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For more information, call 1.866.NEXAVAR or visit www.NEXAVAR.com.

References: 1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74-108. http://caonline.amcancersoc.org/cgi/content/full/55/2/74. Accessed July 30, 2007. 2. Thomas MB, Abbruzzese JL. Opportunities for targeted therapies in hepatocellular carcinoma. J Clin Oncol. 2005;23(31):8093-8108. 3. American Cancer Society. Cancer Facts & Figures 2007. Atlanta, GA: American Cancer Society Inc; 2007. 4. National Cancer Institute. US National Institutes of Health. Adult primary liver cancer (PDQ): treatment. http://www.cancer.gov/cancertopics/pdq/treatment/adultprimary-liver/healthprofessional. Accessed July 26, 2007. 5. Wilson JF. Liver cancer on the rise. Ann Intern Med. 2005;142(12, pt 1):1029-1032. 6. Moradpour D, Blum HE. Pathogenesis of hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2005;17:477-483. 7. Llovet JM. Updated treatment approach to hepatocellular carcinoma. J Gastroenterol. 2005;40:225-235. 8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: hepatobiliary cancers. Version 2.2007. http://www.nccn.org/ professionals/physician_gls/PDF/hepatobiliary.pdf. Accessed August 6, 2007. 9. Dienstag JL, Isselbacher KJ. Tumors of the liver and biliary tract. In: Kasper DL, Fauchi AS, Longo DL, Braunwald E, Hauser SL, Jameson JL, eds. Harrisons Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill Medical Publishing Division; 2005:533-536. 10. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362:1907-1917. 11. Avila MA, Berasain C, Sangro B, Prieto J. New therapies for hepatocellular carcinoma. Oncogene. 2006;25:3866-3884. 12. Weinberg RA. The Biology of Cancer. New York, NY: Garland Science, Taylor & Francis Group LLC; 2007. 13. Llovet J, Ricci S, Mazzaferro V, et al; for the SHARP Investigators Study Group. Sorafenib in Advanced Hepatocellular Carcinoma. N Engl J Med 2008;359:378-90

A Guide to Liver Cancer and Its Treatment

To be given by health care professionals to patients prescribed Nexavar.


63 Chulia Street OCBC Centre East, 6 West Belt, Wayne, NJ 07470 USA 14th oor Singapore 049514 Corporation, Wayne, NJ 2007 Bayer Pharmaceuticals 2100 Powell Street, Emeryville, CA 94608 USA
SS1824807 11/07 Printed in USA

What Is Liver Cancer?


Liver cancer is the sixth most common cancer worldwide but is relatively uncommon in the United States, with about 18,000 new cases each year.1-3 world, liver as Japan, Southeast In some parts of the world (suchcancer is the most common sub-Saharan with more cancer is the Asia, and type of cancerAfrica), liverthan 1 millionmost new cases diagnosed each common type of cancer.4,5 year.4,5 The liver is made up of cells called hepatocytes. When cancer affects these cells, it is called hepatocellular carcinoma, or HCC. There are other types of liver cancer, but they are much less common5 and are not the focus of this brochure.

How Does Liver Cancer Develop?


Liver cancer usually develops when the liver has been damaged by some other disease or condition.2 These conditions may include chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, alcohol consumption, diabetes, genetic disorders, and obesity.2 In a healthy liver, chemical signals tell liver cells when to multiply to form more cells and when to stop multiplying. Liver cancer starts to develop when a cell or group of cells becomes damaged and begins growing abnormally.6 The damaged liver cells produce chemical signals that cause cells to continue multiplying. The damaged cells also send out signals to nearby blood vessels, telling them to grow more blood vessels, so the tumor can receive the oxygen and nutrients it needs to keep growing.2,6

What Is a Staging System, and What Does It Have to Do With My Disease?


Staging is a medical term for describing how far cancer has progressed in a particular patient. Staging the cancer is important, because it helps doctors determine the best course of treatment. There are a number of different staging systems for liver cancer.7,8 One method uses Roman numerals I through IV to designate the stage of disease.
The 4 stages of liver cancer 8
Stage I The tumor is small and found in 1 part of the liver.

