Special Warning : אזהרת שימוש

4.4     Special warnings and precautions for use

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 CTC (Common Toxicity Criteria) Grade 1 and 2 and generally appear during the first six weeks of treatment with sorafenib.
Management of dermatological 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 section 4.8).

Hypertension

An increased incidence of arterial 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 institution of antihypertensive therapy, permanent discontinuation of sorafenib should be considered (see section 4.8).
Aneurysms and artery dissections



The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating Nexavar, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.


Hypoglycaemia
Decreases in blood glucose, in some cases clinically symptomatic and requiring hospitalization due to loss of consciousness, have been reported during sorafenib treatment. In case of symptomatic hypoglycaemia, sorafenib should be temporarily interrupted. Blood glucose levels in diabetic patients should be checked regularly in order to assess if anti-diabetic medicinal product's dosage needs to be adjusted.

Haemorrhage

An increased 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 section 4.8).

Cardiac ischaemia and/or infarction

In a randomised, placebo-controlled, double-blind study (study 1, see section 5.1) the incidence of treatment-emergent cardiac ischaemia/infarction events was higher in the sorafenib group (4.9%) compared with the placebo group (0.4%). In study 3 (see section 5.1) the incidence of treatment- emergent cardiac ischaemia/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 ischaemia and/or infarction (see section 4.8).

QT interval prolongation

Sorafenib has been shown to prolong the QT/QTc interval (see section 5.1), which may lead to an increased risk for ventricular arrhythmias. Use sorafenib with caution in patients who have, or may develop prolongation of QTc, such as patients with a congenital long QT syndrome, patients treated with a high cumulative dose of anthracycline therapy, patients taking certain anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalaemia, hypocalcaemia, or hypomagnesaemia. 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 less than 1% of patients taking sorafenib. In some cases this was not associated with apparent intra-abdominal tumour.
Sorafenib therapy should be discontinued (see section 4.8).

Tumour lysis syndrome (TLS)

Cases of TLS, some fatal, have been reported in postmarketing surveillance in patients treated with sorafenib. Risk factors for TLS include high tumour burden, pre-existing chronic renal insufficiency, 
oliguria, dehydration, hypotension, and acidic urine. These patients should be monitored closely and treated promptly as clinically indicated, and prophylactic hydration should be considered.

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 sections 4.2 and 5.2).

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 sections 4.5 and 4.8).


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 judgement of adequate wound healing.

Elderly population

Cases of renal failure have been reported. Monitoring of renal function should be considered.
Drug-drug interactions

Caution     is recommended when administering sorafenib with compounds that are metabolised/eliminated predominantly by the UGT1A1 (e.g. irinotecan) or UGT1A9 pathways (see section 4.5).

Caution is recommended when sorafenib is co-administered with docetaxel (see section 4.5).

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 section 4.5). 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 two 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; 1.80). 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 section 5.1), symptoms related to the disease (see section 5.1) and progression rate.

Management of suspected adverse drug reactions may require temporary interruption or dose reduction of sorafenib therapy. In study 5 (see section 5.1), 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 section 4.8). Severe hypocalcaemia should be corrected to prevent complications such as QT-prolongation or torsade de pointes (see section QT prolongation).

TSH suppression in DTC
In study 5 (see section 5.1), increases in TSH levels above 0.5mU/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 (Memorial Sloan Kettering Cancer Center) prognostic group, were not included in the phase III clinical study in renal cell carcinoma (see study 1 in section 5.1), and benefit-risk in these patients has not been evaluated.

Information about excipients

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium free”.

Effects on Driving

4.7     Effects on ability to drive and use machines

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.