Starting on SPRYCEL® (Dasatinib) TABLE of CONTENTS

Starting on SPRYCEL® (dasatinib) TABLE OF CONTENTS

2 4 13-18 28 YOU’VE BEEN DIAGNOSED... TALK TO YOUR DOCTOR PATIENT-TO-PATIENT ABOUT... RESOURCES 7 20-23 31 WHAT CAUSES IT? TAKING SPRYCEL® (dasatinib) ADDITIONAL SOURCES FOR INFORMATION AND SUPPORT 9 24-26 A NEW DIRECTION INDICATIONS AND IMPORTANT SAFETY INFORMATION 10 THE GOALS INDICATIONS AND USAGE

SPRYCEL® (dasatinib) is a prescription medicine used to treat adults who have: SELECT IMPORTANT • Newly diagnosed Philadelphia SAFETY INFORMATION chromosome-positive (Ph+) chronic myeloid leukemia SPRYCEL may cause serious side (CML) in chronic phase. The effects, including low blood cell effectiveness of SPRYCEL in counts, bleeding, fluid retention, these patients is based on heart problems, and pulmonary 3 a study that measured two arterial hypertension. Other types of response to treatment common side effects of SPRYCEL (cytogenetic and molecular) by include diarrhea, headache, 1 year. The study is ongoing to cough, skin rash, fever, nausea, find out how SPRYCEL works tiredness, vomiting, muscle pain, over a longer period of time weakness, and infections. This • Ph+ CML who are no longer is not a complete list of all side benefitting from, or did not effects recorded in clinical studies tolerate, other treatment with SPRYCEL. Tell your healthcare including Gleevec® provider if you have any side effects (imatinib mesylate) while taking SPRYCEL.

WITH But it’s important to know that PHILADELPHIA with the treatments available Your doctor is your ongoing today, many people with partner in treatment. Being open CHROMOSOME- Ph+ CML may be able to about what you’re feeling, and POSITIVE (Ph+) continue living productive and asking any questions you may satisfying lives. CHRONIC have are important parts of the partnership. 4 MYELOID Know that you’re LEUKEMIA not alone And don’t forget about

(CML)... You probably have many questions friends and loved ones about the disease and your The news that you have Ph+ CML treatment. The goal of this kit is It’s up to you to decide who you has probably come as a shock to help answer some of those want to talk to about your condition. to you and your loved ones. And questions. And when. But you may find that, you may find yourself feeling sad, given the chance, friends and loved depressed, or afraid. These are very Your healthcare team is the best ones may provide their own very normal reactions. resource for information. special kind of care.

About 70,000 people in America are living with Ph+ CML. And around 6,000 people are newly diagnosed each year.

What is Philadelphia chromosome-positive causes the bone marrow to produce more white blood cells, (Ph+) chronic myeloid even when they are not needed. CML: LET’S leukemia (CML) in These are mostly damaged chronic phase? or immature. Over time, these START extra, unhealthy white blood 5 FROM THE It’s a mouthful, that’s for sure. cells overcrowd healthy white So let’s try to break it down: blood cells, red blood cells, and BEGINNING platelets. 1. Ph+ CML, or chronic myeloid What is leukemia? leukemia, is a type of leukemia. 3. The lack of healthy blood cells It is caused by an abnormal and platelets leads to the signs Leukemia is a kind of blood chromosome in the body and symptoms of Ph+ CML. cancer that begins in the bone called the Philadelphia (or Ph) marrow. That is the soft tissue chromosome. 4. Usually, when people are in the center of your bones that diagnosed with Ph+ CML, they produces all types of blood 2. The Ph chromosome creates are in the “chronic phase.” CML cells. There are different forms what is known as the BCR-ABL symptoms are milder in the of leukemia. The kind you have is cancer gene. When you have chronic phase, compared to called Ph+ CML. Ph+ CML, the BCR-ABL protein later phases.

Please read pages 16-18 for additional Important Safety Information about SPRYCEL. Please read the Patient Information section of the full Prescribing Information on pages 30-31. SPRYCEL (dasatinib) has been prescribed for over 8 years IMPORTANT SAFETY INFORMATION since initial FDA approval, with It is not known if more than 220,000 TKIS: A NEW SPRYCEL® (dasatinib) is safe and effective in children prescriptions DIRECTION IN younger than 18 years old. TREATMENT written. Before you take SPRYCEL, tell Not too long ago, people with your healthcare provider if you: 6 Ph+ CML were given traditional • have problems with your treatments such as chemotherapy. immune system Then a whole new kind of therapy • have liver problems was developed, giving patients more • have heart problems healthcare provider right away treatment options. This new therapy • are lactose intolerant if you are pregnant or plan to is called tyrosine kinase inhibitors • have any other medical become pregnant (TKIs). conditions • are breast-feeding or plan to • are pregnant or planning to breast-feed. It is not known Once people with chronic phase become pregnant. SPRYCEL if SPRYCEL passes into your Ph+ CML start treatment, they can harm your unborn baby. breast milk or if it can harm your may feel well enough to continue Sexually active female patients baby. You and your healthcare their day-to-day activities such of childbearing potential provider should decide if you will as working, spending time with taking SPRYCEL should take SPRYCEL or breast-feed. family, running errands, etc. avoid pregnancy. Talk to your You should not do both

Please read pages 16-18 for additional Important Safety Information about SPRYCEL. Please read the Patient Information section of the full Prescribing Information on pages 30-31. IMPORTANT SAFETY It’s important to THE GOALS OF INFORMATION ABOUT LOW remember that 7 TREATMENT BLOOD CELL COUNTS CML is a chronic WITH ® SPRYCEL (dasatinib) may cause disease. Do your SPRYCEL low red blood cell counts (anemia), part and take your low white blood cell counts (dasatinib) (neutropenia), and low platelet medication daily, counts (thrombocytopenia). as prescribed by The immediate goal of treatment is Your healthcare provider will do your doctor. to reduce any symptoms of CML blood tests to check your blood you may have. The longer-term goal cell counts regularly during your is to decrease cancer cells to a level treatment with SPRYCEL. Call your that is not detectable by testing. healthcare provider right away if This may slow down the disease you have a fever or any signs of an from progressing. infection while taking SPRYCEL.

Please read pages 16-18 for additional Important Safety Information about SPRYCEL. Please read the Patient Information section of the full Prescribing Information on pages 30-31. TALK TO YOUR You may find it helpful to keep a 8 HEALTHCARE pen and paper or journal nearby TEAM ABOUT so that you can make note of any Talk to your doctor SIDE EFFECTS side effect you might feel. right away if you This is also a great way to keep have any side Your doctor and your healthcare track of any questions that come effects. Don’t wait team need to know about any side to your mind. By writing these for your symptoms effect of treatment that bothers you things down, you’ll be able to have or that does not go away. No matter everything you need handy when to get worse! how small the change may seem, you speak with your doctor or other they will want to know about it. member of your healthcare team.

Please read pages 16-18 for Important Safety Information about SPRYCEL. Please read the Patient Information section of the full Prescribing Information on pages 30-31. SIDE EFFECTS Call your healthcare provider This kind of bleeding is also ® OF SPRYCEL right away if you have a fever or known as thrombocytopenia. any signs of an infection while (dasatinib) taking SPRYCEL. If your doctor suspects you have bleeding, he or she will probably Here are some side effects of Low blood cell counts are also do a physical exam and blood tests. SPRYCEL® (dasatinib) that you known as myelosuppression. should be aware of. It is not a Fluid retention complete list of all side effects Bleeding recorded in clinical studies. SPRYCEL may cause your body to SPRYCEL may cause severe hold too much fluid. In severe cases, Low blood cell counts bleeding that can lead to death. fluid may build up in the lining of your lungs, the sac around your heart, or 9 Call your healthcare provider your stomach cavity. SPRYCEL may cause low red blood right away if you have: cell counts (anemia), low white blood • unusual bleeding or bruising Call your healthcare provider cell counts (neutropenia), and low of your skin right away if you get any of these platelet counts (thrombocytopenia). • bright red or dark, symptoms during treatment with Your healthcare provider will do tar-like stools SPRYCEL: blood tests to check your blood • a decrease in your level of • swelling all over your body cell counts regularly during your consciousness, headache, • weight gain treatment with SPRYCEL. or change in speech • shortness of breath and cough

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Please read pages 16-18 for additional Important Safety Information about SPRYCEL. Please read the Patient Information section of the full Prescribing Information on pages 30-31. Talk to your doctor right away if you have any side effects. Don’t wait for your symptoms SIDE EFFECTS to get worse! OF SPRYCEL® (dasatinib) cont’d

Fluid retention in your lungs is 10 also known as pleural effusion.

If your doctor suspects you might have fluid retention, he or she may do a chest x-ray, a computed tomography (CT) scan of your chest and/or an ultrasound of your chest.

Your doctor may be able to manage the fluid retention without having to change your medication.

(continued on next page) SIDE EFFECTS OF If there is concern that you ® SPRYCEL might have PAH, your doctor electrocardiogram (EKG), an may want to do a chest x-ray, (dasatinib) (cont’d) echocardiogram, a cardiac computed an electrocardiogram (EKG), or tomography (CT) scan, or cardiac echocardiography. Heart problems magnetic resonance imaging (MRI). Other common side effects SPRYCEL® (dasatinib) may cause an Pulmonary Arterial of SPRYCEL abnormal heart rate, heart problems, Hypertension (PAH) 11 or a heart attack that can lead to Other common side effects of death. Your healthcare provider SPRYCEL may cause high blood SPRYCEL therapy include: will monitor the potassium and pressure in the vessels of your lungs. • Diarrhea magnesium levels in your blood and PAH may happen at any time during • Headache your heart function. your treatment with SPRYCEL. Your • Cough healthcare provider should check • Skin rash An abnormal heart rate is also your heart and lungs before and • Fever known as an arrhythmia. during your treatment with SPRYCEL. • Nausea • Tiredness If your doctor suspects you Call your healthcare provider right • Vomiting have heart problems, he or she away if you have shortness of • Muscle pain may want to do blood tests, a breath, tiredness, or swelling all • Weakness chest x-ray, Holter monitoring, an over your body (fluid retention). • Infections

For nausea: • Avoid greasy food, nuts, raw • Eat soft, bland foods such as fruits and vegetables, hot or crackers, toast, yogurt, chicken spicy food, alcohol, caffeine, and noodle soup, cottage cheese tomato or citrus juice or sherbet TIPS FOR • Sip water, unsweetened juice, For fatigue: 12 DEALING ginger ale or sports drinks • Decide which things are most • Stay away from greasy, fried, important to do, and try to take WITH NAUSEA, or fatty foods. Avoid tobacco, care of those first DIARRHEA, alcohol and foods with a strong • Don’t force yourself to do more odor such as coffee, onions, than you can manage OR FATIGUE and garlic • Ask friends and family members to help with tasks such as Here are some things For diarrhea: cooking, housework, and you can do to help • Sip fluids or nibble on ice chips errands or popsicles so that you don’t relieve discomfort if you get dehydrated Don’t forget to tell your doctor experience any of these • Eat small meals and snacks about these and/or any other side effects. throughout the day side effects you may have.

