NEXAVAR(r), indicated for the treatment of locally advanced / metastatic renal cell (clear cell) carcinoma in patients who failed prior cytokine therapy or are considered unsuitable for such therapy, has been issued marketing authorization with conditions, pending the results of studies to verify its clinical benefit. Patients should be advised of the nature of the authorization.

NEXAVAR(r) has received nonconditional approval for the treatment of patients with unresectable hepatocellular carcinoma (HCC).

Manufacturer: Bayer Inc. 77 Belfield Road Toronto, Ontario M9W 1G6 http://www.bayer.ca

Date of Revision:

September 16, 2008

Submission Control No: 122663

(c) 2008, Bayer Inc.

(r)

NEXAVAR is a registered trademark, used under license by Bayer Inc.

This product has been approved under the Notice of Compliance with Conditions (NOC/c) policy for one or all of its indicated uses.

What is a Notice of Compliance with Conditions (NOC/c)?

An NOC/c is a form of market approval granted to a product on the basis of promising evidence of clinical effectiveness following review of the submission by Health Canada. Products approved under Health Canada's NOC/c policy are intended for the treatment, prevention or diagnosis of a serious, life-threatening or severely debilitating illness. They have demonstrated promising benefit, are of high quality and possess an acceptable safety profile based on a benefit/risk assessment. In addition, they either respond to a serious unmet medical need in Canada or have demonstrated a significant improvement in the benefit/risk profile over existing therapies. Health Canada has provided access to this product on the condition that sponsors carry out additional clinical trials to verify the anticipated benefit within an agreed upon time frame.

What will be different about this Product Monograph?

The following Product Monograph will contain boxed text at the beginning of each major section clearly stating the nature of the market authorization. Sections for which NOC/c status holds particular significance will be identified in the left margin by the symbol NOC/c. These sections may include, but are not limited to, the following:

• Indications and Clinical Uses;

• Action;

• Warnings and Precautions;

• Adverse Reactions;

• Dosage and Administration; and

• Clinical Trials.

CONTRAINDICATIONS

NEXAVAR (sorafenib tablets) is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing of ingredients, see Product Monograph PART I: DOSAGE FORMS, COMPOSITION AND PACKAGING.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

NEXAVAR (sorafenib tablets) should be prescribed by a qualified healthcare professional who is experienced in the use of antineoplastic therapy NEXAVAR has not been studied in patients with severe hepatic impairment The following are clinically significant adverse events: Hypertension Hemorrhage Cardiac ischemia/infarction Gastrointestinal perforation

General

Drug-Drug Interactions

Caution is recommended when administering sorafenib together with compounds that are metabolized/eliminated predominantly by the UGT1A1 and UGT1A9 pathways (eg, irinotecan) (see DRUG INTERACTIONS) Caution is recommended if sorafenib has to be coadministered with docetaxel as it may result in an increase in docetaxel AUC (see DRUG INTERACTIONS).

Warfarin

Infrequent bleeding events or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on sorafenib therapy (see Monitoring and Laboratory Tests and ADVERSE REACTIONS).

Wound Healing Complications

No formal studies of the effect of sorafenib on wound healing have been conducted. In patients undergoing major surgical procedures, temporary interruption of sorafenib therapy is recommended for precautionary reasons. 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.

Carcinogenesis and Mutagenesis

Carcinogenicity studies have not been performed with NEXAVAR. Positive genotoxic effects were obtained for sorafenib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. One intermediate in the manufacturing process, which is also present in the final drug substance (<0.15%), was positive for mutagenesis in an in vitro bacterial cell assay (Ames test). Sorafenib was not genotoxic in the Ames test (the material contained the intermediate at 0.34%) and in an in vivo mouse micronucleus assay.

Cardiovascular

Cardiac Ischemia and/or Infarction

Cardiac ischemia and/or infarction were reported as common adverse events in subjects treated with NEXAVAR. The incidence rates were higher in NEXAVAR-treated patients than those treated with the placebo in both RCC and HCC pivotal trials (see ADVERSE REACTIONS). Patients with unstable coronary artery disease or recent myocardial infarction (within 6 months) were excluded from these studies. Temporary or permanent discontinuation of NEXAVAR should be considered in patients who develop cardiac ischemia and/or infarction.

Hypertension

An increased incidence of hypertension was observed in sorafenib-treated patients. In the Phase III NEXAVAR RCC clinical trial, hypertension was reported in 17% of sorafenib-treated patients and in 2% of patients in the placebo group. In the Phase III NEXAVAR HCC clinical trial, hypertension was reported in 9% of NEXAVAR-treated patients and 4% of patients in the placebo group. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was amenable to management with standard antihypertensive therapy. In cases of severe or persistent hypertension, or hypertensive crisis despite adequate antihypertensive therapy, permanent discontinuation of sorafenib should be considered. At the beginning of therapy, blood pressure should be monitored on a weekly basis and thereafter should be monitored regularly and treated, if required, in accordance with standard medical practice (see Monitoring and Laboratory Tests and ADVERSE REACTIONS).

Gastrointestinal

Gastrointestinal Perforation

Gastrointestinal perforation is an uncommon event and has been reported in less than 1% of patients taking NEXAVAR. In some cases, this was not associated with apparent intra- abdominal tumour. NEXAVAR therapy should be discontinued in the event of gastrointestinal perforation.

Hematologic

Hemorrhage

An increase in the risk of bleeding may occur following sorafenib administration. In the Phase III NEXAVAR RCC clinical trial, bleeding, regardless of the cause, was found in 15% of sorafenib- treated patients and in 8% of patients in the placebo group. In the Phase III NEXAVAR HCC clinical trial, the incidence of hemorrhagic events was reported in 18.2% of sorafenib-treated patients and in 19.9% of patients in the placebo group. The reported incidence of hemorrhagic events assessed as drug related by the reporting investigator was 7.1% in sorafenib-treated patients and 3.6% in the placebo arm. The incidence of severe bleeding events is uncommon. If any bleeding event necessitates medical intervention, it is recommended that permanent discontinuation of sorafenib should be considered (see ADVERSE REACTIONS).

