Herceptin in combination with Taxotere and carboplatin (TCH), a nonanthracycline regimen, significantly improved disease-free survival (DFS) vs AC T 1

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1 In the adjuvant treatment of HER2+ breast cancer Herceptin in combination with Taxotere and carboplatin (TCH), a nonanthracycline regimen, significantly improved disease-free survival (DFS) vs AC T 1 Adjuvant indications Herceptin is indicated for adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature*) breast cancer: As part of a treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel With docetaxel and carboplatin As a single agent following multi-modality anthracycline-based therapy Metastatic indications Herceptin is indicated: In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease *High-risk features for patients with ER/PR+ breast cancer include: tumor size >2 cm, age <35 years, and histologic and/or nuclear grade 2/3. Please see accompanying brief summary of full Prescribing Information, including Boxed WARNINGS and additional important safety information, on the following pages. 29 Genentech USA, Inc. So. San Francisco, CA All rights reserved /9

2 TCH demonstrated DFS benefit consistent with AC TH 1 DFSat3years 1,2 1. Absolute DFS at3years % (TCH) 88.% (AC TH) 82.3% (AC T).6 TCH vs AC T HR=.67 (95% CI: ).4 P=.6 AC TH vs AC T.2 HR=.6 T (n=173) (95% CI: ) AC TH (n=174) P<.1 TCH (n=175) DFS (years) Number at risk AC T AC TH TCH Proportion event-free AC=doxorubicin/cyclophosphamide T=Taxotere C=carboplatin H=Herceptin 33% reduction in risk of recurrence with TCH (HR=.67, CI: ; P=.6) 4% reduction in risk of recurrence with AC TH (HR=.6, CI: ; P<.1) Reduced risk of congestive heart failure with TCH vs AC TH 1.4% (TCH) vs 2% (AC TH) and.3% (AC T) Boxed WARNINGS and Additional Important Safety Information Herceptin administration can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure and decreased left ventricular ejection fraction. Serious infusion reactions and pulmonary toxicity have occurred; fatal infusion reactions have been reported. Exacerbation of chemotherapy-induced neutropenia has also occurred. Herceptin can cause oligohydramnios and fetal harm when administered to a pregnant woman. The most common adverse reactions associated with Herceptin use were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Taxotere is a registered trademark of sanofi-aventis U.S. LLC. BCIRG 6 study design: Conducted by the Breast Cancer International Research Group (BCIRG), this clinical trial evaluated the efficacy and cardiac safety of two regimens vs control in a 1:1:1 randomization. The TCH arm consisted of concurrent docetaxel, carboplatin, and Herceptin and the AC TH arm consisted of AC (doxorubicin and cyclophosphamide), followed by docetaxel and Herceptin. Control did not include Herceptin. Hormonal and/or radiotherapy were given as appropriate. HR=hazard ratio; CI= confidence interval. References: 1. Herceptin Prescribing Information. Genentech, Inc. March Data on file. Genentech, Inc.

3 Indication ONSOLIS is indicated only for the management of breakthrough pain in patients with cancer, 18 years of age and older, who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least: 6 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 3 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer. WARNINGS: IMPORTANCE OF PROPER PATIENT SELECTION and POTENTIAL FOR ABUSE ONSOLIS contains fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. This should be considered when prescribing or dispensing ONSOLIS in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Schedule II opioid substances, which include morphine, oxycodone, hydromorphone, oxymorphone, and methadone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Serious adverse events, including deaths, in patients treated with other oral transmucosal fentanyl products have been reported. Deaths occurred as a result of improper patient selection (e.g., use in opioid non-tolerant patients) and/or improper dosing. The substitution of ONSOLIS for any other fentanyl product may result in fatal overdose. ONSOLIS is indicated only for the management of breakthrough pain in patients with cancer, 18 years of age and older, who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least: 6 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 3 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer. ONSOLIS is contraindicated for use in opioid non-tolerant patients including those using opioids intermittently, on an as needed basis. ONSOLIS is contraindicated in the management of acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency room. Life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients. Deaths have occurred in opioid non-tolerant patients treated with other fentanyl products. When prescribing, do not convert patients on a mcg per mcg basis from any other oral transmucosal fentanyl product to ONSOLIS. Patients beginning treatment with ONSOLIS must begin with titration from the 2 mcg dose [see Dosage and Administration (2)]. When dispensing, do not substitute an ONSOLIS prescription for any other fentanyl product. Substantial differences exist in the pharmacokinetic profile of ONSOLIS compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl. As a result of these differences, the substitution of ONSOLIS for any other fentanyl product may result in fatal overdose. Special care must be used when dosing ONSOLIS. If the breakthrough pain episode is not relieved, patients should wait at least 2 hours before taking another dose [see Dosage and Administration (2)]. ONSOLIS is intended to be used only in the care of opioid tolerant patients with cancer and only by healthcare professionals who are knowledgeable of, and skilled in, the use of Schedule II opioids to treat cancer pain. Patients and their caregivers must be instructed that ONSOLIS contains a medicine in an amount which can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. All ONSOLIS films must be kept out of the reach of children [see Patient Counseling Information (17)]. The concomitant use of ONSOLIS with CYP3A4 inhibitors may result in an increase in fentanyl plasma concentrations and may cause potentially fatal respiratory depression [see Drug Interactions (7)]. Because of the risk for misuse, abuse, and overdose, ONSOLIS is available only through a restricted distribution program, called the FOCUS Program. Under the FOCUS Program, only prescribers, pharmacies, and patients registered with the program are able to prescribe, dispense, and receive ONSOLIS. To enroll in the FOCUS Program, call ( ONSOLIS) or visit [see Warnings and Precautions (5.3.1)]. Important Safety Information The most serious adverse reactions associated with all opioids including ONSOLIS are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. Follow all patients for symptoms of respiratory depression In ONSOLIS trials, the most common adverse events (frequency 1%) were nausea, vomiting, dizziness, anemia, dehydration, peripheral edema, dyspnea, and somnolence Please see Boxed Warning and brief summary of Prescribing Information on adjacent pages. 1. Onsolis [package insert]. Somerset, NJ: Meda Pharmaceuticals Inc.; MEDA Pharmaceuticals Inc. All rights reserved. Printed in the USA. 1/9 BEM964

4 Introducing Onsolis Unique Delivery System A fentanyl buccal delivery system now approved for the management of breakthrough pain in opioid-tolerant adult patients with cancer. 1 2 mcg 4 mcg 6 mcg 8 mcg 12 mcg Thin (.26 mm) soluble film shown actual size All patients MUST begin treatment using one 2-mcg film Do not switch patients on a mcg per mcg basis from any other oral transmucosal fentanyl product to Onsolis New

5 ONSOLIS (fentanyl buccal soluble film), CII Brief Summary: Please see full prescribing information. PHYSICIANS AND OTHER HEALTHCARE PROVIDERS MUST BECOME FAMILIAR WITH THE IMPORTANT WARNINGS IN THIS LABEL. WARNINGS: IMPORTANCE OF PROPER PATIENT SELECTION and POTENTIAL FOR ABUSE ONSOLIS contains fentanyl, an opioid agonist and a Schedule II controlled substance, with abuse liability similar to other opioid analgesics. This should be considered when prescribing or dispensing ONSOLIS in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Schedule II opioid substances, which include morphine, oxycodone, hydromorphone, oxymorphone, and methadone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Serious adverse events, including deaths, in patients treated with other oral transmucosal fentanyl products have been reported. Deaths occurred as a result of improper patient selection (e.g., use in opioid non-tolerant patients) and/or improper dosing. The substitution of ONSOLIS for any other fentanyl product may result in fatal overdose. ONSOLIS is indicated only for the management of breakthrough pain in patients with cancer, 18 years of age and older, who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least: 6 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 3 mg of oral oxycodone/ day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer. ONSOLIS is contraindicated for use in opioid non-tolerant patients including those using opioids intermittently, on an as needed basis. ONSOLIS is contraindicated in the management of acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency room. Life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients. Deaths have occurred in opioid non-tolerant patients treated with other fentanyl products. When prescribing, do not convert patients on a mcg per mcg basis from any other oral transmucosal fentanyl product to ONSOLIS. Patients beginning treatment with ONSOLIS must begin with titration from the 2 mcg dose [see Dosage and Administration (2)]. When dispensing, do not substitute an ONSOLIS prescription for any other fentanyl product. Substantial differences exist in the pharmacokinetic profile of ONSOLIS compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl. As a result of these differences, the substitution of ONSOLIS for any other fentanyl product may result in fatal overdose. Special care must be used when dosing ONSOLIS. If the breakthrough pain episode is not relieved, patients should wait at least 2 hours before taking another dose [see Dosage and Administration (2)]. ONSOLIS is intended to be used only in the care of opioid tolerant patients with cancer and only by healthcare professionals who are knowledgeable of, and skilled in, the use of Schedule II opioids to treat cancer pain. Patients and their