Please read pages 16-18 for additional Important Safety Information about SPRYCEL. Please read the Patient Information section of the full Prescribing Information on pages 30-31. ® ® Sporanox (itraconazole), Norvir 13 IMPORTANT SAFETY (ritonavir), Reyataz® (atazanavir • medicines whose blood INFORMATION sulfate), Crixivan® (indinavir), levels might change by Viracept® (nelfinavir), Nefazodone taking SPRYCEL, such as: Tell your healthcare provider (serzone®, nefadar), Invirase® Sandimmune® (cyclosporine), about all the medicines you take, (saquinavir), Ketek® (telithromycin), Alfenta® (alfentanil), Fentanyl® including prescription and non- E-mycin® (erythromycin), and (fentanyl), Orap® (pimozide), prescription medicines, vitamins, Biaxin® (clarithromycin). Rapamune® (sirolimus), Prograf® antacids, and herbal supplements. • medicines that decrease (tacrolimus), and Ergomar® the amount of SPRYCEL in (ergotamine). Especially tell your healthcare your bloodstream, such as: provider if you take: Decadron® (dexamethasone), SPRYCEL is best absorbed • medicines that increase the Dilantin® (phenytoin), Tegretol® from your stomach into your amount of SPRYCEL® (dasatinib) (carbamazepine), Rimactane® bloodstream in the presence of in your bloodstream, such as: (rifampin), and Luminal® stomach acid. You should avoid Nizoral® (ketoconazole), (phenobarbital). taking medicines that reduce

(continued on next page) 1 PILL ONCE A DAY WITH OR WITHOUT FOOD

CML is a chronic IMPORTANT SAFETY magnesia), may be taken up to INFORMATION (CONT’D) 2 hours before or 2 hours after disease. Taking SPRYCEL. your pill every day, 14 stomach acid, such as: Tagamet® just as your doctor (cimetidine), Pepcid® (famotidine), Since SPRYCEL therapy may Zantac® (ranitidine), Prilosec® cause bleeding, tell your healthcare prescribed, gives (omeprazole), Protonix® (pantoprazole provider if you are using blood thinner the medicine the ® sodium), Nexium® (esomeprazole), medicine, such as Coumadin best chance to AcipHex® (rabeprazole), and (warfarin sodium) or aspirin. Prevacid® (lansoprazole). work for you. Know the medicines you take. Medicines that neutralize stomach Keep a list of your medicines and acid, such as Maalox® (aluminum show it to your healthcare provider hydroxide/magnesium hydroxide), and pharmacist when you get Tums® (calcium carbonate), or a new medicine. Rolaids® (calcium carbonate and

HERE ARE A FEW THINGS TO REMEMBER ® Your doctor may change your ABOUT TAKING SPRYCEL (dasatinib) dose or tell you to temporarily stop taking SPRYCEL. Do not DOs DON’Ts change your dose or stop taking SPRYCEL without first talking Do take SPRYCEL (dasatinib) at the same Don’t drink grapefruit juice with your doctor. 15 time each day, with or without food. while taking SPRYCEL. If you take too much SPRYCEL, Do swallow SPRYCEL tablets whole Don’t break, cut, or crush the call your doctor or other member of with water. tablets. your healthcare team or go to the nearest hospital emergency room right away. Do tell your pharmacist you’re taking SPRYCEL Don’t skip or change a dose so he or she can ensure that it doesn’t conflict without talking to your doctor. with any other medicines you take. If you miss a dose of SPRYCEL, take your next scheduled dose at its regular time. Do not take 2 doses Do tell your doctor about all the medicines at the same time. Call your doctor, you take, including prescription and non-prescription medicines, vitamins, another member of your healthcare antacids, and herbal supplements. team, or your pharmacist if you are not sure what to do.

Please read pages 16-18 for additional Important Safety Information about SPRYCEL. Please read the Patient Information section of the full Prescribing Information on pages 30-31. ® • Ph+ CML who are no longer right away if you are pregnant or SPRYCEL benefiting from, or did not tolerate, plan to become pregnant (dasatinib) other treatment including Gleevec® • are breast-feeding or plan to (imatinib mesylate) breast-feed. It is not known if INDICATIONS SPRYCEL passes into your breast milk or if it can harm your baby. AND IMPORTANT IMPORTANT SAFETY You and your healthcare provider INFORMATION ABOUT should decide if you will take SAFETY SPRYCEL SPRYCEL or breast-feed. You INFORMATION should not do both It is not known if SPRYCEL is safe and FOR PATIENTS effective in children younger than 18 Tell your healthcare provider years old. about all the medicines you take, INDICATIONS AND USAGE including prescription and non- 16 SPRYCEL® (dasatinib) is a prescription Before you take SPRYCEL, tell prescription medicines, vitamins, medicine used to treat adults who your healthcare provider if you: antacids, and herbal supplements. have: • have problems with your immune Especially tell your healthcare • newly diagnosed Philadelphia system • have liver problems provider if you take: chromosome–positive (Ph+) • medicines that increase the chronic myeloid leukemia (CML) in • have heart problems • are lactose intolerant amount of SPRYCEL in your chronic phase. The effectiveness • have any other medical conditions bloodstream, such as: of SPRYCEL in these patients is ® ® • are pregnant or planning to Nizoral (ketoconazole), Sporanox based on a study that measured become pregnant. SPRYCEL (itraconazole), two types of response to treatment can harm your unborn baby. Norvir® (ritonavir), (cytogenetic and molecular) by 1 Sexually active female patients Reyataz® (atazanavir sulfate), year. The study is ongoing to find of childbearing potential taking Crixivan® (indinavir), Viracept® out how SPRYCEL works over a SPRYCEL should avoid pregnancy. longer period of time Talk to your healthcare provider (continued on next page) SPRYCEL® (dasatinib) from your stomach into your and pharmacist when you get a new IMPORTANT SAFETY bloodstream in the presence of medicine. INFORMATION FOR PATIENTS stomach acid. You should avoid (CONT’D) taking medicines that reduce Take SPRYCEL exactly stomach acid, such as: Tagamet® as prescribed by your (nelfinavir), Nefazodone (serzone®, (cimetidine), Pepcid® (famotidine), healthcare provider nefadar), Invirase® (saquinavir), Zantac® (ranitidine), Prilosec® • Take SPRYCEL with or without Ketek® (telithromycin), E-mycin® (omeprazole), Protonix® (pantoprazole food. Try to take SPRYCEL at the (erythromycin), and Biaxin® sodium), Nexium® (esomeprazole), same time each day (clarithromycin). AcipHex® (rabeprazole), and Prevacid® • Swallow SPRYCEL tablets whole • medicines that decrease (lansoprazole). with water. Do not break, cut, or the amount of SPRYCEL in crush the tablets your bloodstream, such as: Medicines that neutralize stomach • You should not drink grapefruit Decadron® (dexamethasone), acid, such as Maalox® (aluminum juice while taking SPRYCEL Dilantin® (phenytoin), Tegretol® hydroxide/magnesium hydroxide), • If you miss a dose of SPRYCEL, 17 (carbamazepine), Rimactane® Tums® (calcium carbonate), or take your next scheduled dose at (rifampin), and Luminal® Rolaids® (calcium carbonate and its regular time. Do not take two (phenobarbital). magnesia), may be taken up to 2 doses at the same time • medicines whose blood hours before or 2 hours after SPRYCEL. levels might change by SPRYCEL may cause serious taking SPRYCEL, such as: Since SPRYCEL therapy may cause side effects, including: Sandimmune® (cyclosporine), bleeding, tell your healthcare provider • Low Blood Cell Counts: Alfenta® (alfentanil), Fentanyl® if you are using blood thinner medicine, SPRYCEL may cause low red (fentanyl), Orap® (pimozide), such as Coumadin® (warfarin sodium) blood cell counts (anemia), Rapamune® (sirolimus), Prograf® or aspirin. low white blood cell counts (tacrolimus), and Ergomar® (neutropenia), and low platelet (ergotamine). Know the medicines you take. counts (thrombocytopenia). Keep a list of your medicines and SPRYCEL is best absorbed show it to your healthcare provider (continued on next page) SPRYCEL® (dasatinib) cases, fluid may build up in the check your heart and lungs before IMPORTANT SAFETY lining of your lungs, the sac around and during your treatment with INFORMATION FOR PATIENTS your heart, or your stomach cavity. SPRYCEL. Call your healthcare (CONT’D) Call your healthcare provider provider right away if you have right away if you get any of these shortness of breath, tiredness, Your healthcare provider will do symptoms during treatment with or swelling all over your body (fluid blood tests to check your blood SPRYCEL: retention) cell counts regularly during your - swelling all over your body treatment with SPRYCEL. Call your - weight gain Other common side effects of healthcare provider right away if - shortness of breath SPRYCEL therapy include: diarrhea, you have a fever or any signs of an and cough headache, cough, skin rash, fever, nausea, tiredness, vomiting, muscle 18 infection while taking SPRYCEL. • Heart problems: SPRYCEL • Bleeding: SPRYCEL® (dasatinib) may cause an abnormal heart pain, weakness, and infections. may cause severe bleeding that rate, heart problems, or a heart Tell your healthcare provider if you can lead to death. Call your attack that can lead to death. Your have any side effect that bothers you healthcare provider right away if healthcare provider will monitor or that does not go away. These are you have: the potassium and magnesium not all of the possible side effects - unusual bleeding or levels in your blood and your heart of SPRYCEL. For more information, bruising of your skin function ask your healthcare provider or - bright red or dark, • Pulmonary Arterial pharmacist. tar-like stools Hypertension (PAH): SPRYCEL - a decrease in your level of may cause high blood pressure Call your doctor for medical consciousness, headache, in the vessels of your lungs. PAH advice about side effects. or change in speech may happen at any time during You may report side effects • Your body may hold too much your treatment with SPRYCEL. to FDA at 1-800-FDA-1088. fluid (fluid retention): In severe Your healthcare provider should

Please read the Patient Information section of the full Prescribing Information. SPRYCEL, REYATAZ, and COUMADIN are registered trademarks of Bristol-Myers Squibb Company. All other brands listed are the trademarks of their respective owners. The Leukemia & Lymphoma Society® (LLS) www.lls.org 1-914-949-5213 LLS offers weekly online chats. These chats provide a friendly forum CancerCare® for discussing the stresses and www.cancercare.org triumphs shared by those living with 1-800-813-HOPE (4673) CML. They are moderated by an CancerCare offers face-to-face oncology social worker and they are 19 password-protected. support groups led by oncology social workers at their offices in

the New York area. If you don’t HOW TO MEET The National CML Society live in that area, they can help you www.nationalcmlsociety.org OTHERS WHO find support groups in your own 1-877-431-2573 ARE LIVING community. Through CML Connection™, The WITH CML National CML Society organizes This list of resources is provided group meetings around the country. as a convenience. The following organizations provide These meetings provide a time and Bristol-Myers Squibb does not live or online gatherings where you place for connecting with others. endorse and is not responsible for can chat with others about the ups They’re open to CML patients, family information provided by third-party and downs of living with CML. members, and caregivers. organizations.

Please read pages 16-18 for Important Safety Information about SPRYCEL. Please read the Patient Information section of the full Prescribing Information on pages 30-31. ADDITIONAL CancerCare® www.cancercare.org SOURCES FOR 1-800-813-HOPE (4673) INFORMATION Cancer Support Community™ AND SUPPORT www.cancersupportcommunity.org 20 1-888-793-9355 Bristol-Myers Squibb The Leukemia & Lymphoma financial assistance Society (LLS) American Cancer Society® www.lls.org http://www.cancer.org Bristol-Myers Squibb may be able to 1-914-949-5213 1-800-227-2345 provide financial assistance for your treatment. Call 1-800-861-0048 or The National CML Society National Cancer Institute visit www.SPRYCEL.com. www.nationalcmlsociety.org http://www.cancer.gov 1-877-431-2573 1-800-4-CANCER This list of resources is provided as a convenience. American Society of Clinical National Comprehensive Bristol-Myers Squibb does not Oncology: Cancer.Net Cancer Network® endorse and is not responsible for www.cancer.net www.NCCN.org information provided by third-party 1-888-651-3038 1-215-690-0300 organizations.

Please read pages 16-18 for Important Safety Information about SPRYCEL. Please read the Patient Information section of the full Prescribing Information on pages 30-31. TO LEARN MORE ABOUT SPRYCEL® (dasatinib), PLEASE VISIT WWW.SPRYCEL.COM.

All individuals depicted in this guide are models used for illustrative purposes only.

