Nexavar 200 mg film-coated tablets

Each film-coated tablet contains 200 mg of sorafenib (as tosylate).

For a full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Red, round, biconvex film-coated tablets, debossed with Bayer cross on one side and "200" on the other side.

Hepatocellular carcinoma

Nexavar is indicated for the treatment of hepatocellular carcinoma (see section 5.1).

Renal cell carcinoma

Nexavar 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.

Nexavar treatment should be supervised by a physician experienced in the use of anticancer therapies.

Posology

The recommended dose of Nexavar in adults is 400 mg (two tablets of 200 mg) twice daily (equivalent to a total daily dose of 800 mg).

Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.

Posology adjustments

Management of suspected adverse drug reactions may require temporary interruption or dose reduction of Nexavar therapy. When dose reduction is necessary, the Nexavar dose should be reduced to two tablets of 200 mg once daily (see section 4.4).

Paediatric population

The safety and efficacy of Nexavar in children and adolescents aged < 18 years have not yet been established. No data are available.

Elderly population

No dose adjustment is required in the elderly (patients above 65 years of age).

Renal impairment

No dose adjustment is required in patients with mild, moderate or severe renal impairment. No data is available in patients requiring dialysis (see section 5.2).

Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised.

Hepatic impairment

No dose adjustment is required in patients with Child Pugh A or B (mild to moderate) hepatic impairment. No data is available on patients with Child Pugh C (severe) hepatic impairment (see sections 4.4 and 5.2).

Method of administration

For oral use.

It is recommended that sorafenib should be administered without food or with a low or moderate fat meal. If the patient intends to have a high-fat meal, sorafenib tablets should be taken at least 1 hour before or 2 hours after the meal. The tablets should be swallowed with a glass of water.

Hypersensitivity to the active substance or to any of the excipients.

Dermatological toxicities

Hand-foot skin reaction (palmar-plantar erythrodysaesthesia) and rash represent the most common adverse drug reactions with Nexavar. 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 Nexavar. Management of dermatological toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of Nexavar, or in severe or persistent cases, permanent discontinuation of Nexavar (see section 4.8).

Hypertension

An increased incidence of arterial hypertension was observed in Nexavar-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 Nexavar should be considered (see section 4.8).

Haemorrhage

An increased risk of bleeding may occur following Nexavar administration. If any bleeding event necessitates medical intervention it is recommended that permanent discontinuation of Nexavar 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 Nexavar 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 Nexavar 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 Nexavar should be considered in patients who develop cardiac ischaemia and/or infarction (see section 4.8).

QT interval prolongation

Nexavar 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 Nexavar 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 tumor. Sorafenib therapy should be discontinued (see section 4.8).

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 Nexavar 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 Nexavar 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 Nexavar therapy following a major surgical intervention should be based on clinical judgement of adequate wound healing.

Elderly population

The experience with the use of Nexavar in elderly patients is limited. Cases of renal failure have been reported. Monitoring of renal function should be considered.

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 eva luated.

Drug-drug interactions

Caution is recommended when administering Nexavar 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.

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

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 inducer of CYP1A2 and CYP3A4.

P-gp-substrates

In vitro, sorafenib has been shown to inhibit the transport protein p-glycoprotein (P-gp). Increased plasma concentrations of P-gp substrates such as digoxin cannot be excluded with concomitant treatment with sorafenib.

Combination with other anti-neoplastic agents

In clinical studies Nexavar has been administered with a variety of other anti-neoplastic agents at their commonly used dosing regimens including gemcitabine, cisplatin, oxaliplatin, paclitaxel, carboplatin, capecitabine, doxorubicin, irinotecan, docetaxel and cyclophosphamide. Sorafenib had no clinically relevant effect on the pharmacokinetics of gemcitabine, cisplatin, oxaliplatin or cyclophosphamide.

Paclitaxel/carboplatin

Administration of paclitaxel (225 mg/m²) and carboplatin (AUC = 6) with sorafenib ( 400 mg twice daily), administered with a 3-day break in sorafenib dosing (two days prior to and on the day of paclitaxel/carboplatin administration), resulted in no significant effect on the pharmacokinetics of paclitaxel.