Hepatic/Biliary/Pancreatic

Hepatic Impairment

In vitro and in vivo data indicate that sorafenib is primarily metabolized by the liver. Based on the results from one Phase II study, AUC0-8 and Cmax in patients with Child-Pugh B hepatic impairment were greater than the corresponding parameters in patients with Child-Pugh A hepatic impairment. NEXAVAR has not been studied in patients with Child-Pugh C hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). There are limited safety data available for Child-Pugh Class B patients.

Renal

No dose adjustment is required in patients with mild, moderate, or severe renal impairment not requiring dialysis. Sorafenib has not been studied in patients undergoing dialysis (see DOSAGE AND ADMINISTRATION and Product Monograph PART II: DETAILED PHARMACOLOGY). Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised.

Sexual Function/Reproduction

Results from animal studies indicate that sorafenib can impair male and female fertility (see Product Monograph PART II: DETAILED PHARMACOLOGY).

Skin

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 (National Cancer Institute Common Terminology Criteria) Grade 1 and 2 and generally appear during the first six weeks of treatment with sorafenib. Dermatologic toxicities are generally easily managed and 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).

Special Populations

Geriatrics (>=65 years of age)

Analyses of data by demographics suggest that no dose adjustment is required on the basis of patient age (>=65 years of age). No differences in safety or efficacy were observed between older and younger patients.

Nursing Women

It is not known whether sorafenib is excreted in human milk. In animals, sorafenib and/or its metabolites were excreted in milk. Because many drugs are excreted in human milk and because the effects of sorafenib on infants have not been studied, woman should discontinue breastfeeding during sorafenib treatment.

Pediatrics (<18 years of age)

The safety and effectiveness of sorafenib in pediatric patients has not been established.

Pregnancy

There are no adequate and well-controlled studies in pregnant women using sorafenib. In animals, sorafenib has been shown to be teratogenic and embryotoxic. Adequate contraception should be used during therapy and for at least 2 weeks after completion of therapy. Women of childbearing potential must be apprised of the potential hazard to the fetus, which includes severe malformation (teratogenicity), failure to thrive and fetal death (embryotoxicity). Sorafenib should not be used during pregnancy. Prescribers may only consider the use of sorafenib in pregnant women if the potential benefits justify the potential risks to the fetus (see Product Monograph PART II: DETAILED PHARMACOLOGY).

Monitoring and Laboratory Tests

Patients taking warfarin concomitantly should be monitored regularly for changes in prothrombin time, INR, and for clinical bleeding episodes. Complete blood counts [CBC] should be performed and phosphate, lipase, and amylase levels should be measured at the beginning of treatment and at regular intervals thereafter. At the beginning of therapy, blood pressure should be monitored on a weekly basis and thereafter should be monitored regularly and treated, if required, in accordance with standard medical practice.

DRUG INTERACTIONS

Overview

Sorafenib is metabolized primarily in the liver undergoing oxidative metabolism mediated by CYP3A4 as well as glucuronidation mediated by UGT1A9.

Drug-Drug Interactions

CYP3A4 Inducers

Chronic concomitant administration of rifampin with a single dose of sorafenib resulted in a 24% decrease in the combined AUC of sorafenib and its active primary metabolite when rifampin was coadministered with sorafenib. The clinical significance of this overall decrease in drug exposure is unknown. Other inducers of CYP3A4 activity (eg, hypericum perforatum [also known as St. John's wort], phenytoin, carbamazepine, phenobarbital, and dexamethasone) may also increase the metabolism of sorafenib and decrease its exposure.

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 subclinical dose (50 mg) of sorafenib.

CYP2C9 Substrates

The possible effect of sorafenib on warfarin, a CYP2C9 substrate, was assessed in sorafenib- treated patients compared to placebo-treated patients. The concomitant treatment with sorafenib and warfarin did not result in changes in mean PT-INR compared to placebo. However, patients taking warfarin should have their INR checked regularly (see WARNINGS AND PRECAUTIONS and Product Monograph PART II: DETAILED PHARMACOLOGY).

CYP Isoform-selective Substrates

Concomitant administration of sorafenib and midazolam, dextromethorphan or omeprazole, which are substrates of cytochromes CYP3A4, CYP2D6 and CYP2C19, respectively, following 4 weeks of sorafenib administration 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.

UGT1A9 Inhibitors

An in vitro study has revealed a number of drugs affected UGT1A9-mediated sorafenib glucuronidation with an IC50 value below 100 mM. They were atorvastatin (IC50 = 67 mM), ketoconazole (87 mM), mefenamic acid (28 mM), erlotinib (69 mM), and niflumic acid (1.2 mM). The clinical relevance of these drug interactions has not been tested.

Combination with Other Antineoplastic Agents

NEXAVAR is approved only as monotherapy in the treatment of RCC and HCC (see

INDICATIONS AND CLINICAL USE). In clinical studies, sorafenib has been administered together with a variety of other antineoplastic agents at their commonly-used dosing regimens, including gemcitabine, oxaliplatin, doxorubicin, and irinotecan. Sorafenib had no effect on the pharmacokinetics of gemcitabine or oxaliplatin. Concomitant treatment with sorafenib resulted in a 21% increase in the AUC of doxorubicin. When administered with irinotecan, whose active metabolite SN-38 is further metabolized 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 WARNINGS AND PRECAUTIONS). A clinical study has revealed that administration of sorafenib 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 Cmax (see WARNINGS AND PRECAUTIONS).