SPRYCEL is a registered trademark of Bristol-Myers Squibb Company. ©2014 Bristol-Myers Squibb Company. All rights reserved. 729US14BR01552-06-01 8/14 Spycl0514PI_729US14BR01092_0101wip2__ 5/1/14 3:16 PM Page 1

HIGHLIGHTS OF PRESCRIBING INFORMATION • Cardiac Dysfunction: Monitor patients for signs or symptoms and treat These highlights do not include all the information needed to use SPRYCEL safely appropriately. (5.5, 6.1) and effectively. See full prescribing information for SPRYCEL. • Pulmonary Arterial Hypertension (PAH): SPRYCEL (dasatinib) may increase the risk of developing PAH which may be reversible on discontinuation. Consider SPRYCEL® (dasatinib) Tablet for Oral Use baseline risk and evaluate patients for signs and symptoms of PAH during Initial U.S. Approval: 2006 treatment. Stop SPRYCEL if PAH is confirmed. (5.6) – – – – – – – – – – – – – – INDICATIONS AND USAGE – – – – – – – – – – – – – • Embryo-fetal Toxicity: SPRYCEL can cause fetal harm. Advise females of the SPRYCEL is a kinase inhibitor indicated for the treatment of potential risk to the fetus. (5.7, 8.1, 8.8) • newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic – – – – – – – – – – – – – – – – ADVERSE REACTIONS – – – – – – – – – – – – – – myeloid leukemia (CML) in chronic phase. The trial is ongoing and further data Most common adverse reactions (≥15%) in patients with newly diagnosed chronic will be required to determine long-term outcome. (1, 14) phase CML included myelosuppression, fluid retention, and diarrhea. Most common • adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML adverse reactions (≥20%) in patients with resistance or intolerance to prior imatinib with resistance or intolerance to prior therapy including imatinib. (1, 14) therapy included myelosuppression, fluid retention events, diarrhea, headache, • adults with Philadelphia chromosome-positive acute lymphoblastic leukemia dyspnea, skin rash, fatigue, nausea, and hemorrhage. (6) (Ph+ ALL) with resistance or intolerance to prior therapy. (1, 14) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at – – – – – – – – – – – – – DOSAGE AND ADMINISTRATION – – – – – – – – – – – – 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. • Chronic phase CML: 100 mg once daily. (2) – – – – – – – – – – – – – – – DRUG INTERACTIONS – – – – – – – – – – – – – – • Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL: • CYP3A4 Inhibitors: May increase dasatinib drug levels and should be avoided. If 140 mg once daily. (2) coadministration cannot be avoided, monitor closely and consider reducing Administer orally, with or without a meal. Do not crush or cut. (2) SPRYCEL dose. (2.1, 7.1) – – – – – – – – – – – – DOSAGE FORMS AND STRENGTHS – – – – – – – – – – – – • CYP3A4 Inducers: May decrease dasatinib drug levels. If coadministration Tablets: 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg. (3, 16) cannot be avoided, consider increasing SPRYCEL dose. (2.1, 7.2) – – – – – – – – – – – – – – – CONTRAINDICATIONS – – – – – – – – – – – – – – – • Antacids: May decrease dasatinib drug levels. Avoid simultaneous administration. If needed, administer the antacid at least 2 hours prior to or None. (4) 2 hours after the dose of SPRYCEL. (7.2) – – – – – – – – – – – – – WARNINGS AND PRECAUTIONS – – – – – – – – – – – – • H2 Antagonists/Proton Pump Inhibitors: May decrease dasatinib drug levels. • Myelosuppression and Bleeding Events: Severe thrombocytopenia, neutropenia, Consider antacids in place of H2 antagonists or proton pump inhibitors. (7.2) and anemia may occur. Use caution if used concomitantly with medications that – – – – – – – – – – – – USE IN SPECIFIC POPULATIONS – – – – – – – – – – – – – inhibit platelet function or anticoagulants. Monitor complete blood counts regularly. Transfuse and interrupt SPRYCEL when indicated. (2.3, 5.1, 5.2, 6.1) • Nursing Mothers: Discontinue drug or nursing taking into consideration the importance of the drug to the mother. (8.3) • Fluid Retention: Fluid retention, sometimes severe, including ascites, edema, and pleural and pericardial effusions. Manage with appropriate supportive care • Hepatic Impairment: Use SPRYCEL with caution in patients with hepatic measures. (5.3, 6.1) impairment. (8.6) • QT Prolongation: Use SPRYCEL with caution in patients who have or may See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. develop prolongation of the QT interval. (5.4) Revised: 5/2014

FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 8.5 Geriatric Use 2 DOSAGE AND ADMINISTRATION 8.6 Hepatic Impairment 2.1 Dose Modification 8.7 Renal Impairment 2.2 Dose Escalation 8.8 Females of Reproductive Potential 2.3 Dose Adjustment for Adverse Reactions 10 OVERDOSAGE 3 DOSAGE FORMS AND STRENGTHS 11 DESCRIPTION 4 CONTRAINDICATIONS 12 CLINICAL PHARMACOLOGY 5 WARNINGS AND PRECAUTIONS 12.1 Mechanism of Action 5.1 Myelosuppression 12.3 Pharmacokinetics 5.2 Bleeding Related Events 13 NONCLINICAL TOXICOLOGY 5.3 Fluid Retention 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.4 QT Prolongation 14 CLINICAL STUDIES 5.5 Congestive Heart Failure, Left Ventricular Dysfunction, and 14.1 Newly Diagnosed Chronic Phase CML Myocardial Infarction 14.2 Imatinib-resistant or Intolerant CML or Ph+ ALL 5.6 Pulmonary Arterial Hypertension 16 HOW SUPPLIED/STORAGE AND HANDLING 5.7 Embryo-fetal Toxicity 16.1 How Supplied 6 ADVERSE REACTIONS 16.2 Storage 6.1 Chronic Myeloid Leukemia (CML) 16.3 Handling and Disposal 6.2 Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia 17 PATIENT COUNSELING INFORMATION (Ph+ ALL) 17.1 Bleeding 6.3 Additional Data From Clinical Trials 17.2 Myelosuppression 6.4 Postmarketing Experience 17.3 Fluid Retention 7 DRUG INTERACTIONS 17.4 Embryo-fetal Toxicity 7.1 Drugs That May Increase Dasatinib Plasma Concentrations 17.5 Gastrointestinal Complaints 7.2 Drugs That May Decrease Dasatinib Plasma Concentrations 17.6 Pain 7.3 Drugs That May Have Their Plasma Concentration Altered By Dasatinib 17.7 Fatigue 8 USE IN SPECIFIC POPULATIONS 17.8 Rash 8.1 Pregnancy 17.9 Lactose 8.3 Nursing Mothers 17.10 Missed Dose 8.4 Pediatric Use * Sections or subsections omitted from the full prescribing information are not listed. Spycl0514PI_729US14BR01092_0101wip2__ 5/1/14 3:16 PM Page 2

FULL PRESCRIBING INFORMATION SPRYCEL® (dasatinib) 1 INDICATIONS AND USAGE Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia (Continued) SPRYCEL® (dasatinib) is indicated for the treatment of adults with • newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid 1. Check if cytopenia is related to leukemia leukemia (CML) in chronic phase. The effectiveness of SPRYCEL is based on (marrow aspirate or biopsy). cytogenetic response and major molecular response rates [see Clinical Studies 2. If cytopenia is unrelated to leukemia, stop (14.1)]. The trial is ongoing and further data will be required to determine Accelerated SPRYCEL until ANC ≥1.0 × 109/L and 9 long-term outcome. Phase CML, ANC* platelets ≥20 × 10 /L and resume at the Blast Phase CML <0.5 × 109/L original starting dose. • chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with and Ph+ ALL or resistance or intolerance to prior therapy including imatinib. 3. If recurrence of cytopenia, repeat Step 1 (starting dose Platelets and resume SPRYCEL at a reduced dose • Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) 140 mg <10 × 109/L of 100 mg once daily (second episode) or with resistance or intolerance to prior therapy. once daily) 80 mg once daily (third episode). 2 DOSAGE AND ADMINISTRATION 4. If cytopenia is related to leukemia, The recommended starting dosage of SPRYCEL for chronic phase CML is 100 mg consider dose escalation to 180 mg once administered orally once daily. The recommended starting dosage of SPRYCEL for daily. accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL is 140 mg *ANC: absolute neutrophil count administered orally once daily. Tablets should not be crushed or cut; they should be swallowed whole. SPRYCEL can be taken with or without a meal, either in the morning or in the evening. Non-hematological adverse reactions In clinical studies, treatment with SPRYCEL was continued until disease progression If a severe non-hematological adverse reaction develops with SPRYCEL use, treatment or until no longer tolerated by the patient. The effect of stopping treatment after the must be withheld until the event has resolved or improved. Thereafter, treatment can be achievement of a complete cytogenetic response (CCyR) has not been investigated. resumed as appropriate at a reduced dose depending on the initial severity of the event. 2.1 Dose Modification 3 DOSAGE FORMS AND STRENGTHS Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 SPRYCEL (dasatinib) Tablets are available as 20-mg, 50-mg, 70-mg, 80-mg, 100-mg, inducers may decrease dasatinib plasma concentrations and should be avoided and 140-mg white to off-white, biconvex, film-coated tablets [see How Supplied (16.1)]. (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital). 4 CONTRAINDICATIONS St. John’s Wort may decrease dasatinib plasma concentrations unpredictably and None. should be avoided. If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, a SPRYCEL dose increase should be considered. 5 WARNINGS AND PRECAUTIONS If the dose of SPRYCEL is increased, the patient should be monitored carefully for 5.1 Myelosuppression toxicity [see Drug Interactions (7.2)]. Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3 or 4) Concomitant Strong CYP3A4 inhibitors: CYP3A4 inhibitors (eg, ketoconazole, thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, patients with advanced phase CML or Ph+ ALL than in chronic phase CML. In a dose- saquinavir, telithromycin, and voriconazole) may increase dasatinib plasma optimization trial in patients with resistance or intolerance to prior imatinib therapy concentrations. Grapefruit juice may also increase plasma concentrations of dasatinib and chronic phase CML, Grade 3 or 4 myelosuppression was reported less frequently and should be avoided. in patients treated with 100 mg once daily than in patients treated with other dosing Selection of an alternate concomitant medication with no or minimal enzyme regimens. inhibition potential, if possible, is recommended. If SPRYCEL must be administered Perform complete blood counts weekly for the first 2 months and then monthly with a strong CYP3A4 inhibitor, a dose decrease should be considered. Based on thereafter, or as clinically indicated. Myelosuppression was generally reversible and pharmacokinetic studies, a dose decrease to 20 mg daily should be considered for usually managed by withholding SPRYCEL temporarily or dose reduction [see Dosage patients taking SPRYCEL 100 mg daily. For patients taking SPRYCEL 140 mg daily, a and Administration (2.3) and Adverse Reactions (6.1)]. dose decrease to 40 mg daily should be considered. These reduced doses of SPRYCEL 5.2 Bleeding Related Events are predicted to adjust the area under the curve (AUC) to the range observed without CYP3A4 inhibitors. However, there are no clinical data with these dose adjustments in In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet patients receiving strong CYP3A4 inhibitors. If SPRYCEL is not tolerated after dose dysfunction in vitro. In all clinical studies, severe central nervous system (CNS) reduction, either the strong CYP3A4 inhibitor must be discontinued, or SPRYCEL hemorrhages, including fatalities, occurred in 1% of patients receiving SPRYCEL. should be stopped until treatment with the inhibitor has ceased. When the strong Severe gastrointestinal hemorrhage, including fatalities, occurred in 4% of patients and inhibitor is discontinued, a washout period of approximately 1 week should be allowed generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients. Most bleeding events were associated with before the SPRYCEL dose is increased. [See Drug Interactions (7.1).] severe thrombocytopenia. 2.2 Dose Escalation Patients were excluded from participation in initial SPRYCEL clinical studies if they took In clinical studies of adult CML and Ph+ ALL patients, dose escalation to 140 mg once medications that inhibit platelet function or anticoagulants. In subsequent trials, the use daily (chronic phase CML) or 180 mg once daily (advanced phase CML and Ph+ ALL) of anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) was was allowed in patients who did not achieve a hematologic or cytogenetic response allowed concurrently with SPRYCEL if the platelet count was >50,000–75,000 per at the recommended starting dosage. microliter. Exercise caution if patients are required to take medications that inhibit 2.3 Dose Adjustment for Adverse Reactions platelet function or anticoagulants. Myelosuppression 5.3 Fluid Retention In clinical studies, myelosuppression was managed by dose interruption, dose SPRYCEL is associated with fluid retention. In clinical trials, severe fluid retention was reduction, or discontinuation of study therapy. Hematopoietic growth factor has been reported in up to 10% of patients. Severe ascites, pulmonary edema, and generalized used in patients with resistant myelosuppression. Guidelines for dose modifications edema were each reported in ≤1% of patients. Patients who develop symptoms are summarized in Table 1. suggestive of pleural effusion, such as dyspnea or dry cough, should be evaluated by Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia chest x-ray. Severe pleural effusion may require thoracentesis and oxygen therapy. Fluid retention events were typically managed by supportive care measures that 1. S top SPRYCEL until ANC ≥1.0 × 109/L include diuretics or short courses of steroids. In dose-optimization studies, fluid and platelets ≥50 × 109/L. retention events were reported less frequently with once daily dosing than with other 2. Resume treatment with SPRYCEL at the dosing regimens. original starting dose if recovery occurs in 5.4 QT Prolongation ANC* ≤7 days. Chronic Phase data suggest that dasatinib has the potential to prolong cardiac ventricular <0.5 × 109/L 9 In vitro CML 3. If platelets <25 × 10 /L or recurrence of repolarization (QT interval). Of the 2440 patients treated with SPRYCEL in clinical (starting dose or ANC <0.5 × 109/L for >7 days, repeat Step 1 and resume SPRYCEL at a studies, 16 patients (1%) had QTc prolongation reported as an adverse reaction. 100 mg Platelets Twenty-two patients (1%) experienced a QTcF >500 ms. In 865 patients with leukemia once daily) <50 × 109/L reduced dose of 80 mg once daily for second episode. For third episode, further treated with SPRYCEL in five Phase 2 single-arm studies, the maximum mean changes reduce dose to 50 mg once daily (for in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms. newly diagnosed patients) or discontinue Administer SPRYCEL with caution to patients who have or may develop prolongation SPRYCEL (for patients resistant or of QTc. These include patients with hypokalemia or hypomagnesemia, patients with intolerant to prior therapy including congenital long QT syndrome, patients taking anti-arrhythmic medicines or other imatinib). medicinal products that lead to QT prolongation, and cumulative high-dose (Continued) anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration. Spycl0514PI_729US14BR01092_0101wip2__ 5/1/14 3:16 PM Page 3