Co-administration of paclitaxel (225 mg/m², once every 3 weeks) and carboplatin (AUC=6) with sorafenib (400 mg twice daily, without a break in sorafenib dosing) resulted in a 47% increase in sorafenib exposure, a 29% increase in paclitaxel exposure and a 50% increase in 6-OH paclitaxel exposure. The pharmacokinetics of carboplatin were unaffected.

These data indicate no need for dose adjustments when paclitaxel and carboplatin are co-administered with sorafenib with a 3-day break in sorafenib dosing (two days prior to and on the day of paclitaxel/carboplatin administration). The clinical significance of the increases in sorafenib and paclitaxel exposure, upon co-administration of sorafenib without a break in dosing, is unknown.

Capecitabine

Co-administration of capecitabine (750-1050 mg/m² twice daily, Days 1-14 every 21 days) and sorafenib (200 or 400 mg twice daily, continuous uninterrupted administration) resulted in no significant change in sorafenib exposure, but a 15-50% increase in capecitabine exposure and a 0-52% increase in 5-FU exposure. The clinical significance of these small to modest increases in capecitabine and 5-FU exposure when co-administered with sorafenib is unknown.

Doxorubicin/Irinotecan

Concomitant treatment with Nexavar resulted in a 21 % increase in the AUC of doxorubicin. When administered with irinotecan, whose active metabolite SN-38 is further metabolised by the UGT1A1 pathway, there was a 67 - 120 % increase in the AUC of SN-38 and a 26 - 42 % increase in the AUC of irinotecan. The clinical significance of these findings is unknown (see section 4.4).

Docetaxel

Docetaxel (75 or 100 mg/m² administered once every 21 days) when co-administered with sorafenib (200 mg twice daily or 400 mg twice daily administered on Days 2 through 19 of a 21-day cycle with a 3-day break in dosing around administration of docetaxel) resulted in a 36-80 % increase in docetaxel AUC and a 16-32 % increase in docetaxel C_max. Caution is recommended when sorafenib is co-administered with docetaxel (see section 4.4).

Combination with other agents

Neomycin

Co-administration of neomycin, a non-systemic antimicrobial agent used to eradicate gastrointestinal flora, interferes with the enterohepatic recycling of sorafenib (see section 5.2, Metabolism and Elimination), resulting in decreased sorafenib exposure. In healthy volunteers treated with a 5-day regimen of neomycin the average exposure to sorafenib decreased by 54%. Effects of other antibiotics have not been studied, but will likely depend on their ability to interfere with microorganisms with glucuronidase activity.

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. Nexavar 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.

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

Results from animal studies further indicate that sorafenib can impair male and female fertility (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed. There is no evidence that Nexavar affects the ability to drive or to operate machinery.

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, rash, alopecia and hand-foot syndrome (corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRA).

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 data available).

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

* The adverse reactions may have a life-threatening or fatal outcome. Such events are either uncommon or less frequent than uncommon.

** Hand foot syndrome corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRA.

Further information on selected adverse drug reactions

Congestive heart failure: In company sponsored clinical trials congestive heart failure was reported as an adverse event in 1.9% of patients treated with sorafenib (N= 2276). In study 11213 (RCC) adverse events consistent with congestive heart failure were reported in 1.7% of patients treated with sorafenib and 0.7% receiving placebo. In study 100554 (HCC), 0.99% of those treated with sorafenib and 1.1% receiving placebo were reported with these events.

Laboratory test abnormalities

Increased lipase and amylase were very commonly reported. CTCAE Grade 3 or 4 lipase elevations occurred in 11 % and 9 % of patients in the Nexavar group in study 1 (RCC) and study 3 (HCC), respectively, compared to 7 % and 9 % of patients in the placebo group. CTCAE Grade 3 or 4 amylase elevations were reported in 1 % and 2 % of patients in the Nexavar group in study 1 and study 3, respectively, compared to 3 % of patients in each placebo group. Clinical pancreatitis was reported in 2 of 451 Nexavar treated patients (CTCAE Grade 4) in study 1, 1 of 297 Nexavar treated patients in study 3 (CTCAE Grade 2), and 1 of 451 patients (CTCAE Grade 2) in the placebo group in study 1.