In Vitro Studies on Enzyme Inhibition

Sorafenib inhibits glucuronidation by the UGT1A1 and UGT1A9 pathways. Systemic exposure to substrates of UGT1A1 and UGT1A9 may be increased when coadministered with sorafenib. Sorafenib inhibits CYP2B6 and CYP2C8 in vitro with Ki values of 6 and 1-2 uM, respectively. Systemic exposure to substrates of CYP2B6 and CYP2C8 may increase when coadministered with sorafenib (see Product Monograph PART II: DETAILED PHARMACOLOGY).

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.

Drug-Food Interactions

It is recommended that sorafenib be administered without food or together with a low-fat or moderate-fat meal. Following oral administration, sorafenib reaches peak plasma levels in approximately 3 hours. When given with a moderate-fat meal, bioavailability is similar to that in the fasted state. With a high-fat meal, sorafenib bioavailability is reduced by 29% compared to administration in the fasted state (see DOSAGE AND ADMINISTRATION).

Drug-Herb Interactions

Interactions with herbal products have not been established. St. John's wort (an inducer of CYP3A4 activity) may increase metabolism of sorafenib and thus decrease sorafenib concentrations.

Drug-Laboratory Interactions

Interactions with results of laboratory tests have not been established.

Drug-Lifestyle Interactions

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

DOSAGE AND ADMINISTRATION

Dosing Considerations

No dose adjustment is required on the basis of patient age (65 years or above), gender, or body weight The safety and effectiveness of sorafenib in pediatric patients has not been established

Based on the results from one Phase II study, subjects with Child-Pugh B hepatic impairment had greater systemic exposure than those with Child-Pugh A hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). Sorafenib has not been studied in patients with Child- Pugh C hepatic impairment (see Product Monograph PART II: DETAILED PHARMACOLOGY) No dose adjustment is required in patients with mild, moderate, or severe renal impairment not requiring dialysis. Sorafenib has not been studied in patients undergoing dialysis (see Product Monograph PART II: DETAILED PHARMACOLOGY)

Recommended Dose

The recommended daily dose of NEXAVAR (sorafenib tablets) is 400 mg (2 x 200 mg tablets) taken twice a day (equivalent to total daily dose of 800 mg) without food or with a low-fat or moderate-fat meal. Treatment should be continued until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

Dosage Adjustment

Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of sorafenib therapy. When dose reduction is necessary, the sorafenib dose should be reduced to 400 mg daily (see Table 6 below and WARNINGS AND PRECAUTIONS).

Table 6 - Suggested Dose Modification for Skin Toxicity

Missed Dose

The missed dose should be taken as soon as the patient remembers. However, if it is almost time for the next dose, the missed dose should be skipped and the patient should take his/her next dose as scheduled. A double dose should not be administered to make up for forgotten individual doses.

Administration

For oral use. To be swallowed with a glass of water.

OVERDOSAGE

For management of suspected drug overdose, contact your regional poison control centre. The highest dose of sorafenib studied clinically is 800 mg twice daily. The adverse reactions observed at this dose were primarily diarrhea, grade 3 hypertension, dyspnea, and dermatologic events (rash/desquamation). There is no specific treatment for sorafenib overdose. In the event of suspected overdose, sorafenib should be withheld and supportive care instituted. Vital signs, complete blood count (CBC) with differential and platelet count should be monitored periodically. Fluid and electrolyte status should be monitored in patients with vomiting and diarrhea. Serum lipase should be monitored in patients with abdominal pain. Administration of activated charcoal may be appropriate in some cases.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Sorafenib was shown to inhibit multiple intracellular (c-CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-ss). Several of these kinases are thought to be involved in tumour cell signaling, angiogenesis, and apoptosis. Sorafenib inhibited cell proliferation of the human hepatocellular carcinoma PLC/PRF/5 and HepG2 cell lines, and renal cell carcinoma (786-O cell line), and tumour growth of several human tumour xenografts (PLC/PRF/5 cell line) in immunocompromised mice. A reduction in tumour angiogenesis and increases in tumour apoptosis was seen in the xenograft models of human hepatocellular and renal cell carcinoma cell lines. Additionally, a reduction in Raf/MEK/ERK signaling was seen in human hepatocellular carcinoma PLC/PRF/5 and HepG2 cell lines.

Pharmacokinetics

Absorption and Distribution

After administration of sorafenib tablets, the mean relative bioavailability is 38-49% when compared to an oral solution. Following oral administration, sorafenib reaches peak plasma levels in approximately 3 hours. When given with a moderate-fat meal (30% fat; 700 calories), bioavailability is similar to that in the fasted state. With a high-fat meal (50% fat; 900 calories), sorafenib bioavailability is reduced by 29% compared to administration in the fasted state. Mean Cmax and AUC increase less than proportionally beyond doses of 400 mg administered orally twice daily. Multiple dosing of sorafenib for 7 days results 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. In vitro binding of sorafenib to human plasma proteins is 99.5%.

Metabolism and Elimination

Sorafenib is metabolized primarily in the liver undergoing oxidative metabolism mediated by CYP3A4 as well as glucuronidation mediated by UGT1A9. 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 and 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 feces, and 19% of the dose excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51% of the dose, was found in feces but not in urine. The elimination half-life of sorafenib is approximately 25-48 hours.

Special Populations and Conditions

Gender

Analyses of pharmacokinetic and safety data in male and female subgroups suggest that no dose adjustments are necessary based on patient gender.

Geriatrics (>=65 years of age)

Analyses of data suggest that no dose adjustments are necessary based on patient age.

Pediatrics (<18 years of age)

There are no pharmacokinetic data in pediatric patients.

Hepatic Impairment

Sorafenib is cleared primarily by the liver. The results of one Phase II study revealed 36% and 54% higher AUC0-8 and Cmax in patients with Child-Pugh B hepatic impairment (n = 6) compared to patients with Child-Pugh A hepatic impairment (n = 14) in subjects administered 400 mg bid NEXAVAR (see Table 7 below).The pharmacokinetics of sorafenib has not been studied in patients with severe (Child-Pugh C) hepatic impairment (see WARNINGS AND PRECAUTIONS).