SPRYCEL® (dasatinib) SPRYCEL® (dasatinib) 5.5 Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial The most frequently reported adverse reactions reported in ≥20% of patients with Infarction resistance or intolerance to prior imatinib therapy included myelosuppression, fluid Cardiac adverse reactions were reported in 7% of 258 patients taking SPRYCEL, retention events, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and including, 1.6% of patients with cardiomyopathy, heart failure congestive, diastolic hemorrhage. dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Monitor The most frequently reported serious adverse reactions in patients with newly patients for signs or symptoms consistent with cardiac dysfunction and treat diagnosed chronic phase CML included pleural effusion (4%), hemorrhage (2%), appropriately. congestive heart failure (1%), pulmonary hypertension (1%), and pyrexia (1%). The 5.6 Pulmonary Arterial Hypertension most frequently reported serious adverse reactions in patients with resistance or SPRYCEL may increase the risk of developing pulmonary arterial hypertension (PAH) intolerance to prior imatinib therapy included pleural effusion (11%), gastrointestinal which may occur any time after initiation, including after more than one year of bleeding (4%), febrile neutropenia (4%), dyspnea (3%), pneumonia (3%), pyrexia (3%), treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH diarrhea (3%), infection (2%), congestive heart failure/cardiac dysfunction (2%), may be reversible on discontinuation of SPRYCEL. Evaluate patients for signs and pericardial effusion (1%), and CNS hemorrhage (1%). symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and 6.1 Chronic Myeloid Leukemia (CML) during treatment. If PAH is confirmed, SPRYCEL should be permanently discontinued. Adverse reactions (excluding laboratory abnormalities) that were reported in at least 5.7 Embryo-fetal Toxicity 10% of patients are shown in Table 2 for newly diagnosed patients with chronic phase SPRYCEL can cause fetal harm when administered to a pregnant woman. Adverse CML and Tables 3 and 4 for CML patients with resistance or intolerance to prior fetal and infant outcomes have been reported from women who have taken SPRYCEL imatinib therapy. during pregnancy. In animal reproduction studies, embryo-fetal toxicities, including skeletal malformations, were observed in rats and rabbits at plasma concentrations Table 2: Adverse Reactions Reported in ≥10% of Patients with Newly Diagnosed below those in humans receiving therapeutic doses of dasatinib. If SPRYCEL is used Chronic Phase CML (minimum of 36 months follow up) during pregnancy, or if the patient becomes pregnant while taking SPRYCEL, the All Grades Grade 3/4 patient should be apprised of the potential hazard to the fetus [see Use in Specific SPRYCEL Imatinib SPRYCEL Imatinib Populations (8.1)]. (n=258) (n=258) (n=258) (n=258) Advise females of reproductive potential to avoid pregnancy, which may include the use Preferred Term Percent (%) of Patients of contraception, during treatment with SPRYCEL [see Use in Specific Populations (8.8)]. Fluid retention 31 44 3 1 6 ADVERSE REACTIONS Pleural effusion 19 <1 2 0 The following adverse reactions are discussed in greater detail in other sections of the Superficial localized edema 13 37 0 <1 labeling: Generalized edema 3 7 0 0 • Myelosuppression [see Dosage and Administration (2.3) and Warnings and Congestive heart failure/ 2 1 <1 <1 Precautions (5.1)]. cardiac dysfunctiona • Bleeding related events [see Warnings and Precautions (5.2)]. Pericardial effusion 3 1 1 0 • Fluid retention [see Warnings and Precautions (5.3)]. Pulmonary hypertension 2 0 <1 0 • QT prolongation [see Warnings and Precautions (5.4)]. Pulmonary edema 1 0 0 0 • Congestive heart failure, left ventricular dysfunction, and myocardial infarction Diarrhea 21 22 1 1 [see Warnings and Precautions (5.5)]. Headache 13 11 0 0 • Pulmonary Arterial Hypertension [see Warnings and Precautions (5.6)]. Musculoskeletal pain 13 17 0 <1 Because clinical trials are conducted under widely varying conditions, adverse Rashb 13 18 0 2 reaction rates observed in the clinical trials of a drug cannot be directly compared to Nausea 10 24 0 0 rates in the clinical trials of another drug and may not reflect the rates observed in practice. Fatigue 9 11 <1 0 The data described below reflect exposure to SPRYCEL in clinical studies including Myalgia 6 12 0 0 258 patients with newly diagnosed chronic phase CML and in 2182 patients with Hemorrhagec 7 7 1 1 imatinib resistant or intolerant CML or Ph+ ALL. Gastrointestinal bleeding 2 1 1 0 In the newly diagnosed chronic phase CML trial with a minimum of 36 months follow Other bleedingd 6 5 0 1 up and median duration of therapy of 37 months, the median average daily dose was CNS bleeding 0 <1 0 <1 99 mg. Vomiting 5 11 0 0 In the imatinib resistant or intolerant CML or Ph+ ALL clinical trials, 1520 patients had Muscle spasms 5 21 0 <1 a minimum of 2 years follow up and 662 patients with chronic phase CML had a minimum of 60 months follow up (starting dosage 100 mg once daily, 140 mg once a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic daily, 50 mg twice daily, or 70 mg twice daily). Among patients with chronic phase dysfunction, ejection fraction decreased, and left ventricular dysfunction. CML and resistance or intolerance to prior imatinib therapy, the median duration b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash of treatment with SPRYCEL 100 mg once daily was 37 months (range 1–65 months). papular, rash pustular, skin exfoliation, and rash vesicular. The median duration of treatment with SPRYCEL 140 mg once daily was 15 months c Adverse reaction of special interest with <10% frequency. (range 0.03–36 months) for accelerated phase CML, 3 months (range 0.03–29 months) d Includes conjunctival hemorrhage, ear hemorrhage, ecchymosis, epistaxis, for myeloid blast phase CML, and 3 months (range 0.1–10 months) for lymphoid eye hemorrhage, gingival bleeding, hematoma, hematuria, hemoptysis, blast CML. intra-abdominal hematoma, petechiae, scleral hemorrhage, uterine hemorrhage, and The majority of SPRYCEL-treated patients experienced adverse reactions at some vaginal hemorrhage. time. In the newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 6% of SPRYCEL-treated patients with a minimum of 12 months The cumulative rates of the majority of adverse reactions (all grades) in newly follow up. After a minimum of 36 months follow up, the cumulative discontinuation diagnosed patients with chronic phase CML were similar after 12 and 36 months rate was 9%. Among patients with resistance or intolerance to prior imatinib therapy, minimum follow up including congestive heart failure/cardiac dysfunction (2% vs 2%), the rates of discontinuation for adverse reactions at 2 years were 15% in chronic pericardial effusion (2% vs 3%), pulmonary edema (<1% vs 1%), gastrointestinal phase CML for all dosages, 16% in accelerated phase CML, 15% in myeloid blast bleeding (2% vs 2%), diarrhea (18% vs 21%), and generalized edema (3% vs 3%). phase CML, 8% in lymphoid blast phase CML, and 8% in Ph+ ALL. In a dose- Cumulative adverse reaction rates (all grades) that increased between 12 months and optimization trial in patients with resistance or intolerance to prior imatinib therapy 36 months minimum follow up included overall fluid retention (23% vs 31%), pleural and chronic phase CML with a minimum of 60 months follow up, the rate effusion (12% vs 19%), and superficial edema (10% vs 13%). A total of 9 patients of discontinuation for adverse reactions was 18% in patients treated with 100 mg (3.5%) discontinued due to pleural effusion in the trial. once daily. At 36 months, there were 17 deaths in the dasatinib-treated patients (6.6%) and The most frequently reported adverse reactions reported in ≥10% of patients in newly 20 deaths in the imatinib-treated patients (7.7%); 1 in each group was judged by the diagnosed chronic phase CML included myelosuppression, fluid retention events investigator as related to study therapy. (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, rash, and nausea. Pleural effusions were reported in 50 patients (see Table 2). Spycl0514PI_729US14BR01092_0101wip2__ 5/1/14 3:16 PM Page 4

SPRYCEL® (dasatinib) SPRYCEL® (dasatinib)