Hypophosphataemia was a very common laboratory finding, observed in 45 % and 35 % of Nexavar treated patients compared to 12 % and 11 % of placebo patients in study 1 and study 3, respectively. CTCAE Grade 3 hypophosphataemia (1 – 2 mg/dl) in study 1 occurred in 13 % of Nexavar treated patients and 3 % of patients in the placebo group, in study 3 in 11 % of Nexavar treated patients and 2 % of patients in the placebo group. There were no cases of CTCAE Grade 4 hypophosphataemia (< 1 mg/dl) reported in either Nexavar or placebo patients in study 1, and 1 case in the placebo group in study 3. The aetiology of hypophosphataemia associated with Nexavar is not known.

CTCAE Grade 3 or 4 laboratory abnormalities occurring in 5 % of Nexavar treated patients included lymphopenia and neutropenia.

There is no specific treatment for Nexavar overdose. The highest dose of sorafenib studied clinically is 800 mg twice daily. The adverse events observed at this dose were primarily diarrhoea and dermatological events. In the event of suspected overdose Nexavar should be withheld and supportive care instituted where necessary.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE05

Sorafenib is a multikinase inhibitor which has demonstrated both anti-proliferative and anti-angiogenic properties in vitro and in vivo.

Mechanism of action and pharmacodynamic effects

Sorafenib is a multikinase inhibitor that decreases tumour cell proliferation in vitro. Sorafenib inhibits tumour growth of a broad spectrum of human tumour xenografts in athymic mice accompanied by a reduction of tumour angiogenesis. Sorafenib inhibits the activity of targets present in the tumour cell (CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and in the tumour vasculature (CRAF, VEGFR-2, VEGFR-3, and PDGFR-ß). RAF kinases are serine/threonine kinases, whereas c-KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-ß are receptor tyrosine kinases.

Clinical efficacy

The clinical safety and efficacy of Nexavar have been studied in patients with hepatocellular carcinoma (HCC) and in patients with advanced renal cell carcinoma (RCC).

Hepatocellular carcinoma

Study 3 (study 100554) was a Phase III, international, multi-centre, randomised, double blind, placebo-controlled study in 602 patients with hepatocellular carcinoma. Demographics and baseline disease characteristics were comparable between the Nexavar and the placebo group with regard to ECOG status (status 0: 54 % vs. 54 %; status 1: 38 % vs. 39 %; status 2: 8 % vs. 7 %), TNM stage (stage I: <1 % vs. <1 %; stage II: 10.4 % vs. 8.3 %; stage III: 37.8 % vs. 43.6 %; stage IV: 50.8 % vs. 46.9 %), and BCLC stage (stage B: 18.1 % vs. 16.8 %; stage C: 81.6 % vs. 83.2 %; stage D: < 1 % vs. 0 %).

The study was stopped after a planned interim analysis of OS had crossed the prespecified efficacy boundary. This OS analysis showed a statistically significant advantage for Nexavar over placebo for OS (HR: 0.69, p = 0.00058, see Table 2).

There are limited data from this study in patients with Child Pugh B liver impairment and only one patient with Child Pugh C had been included.

Table 2: Efficacy Results from study 3 (study 100554) in hepatocellular carcinoma

CI=Confidence interval, HR=Hazard ratio (Nexavar over placebo)

*statistically significant as the p-value was below the prespecified O'Brien Fleming stopping boundary of 0.0077

**independent radiological review

A second Phase III, international, multi-centre, randomised, double blind, placebo-controlled study (Study 4, 11849) eva luated the clinical benefit of Nexavar in 226 patients with advanced hepatocellular carcinoma. This study, conducted in China, Korea and Taiwan confirmed the findings of Study 3 with respect to the favourable benefit-risk profile of Nexavar (HR (OS): 0.68, p = 0.01414).