Renal Impairment

In a clinical pharmacology study, the pharmacokinetics of sorafenib were evaluated following administration of a single 400 mg dose to subjects with normal renal function and in subjects with mild (Clcr 50-80 mL/min), moderate (Clcr 30 to < 50 mL/min), or severe (Clcr < 30mL/min) renal impairment, not requiring dialysis. There was no relationship observed between sorafenib exposure and renal function. No dosage adjustment is necessary based on mild, moderate or severe renal impairment not requiring dialysis (see WARNINGS AND PRECAUTIONS).

STORAGE AND STABILITY

Store at controlled room temperature (15-30oC) in a dry place. Do not use after the expiry date stated on bottle. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. Keep out of the reach and sight of children and pets.

DOSAGE FORMS, COMPOSITION AND PACKAGING

NEXAVAR (sorafenib tablets) is supplied as round, biconvex, red film-coated tablets containing 200 mg of sorafenib (as 274 mg of sorafenib tosylate). Tablets are debossed with the "Bayer cross" on one side and "200" on the other side. Tablet core: Croscarmellose sodium, microcrystalline cellulose, hydroxypropylmethyl cellulose, sodium lauryl sulfate, magnesium stearate Film-coat: hydroxypropylmethyl cellulose, macrogol, titanium dioxide, ferric oxide red Packaging: bottles of 120 tablets

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

sorafenib tosylate

Chemical name:

4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]- ureido}phenoxy)-N2-methylpyridine-2-carboxamide 4- methylbenzenesulfonate

Molecular weight:

637.0 g/mole

Structural formula:

F

F F

Cl O

O

N N

H H

O

N

O

S OH O

CH3

Physicochemical properties:

Sorafenib is supplied as a tosylate salt and is a white to

yellowish or brownish solid with a molecular formula of C21H16ClF3N4O3 x C7H8O3S. Sorafenib tosylate is practically insoluble in aqueous media, slightly soluble in ethanol and soluble in Polyethylene Glycol (PEG) 400.

CLINICAL TRIALS

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

Hepatocellular Carcinoma

Study 100554

Study demographics and trial design

Study 100554 was a Phase III, international, multicentre, randomised, double-blind, placebo- controlled trial in 602 patients with hepatocellular carcinoma. Overall survival (OS) and time to symptomatic progression (TTSP) were co-primary endpoints of this study, time to progression (TTP) a secondary endpoint. Demographics and baseline disease characteristics were comparable between the NEXAVAR and placebo groups with regard to age, gender, race, performance status, etiology (including hepatitis B, hepatitis C, and alcoholic liver disease), TNM stage (sorafenib vs placebo, 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%), presence of macroscopic vascular invasion (36% vs 41%) and extrahepatic tumour spread (53% vs 50%), BCLC stage (Stage B: 18.1% vs 16.8%; Stage C: 81.6% vs 83.2%; Stage D: <1% vs 0%) and liver function (Child-Pugh A: 95% vs 98%; Child-Pugh B: 5% vs 2%). Only one patient with Child-Pugh C liver dysfunction was treated in the study. Enrolment of subjects with Child- Pugh B or C was a protocol violation. Prior treatment included surgical resection procedures (19.1% vs 20.5%), locoregional therapies (including radiofrequency ablation, percutaneous ethanol injection, and transarterial chemoembolisation: 38.8% vs 40.6%), radiotherapy (4.3% vs 5.0%), and systemic therapy (3.0% vs 5.0%).

Study results

The study was stopped after a planned interim analysis of OS had crossed the prespecified efficacy boundary. The definitive results from this analysis showed a statistically significant advantage for NEXAVAR over placebo for OS (HR: 0.69, P= 0.00058, see Table 8 and Figure 1). This advantage was consistent across almost all subsets analysed. In the prespecified stratification factors (ECOG status, presence, or absence of macroscopic vascular invasion and/or extrahepatic tumour spread, and region), the hazard ratio consistently favoured NEXAVAR over placebo. The time to tumour progression (TTP, by independent radiological review) was significantly larger in the NEXAVAR arm (HR: 0.58, P=0.000007, see Table 8). The analysis of the co-primary endpoint TTSP was not statistically significant. Efficacy and safety could not be evaluated in Child-Pugh B subjects enrolled in this study due to limited data (n = 20).

Table 8 - Efficacy Results from Study 100554 in Hepatocellular Carcinoma

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

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

* * independent radiological review

Figure 1 Kaplan-Meier Curve of Overall Survival in Study 100554, Intent-to-treat Population

NOC/c

Renal Cell Carcinoma

Study 11213

Study demographics and trial design

Study 11213 (1, 2) was a multicentre, randomized, double blind, placebo-controlled trial in patients with locally advanced / metastatic RCC who had received prior systemic therapy. Patients with clear cell carcinoma and low/intermediate MSKCC prognostic criteria without brain metastases were recruited for the study. Patients were randomized to sorafenib 400 mg twice daily (N=451) or to placebo (N=452). Study endpoints included overall survival, progression-free survival (PFS) and tumour response rate.

Table 9

summarizes the demographic and disease characteristics of the study population analyzed. Baseline demographics and patient characteristics were well balanced for both treatment groups. The median time from initial diagnosis of RCC to randomization was 1.6 and

1.9 years for the NEXAVAR (sorafenib tosylate) and placebo groups, respectively. The median age of the patients was 59 years (range 19-86). Approximately half of the patients had an ECOG performance status of 0 and half of the patients were in the low Motzer prognostic group.

Table 9 - Demographics and Disease Characteristics - Study 11213

1. Race was not collected from the 204 patients enrolled in France due to local regulations.

2. Includes patients for whom intent of therapy was not reported and therefore their removal cannot be assessed.

Study results

The efficacy data generated in this study are summarized in Table 10 below. The median progression-free survival (PFS) for patients randomized to NEXAVAR (167 days) was double that observed for patients randomized to placebo (84 days), representing a 56% reduction in risk of progression for patients receiving sorafenib compared to placebo.