Table 3: Adverse Reactions Reported in ≥10% of Patients with Chronic Phase Table 4: Adverse Reactions Reported in ≥10% of Patients with Advanced Phase CML Resistant or Intolerant to Prior Imatinib Therapy (minimum of CML Resistant or Intolerant to Prior Imatinib Therapy (Continued) 60 months follow up) 140 mg Once Daily 100 mg Once Daily Myeloid Lymphoid Chronic Accelerated Blast Blast (n=165) (n=157) (n=74) (n=33) All Grade All Grade All Grade All Grade Grades 3/4 Grades 3/4 Grades 3/4 Grades 3/4 Preferred Term Percent (%) of Patients Preferred Term Percent (%) of Patients Fluid retention 42 5 Nausea 19 1 23 1 21 3 Superficial localized edema 21 0 Skin rashb 15 0 16 1 21 0 Pleural effusion 24 4 Arthralgia 10 0 51 00 Generalized edema 40 Infection (including 10 6 14 7 90 bacterial, viral, fungal, Pericardial effusion 21 and non-specified) Congestive heart failure/ 00 Hemorrhage 26 8 19 9 24 9 a cardiac dysfunction Gastrointestinal bleeding 86 97 93 Pulmonary edema 00 CNS bleeding 11 00 33 Headache 33 1 Vomiting 11 1 12 0 15 0 Diarrhea 28 2 Pyrexia 11 2 18 3 60 Fatigue 26 4 Febrile neutropenia 44 12 12 12 12 Dyspnea 24 2 Musculoskeletal pain 22 2 a Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, Nausea 18 1 cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure. Skin rashb 18 2 b Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, Myalgia 13 0 generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash Arthralgia 12 1 follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, Infection (including 13 1 rash pustular, skin exfoliation, skin irritation, urticaria vesiculosa, and rash vesicular. bacterial, viral, fungal, and non-specified) a bL oratory Abnormalities Abdominal pain 12 1 Hemorrhage 11 1 Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 neutropenia, thrombocytopenia, and anemia was higher in patients Gastrointestinal bleeding 21 with advanced phase CML than in chronic phase CML (Tables 5 and 6). CNS bleeding 00Myelosuppression was reported in patients with normal baseline laboratory values as Pruritus 10 1 well as in patients with pre-existing laboratory abnormalities. Pain 10 1 In patients who experienced severe myelosuppression, recovery generally occurred a Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, following dose interruption or reduction; permanent discontinuation of treatment cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction occurred in 2% of patients with newly diagnosed chronic phase CML and 5% of decreased, and ventricular failure. patients with resistance or intolerance to prior imatinib therapy [see Warnings and b Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, Precautions (5.1)]. generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash Grade 3 or 4 elevations of transaminase or bilirubin and Grade 3 or 4 hypocalcemia, follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML rash pustular, skin exfoliation, skin irritation, urticaria vesiculosa, and rash vesicular. but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML. Elevations in transaminase or bilirubin were usually managed with With a minimum follow up of 60 months (see Table 3), the cumulative rates of the dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia during majority of adverse reactions (all grades) in patients with chronic phase CML treated the course of SPRYCEL therapy often had recovery with oral calcium supplementation. with a starting dose of 100 mg once daily were identical with a minimum follow up of Laboratory abnormalities reported in patients with newly diagnosed chronic phase 24 and 60 months including congestive heart failure/cardiac dysfunction, pericardial CML are shown in Table 5. There were no discontinuations of SPRYCEL therapy in this effusion, pulmonary edema, and gastrointestinal bleeding or similar for diarrhea (27% patient population due to biochemical laboratory parameters. vs 28%), and generalized edema (3% vs 4%). Cumulative adverse reaction rates (all grades) that increased between 24 months and 60 months minimum follow up Table 5: CTC Grade 3/4 Laboratory Abnormalities in Patients with Newly included: overall fluid retention (34% vs 42%), pleural effusion (18% vs 24%), and Diagnosed Chronic Phase CML (minimum of 36 months follow up) superficial edema (18% vs 21%). The cumulative rate of Grade 3 or 4 pleural effusion was 2% versus 4%, respectively. SPRYCEL Imatinib (n=258) (n=258) Table 4: Adverse Reactions Reported in ≥10% of Patients with Advanced Phase Percent (%) of Patients CML Resistant or Intolerant to Prior Imatinib Therapy Hematology Parameters 140 mg Once Daily Neutropenia 24 21 Myeloid Lymphoid Thrombocytopenia 19 11 Accelerated Blast Blast Anemia 12 9 (n=157) (n=74) (n=33) Biochemistry Parameters All Grade All Grade All Grade Hypophosphatemia 7 28 Grades 3/4 Grades 3/4 Grades 3/4 Hypokalemia 0 2 Preferred Term Percent (%) of Patients Hypocalcemia 3 2 Fluid retention 35 8 34 7 21 6 Elevated SGPT (ALT) <1 2 Superficial 18 1 14 0 30 Elevated SGOT (AST) <1 1 localized edema Elevated Bilirubin 1 0 Pleural effusion 21 7 20 7 21 6 Elevated Creatinine 1 1 Generalized edema 10 30 00 CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 109/L, Grade 4 <0.5 × 109/L); thrombo- Pericardial effusion 31 00 00 cytopenia (Grade 3 ≥25–<50 × 109/L, Grade 4 <25 × 109/L); anemia (hemoglobin Grade 3 Congestive heart failure/ 00 40 00 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal cardiac dysfunctiona range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × Pulmonary edema 10 43 00 ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia Headache 27 1 18 1 15 3 (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Diarrhea 31 3 20 5 18 0 Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3. 0–2.5 mmol/L, Grade 4 <2.5 mmol/L). Fatigue 19 2 20 1 93 Dyspnea 20 3 15 3 33 Musculoskeletal pain 11 0 81 00 (Continued) Spycl0514PI_729US14BR01092_0101wip2__ 5/1/14 3:16 PM Page 5

SPRYCEL® (dasatinib) SPRYCEL® (dasatinib) Laboratory abnormalities reported in patients with CML resistant or intolerant to Investigations: 1%–<10% – weight increased, weight decreased; 0.1%–<1% – imatinib who received the recommended starting doses of SPRYCEL are shown by blood creatine phosphokinase increased. disease phase in Table 6. Infections and Infestations: 1%–<10% – pneumonia (including bacterial, viral, and Table 6: CTC Grade 3/4 Laboratory Abnormalities in Clinical Studies of fungal), upper respiratory tract infection/inflammation, herpes virus infection, CML: Resistance or Intolerance to Prior Imatinib Therapy enterocolitis infection, sepsis (including fatal outcomes [0.2%]). Chronic Phase CML Advanced Phase CML Metabolism and Nutrition Disorders: 1%–<10% – anorexia, appetite disturbances, 100 mg Once Daily 140 mg Once Daily hyperuricemia; 0.1%–<1% – hypoalbuminemia. Accelerated Myeloid Lymphoid Cardiac Disorders: 1%–<10% – arrhythmia (including tachycardia), palpitations; Phase Blast Phase Blast Phase 0.1%–<1% – angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia (n=165) (n=157) (n=74) (n=33) (including ventricular tachycardia); <0.1% – cor pulmonale, myocarditis, acute Percent (%) of Patients coronary syndrome. Hematology Parameters* Eye Disorders: 1%–<10% – visual disorder (including visual disturbance, vision Neutropenia 36 58 77 79 blurred, and visual acuity reduced), dry eye; 0.1%–<1% – conjunctivitis; Thrombocytopenia 24 63 78 85 <0.1% – visual impairment. Anemia 13 47 74 52 Vascular Disorders: 1%–<10% – flushing, hypertension; 0.1%–<1% – hypotension, Biochemistry Parameters thrombophlebitis; <0.1% – livedo reticularis. Hypophosphatemia 10 13 12 18 Psychiatric Disorders: 1%–<10% – insomnia, depression; 0.1%–<1% – anxiety, Hypokalemia 2711 15 affect lability, confusional state, libido decreased. Hypocalcemia <1 4912 – gynecomastia, Elevated SGPT (ALT) 02 5 3 Reproductive System and Breast Disorders: 0.1%–<1% menstruation irregular. Elevated SGOT (AST) <1 04 3 Elevated Bilirubin <1 13 6 Injury, Poisoning, and Procedural Complications: 1%–<10% – contusion. Elevated Creatinine 02 8 0 Ear and Labyrinth Disorders: 1%–<10% – tinnitus; 0.1%–<1% – vertigo. CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 109/L, Grade 4 <0.5 × 109/L); Hepatobiliary Disorders: 0.1%–<1% – cholestasis, cholecystitis, hepatitis. thrombocytopenia (Grade 3 ≥25–<50 × 109/L, Grade 4 <25 × 109/L); anemia (hemoglobin Renal and Urinary Disorders: 0.1%–<1% – urinary frequency, renal failure, proteinuria. Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Neoplasms Benign, Malignant, and Unspecified: 0.1%–<1% – tumor lysis syndrome. Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); Immune System Disorders: 0.1%–<1% – hypersensitivity (including erythema hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia nodosum). (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L, Grade 4 <2.5 mmol/L). 6.4 Postmarketing Experience * Hematology parameters for 100 mg once-daily dosing in chronic phase CML reflects The following additional adverse reactions have been identified during post approval 60 month minimum follow up. use of SPRYCEL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or Among chronic phase CML patients with resistance or intolerance to prior establish a causal relationship to drug exposure. imatinib therapy, cumulative Grade 3 or 4 cytopenias were similar at 2 and 5 years Cardiac disorders: atrial fibrillation/atrial flutter including: neutropenia (36% vs 36%), thrombocytopenia (23% vs 24%), and anemia (13% vs 13%). Vascular disorders: thrombosis/embolism (including pulmonary embolism, deep vein thrombosis) 6.2 Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Respiratory, thoracic, and mediastinal disorders: interstitial lung disease, pulmonary arterial hypertension A total of 135 patients with Ph+ ALL were treated with SPRYCEL in clinical studies. The median duration of treatment was 3 months (range 0.03–31 months). The safety 7 DRUG INTERACTIONS profile of patients with Ph+ ALL was similar to those with lymphoid blast phase CML. 7.1 Drugs That May Increase Dasatinib Plasma Concentrations The most frequently reported adverse reactions included fluid retention events, such as pleural effusion (24%) and superficial edema (19%), and gastrointestinal disorders, CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. In a trial of 18 patients with solid such as diarrhea (31%), nausea (24%), and vomiting (16%). Hemorrhage (19%), tumors, 20-mg SPRYCEL once daily coadministered with 200 mg of ketoconazole pyrexia (17%), rash (16%), and dyspnea (16%) were also frequently reported. The twice daily increased the dasatinib Cmax and AUC by four- and five-fold, respectively. most frequently reported serious adverse reactions included pleural effusion (11%), Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 may increase exposure gastrointestinal bleeding (7%), febrile neutropenia (6%), infection (5%), pyrexia (4%), to dasatinib and should be avoided. In patients receiving treatment with SPRYCEL, pneumonia (3%), diarrhea (3%), nausea (2%), vomiting (2%), and colitis (2%). close monitoring for toxicity and a SPRYCEL dose reduction should be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided 6.3 Additional Data From Clinical Trials [see Dosage and Administration (2.1)]. The following adverse reactions were reported in patients in the SPRYCEL clinical 7.2 Drugs That May Decrease Dasatinib Plasma Concentrations studies at a frequency of ≥10%, 1%–<10%, 0.1%–<1%, or <0.1%. These events are included on the basis of clinical relevance. CYP3A4 Inducers: When a single morning dose of SPRYCEL was administered following 8 days of continuous evening administration of 600 mg of rifampin, a potent Gastrointestinal Disorders: 1%–<10% – mucosal inflammation (including mucositis/ CYP3A4 inducer, the mean Cmax and AUC of dasatinib were decreased by 81% and stomatitis), dyspepsia, abdominal distension, constipation, gastritis, colitis (including 82%, respectively. Alternative agents with less enzyme induction potential should be neutropenic colitis), oral soft tissue disorder; 0.1%–<1% – ascites, dysphagia, anal considered. If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase fissure, upper gastrointestinal ulcer, esophagitis, pancreatitis; <0.1% – protein losing gastroenteropathy, ileus. in SPRYCEL should be considered [see Dosage and Administration (2.1)]. Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. In General Disorders and Administration Site Conditions: 1%–<10% – asthenia, pain, chest pain, chills; 0.1%–<1% – malaise, temperature intolerance. a trial of 24 healthy subjects, administration of 30 mL of aluminum hydroxide/ magnesium hydroxide 2 hours prior to a single 50-mg dose of SPRYCEL was associated Skin and Subcutaneous Tissue Disorders: 1%–<10% – pruritus, alopecia, acne, dry with no relevant change in dasatinib AUC; however, the dasatinib Cmax increased 26%. skin, hyperhidrosis, urticaria, dermatitis (including eczema); 0.1%–<1% – pigmentation When 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, acute febrile same subjects concomitantly with a 50-mg dose of SPRYCEL, a 55% reduction in neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome. dasatinib AUC and a 58% reduction in Cmax were observed. Simultaneous administration Respiratory, Thoracic, and Mediastinal Disorders: ≥10% – cough; 1%–<10% – of SPRYCEL with antacids should be avoided. If antacid therapy is needed, the antacid lung infiltration, pneumonitis, pulmonary hypertension; 0.1%–<1% – asthma, dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL. bronchospasm; <0.1% – acute respiratory distress syndrome. H2 Antagonists/Proton Pump Inhibitors: Long-term suppression of gastric acid – neuropathy (including peripheral neuropathy), Nervous System Disorders: 1%–<10% secretion by H2 antagonists or proton pump inhibitors (eg, famotidine and omeprazole) dizziness, dysgeusia, somnolence; 0.1%–<1% – amnesia, tremor, syncope; <0.1% – is likely to reduce dasatinib exposure. In a trial of 24 healthy subjects, administration convulsion, cerebrovascular accident, transient ischemic attack, optic neuritis, VIIth of a single 50-mg dose of SPRYCEL 10 hours following famotidine reduced the AUC nerve paralysis. and Cmax of dasatinib by 61% and 63%, respectively. In a trial of 14 healthy subjects, Blood and Lymphatic System Disorders: 1%–<10% – pancytopenia; <0.1% – administration of a single 100-mg dose of SPRYCEL 22 hours following a 40-mg aplasia pure red cell. omeprazole dose at steady state reduced the AUC and Cmax of dasatinib by 43% and Musculoskeletal and Connective Tissue Disorders: 1%–<10% – muscular 42%, respectively. The concomitant use of H2 antagonists or proton pump inhibitors weakness, musculoskeletal stiffness, muscle spasm; 0.1%–<1% – rhabdomyolysis, with SPRYCEL is not recommended. The use of antacids (at least 2 hours prior to or tendonitis, muscle inflammation. 2 hours after the dose of SPRYCEL) should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving SPRYCEL therapy. Spycl0514PI_729US14BR01092_0101wip2__ 5/1/14 3:16 PM Page 6

