Actions), woman must not breastfeed during sorafenib treatment.
Use in children: The safety and efficacy of Nexavar in children and adolescents <18 years have not yet been established. No data are available.
Use in the elderly: Cases of renal failure have been reported. Monitoring of renal function should be considered.