Table 10 - Efficacy (PFS and Hazard Ratio) Results from Study 11213

Progression-free survival in the intent-to-treat population was evaluated by blinded independent radiological review using RECIST criteria. Figure 2 depicts Kaplan-Meier curves for PFS. The PFS analysis was a two-sided Log-Rank test stratified by Motzer/MSKCC prognostic risk category (3) and country.

Figure 2 - Kaplan-Meier Curves for Progression-Free Survival - Study 11213

Placebo (N=385) Median: 2.76 Months

Progression-free Survival Probability (%)

HR: 0.44 p<0.000001

Months from Randomization

HR (Hazard Ratio) is from Cox regression model with the following covariates: Motzer/MSKCC prognostic risk category (3) and country. P-value is from two-sided Log-Rank test stratified by Motzer/MSKCC prognostic risk category (3) and country. A series of patient subsets were examined in exploratory univariate analyses of PFS. These results are shown in Figure 3. The effect of sorafenib on PFS was consistent across these subsets, including patients with no prior IL-2 or Interferon therapy (N=137), for whom the median PFS was 172 days on NEXAVAR compared to 85 days on placebo.

Figure 3 - Progression-Free Survival in Patient Subgroups (Hazard Ratio and 95% Cl for NEXAVAR : Placebo) - Study 11213

NEXAVAR benefit Placebo benefit

Age <65 years Age >=65 years

ECOG PS 0

ECOG PS 1

Prior therapy for metastatic disease Time from diagnosis <1.5 year Time from diagnosis >=1.5 year

0 0.5 1.0 1.5

Hazard ratio

Tumour response was determined by independent radiological review according to RECIST criteria. In the NEXAVAR group, 80% (268/335) of the patients had best response of stable disease or better compared to 55% (186/337) of the patients in the placebo group. Overall, 7 (2%) sorafenib patients and 0 (0%) placebo patients had a confirmed partial response, and 261 (78%) sorafenib patients and 186 (55%) placebo patients had stable disease. Overall, 293 patients in the NEXAVAR group and 281 patients in the placebo group had at least one postbaseline radiographic tumour evaluation available for independent review. There was a trend towards more tumour shrinkage in patients treated with NEXAVAR (see Figure 4); 74% of sorafenib patients had some degree of tumour shrinkage, compared to 20% of placebo patients.

Figure 4 - Maximum Percent Reduction of Target Lesions by Patient, Using Independent Review of Scans in Study 11213

Maximum Percent Reduction in Tumour Measurement

Placebo

Sorafenib

10 0

50 100 150 200 250

Patient number

-2 0

-4 0

-6 0

-8 0

10 0

50 10 0

Pa t i e n t n u m b e r

20 0

74%

Maximum percentage reduction in tumour burden from baseline for individual patients, each of whom is represented by a bar on the graph. Bars pointing in the positive direction of the Y axis represent patients whose tumours grew, while bars pointing in the negative direction represent patients with tumour shrinkage.

At the first interim survival analysis, based on 220 deaths, overall survival was longer for NEXAVAR than placebo with a hazard ratio (NEXAVAR over placebo) of 0.72. The differences in the results were not statistically significant due to the interim nature of the data. At the time of the second planned interim analysis based on 367 deaths, survival was longer in patients treated with NEXAVAR (171 deaths in the NEXAVAR arm and 196 deaths in the placebo arm) with a hazard ratio of 0.77. This analysis included 200 placebo patients that had crossed over to NEXAVAR treatment. The Kaplan Meier curves for OS constructed at this time are shown in Figure 5. Furthermore, The OS rate at 6 months was 87.1% for the patients treated with NEXAVAR and 80.1% for the placebo group. OS rate at 12 months was 64.9% for patients treated with NEXAVAR and 59.0% for the placebo group. The two curves (NEXAVAR and placebo) cross at Day 696, as observed in Figure 5, due to one death in the NEXAVAR arm. At this time point, where only 6 at-risk patients are evaluable (n=4 on NEXAVAR, n=2 on placebo), differences in survival between treatment groups are inconclusive. The trend for longer OS in the NEXAVAR arm was not statistically significant due to the interim nature of the data. Additional analyses are planned as the survival data mature.

Figure 5 - Kaplan-Meier Curves for Overall Survival (Second Interim Analysis)

NEXAVAR (N=451)

Survival Probability

Study 100391

Study demographics and trial design

Study 100391 (4, 5) was a randomized discontinuation trial in patients with various metastatic malignancies. The primary endpoint was percentage of randomized patients remaining progression-free at 24 weeks. All patients received sorafenib for the first 12 weeks. Radiologic assessment was repeated at Week 12: patients with <25% change in bidimensional tumour measurements from baseline were randomized to NEXAVAR or placebo for a further 12 weeks; patients who were randomized to placebo were permitted to crossover to open-label sorafenib upon progression; patients with >=25% tumour shrinkage continued sorafenib; patients with tumour growth >=25% discontinued treatment.

Study results

Two hundred and two patients with RCC were enrolled in Study 100391, including patients who received no prior therapy and patients with tumour histology other than clear cell carcinoma. Seventy-nine RCC patients remained on open-label sorafenib after the first 12 weeks of study therapy. At 24 weeks the progression-free rate for the 65 randomized RCC patients was significantly higher (P=0.0077) for the NEXAVAR group (16 of 32 patients [50.0%]) than for the placebo group (6 of 33 patients [18.2%]). The RCC patients randomized to NEXAVAR had a significantly longer median PFS (163 days) compared to patients randomized to placebo (41 days; P=0.0001; hazard ratio 0.29).

DETAILED PHARMACOLOGY

This section includes animal data on sorafenib pharmacology not derived from human studies.