SPRYCEL® (dasatinib) SPRYCEL® (dasatinib) 7.3 Drugs That May Have Their Plasma Concentration Altered By Dasatinib 10 OVERDOSAGE CYP3A4 Substrates: Single-dose data from a trial of 54 healthy subjects indicate that Experience with overdose of SPRYCEL in clinical studies is limited to isolated cases. the mean Cmax and AUC of simvastatin, a CYP3A4 substrate, were increased by 37% and The highest overdosage of 280 mg per day for 1 week was reported in two patients 20%, respectively, when simvastatin was administered in combination with a single and both developed severe myelosuppression and bleeding. Since SPRYCEL is 100-mg dose of SPRYCEL. Therefore, CYP3A4 substrates known to have a narrow associated with severe myelosuppression [see Warnings and Precautions (5.1) and therapeutic index such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, Adverse Reactions (6.1)], patients who ingested more than the recommended dosage fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, should be closely monitored for myelosuppression and given appropriate supportive dihydroergotamine) should be administered with caution in patients receiving SPRYCEL. treatment. 8 USE IN SPECIFIC POPULATIONS Acute overdose in animals was associated with cardiotoxicity. Evidence of 8.1 Pregnancy cardiotoxicity included ventricular necrosis and valvular/ventricular/atrial hemorrhage at single doses ≥100 mg/kg (600 mg/m2) in rodents. There was a tendency for Pregnancy Category D increased systolic and diastolic blood pressure in monkeys at single doses ≥10 mg/kg Risk Summary (120 mg/m2). SPRYCEL can cause fetal harm when administered to a pregnant woman. There are 11 DESCRIPTION no studies with SPRYCEL in pregnant women. However, in animal reproduction SPRYCEL (dasatinib) is a kinase inhibitor. The chemical name for dasatinib is studies, embryo-fetal toxicities, including skeletal malformations, were observed at N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4- dasatinib doses producing plasma concentrations below those in humans receiving pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate. The molecular formula is therapeutic doses of dasatinib. If SPRYCEL is used during pregnancy, or if the patient C22H26ClN7O2S • H2O, which corresponds to a formula weight of 506.02 becomes pregnant while taking SPRYCEL, the patient should be apprised of the (monohydrate). The anhydrous free base has a molecular weight of 488.01. Dasatinib potential risk to the fetus. [See Warnings and Precautions (5.7).] has the following chemical structure: Data HO Based on human experience, dasatinib is suspected to cause congenital N H O Cl malformations, including neural tube defects, and harmful pharmacological effects on N N S the fetus when administered during pregnancy. N · H2 O Clinical Considerations N N N H Fetal/Neonatal Adverse Reactions H3C Transplacental transfer of dasatinib has been reported. Dasatinib has been measured CH 3 in fetal plasma and amniotic fluid and concentrations were found to be comparable to those in maternal plasma. Hydrops fetalis and fetal bicytopenia have been reported Dasatinib is a white to off-white powder. The drug substance is insoluble in water and with maternal exposure to dasatinib. There have been other reports of maternal slightly soluble in ethanol and methanol. SPRYCEL tablets are white to off-white, dasatinib exposure with no adverse fetal outcomes noted. biconvex, film-coated tablets containing dasatinib, with the following inactive Animal Data ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of In nonclinical studies, at plasma concentrations below those observed in humans hypromellose, titanium dioxide, and polyethylene glycol. receiving therapeutic doses of dasatinib, embryo-fetal toxicities were observed in rats and rabbits. Fetal death was observed in rats. In both rats and rabbits, the lowest doses 12 CLINICAL PHARMACOLOGY 2 of dasatinib tested (rat: 2.5 mg/kg/day [15 mg/m /day] and rabbit: 0.5 mg/kg/day 12.1 Mechanism of Action [6 mg/m2/day]) resulted in embryo-fetal toxicities. These doses produced maternal AUCs of 105 ng•hr/mL and 44 ng•hr/mL (0.1-fold the human AUC) in rats and rabbits, Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC respectively. Embryo-fetal toxicities included skeletal malformations at multiple sites family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, (scapula, humerus, femur, radius, ribs, and clavicle), reduced ossification (sternum; dasatinib is predicted to bind to multiple conformations of the ABL kinase. thoracic, lumbar, and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body), In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib edema, and microhepatia. In a pre- and postnatal development study in rats, mesylate sensitive and resistant disease. Dasatinib inhibited the growth of chronic administration of dasatinib from gestation day (GD) 16 through lactation day (LD) 20, myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines GD 21 through LD 20, or LD 4 through LD 20 resulted in extensive pup mortality at overexpressing BCR-ABL. Under the conditions of the assays, dasatinib was able to maternal exposures that were below the exposures in patients treated with dasatinib overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, at the recommended labeling dose. activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), 8.3 Nursing Mothers and multi-drug resistance gene overexpression. It is unknown whether SPRYCEL is present in human milk. However, dasatinib was 12.3 Pharmacokinetics present in the milk of lactating rats. Because many drugs are excreted in human milk Absorption and because of the potential for serious adverse reactions in nursing infants from Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and SPRYCEL, a decision should be made whether to discontinue nursing or to discontinue 6 hours (Tmax) following oral administration. Dasatinib exhibits dose proportional the drug, taking into account the importance of the drug to the mother. increases in AUC and linear elimination characteristics over the dose range of 15 mg 8.4 Pediatric Use to 240 mg/day. The overall mean terminal half-life of dasatinib is 3 to 5 hours. The safety and efficacy of SPRYCEL in patients less than 18 years of age have not been Data from a trial of 54 healthy subjects administered a single, 100-mg dose of established. dasatinib 30 minutes following consumption of a high-fat meal resulted in a 14% increase in the mean AUC of dasatinib. The observed food effects were not clinically 8.5 Geriatric Use relevant. In the newly diagnosed chronic phase CML trial, 25 patients (10%) were 65 years of Distribution age and over and 7 patients (3%) were 75 years of age and over. Of the 2182 patients in clinical studies of SPRYCEL with resistance or intolerance to imatinib therapy, 547 In patients, dasatinib has an apparent volume of distribution of 2505 L, suggesting (25%) were 65 years of age and over and 105 (5%) were 75 years of age and over. that the drug is extensively distributed in the extravascular space. Binding of dasatinib No differences in efficacy were observed between older and younger patients. and its active metabolite to human plasma proteins in vitro was approximately Compared to patients under age 65 years, patients aged 65 years and older are more 96% and 93%, respectively, with no concentration dependence over the range of likely to experience toxicity. 100 to 500 ng/mL. 8.6 Hepatic Impairment Metabolism The effect of hepatic impairment on the pharmacokinetics of dasatinib was evaluated Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 in healthy volunteers with normal liver function and patients with moderate enzyme 3A4. CYP3A4 was the primary enzyme responsible for the formation of the (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment. Compared active metabolite. Flavin-containing monooxygenase 3 (FMO-3) and uridine to the healthy volunteers with normal hepatic function, the dose-normalized diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation pharmacokinetic parameters were decreased in the patients with hepatic impairment. of dasatinib metabolites. No dosage adjustment is necessary in patients with hepatic impairment The exposure of the active metabolite, which is equipotent to dasatinib, represents [see Clinical approximately 5% of the dasatinib AUC. This indicates that the active metabolite of Pharmacology (12.3)]. Caution is recommended when administering SPRYCEL to patients with hepatic impairment. dasatinib is unlikely to play a major role in the observed pharmacology of the drug. Dasatinib also had several other inactive oxidative metabolites. 8.7 Renal Impairment Dasatinib is a weak time-dependent inhibitor of CYP3A4. At clinically relevant There are currently no clinical studies with SPRYCEL in patients with impaired renal concentrations, dasatinib does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or function. Less than 4% of dasatinib and its metabolites are excreted via the kidney. 2E1. Dasatinib is not an inducer of human CYP enzymes. 8.8 Females of Reproductive Potential Elimination SPRYCEL can cause fetal harm when administered during pregnancy. Advise female Elimination is primarily via the feces. Following a single oral dose of [14C]-labeled patients of reproductive potential to avoid pregnancy, which may include the use of dasatinib, approximately 4% and 85% of the administered radioactivity was recovered contraception, during treatment. Advise patients to contact their healthcare provider in the urine and feces, respectively, within 10 days. Unchanged dasatinib accounted if they become pregnant, or if pregnancy is suspected, while taking SPRYCEL [see Use for 0.1% and 19% of the administered dose in urine and feces, respectively, with the in Specific Populations (8.1)]. remainder of the dose being metabolites. Spycl0514PI_729US14BR01092_0101wip2__ 5/1/14 3:16 PM Page 7

