Sorafenib Accord · 4.1 Therapeutic indications · 1

HOS-288775 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The most important serious adverse reactions were myocardial infarction/ischaemia, gastrointestinal perforation, drug induced hepatitis, haemorrhage, and hypertension/hypertensive crisis. The most common adverse reactions were diarrhoea, fatigue, alopecia, infection, hand foot skin reaction (corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRA) and rash. Tabulated list of adverse reactions Adverse reactions reported in multiple clinical trials or through post-marketing use are listed below in table 1, by system organ class (in MedDRA) and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 1: All adverse reactions reported in patients in multiple clinical trials or through post- marketing use System Very common Common Uncommon Rare Not known organ class Infections infection folliculitis and infestations Blood and lymphopenia leucopenia lymphatic neutropenia system anaemia disorders thrombocytopenia Immune hypersensitivity angioedema system reactions disorders (including skin reactions and urticaria) anaphylactic reaction Endocrine hypothyroidism hyperthyroidism disorders Metabolism anorexia hypocalcaemia dehydration tumour lysis and nutrition hypo- hypokalaemia syndrome disorders phosphataemia hyponatraemia hypoglycaemia Psychiatric depression disorders Nervous peripheral sensory reversible encephalo- system

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HOS-288771 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-288770 · has-indication-information · PDF-Seite 2

Hepatocellular carcinoma Sorafenib Accord is indicated for the treatment of hepatocellular carcinoma (see section 5.1). Renal cell carcinoma Sorafenib Accord is indicated for the treatment of 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 Sorafenib Accord is indicated for the treatment of patients with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to radioactive iodine.

HOS-288773 · has-interaction-information · PDF-Seite 6

Inducers of metabolic enzymes Administration of rifampicin for 5 days before administration of a single dose of sorafenib resulted in an average 37% reduction of sorafenib AUC. Other inducers of CYP3A4 activity and/or glucuronidation (e.g. Hypericum perforatum also known as St. John’s wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) may also increase metabolism of sorafenib and thus decrease sorafenib concentrations. CYP3A4 inhibitors Ketoconazole, a potent inhibitor of CYP3A4, administered once daily for 7 days to healthy male volunteers did not alter the mean AUC of a single 50 mg dose of sorafenib. These data suggest that clinical pharmacokinetic interactions of sorafenib with CYP3A4 inhibitors are unlikely. CYP2B6, CYP2C8 and CYP2C9 substrates 6 Sorafenib inhibited CYP2B6, CYP2C8 and CYP2C9 in vitro with similar potency. However, in clinical pharmacokinetic studies, concomitant administration of sorafenib 400 mg twice daily with cyclophosphamide, a CYP2B6 substrate, or paclitaxel, a CYP2C8 substrate, did not result in a clinically meaningful inhibition. These data suggest that sorafenib at the recommended dose of 400 mg twice daily may not be an in vivo inhibitor of CYP2B6 or CYP2C8. Additionally, concomitant treatment with sorafenib and warfarin, a CYP2C9 substrate, did not result in changes in mean PT-INR compared to placebo. Thus, also the risk for a clinically relevant in vivo inhibition of CYP2C9 by sorafenib may be expected to be low. However, patients taking warfarin or phenprocoumon should have their INR checked regularly (see section 4.4). CYP3A4, CYP2D6 and CYP2C19 substrates Concomitant administration of sorafenib and midazolam, dextromethorphan or omeprazole, which are substrates for cytochromes CYP3A4, CYP2D6 and CYP2C19 respectively, did not alter the exposure of these agents. This indicates that sorafenib is neither an inhibitor nor an inducer of these cytochrome P450 isoenzymes. Therefore, clinical pharmacokinetic interactions of sorafenib with substrates of these enzymes are unlikely. UGT1A1 and UGT1A9 substrates In vitro, sorafenib inhibited glucuronidation via UGT1A1 and UGT1A9. The clinical relevance of this finding is unknown (see below and section 4.4). In vitro studies of CYP enzyme induction CYP1A2 and CYP3A4 activities were not altered after treatment of cultured human hepatocytes with sorafenib, indicating that sorafenib is unlikely to be an indu

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HOS-288774 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential/Contraception Women of childbearing potential must use effective contraception during treatment. Pregnancy There are no data on the use of sorafenib in pregnant women. Studies in animals have shown reproductive toxicity including malformations (see section 5.3). In rats, sorafenib and its metabolites were demonstrated to cross the placenta and sorafenib is anticipated to cause harmful effects on the foetus. 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. 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 section 5.3), women must not breast-feed during sorafenib treatment. Fertility 8 Results from animal studies further indicate that sorafenib can impair male and female fertility (see section 5.3).

HOS-288772 · has-warning-information · PDF-Seite 3

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). 3 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 vascular endothelial growth factor (VEGF) pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating Sorafenib Accord, 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%) comp

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