Nonclinical Pharmacology

Sorafenib is a multikinase inhibitor that decreases cell proliferation of some tumour cell lines in vitro. Sorafenib inhibits tumour growth of the murine renal cell carcinoma, RENCA, and a broad spectrum of human tumour xenografts (786-O, HCT-116, NCI-H460, MiaPaCa-2, SK-OV-3, DLD-1, A549, CAKI-1, LOX, NCI-H23, MDA-MB-231, COLO-235, HT-29, MV4; 11, PLC-PRF-5, BxPC3, UACC-62 and PC3) 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, KIT, and FLT-3) and in the tumour vasculature (CRAF, VEGFR-2, VEGFR-3, and PDGFR-ss). RAF kinases are serine/threonine kinases, whereas KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-ss are receptor tyrosine kinases. Mutation of BRAF has been associated with melanoma, KIT has been associated with gastrointestinal stromal tumours, and FLT-3 has been associated with acute myelogenous leukemia.

(6-8)

Safety Pharmacology

A comprehensive program of safety pharmacology studies was conducted with sorafenib. Cardiac and pulmonary functions were investigated in anesthetized dogs after single intraduodenal doses, complemented by in vitro electrophysiological studies. However, the potential effects of the main human metabolite M-2 (which is absent in dogs) on blood pressure, heart rate and ECG parameters, were not examined in these studies. Potential effects on diuresis, blood pharmacological parameters, blood glucose, CNS function, and gastrointestinal (GI) tract were investigated in rats after single oral doses. The results did not indicate relevant adverse findings.

Nonclinical Pharmacokinetics

The pharmacokinetics of sorafenib (absorption, distribution, metabolism and elimination) has been studied in humans and is discussed in the Human Pharmacology section and in Product Monograph PART I: ACTION AND CLINICAL PHARMACOLOGY. Other pharmacokinetic information derived from nonclinical studies is described below. The protein binding of sorafenib was high and species-dependent. The fraction unbound to plasma proteins (fu) was about 0.5% in mouse, rat, and man, 0.9% in dogs, and 2.0% in rabbits, respectively. Albumin was identified as an important binding component in human plasma. In vitro studies with cultured human hepatocytes indicated that sorafenib exhibited no inductive potential on major CYP isoforms. The inhibitory effect of sorafenib on different CYP and UGT isoforms has been studied in human liver microsomes in vitro. Sorafenib inhibits glucuronidation by the UGT1A1 and UGT1A9 pathways. Systemic exposure to substrates of UGT1A1 and UGT1A9 may be increased when coadministered with sorafenib. Only small inhibitory effects on CYP2C19, CYP2D6 and CYP3A4 were observed, as indicated by Ki values of 17uM, 22uM, and 29uM. Sorafenib inhibits CYP2B6 and CYP2C8 in vitro with Ki values of 6 and 1-2 uM, respectively. Systemic exposure to substrates of CYP2B6 and CYP2C8 may increase when coadministered with sorafenib. Sorafenib is a competitive inhibitor of CYP2C9 with a Ki value of 7-8 uM. In rats, [14C]sorafenib and/or its radiolabeled metabolites penetrated the placental barrier at a low to moderate extent. The radioactivity was homogeneously distributed to most fetal organs and tissues. None of the fetal organs and tissues exceeded the analogous maternal organ/tissue exposure, except fetal brain where exposure was 2.3 fold higher than in the brain of the dams. After oral administration of [14C]sorafenib tosylate, the radioactivity was secreted to a remarkable amount into the milk of lactating rats.

Human Pharmacology

Absorption and Distribution

After administration of sorafenib tablets, the mean relative bioavailability is 38-49% when compared to an oral solution. Following oral administration, sorafenib reaches peak plasma levels in approximately 3 hours. When given with a moderate-fat meal, bioavailability is similar to that in the fasted state. With a high-fat meal, sorafenib bioavailability is reduced by 29% compared to administration in the fasted state. Mean Cmax and AUC increase less than proportionally beyond doses of 400 mg administered orally twice daily. Multiple dosing of sorafenib for 7 days results 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.

(9)

Metabolism and Elimination

Sorafenib is metabolized primarily in the liver undergoing oxidative metabolism mediated by CYP3A4 as well as glucuronidation mediated by UGT1A9. 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. Concomitant administration of sorafenib and midazolam, dextromethorphan or omeprazole, which are substrates of cytochromes CYP3A4, CYP2D6, and CYP2C19, respectively, following 4 weeks of sorafenib administration did not alter the exposure of these agents. The possible effect of sorafenib on a CYP2C9 substrate was assessed in patients receiving sorafenib or placebo in combination with warfarin. The mean changes from baseline in PT-INR in RCC patients were not higher in sorafenib-treated patients compared to placebo patients, suggesting that sorafenib may not be an inhibitor of CYP2C9 (see Nonclinical Pharmacokinetics and Product Monograph PART I: DRUG INTERACTIONS). 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 and comprises approximately 9-16% of circulating analytes at steady state (see Nonclinical Pharmacokinetics and Product Monograph PART I: DRUG INTERACTIONS). 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 feces, and 19% of the dose excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51% of the dose, was found in feces but not in urine. The elimination half-life of sorafenib is approximately 25-48 hours.