SPRYCEL® (dasatinib) SPRYCEL® (dasatinib) Effects of Age and Gender After 36 months follow up, median time to confirmed CCyR was 3.1 months in Pharmacokinetic analyses of demographic data indicate that there are no clinically 214 SPRYCEL responders and 5.8 months in 201 imatinib responders. Median time to relevant effects of age and gender on the pharmacokinetics of dasatinib. MMR after 36 months follow up was 8.9 months in 179 SPRYCEL responders and 13.4 months in 146 imatinib responders. Hepatic Impairment Dasatinib doses of 50 mg and 20 mg were evaluated in eight patients with moderate At 36 months, 8 patients (3%) on the dasatinib arm progressed to either accelerated (Child-Pugh class B) and seven patients with severe (Child-Pugh class C) hepatic phase or blast crisis while 13 patients (5%) on the imatinib arm progressed to either impairment, respectively. Matched controls with normal hepatic function (n=15) were accelerated phase or blast crisis. also evaluated and received a dasatinib dose of 70 mg. Compared to subjects with The rate of MMR at any time in each risk group determined by Hasford score was higher normal liver function, patients with moderate hepatic impairment had decreases in in the SPRYCEL group compared with the imatinib group (low risk: 81% and 64%; dose-normalized Cmax and AUC by 47% and 8%, respectively. Patients with severe intermediate risk: 64% and 56%; high risk: 61% and 42%, respectively). hepatic impairment had dose-normalized Cmax decreased by 43% and AUC decreased by 28% compared to the normal controls. BCR-ABL sequencing was performed on blood samples from patients in the newly diagnosed trial who discontinued dasatinib or imatinib therapy. Among dasatinib-treated These differences in Cmax and AUC are not clinically relevant. Dose adjustment is not necessary in patients with hepatic impairment. patients the mutations detected were T315I, F317I/L, and V299L. 13 NONCLINICAL TOXICOLOGY Dasatinib does not appear to be active against the T315I mutation, based on in vitro data. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a two-year carcinogenicity study, rats were administered oral doses of dasatinib at 14.2 Imatinib-Resistant or Intolerant CML or Ph+ ALL 0.3, 1, and 3 mg/kg/day. The highest dose resulted in a plasma drug exposure (AUC) The efficacy and safety of SPRYCEL were investigated in adult patients with CML level approximately 60% of the human exposure at 100 mg once daily. Dasatinib or Ph+ ALL whose disease was resistant to or who were intolerant to imatinib: induced a statistically significant increase in the combined incidence of squamous cell 1158 patients had chronic phase CML, 858 patients had accelerated phase, myeloid carcinomas and papillomas in the uterus and cervix of high-dose females and prostate blast phase, or lymphoid blast phase CML, and 130 patients had Ph+ ALL. In a clinical adenoma in low-dose males. trial in chronic phase CML, resistance to imatinib was defined as failure to achieve a Dasatinib was clastogenic when tested in vitro in Chinese hamster ovary cells, with and complete hematologic response (CHR; after 3 months), major cytogenetic response without metabolic activation. Dasatinib was not mutagenic when tested in an in vitro (MCyR; after 6 months), or complete cytogenetic response (CCyR; after 12 months); or bacterial cell assay (Ames test) and was not genotoxic in an in vivo rat micronucleus study. loss of a previous molecular response (with concurrent ≥10% increase in Ph+ Dasatinib did not affect mating or fertility in male and female rats at plasma drug metaphases), cytogenetic response, or hematologic response. Imatinib intolerance was exposure (AUC) similar to the human exposure at 100 mg daily; however, dasatinib defined as inability to tolerate 400 mg or more of imatinib per day or discontinuation of induced embryo lethality. In repeat dose studies, administration of dasatinib resulted in imatinib because of toxicity. reduced size and secretion of seminal vesicles, and immature prostate, seminal vesicle, and testis. The administration of dasatinib resulted in uterine inflammation and Results described below are based on a minimum of 2 years follow up after the start of mineralization in monkeys, and cystic ovaries and ovarian hypertrophy in rodents. SPRYCEL therapy in patients with a median time from initial diagnosis of approximately 5 years. Across all studies, 48% of patients were women, 81% were white, 15% were 14 CLINICAL STUDIES black or Asian, 25% were 65 years of age or older, and 5% were 75 years of age or 14.1 Newly Diagnosed Chronic Phase CML older. Most patients had long disease histories with extensive prior treatment, including An open-label, multicenter, international, randomized trial was conducted in adult imatinib, cytotoxic chemotherapy, interferon, and stem cell transplant. Overall, 80% of patients with newly diagnosed chronic phase CML. A total of 519 patients were patients had imatinib-resistant disease and 20% of patients were intolerant to imatinib. randomized to receive either SPRYCEL 100 mg once daily or imatinib 400 mg once The maximum imatinib dose had been 400–600 mg/day in about 60% of the patients daily. Patients with a history of cardiac disease were included in this trial except those and >600 mg/day in 40% of the patients. which had a myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation. The primary endpoint was The primary efficacy endpoint in chronic phase CML was MCyR, defined as elimination the rate of confirmed complete cytogenetic response (CCyR) within 12 months. (CCyR) or substantial diminution (by at least 65%, partial cytogenetic response) of Ph+ Confirmed CCyR was defined as a CCyR noted on two consecutive occasions (at least hematopoietic cells. The primary efficacy endpoint in accelerated phase, myeloid blast 28 days apart). phase, lymphoid blast phase CML, and Ph+ ALL was major hematologic response (MaHR), defined as either a CHR or no evidence of leukemia (NEL). Median age was 46 years in the SPRYCEL group and 49 years in the imatinib groups, with 10% and 11% of patients ≥65 years of age. There were slightly more male than Chronic Phase CML female patients in both groups (59% vs 41%). Fifty-three percent of all patients were Dose-Optimization Trial: A randomized, open-label trial was conducted in patients with Caucasian and 39% were Asian. At baseline, the distribution of Hasford Scores was similar in the SPRYCEL and imatinib treatment groups (low risk: 33% and 34%; chronic phase CML to evaluate the efficacy and safety of SPRYCEL administered once intermediate risk: 48% and 47%; high risk: 19% and 19%, respectively). With a daily compared with SPRYCEL administered twice daily. Patients with significant cardiac minimum of 12 months follow up, 85% of patients randomized to SPRYCEL and 81% diseases, including myocardial infarction within 6 months, congestive heart failure of patients randomized to imatinib were still on study. within 3 months, significant arrhythmias, or QTc prolongation were excluded from the trial. The primary efficacy endpoint was MCyR in patients with imatinib-resistant CML. With a minimum of 24 months follow up, 77% of patients randomized to SPRYCEL and 75% of patients randomized to imatinib were still on study and with a minimum of A total of 670 patients, of whom 497 had imatinib-resistant disease, were randomized 36 months follow up, 71% and 69% of patients, respectively, were still on study. to the SPRYCEL 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily group. Median duration of treatment was 22 months. Efficacy results are summarized in Table 7. Efficacy was achieved across all SPRYCEL treatment groups with the once daily Table 7: Efficacy Results in Newly Diagnosed Patients with Chronic Phase schedule demonstrating comparable efficacy (non-inferiority) to the twice daily schedule CML on the primary efficacy endpoint (difference in MCyR 1.9%; 95% CI [–6.8%–10.6%]). SPRYCEL Imatinib p-value (n=259) (n=260) Efficacy results are presented in Table 8 for patients with chronic phase CML who received the recommended starting dose of 100 mg once daily. Additional efficacy Response Rate (95% CI) results in this patient population are described after the table. Results for all patients Confirmed CCyRa with chronic phase CML, regardless of dosage (a starting dosage of 100 mg once daily, within 12 months 76.8% (71.2–81.8) 66.2% (60.1–71.9) p=0.007* 140 mg once daily, 50 mg twice daily, or 70 mg twice daily), were consistent with within 24 months 80.3% 74.2% –** those for patients treated with 100 mg once daily. within 36 months 82.6% 77.3% –** Major Molecular Responseb Table 8: Efficacy of SPRYCEL in Imatinib Resistant or Intolerant Chronic 12 months 52.1% (45.9–58.3) 33.8% (28.1–39.9) p<0.0001* Phase CML (minimum of 24 months follow up) 24 months 64.5% (58.3–70.3) 50% (43.8–56.2) –** 100 mg Once Daily 36 months 69.1% (63.1–74.7) 56.2% (49.9–62.3) –** (n=167) a Confirmed CCyR is defined as a CCyR noted on two consecutive occasions at least CHRa% (95% CI) 92% (86–95) 28 days apart. MCyRb% (95% CI) 63% (56–71) b Major molecular response (at any time) was defined as BCR-ABL ratios ≤0.1% by RQ-PCR in peripheral blood samples standardized on the International scale. These CCyR% (95% CI) 50% (42–58) are cumulative rates representing minimum follow up for the time frame specified. a CHR (response confirmed after 4 weeks): WBC ≤ institutional ULN, platelets * Adjusted for Hasford Score and indicated statistical significance at a pre-defined <450,000/mm3, no blasts or promyelocytes in peripheral blood, <5% myelocytes nominal level of significance. plus metamyelocytes in peripheral blood, basophils in peripheral blood <20%, ** Formal statistical comparison of cCCyR and MMR rates was only performed at the and no extramedullary involvement. time of the primary endpoint (cCCyR within 12 months). b MCyR combines both complete (0% Ph+ metaphases) and partial (>0%–35%) CI = confidence interval. responses. Spycl0514PI_729US14BR01092_0101wip2__ 5/1/14 3:16 PM Page 8