Below are definitions of some other terms used to describe the stages of liver cancer. Localized resectablethis means that the tumor is located in one part of the liver and can be surgically removed (resected) Localized unresectablethe cancer is in one part of the liver but cannot be removed by surgery either because of its location or because the part of the liver without cancer is not healthy enough Advanceda general term that means the cancer has spread to more than one part of the liver and may have spread to other parts of the body Recurrentrecurrent disease is cancer that has come backeither to the liver or to another part of the bodyafter initial treatment or surgery

Lung

Liver

Stage II There are several small tumors or a single tumor that has spread to nearby blood vessels. Lymph nodes Stage III There are 1 or more tumors that might have spread to nearby parts of the body, such as the stomach, blood vessels, or lymph nodes. Stage IV There are 1 or more tumors in the liver, and cancer cells have spread to other parts of the body.

Gallbladder

At What Stage Are Most People With Liver Cancer Diagnosed?


Its not unusual for liver cancer to be diagnosed at more advanced stages, because many people dont have unusual symptoms in the early stages of the disease.9 The majority of patients are diagnosed are The majority (60% to 70%) at more advanced stages.7,10 diagnosed at more advanced stages.7,10

Common bile duct

Stomach
Pancreas

Duodenum

Adapted from Getty Images/Nucleus Medical Art.

Talk to Your Health Care Team Staging is important, because it helps doctors determine which type of treatment to use in individual patients.7
Your health care providers are your best source of information and advice about diagnosis and treatment of liver cancer.

How Is Liver Cancer Treated?


Treatment depends on the type of liver cancer, the stage of the cancer, how well the liver is functioning, the overall health of the patient, his or her personal preferences, and a dialogue between the patient and doctor.8 If liver cancer is diagnosed early, surgery is often an option.8

What if These Options Are Not Right for Me?


If surgery or the other treatment options outlined are not right for you, your doctor may prescribe a therapy called Nexavar. Nexavar is indicated for the treatment of patients with unresectable HCC.

Surgical removal of the tumor


If the tumor is small and liver function is good, surgery to remove the tumor and nearby tissue (called surgical resection) is usually recommended.8 If the tumor is localized but cannot be removed by surgery, either because the tumor is in a location that makes surgery too dangerous or because the rest of the liver is not healthy enough, there are other treatment options.

Until the recent approval of Nexavar, recent approval of Nexavar, there were no Food and Drug Administration no Health Science Authority (HSA)approved drug treatments proven (FDA)approved drug treatments proven to extend the lives of patients with extend the lives of patients with unresectable HCC. unresectable HCC.
Treatment with Nexavar has been shown to increase overall survival in patients with unresectable HCC. In a large study of 602 patients, Nexavar increased survival time (10.7 months with Nexavar vs 7.9 months with placebo) and the time until the tumor progressed or grew (5.5 months with Nexavar vs 2.8 months with placebo).13 This was the rst time any therapy was This was the first time any therapy was proven to extend survival in patients with unresectable rst HCC. As a result, Nexavar became the first medication HSA to be approved by the FDA for the treatment of patients with unresectable HCC. In this same study, Nexavar was generally well tolerated by patients, but some serious side effects occurred. The most common side effects associated with Nexavar were diarrhea, fatigue, abdominal pain, weight loss, anorexia, nausea, handfoot skin reaction, and rash/desquamation. Please see additional safety information on pages 11-13 of this booklet and the abbrevated Patient Prescribing on pages 14-15. Patient Prescribing InformationInformation on pages 14-15.

Liver transplantation
Liver transplantation may be considered if the tumor is confined to the liver but cannot be removed surgically.8 However, if the tumor is too large or widespread, transplantation would not be an appropriate option.5

Ablation (destruction) of part of the liver


If the tumor is limited to one part of the liver but cannot be removed surgically, there are treatments that may be used to destroy the tumor and surrounding tissue. The medical term for this kind of treatment is ablation. Some methods to accomplish this are percutaneous ethanol injection, radiofrequency ablation, and chemoembolization.7 This type of treatment may use sources of extreme heat or coldsuch as lasers or freezingor chemicals such as acids to destroy the tumor.7 These procedures are performed by a doctor, usually in the hospital. Please see Patient Prescribing Information on pages 14-15.

What Is Nexavar?
Nexavar is a prescription oral anticancer medicine used to treat adults with a form of liver cancer known as hepatocellular carcinoma (HCC). Nexavar is called a kinase inhibitor, one of a class of therapies often called targeted therapies. Kinases are special kinds of proteins, called enzymes, that are believed to be involved in the signaling that controls the growth of tumor cells and new blood vessels that give the tumor its blood supply.11

How Does Nexavar Work?