(9)

TOXICOLOGY

Single-Dose and Repeat-Dose Toxicity

The highest single oral sorafenib dose of 1460 mg/kg applied to rats and mice was tolerated without any sign of toxicity. In dogs, a single oral sorafenib dose of 1000 mg/kg was well tolerated; the only sign of toxicity was vomiting. Short-term repeated daily administration of sorafenib was relatively well tolerated in animals. Cumulative toxicity was evident after long-term administration (rats up to 6 months, mice up 3 months, dogs up to 12 months) with a decrease of the threshold dose for significant lesions with duration of exposure. Remarkable clinical signs of toxicity consisted of skin reactions and bloody diarrhea in dogs. Hematological changes were moderate, blood clinical chemistry revealed mainly signs of hepatic toxicity. Histopathology revealed degeneration and regeneration/repair processes in multiple organ systems including liver, kidneys, lymphoreticular/hematopoietic system, gastrointestinal tract, pancreas, adrenals, reproductive organs, skin, teeth, and bone. The majority of morphological lesions was fully reversible or showed at least a tendency for recovery. The maximum tolerable long-term dose based on survival was 2.5 mg/kg/day (15 mg/m2/day, AUC0-24h about 34 mg *h/L) in rats, 100 mg/kg/day (300 mg/m2/day, AUC0-24h about 147 mg *h/L) in mice, and 30 mg/kg/day (600 mg/m2/day, AUC0-24h about 22 mg *h/L) in dogs. Significant toxicities in animals were observed at doses and corresponding plasma concentrations of sorafenib that were in the range of or below those in cancer patients after the recommended daily dose of 400 mg bid sorafenib.

Carcinogenicity, Genotoxicity, Reproductive Toxicity

Carcinogenicity studies have not been performed with sorafenib. Positive genotoxic effects were obtained for sorafenib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. One intermediate in the manufacturing process, which is also present in the final drug substance (< 0.15%), was positive for mutagenesis in an in vitro bacterial cell assay (Ames test). Sorafenib was not genotoxic in the Ames test (the material contained the intermediate at 0.34%) and in an in vivo mouse micronucleus assay. Results from the repeat-dose toxicity studies indicate a potential of sorafenib to impair reproduction performance and fertility - various effects were observed in male and female reproductive organs. In developmental toxicity studies in rats and rabbits, the no-observed- adverse-effect-level was determined to be 0.2 mg/kg/day in rats and 1 mg/kg/day in rabbits. At the next highest dose level tested, clear embryo-fetal toxicity and teratogenicity were demonstrated at oral doses of 1 mg/kg/day in rats and 3 mg/kg/day in rabbits.

Other Toxicology Information

Based on findings in repeat-dose toxicity studies using growing animals, there is a potential risk to children and adolescents regarding effects on structure and composition of bone and teeth. Toxicological evaluations of the main human metabolite (M-2) and of impurities in the drug substance indicated no significant contribution to the overall toxicological profile and risk assessment.

REFERENCES

Escudier B, Szczylik C, Eisen T, Stadler WM, Schwartz B, Shan M, et al. Randomized Phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). J Clin Oncol 2005; 23(16 Suppl):380. Bayer Data on File. Study 11213. West Haven CT: Bayer Pharmaceutical Corporation; 2005. Report No. : MRR 00170. Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004; 22(3):454-63. Ratain MJ, Flaherty KT, Stadler WM, O'Dwyer P, Kaye S, Xiong H, et al. Preliminary antitumor activity of BAY 43-9006 in metastatic renal cell carcinoma and other advanced refractory solid tumors in a phase II randomized discontinuation trial (RDT). J Clin Oncol 2004. Bayer Data on File. Study 100391 Part B. West Haven CT: Bayer Pharmaceuticals Corporation; 2005. Report No. : MRR 00158. Wilhelm S, Chien DS. BAY 43-9006: preclinical data. Curr Pharm Des 2002; 8(25):2255- 7. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64(19):7099-109. Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 2006; 66(24):11851-8. Strumberg D, Richly H, Hilger RA, Schleucher N, Korfee S, Tewes M, et al. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 2005; 23(5):965-72. IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

NEXAVAR (sorafenib tablets), indicated for the treatment of locally advanced / metastatic renal cell (clear cell) carcinoma (RCC) in patients who failed prior cytokine therapy or are considered unsuitable for such therapy, has been approved with conditions, pending the results of studies to verify its clinical benefit. For more information, patients are advised to contact their health care provider.

NEXAVAR (sorafenib tablets) has received nonconditional approval for the treatment of patients with hepatocellular cancer (HCC).

What is a Notice of Compliance with Conditions (NOC/c)?

An NOC/c is a form of market approval granted to a product on the basis of promising evidence of clinical effectiveness following review of the submission by Health Canada.

Products approved under Health Canada's NOC/c policy are intended for the treatment, prevention or diagnosis of a serious, life-threatening or severely debilitating illness. They have demonstrated promising benefit, are of high quality and possess an acceptable safety profile based on a benefit/risk assessment. In addition, they either respond to a serious unmet medical need in Canada or have demonstrated a significant improvement in the benefit/risk profile over existing therapies. Health Canada has provided access to this product on the condition that sponsors carry out additional clinical trials to verify the anticipated benefit within an agreed upon time frame.

PrNEXAVAR(r)

sorafenib tablets

This leaflet is Part 3 of a three-part "Product Monograph" published when NEXAVAR was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about NEXAVAR. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

NEXAVAR is used to treat liver cancer (hepatocellular carcinoma) which cannot be removed by surgery.

NEXAVAR is also used to treat kidney cancer (locally advanced / metastatic renal cell (clear cell) carcinoma) in adults who failed prior cytokine therapy or are considered unsuitable for such therapy.

What it does:

NEXAVAR is a multikinase inhibitor. As an anticancer agent, it works by slowing down the rate of tumour growth and cutting off the blood supply that keeps tumours growing.

When it should not be used:

Do not take NEXAVAR if you are allergic (hypersensitive) to sorafenib tosylate or any of the other ingredients of NEXAVAR.

What the medicinal ingredient is:

Sorafenib tosylate

What the nonmedicinal ingredients are:

The other tablet ingredients are: croscarmellose sodium, microcrystalline cellulose, hydroxypropylmethyl cellulose, sodium lauryl sulfate, magnesium stearate.

The tablet coating contains: hydroxypropylmethyl cellulose, macrogol, titanium dioxide, ferric oxide red.