SPRYCEL® (dasatinib) SPRYCEL® (dasatinib) In the SPRYCEL 100 mg once daily group, median time to MCyR was 2.9 months (95% 16 HOW SUPPLIED/STORAGE AND HANDLING CI: [2.8%–3.0%]) with a minimum of 24 months follow up. Based on the Kaplan-Meier 16.1 How Supplied estimates, 93% (95% CI: [88%–98%]) of patients who had achieved an MCyR SPRYCEL® (dasatinib) tablets are available as described in Table 10. maintained that response for 18 months. In the 100 mg once daily group, MMR was achieved in 43% of all randomized patients within 5 years. The estimated rate of Table 10: SPRYCEL Trade Presentations progression-free survival and overall survival at 2 years in all patients treated with Tablets 100 mg once daily was 80% (95% CI: [73%–87%]) and 91% (95% CI: [86%–96%]), NDC Number Strength Description per Bottle respectively. Based on data six years after the last patient was enrolled in the trial, white to off-white, biconvex, round, film- 64% were known to be alive at 5 years, 22% were known to have died prior to 5 years 0003-0527-11 20 mg coated tablet with “BMS” debossed on one 60 and 14% had an unknown 5-year survival status. side and “527” on the other side By 5 years, transformation to either accelerated or blast phase occurred in eight white to off-white, biconvex, oval, film- 0003-0528-11 50 mg coated tablet with “BMS” debossed on one 60 patients on treatment. side and “528” on the other side Advanced Phase CML and Ph+ ALL white to off-white, biconvex, round, film- Dose-Optimization Trial: One randomized open-label trial was conducted in patients 0003-0524-11 70 mg coated tablet with “BMS” debossed on one 60 side and “524” on the other side with advanced phase CML (accelerated phase CML, myeloid blast phase CML, or lymphoid blast phase CML) to evaluate the efficacy and safety of SPRYCEL white to off-white, biconvex, triangle, film- 0003-0855-22 80 mg coated tablet with “BMS” and “80” (BMS 30 administered once daily compared with SPRYCEL administered twice daily. The over 80) debossed on one side and “855” primary efficacy endpoint was MaHR. A total of 611 patients were randomized to on the other side either the SPRYCEL 140 mg once daily or 70 mg twice daily group. Median duration of treatment was approximately 6 months for both treatment groups. The once daily white to off-white, biconvex, oval, film- schedule demonstrated comparable efficacy (non-inferiority) to the twice daily 0003-0852-22 100 mg coated tablet with “BMS 100” debossed 30 on one side and “852” on the other side schedule on the primary efficacy endpoint. The efficacy and safety of SPRYCEL were also investigated in patients with Ph+ ALL white to off-white, biconvex, round, 0003-0857-22 140 mg film-coated tablet with “BMS” and “140” 30 in one randomized trial (starting dosage 140 mg once daily or 70 mg twice daily) and (BMS over 140) debossed on one side one single-arm trial (starting dosage 70 mg twice daily). The primary efficacy and “857” on the other side endpoint was MaHR. A total of 130 patients were enrolled in these studies. The median duration of therapy was 3 months. 16.2 Storage ® Response rates are presented in Table 9. SPRYCEL tablets should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Table 9: Efficacy of SPRYCEL in Imatinib Resistant or Intolerant Advanced 16.3 Handling and Disposal Phase CML and Ph+ ALL SPRYCEL is an antineoplastic product. Follow special handling and disposal procedures. 140 mg Once Daily SPRYCEL (dasatinib) tablets consist of a core tablet (containing the active drug Accelerated Myeloid Blast Lymphoid Blast Ph+ ALL substance), surrounded by a film coating to prevent exposure of pharmacy and clinical personnel to the active drug substance. However, if tablets are inadvertently crushed or (n=158) (n=75) (n=33) (n=40) broken, pharmacy and clinical personnel should wear disposable chemotherapy gloves. MaHRa 66% 28% 42% 38% Personnel who are pregnant should avoid exposure to crushed or broken tablets. (95% CI) (59–74) (18–40) (26–61) (23–54) 17 PATIENT COUNSELING INFORMATION CHRa 47% 17% 21% 33% See FDA-Approved Patient Labeling. (95% CI) (40–56) (10–28) (9–39) (19–49) 17.1 Bleeding NELa 19% 11% 21% 5% Patients should be informed of the possibility of serious bleeding and to report (95% CI) (13–26) (5–20) (9–39) (1–17) immediately any signs or symptoms suggestive of hemorrhage (unusual bleeding or easy bruising). MCyRb 39% 28% 52% 70% (95% CI) (31–47) (18–40) (34–69) (54–83) 17.2 Myelosuppression Patients should be informed of the possibility of developing low blood cell counts; they CCyR 32% 17% 39% 50% should be instructed to report immediately should fever develop, particularly in (95% CI) (25–40) (10–28) (23–58) (34–66) association with any suggestion of infection. a Hematologic response criteria (all responses confirmed after 4 weeks): Major 17.3 Fluid Retention hematologic response: (MaHR) = complete hematologic response (CHR) + no Patients should be informed of the possibility of developing fluid retention (swelling, weight evidence of leukemia (NEL). gain, or shortness of breath) and to seek medical attention if those symptoms arise. CHR: WBC ≤ institutional ULN, ANC ≥1000/mm3, platelets ≥100,000/mm3, no 17.4 Embryo-fetal Toxicity blasts or promyelocytes in peripheral blood, bone marrow blasts ≤5%, <5% Patients should be informed that SPRYCEL can cause fetal harm when administered myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral to a pregnant woman. Women should be advised of the potential hazard to the fetus blood <20%, and no extramedullary involvement. and to avoid becoming pregnant. If SPRYCEL is used during pregnancy, or if the NEL: same criteria as for CHR but ANC ≥500/mm3 and <1000/mm3, or platelets patient becomes pregnant while taking SPRYCEL, the patient should be apprised of ≥20,000/mm3 and ≤100,000/mm3. the potential hazard to the fetus [see Warnings and Precautions (5.7) and Use in b MCyR combines both complete (0% Ph+ metaphases) and partial (>0%–35%) responses. Specific Populations (8.1, 8.8)]. CI = confidence interval ULN = upper limit of normal range. 17.5 Gastrointestinal Complaints Patients should be informed that they may experience nausea, vomiting, or diarrhea In the SPRYCEL 140 mg once daily group, the median time to MaHR was 1.9 months with SPRYCEL. If these symptoms are significant, they should seek medical attention. for patients with accelerated phase CML, 1.9 months for patients with myeloid blast 17.6 Pain phase CML, and 1.8 months for patients with lymphoid blast phase CML. Patients should be informed that they may experience headache or musculoskeletal pain with SPRYCEL. If these symptoms are significant, they should seek medical In patients with myeloid blast phase CML, the median duration of MaHR was 8 months attention. and 9 months for the 140 mg once daily group and the 70 mg twice daily group, 17.7 Fatigue respectively. In patients with lymphoid blast phase CML, the median duration of MaHR Patients should be informed that they may experience fatigue with SPRYCEL. If this was 5 months and 8 months for the 140 mg once daily group and the 70 mg twice daily symptom is significant, they should seek medical attention. group, respectively. In patients with Ph+ ALL who were treated with SPRYCEL 140 mg once daily, the median duration of MaHR was 4.6 months. The medians of 17.8 Rash progression-free survival for patients with Ph+ ALL treated with SPRYCEL Patients should be informed that they may experience skin rash with SPRYCEL. If this 140 mg once daily and 70 mg twice daily were 4.0 months and 3.5 months, respectively. symptom is significant, they should seek medical attention. 17.9 Lactose Patients should be informed that SPRYCEL contains 135 mg of lactose monohydrate in a 100-mg daily dose and 189 mg of lactose monohydrate in a 140-mg daily dose. 17.10 Missed Dose If the patient misses a dose of SPRYCEL, the patient should take the next scheduled dose at its regular time. The patient should not take two doses at the same time. Spycl0514PI_729US14BR01092_0101wip2__ 5/1/14 3:16 PM Page 9

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PATIENT INFORMATION • medicines whose blood levels might change by taking SPRYCEL, such as: SPRYCEL® (Spry-sell) ® ® (dasatinib) Sandimmune (cyclosporine), Rapamune (sirolimus), Tablets Alfenta® (alfentanil), Prograf® (tacrolimus),

Read the Patient Information that comes with SPRYCEL before you start taking it and Fentanyl® (fentanyl), Ergomar® (ergotamine). each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or Orap® (pimozide), treatment.

What is SPRYCEL? SPRYCEL is best absorbed from your stomach into your bloodstream in the presence of stomach acid. You should avoid taking medicines that reduce SPRYCEL® is a prescription medicine used to treat adults who have: stomach acid, such as:

• newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid Tagamet® (cimetidine), Protonix® (pantoprazole sodium), leukemia (CML) in chronic phase. Pepcid® (famotidine), Nexium® (esomeprazole), • Ph+ CML who no longer benefit from, or did not tolerate, other treatment, including Gleevec® (imatinib mesylate). Zantac® (ranitidine), AcipHex® (rabeprazole),

• Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) Prilosec® (omeprazole), Prevacid® (lansoprazole). who no longer benefit from, or did not tolerate, other treatment. Medicines that neutralize stomach acid, such as Maalox® (aluminum It is not known if SPRYCEL is safe and effective in children younger than 18 years old. hydroxide/magnesium hydroxide), Tums® (calcium carbonate), or Rolaids® (calcium carbonate and magnesia), may be taken up to 2 hours before or 2 hours What should I tell my healthcare provider before taking SPRYCEL? after SPRYCEL.

Before you take SPRYCEL, tell your healthcare provider if you: Since SPRYCEL therapy may cause bleeding, tell your healthcare provider if you are using blood thinner medicine, such as Coumadin® (warfarin sodium) or aspirin. • have problems with your immune system Know the medicines you take. Keep a list of your medicines and show it to your • have liver problems healthcare provider and pharmacist when you get a new medicine.

• have heart problems How should I take SPRYCEL? • are lactose intolerant Take SPRYCEL exactly as prescribed by your healthcare provider. • have any other medical conditions • Take SPRYCEL with or without food. Try to take SPRYCEL at the same time • are pregnant or planning to become pregnant. SPRYCEL can harm your each day. unborn baby. Sexually active female patients of childbearing potential taking SPRYCEL should avoid pregnancy. Talk to your healthcare provider right away • Swallow SPRYCEL tablets whole. Do not break, cut, or crush the tablets. if you are pregnant or plan to become pregnant. • You should not drink grapefruit juice while taking SPRYCEL. • are breastfeeding or plan to breastfeed. It is not known if SPRYCEL passes into your breast milk or if it can harm your baby. You and your healthcare • Your healthcare provider may: provider should decide if you will take SPRYCEL or breastfeed. You should not do both. o change your dose of SPRYCEL or

Tell your healthcare provider about all the medicines you take, including o tell you to temporarily stop taking SPRYCEL. prescription and non-prescription medicines, vitamins, antacids, and herbal supplements. • Do not change your dose or stop taking SPRYCEL without first talking with your healthcare provider. Especially tell your healthcare provider if you take: • If you miss a dose of SPRYCEL, take your next scheduled dose at its regular • medicines that increase the amount of SPRYCEL in your bloodstream, time. Do not take two doses at the same time. Call your healthcare provider or such as: pharmacist if you are not sure what to do.

Nizoral® (ketoconazole), Nefazodone (serzone, nefadar), • If you take too much SPRYCEL, call your healthcare provider or go to the nearest hospital emergency room right away. Sporanox® (itraconazole), Invirase® (saquinavir), What are the possible side effects of SPRYCEL? Norvir® (ritonavir), Ketek® (telithromycin), SPRYCEL may cause serious side effects, including: Reyataz® (atazanavir sulfate), E-mycin® (erythromycin),

® ® • Low Blood Cell Counts: SPRYCEL may cause low red blood cell counts (anemia), Crixivan (indinavir), Biaxin (clarithromycin). low white blood cell counts (neutropenia), and low platelet counts (thrombocytopenia). Your healthcare provider will do blood tests to check your Viracept® (nelfinavir), blood cell counts regularly during your treatment with SPRYCEL. Call your healthcare provider right away if you have a fever or any signs of an infection • medicines that decrease the amount of SPRYCEL in your bloodstream, while taking SPRYCEL. such as:

Decadron® (dexamethasone), Rimactane® (rifampin), • Bleeding: SPRYCEL may cause severe bleeding that can lead to death. Call your healthcare provider right away if you have: Dilantin® (phenytoin), Luminal® (phenobarbital). o unusual bleeding or bruising of your skin Tegretol® (carbamazepine), o bright red or dark tar-like stools

o a decrease in your level of consciousness, headache, or change in speech. Spycl0514PI_729US14BR01092_0101wip2__ 5/1/14 3:16 PM Page 10

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• Your body may hold too much fluid (fluid retention): In severe cases, fluid may build up in the lining of your lungs, the sac around your heart, or your stomach cavity. Call your healthcare provider right away if you get any of these symptoms during treatment with SPRYCEL: o swelling all over your body o weight gain o shortness of breath and cough. • Heart problems. SPRYCEL may cause an abnormal heart rate, heart problems or a heart attack. Your healthcare provider will monitor the potassium and magnesium levels in your blood, and your heart function. • Pulmonary Arterial Hypertension (PAH). SPRYCEL may cause high blood pressure in the vessels of your lungs. PAH may happen at any time during your treatment with SPRYCEL. Your healthcare provider should check your heart and lungs before and during your treatment with SPRYCEL. Call your healthcare provider right away if you have shortness of breath, tiredness, or swelling all over your body (fluid retention). Other common side effects of SPRYCEL therapy include: • diarrhea • tiredness • headache • vomiting • cough • muscle pain • skin rash • weakness • fever • infections • nausea Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of SPRYCEL. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store SPRYCEL? • Store SPRYCEL at room temperature, between 68°F to 77°F (20°C to 25°C). • Ask your healthcare provider or pharmacist about the right way to throw away outdated or unused SPRYCEL. • Women who are pregnant should not handle crushed or broken SPRYCEL tablets. • Keep SPRYCEL and all medicines out of the reach of children and pets. General information about SPRYCEL Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use SPRYCEL for a condition for which it is not prescribed. Do not give SPRYCEL to other people even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about SPRYCEL. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about SPRYCEL that is written for healthcare professionals. For more information, go to www.sprycel.com or call 1-800-332-2056. What are the ingredients in SPRYCEL? Active ingredient: dasatinib Inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol.

This Patient Package Insert has been approved by the U.S. Food and Drug Administration. Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA Product of Ireland

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