caregivers must be instructed that ONSOLIS contains a medicine in an amount which can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. All ONSOLIS films must be kept out of the reach of children [see Patient Counseling Information (17)]. The concomitant use of ONSOLIS with CYP3A4 inhibitors may result in an increase in fentanyl plasma concentrations and may cause potentially fatal respiratory depression [see Drug Interactions (7)]. Because of the risk for misuse, abuse, and overdose, ONSOLIS is available only through a restricted distribution program, called the FOCUS Program. Under the FOCUS Program, only prescribers, pharmacies, and patients registered with the program are able to prescribe, dispense, and receive ONSOLIS. To enroll in the FOCUS Program, call ( ONSOLIS) or visit [see Warnings and Precautions (5.3.1)]. INDICATIONS AND USAGE ONSOLIS (fentanyl buccal soluble film) is an opioid analgesic indicated only for the management of breakthrough pain in patients with cancer, 18 years of age and older, who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least: 6 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 3 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer. This product must not be used in opioid non-tolerant patients because life-threatening respiratory depression could occur in patients not taking chronic opiates. For this reason, ONSOLIS is contraindicated in the management of acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency room. ONSOLIS is intended to be used only in the care of opioid tolerant patients with cancer and only by healthcare professionals who are knowledgeable of, and skilled in, the use of Schedule II opioids to treat cancer pain. CONTRAINDICATIONS Because life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients, ONSOLIS is contraindicated in the management of acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency room. This product must not be used in opioid non-tolerant patients. Patients considered opioid tolerant are those who are taking at least: 6 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 3 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for a week or longer. ONSOLIS is contraindicated in patients with known intolerance or hypersensitivity to any of its components or the drug fentanyl. Anaphylaxis and hypersensitivity have been reported in association with the use of other oral transmucosal fentanyl products. DOSAGE AND ADmINISTRATION As with all opioids, the safety of patients using such products is dependent on healthcare professionals prescribing them in strict conformity with their approved labeling with respect to patient selection, dosing, and proper conditions for use. Only prescribers enrolled in the FOCUS Program may prescribe ONSOLIS [see Warnings and Precautions (5.3.1)]. Dose Titration The goal of dose titration is to find the individual patient s effective and tolerable dose. The dose of ONSOLIS is not predicted from the daily maintenance dose of opioid used to manage the persistent cancer pain and MUST be determined by dose titration. Starting Dose: Individually titrate ONSOLIS to a dose that provides adequate analgesia with tolerable side effects. All patients MUST begin treatment using one 2 mcg ONSOLIS film. Due to differences in pharmacokinetic properties and individual variability, patients switching from another oral transmucosal fentanyl product must be started on no greater than 2 mcg of ONSOLIS. When prescribing, do not switch patients on a mcg per mcg basis from any other oral transmucosal fentanyl product to ONSOLIS as ONSOLIS is not equivalent on a mcg per mcg basis with any other fentanyl product. ONSOLIS is NOT a generic version of any other oral transmucosal fentanyl product. From the initial dose, closely follow patients and change the dosage level until the patient reaches a dose that provides adequate analgesia. If adequate pain relief is not achieved after one 2 mcg ONSOLIS film, titrate using multiples of the 2 mcg ONSOLIS film (for doses of 4, 6, or 8 mcg). Increase the dose by 2 mcg in each subsequent episode until the patient reaches a dose that provides adequate analgesia with tolerable side effects. Do not use more than four of the 2 mcg ONSOLIS films simultaneously. When multiple 2 mcg ONSOLIS films are used, they should not be placed on top of each other and may be placed on both sides of the mouth. If adequate pain relief is not achieved after 8 mcg ONSOLIS (i.e., four 2 mcg ONSOLIS films), and the patient has tolerated the 8 mcg dose, treat the next episode by using one 12 mcg ONSOLIS film. Doses above 12 mcg ONSOLIS should not be used. Once adequate pain relief is achieved with a dose between 2 and 8 mcg ONSOLIS, the patient should use or safely dispose of all remaining 2 mcg ONSOLIS films [see Disposal of ONSOLIS (16.2)]. Patients who require 12 mcg ONSOLIS, should dispose of all remaining unused 2 mcg ONSOLIS films [see Disposal of ONSOLIS (16.2)]. The patient should then get a prescription for ONSOLIS films of the dose determined by titration (i.e., 2, 4, 6, 8, or 12 mcg) to treat subsequent episodes. Single doses should be separated by at least 2 hours. ONSOLIS should only be used once per breakthrough cancer pain episode, i.e., ONSOLIS should not