Nexavar is designed to interfere with 2 signaling processes on cancer cells and tumor blood vessels.
How Nexavar may work on tumor cells and tumor vessels12

Signal

Nexavar

1. Blocks tumor cell signals so cancer cells cant grow and divide

Cancer cell

Signal

Nexavar

2. Reduces the formation of new blood vessels that provide oxygen and nutrients needed for cancer cells to keep growing

Tumor blood vessel

By slowing tumor growth and reducing the blood supply of the tumor, Nexavar may prevent the growth and spread of cancer. These processes can also be important to normal cells, so targeted therapies like Nexavar may affect some normal cells as well.

8
Please see Patient Prescribing Information on pages 14-15.

How Is Nexavar Taken?


Nexavar tablets are taken by mouth and swallowed whole. Do not chew the tablets. Nexavar should always be taken as directed by your doctor. It is usually taken as two 200-mg tablets twice daily for a total of 4 pills a day. Take Nexavar without food (at least 1 hour before or 2 hours after a meal) If you miss a dose of Nexavar, skip the missed dose not and take your next dose at your regular time. Do not try to catch up or double your dose of Nexavar try to catch up or double your dose of Nexavar Call your doctor right away if you take more than your prescribed dose Patients stay on Nexavar as long as their doctors think it is helping them. Sometimes the dose of Nexavar is reduced and/or interrupted for a short period if side effects become a problem. In some cases, Nexavar treatment is stopped. Always take Nexavar as directed by your doctor to help you get the most benefit out of your therapy.

What Should I Tell My Doctor Before Starting Nexavar and While Taking Nexavar?
You should speak to your doctor right away if you think that you are pregnant, because Nexavar may cause birth defects or death of an unborn baby. Women should not get pregnant while undergoing treatment with Nexavar and for at least 2 weeks after stopping treatment Both men and women should use effective birth control measures while taking Nexavar and for at least 2 weeks after stopping treatment Tell your doctor if you are breastfeeding or planning to breastfeed You should also tell your doctor or health care provider if you have allergies, heart problems or chest pain, bleeding, high blood pressure, kidney or liver problems, if you are planning to become pregnant, and about any other conditions you may have. You should tell your doctor or health care provider about all medications you are taking (including any nonprescription medications, vitamins, or herbal medicines). Also, talk to your doctor or health care provider before taking any new medication. Nexavar and certain other medicines can interact with each other and cause serious side effects. Especially, tell your doctor if you take warfarin (Coumadin).* If you need to have a surgical or dental procedure, you should inform your doctor or health care provider that you are taking Nexavar. Let your doctor or health care provider know if you have ever had an allergic reaction to Nexavar. If you experience any symptom that bothers you or does not go away, contact your doctor or health care provider, or seek medical attention as soon as possible.

Recommended daily dose

AM 400 mg (2 For more information,x 200-mg tablets) twice daily together with Nexavar should be taken without food or a low- or Patients who to call 1.866.NEXAVAR moderate-fat meal.take Nexavar atintend 1 hour have a high-fat meal should least before or 2 hours after the meal. The tablets should be or visit www.NEXAVAR.com. PM taken with a glass of water.
2 tablets 2 tablets Shown at actual size

10
Please see Patient Prescribing Information on pages 14-15.
*Coumadin is a registered trademark of the Bristol-Myers Squibb Company.

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What Are Possible Side Effects of Nexavar?


Nexavar may cause serious side effects, including Decreased blood flow to the heart and heart attack. Get emergency help right away and call your doctor if you get symptoms such as chest pain, shortness of breath, feel light-headed or faint, nausea, vomiting, or sweating a lot Bleeding problems. Nexavar may increase your chance of bleeding. Tell your doctor if you have any bleeding while taking Nexavar High blood pressure. Your blood pressure should be checked weekly during the first 6 weeks of starting Nexavar. Your high blood pressure should be checked regularly and any high blood pressure should be treated while you are taking Nexavar A skin problem called hand-foot skin reaction. This causes redness, pain, swelling, or blisters on the palms of your hands or soles of your feet. If you get this side effect, your doctor may change your dose or stop treatment for some time Perforation of the bowel. Tell your doctor right away if you get high fever, nausea, vomiting, or severe abdominal pain Possible wound healing problems. If you need to have a surgical or dental procedure, tell your doctor that you are taking Nexavar. Nexavar may need to be stopped until your wound heals after some types of surgery Birth defects or death of an unborn baby. Other side effects with Nexavar may include Rash, redness, itching or peeling of your skin Hair thinning or patchy hair loss

Diarrhea (frequent and/or loose bowel movements) Nausea or vomiting Mouth sores Weakness Loss of appetite Numbness, tingling, or pain in your hands and feet Abdominal pain Tiredness Weight loss These are not all the side effects with Nexavar. Ask your doctor or pharmacist for more information. Remember: your doctor or health care provider is the best source of information regarding you and your health.