What dosage forms it comes in:

NEXAVAR is supplied as a tablet containing 200 mg of sorafenib. These tablets are red, round and film-coated, with the Bayer cross on one side and "200" on the other side. They come in bottles containing 120 tablets.

IMPORTANT: PLEASE READ

WARNINGS AND PRECAUTIONS

• Warfarin (COUMADIN(r)), an anticoagulant used to prevent blood clots

Serious Warnings and Precautions

This drug should be prescribed and managed only by a doctor experienced in anticancer drugs.

NEXAVAR has not been studied in patients who have severe liver problems.

Of note, possible serious side-effects with NEXAVAR include high blood pressure, bleeding, heart attack and gastrointestinal (bowel) perforation.

BEFORE you use NEXAVAR talk to your doctor or pharmacist if:

You have high blood pressure. NEXAVAR can raise blood pressure. Your doctor will instruct you to monitor your blood pressure and may give you medicine to treat your high blood pressure.

You have bleeding problems, or are taking warfarin.

Treatment with NEXAVAR may lead to a higher risk of bleeding. If you are taking warfarin, which thins the blood to prevent blood clots, there may be a greater risk of bleeding.

You are going to have surgery or dental procedure, or if you had an operation recently. NEXAVAR might affect the way your wounds heal. You will usually be taken off NEXAVAR if you are having an operation. Your doctor will decide when to start with NEXAVAR again.

You have kidney or liver problems (in addition to cancer)

You are pregnant, may be pregnant or are thinking about becoming pregnant. NEXAVAR may reduce fertility in both men and women. NEXAVAR can harm an unborn baby. You must use effective contraception while you take NEXAVAR.

You are breast-feeding. You should not breast-feed during NEXAVAR treatment because it could harm the baby.

You have had a history of heart problems NEXAVAR should not be given to children.

INTERACTIONS WITH THIS MEDICATION

Drugs that may interact with NEXAVAR include:

Rifampin (ROFACT(r), RIFADIN(r)), an antibiotic

St John's Wort, a herbal treatment for depression

Phenytoin (DILANTIN(r)), carbamazepine (TEGRETOL(r)), dexamethasone (MAXIDEX(r)) or Phenobarbital (BELLERGAL SPACETABS(r)), treatments for epilepsy and other conditions

Doxorubicin (ADRIAMYCIN PFS , CAELYX ,

MYOCET(r)), docetaxel (TAXOTERE(r)), and irinotecan (CAMPTOSAR(r)), which are other cancer treatments

Tell your doctor or pharmacist if you are taking these or any other medicines even those not prescribed (including any over- the-counter drugs, vitamins, or herbal medicines).

See also ABOUT THIS MEDICATION: When it should not be used, and SIDE EFFECTS AND WHAT TO DO ABOUT THEM.

PROPER USE OF THIS MEDICATION

Usual dose

The usual dose of NEXAVAR in adults is two 200 mg tablets, twice daily.

How to take NEXAVAR

Swallow NEXAVAR tablets with a glass of water, without food or with a low- to moderate-fat meal. Always take NEXAVAR exactly as your doctor has told you to. Check with your doctor or pharmacist if you are not sure. It is important to take NEXAVAR at about the same times each day.

Overdose

Tell your doctor immediately or contact the nearest poison control centre or the emergency room of the nearest hospital if you (or anyone else) have taken more than your prescribed dose.

Missed Dose

If you have missed a dose, take it as soon as you remember. If it is nearly time for the next dose, forget about the missed one and carry on as normal. Do not take a double dose to make up for forgotten individual doses.

How long will I take NEXAVAR?

Your doctor will continue to treat you with NEXAVAR as long as you are thought to be benefiting from therapy.

IMPORTANT: PLEASE READ

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

NEXAVAR can have side effects, like all medicines, but not everybody gets them. For further information about any of these effects, ask a doctor or pharmacist.

If you experience any symptom that bothers you or does not go away, or severe side effects such as high blood pressure, bleeding or skin reactions, contact your doctor or seek medical attention as soon as possible.

Very common side effects

(may affect 10 or more in every 100 people)

diarrhea

feeling sick (nausea)

throwing up (vomiting)

constipation

loss of appetite

loss of weight

feeling weak or tired

pain (including mouth pain, abdominal pain, headache, bone pain, joint pain and muscle pain)

hair loss

flushed or painful palms or soles (hand-foot skin reaction)

itching or rash

inflamed, dry or scaly skin that sheds

bleeding (hemorrhage) including bleeds from the mouth, nose, stomach or gut, rectum or back passage, lungs or windpipe, bleeding nail beds and blood blisters.

high blood pressure, or increases in blood pressure

breathlessness

inflamed or dry mouth, tongue pain

Common side effects

(may affect 1 to 9 in every 100 people)

flushing

acne

flu-like illness

fever

indigestion or heartburn

difficulty swallowing

depression

erection problems (impotence)

hoarseness

heart attack (severe chest pain, shortness of breath, cold sweat, etc.)

kidney failure

infection/inflammation of the gallbladder and/or bile ducts

This is not a complete list of side effects. For any unexpected effects while taking NEXAVAR, contact your doctor or pharmacist.

IMPORTANT: PLEASE READ

HOW TO STORE IT

MORE INFORMATION

Store at room temperature between 15-30oC in a dry place.

Do not use the tablets after the expiry date. This is shown on the bottle.

Keep out of the reach and sight of children and pets. This medicine does not need any other special storage

conditions.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

This document plus the full product monograph, prepared for health professionals can be found at:

http://www.bayer.ca

or by contacting the sponsor, Bayer Inc.

at: 1-800-265-7382.

This leaflet was prepared by: Bayer Inc.

77 Belfield Road

Toronto, Ontario M9W 1G6 Canada

Last revised: September 16, 2008

(c)2008, Bayer Inc.

(r) NEXAVAR is a registered trademark, used under license by Bayer Inc.