In the prespecified stratification factors (ECOG status, presence or absence of macroscopic vascular invasion and/or extrahepatic tumour spread) of both Study 3 and 4, the hazard ratio consistently favoured Nexavar over placebo. Exploratory subgroup analyses suggested that patients with distant metastases at baseline derived a less pronounced treatment effect.

Renal cell carcinoma

The safety and efficacy of Nexavar in the treatment of advanced renal cell carcinoma (RCC) were investigated in two clinical studies:

Study 1 (study 11213) was a Phase III, multi-centre, randomised, double blind, placebo-controlled study in 903 patients. Only patients with clear cell renal carcinoma and low and intermediate risk MSKCC (Memorial Sloan Kettering Cancer Center) were included. The primary endpoints were overall survival and progression-free survival (PFS).

Approximately half of the patients had an ECOG performance status of 0, and half of the patients were in the low risk MSKCC prognostic group.

PFS was eva luated by blinded independent radiological review using RECIST criteria. The PFS analysis was conducted at 342 events in 769 patients. The median PFS was 167 days for patients randomised to Nexavar compared to 84 days for placebo patients (HR = 0.44; 95 % CI: 0.35 - 0.55; p < 0.000001). Age, MSKCC prognostic group, ECOG PS and prior therapy did not affect the treatment effect size.

An interim analysis (second interim analysis) for overall survival was conducted at 367 deaths in 903 patients. The nominal alpha value for this analysis was 0.0094. The median survival was 19.3 months for patients randomised to Nexavar compared to 15.9 months for placebo patients (HR = 0.77; 95 % CI: 0.63 - 0.95; p = 0.015). At the time of this analysis, about 200 patients had crossed-over to sorafenib from the placebo group.

Study 2 was a Phase II, discontinuation study in patients with metastatic malignancies, including RCC. Patients with stable disease on therapy with Nexavar were randomised to placebo or continued Nexavar therapy. Progression-free survival in patients with RCC was significantly longer in the Nexavar group (163 days) than in the placebo group (41 days) (p = 0.0001, HR = 0.29).

QT interval prolongation

In a clinical pharmacology study, QT/QTc measurements were recorded in 31 patients at baseline (pre-treatment) and post-treatment. After one 28-day treatment cycle, at the time of maximum concentration of sorafenib, QTcB was prolonged by 4 ±19 msec and QTcF by 9 ±18 msec, as compared to placebo treatment at baseline. No subject showed a QTcB or QTcF >500 msec during the post-treatment ECG monitoring (see section 4.4).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies, in all subsets of the paediatric population, in kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumour of the kidney) and liver and intrahepatic bile duct carcinoma (excluding hepatoblastoma).

Absorption and distribution

After administration of Nexavar tablets the mean relative bioavailability is 38 - 49 % when compared to an oral solution. The absolute bioavailability is not known. Following oral administration sorafenib reaches peak plasma concentrations in approximately 3 hours. When given with a high-fat meal sorafenib absorption was reduced by 30 % compared to administration in the fasted state.

Mean C_max and AUC increased less than proportionally beyond doses of 400 mg administered twice daily. In vitro binding of sorafenib to human plasma proteins is 99.5 %.

Multiple dosing of Nexavar for 7 days resulted in a 2.5- to 7-fold accumulation compared to single dose administration. Steady state plasma sorafenib concentrations are achieved within 7 days, with a peak to trough ratio of mean concentrations of less than 2.

Biotransformation and elimination

The elimination half-life of sorafenib is approximately 25 - 48 hours. Sorafenib is metabolised primarily in the liver and undergoes oxidative metabolism, mediated by CYP 3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib conjugates may be cleaved in the gastrointestinal tract by bacterial glucuronidase activity, allowing reabsorption of unconjugated drug. Co-administration of neomycin has been shown to interfere with this process, decreasing the mean bioavailability of sorafenib by 54%.

Sorafenib accounts for approximately 70 - 85 % of the circulating analytes in plasma at steady state. Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows in vitro potency similar to that of sorafenib. This metabolite comprises approximately 9 - 16 % of circulating analytes at steady state.

Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96 % of the dose was recovered within 14 days, with 77 % of the dose excreted in faeces, and 19 % of the dose excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51 % of the dose, was found in faeces but not in urine, indicating that biliary excretion of unchanged drug might contribute to the elimination of sorafenib.

Pharmacokinetics in special populations

Analyses of demographic data suggest that there is no relationship between pharmacokinetics and age (up to 65 years), gender or body weight.

Paediatric population

No studies have been conducted to investigate the pharmacokinetics of sorafenib in paediatric patients.

Race

There are no clinically relevant differences in pharmacokinetics between Caucasian and Asian subjects.

Renal impairment

In four Phase I clinical trials, steady state exposure to sorafenib was similar in patients with mild or moderate renal impairment compared to the exposures in patients with normal renal function. In a clinical pharmacology study (single dose of 400 mg sorafenib), no relationship was observed between sorafenib exposure and renal function in subjects with normal renal function, mild, moderate or severe renal impairment. No data is available in patients requiring dialysis.

Hepatic impairment

In hepatocellular carcinoma (HCC) patients with Child-Pugh A or B (mild to moderate) hepatic impairment, exposure values were comparable and within the range observed in patients without hepatic impairment. The pharmacokinetics (PK) of sorafenib in Child-Pugh A and B non-HCC patients were similar to the PK in healthy volunteers. There are no data for patients with Child-Pugh C (severe) hepatic impairment. Sorafenib is mainly eliminated via the liver, and exposure might be increased in this patient population.

The preclinical safety profile of sorafenib was assessed in mice, rats, dogs and rabbits.

Repeat-dose toxicity studies revealed changes (degenerations and regenerations) in various organs at exposures below the anticipated clinical exposure (based on AUC comparisons).

After repeated dosing to young and growing dogs effects on bone and teeth were observed at exposures below the clinical exposure. Changes consisted in irregular thickening of the femoral growth plate, hypocellularity of the bone marrow next to the altered growth plate and alterations of the dentin composition. Similar effects were not induced in adult dogs.

The standard program of genotoxicity studies was conducted and positive results were obtained as an increase in structural chromosomal aberrations in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity in the presence of metabolic activation was seen. Sorafenib was not genotoxic in the Ames test or in the in vivo mouse micronucleus assay. One intermediate in the manufacturing process, which is also present in the final active substance (< 0.15 %), was positive for mutagenesis in an in vitro bacterial cell assay (Ames test). Furthermore, the sorafenib batch tested in the standard genotoxicity battery included 0.34 % PAPE.

Carcinogenicity studies have not been conducted with sorafenib.

No specific studies with sorafenib have been conducted in animals to eva luate the effect on fertility. An adverse effect on male and female fertility can however be expected because repeat-dose studies in animals have shown changes in male and female reproductive organs at exposures below the anticipated clinical exposure (based on AUC). Typical changes consisted of signs of degeneration and retardation in testes, epididymides, prostate, and seminal vesicles of rats. Female rats showed central necrosis of the corpora lutea and arrested follicular development in the ovaries. Dogs showed tubular degeneration in the testes and oligospermia.

Sorafenib has been shown to be embryotoxic and teratogenic when administered to rats and rabbits at exposures below the clinical exposure. Observed effects included decreases in maternal and foetal body weights, an increased number of foetal resorptions and an increased number of external and visceral malformations.

Tablet core:

Croscarmellose sodium

Microcrystalline cellulose

Hypromellose

Sodium laurilsulfate

Magnesium stearate

Tablet coating:

Hypromellose

Macrogol (3350)

Titanium dioxide (E 171)

Ferric oxide red (E 172)

Not applicable.

3 years

Do not store above 25°C.

112 film-coated tablets (4 x 28) in transparent (PP/Aluminium) blister packs.

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

Bayer Pharma AG

13342 Berlin

Germany

EU/1/06/342/001

Date of first authorisation: 19 July 2006

Date of renewal: 21 July 2011

24^th October 2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.