What Patient Support Programs Are Available?


The REACH (Resources for Expert Assistance and Care Helpline) program can help you understand and access insurance coverage, as well as obtain Nexavar through a specialty pharmacy provider (SPP). To contact REACH, please call 1.87.REACH.4.IT (1.877.322.4448). NexConnectTM is a patient support program provided by Nexavar. It offers patient education materials that complement your doctor-recommended Nexavar treatment plan. To enroll in NexConnect, please visit www.NEXAVAR.com or call 1.866.NEXAVAR (1.866.639.2827). Both REACH and NexConnect counselors are available Monday through Friday, 9 AM to 8 PM ET. Visit www.NEXAVAR.com for a comprehensive list of resources.

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Please see Patient Prescribing Information on pages 14-15.

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NEXAVAR Film-coated Tablet 200 mg. Approved name(s) of the active ingredient Sorafenib Tosylate 200 mg. Indication Treatment of patients with unresectable hepatocellular carcinoma (HCC). Treatment of patients with advanced renal cell carcinoma who have failed prior systemic therapy or are considered unsuitable for such therapy. Dosage and method of administration The recommended daily dose is 400 mg (2 x 200 mg tablets) taken twice a day, either without food or together with a moderate fat meal. Treatment should be continued until the patient is no longer clinically beneting from therapy or until unacceptable toxicity occurs. Management of suspected adverse drug reactions may require temporary interruption and/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. Contraindications known severe hypersensitivity to sorafenib or any of the excipients in the tablet. Special warnings and special precautions for use The safety and effectiveness of Nexavar in paediatric patients has not been established. Nexavar should not be used during pregnancy. Breastfeeding should be discontinued during Nexavar therapy. 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 (National Cancer Institute Common Toxicity Criteria) Grade 1 and 2 and generally appear during the rst six weeks of treatment with Nexavar. Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modication of Nexavar, or in severe or persistent cases, permanent discontinuation of Nexavar. An increased incidence of hypertension was observed in Nexavartreated patients. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was amenable to management with standard antihypertensive therapy. Blood pressure should be monitored regularly and treated, if required, in accordance with standard medical practice. In cases of severe or persistent hypertension, or hypertensive crisis despite adequate antihypertensive therapy, permanent discontinuation of Nexavar should be considered. An increase in the risk of bleeding may occur following Nexavar administration. The incidence of severe bleeding events is uncommon. If any bleeding event necessitates medical intervention, it is recommended that permanent discontinuation of Nexavar should be considered. Infrequent

bleeding events or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on Nexavar therapy. Patients taking warfarin concomitantly should be monitored regularly for changes in prothrombin time, INR and for clinical bleeding episodes. No formal studies of the effect of Nexavar on wound healing have been conducted. In patients undergoing major surgical procedures, temporary interruption of Nexavar 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 Nexavar therapy following a major surgical intervention should be based on clinical judgment of adequate wound healing. In Study 11213, the incidence of treatment-emergent cardiac ischemia/infarction events was higher in the NEXAVAR group (2.9%) compared with the placebo group (0.4%). In Study 100554, the incidence of treatment-emergent cardiac ischaemia/infarction events was 2.7% in sorafenib patients compared with 1.7% 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. 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. 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. Undesirable effects The most common adverse reactions were diarrhoea, rash, alopecia and hand-foot skin syndrome. Very common: Lymphopenia, fatigue, pain (including mouth, abdominal, bone, tumour pain, and headache,) increased amylase increased lipase, rash, alopecia, hand foot syndrome, pruritus, erythema, diarrhoea, nausea, vomiting, haemorrhage, hypertension, hypophosphataemia. For a full listing of undesirable effects, please refer to the full product insert. For further prescribing information, please contact: Bayer (South East Asia) Pte Ltd 63 Chulia Street OCBC Centre East 14th Floor Singapore 049514. Date of revision of text 14 July 2008.

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