be redosed within an episode. During any episode of breakthrough cancer pain, if adequate pain relief is not achieved after ONSOLIS, the patient may use a rescue medication (after 3 minutes) as directed by their healthcare provider. Dose Titration ONSOLIS is available in five dosage strengths: 2, 4, 6, 8, and 12 mcg The initial dose is 2 mcg ONSOLIS Titrate by incrementally increasing the dose once per episode Fentanyl dose 2 mcg 4 mcg 6 mcg 8 mcg 12 mcg 12 mcg Using 2 mcg ONSOLIS film(s) ONSOLIS film Using If adequate pain relief is achieved, treat subsequent breakthrough cancer pain episodes using the determined dose. ONSOLIS should only be used once per episode. ONSOLIS dosing should be separated by at least 2 hours. During any episode, if adequate pain relief is not achieved within 3 minutes, the patient may use a rescue medication as directed. Dosage Adjustment During maintenance treatment, if the prescribed dose no longer adequately manages the breakthrough cancer pain episode for several consecutive episodes, increase the dose of ONSOLIS as described in Dose Titration (2.1). Once a successful dose has been found, each episode is treated with a single film. ONSOLIS should be limited to four or fewer doses per day. Consider increasing the dose of the around-the-clock opioid medicine used for persistent cancer pain in patients experiencing more than four breakthrough cancer pain episodes daily. Administration of ONSOLIS Use the tongue to wet the inside of the cheek or rinse the mouth with water to wet the area for placement of ONSOLIS. Open the ONSOLIS package immediately prior to product use. Place the entire ONSOLIS film near the tip of a dry finger with the pink side facing up and hold in place. Place the pink side of the ONSOLIS film against the inside of the cheek. Press and hold the ONSOLIS film in place for 5 seconds. The ONSOLIS film should stay in place on its own after this period. Liquids may be consumed after 5 minutes. An ONSOLIS film, if chewed and swallowed, might result in lower peak concentrations and lower bioavailability than when used as directed [see Clinical Pharmacology Pharmacokinetics (12.3)]. The ONSOLIS film should not be cut or torn prior to use. The ONSOLIS film will dissolve within 15 to 3 minutes after application. The film should not be manipulated with the tongue or finger(s) and eating food should be avoided until the film has dissolved. WARNINGS AND PRECAUTIONS See Boxed Warning - WARNINGS: IMPORTANCE OF PROPER PATIENT SELECTION and POTENTIAL FOR ABUSE Respiratory Depression (Hypoventilation) Respiratory depression is the chief hazard of opioid agonists, including fentanyl, the active ingredient in ONSOLIS. Respiratory depression is more likely to occur in patients with underlying respiratory disorders and elderly or debilitated patients, usually following large initial doses in opioid non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the sighing pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous. Patient/Caregiver Instructions Patients and their caregivers must be instructed that ONSOLIS contains a medicine in an amount which can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid-tolerant. Patients and their caregivers must be instructed to keep ONSOLIS out of the reach of children. [see How Supplied (16.3), Storage and Handling (16.1), and Patient Counseling Information (17)]. Physicians and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure. ONSOLIS Dispensing When dispensing, do not substitute an ONSOLIS prescription for any other fentanyl product. Substantial differences exist in the pharmacokinetic profile of ONSOLIS compared to other fentanyl products (e.g., see Figure 1) that result in clinically important differences in the extent of absorption of fentanyl. As a result of these differences, the substitution of ONSOLIS for any other fentanyl product may result in fatal overdose. ONSOLIS is NOT a generic version of any other transmucosal fentanyl product.

6 ONSOLIS Distribution Program ONSOLIS is available only through a restricted distribution program called the FOCUS Program. Under the FOCUS Program, only prescribers, pharmacies, and patients registered with the program are able to prescribe, dispense, and receive ONSOLIS. This program provides educational materials, patient counseling and facilitated distribution of the drug. To enroll in the FOCUS Program, call ( ONSOLIS) or visit Prescribers and patients are required to understand the risks of therapy with ONSOLIS. Prescribers are required to understand the information in the prescribing information and to: Ensure proper patient selection, including that the patient is opioid tolerant Educate patients about the benefits and risks of treatment with ONSOLIS and ensure that the patient receives the Medication Guide Complete the FOCUS Program prescriber enrollment form; sign and fax the form to the FOCUS Program Obtain the patient s signature on the patient enrollment form; sign and fax the form to the FOCUS Program Follow FOCUS Program-specific procedures for prescribing ONSOLIS using a courier Additive CNS Depressant Effects The concomitant use of ONSOLIS with other CNS depressants, including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, and alcoholic beverages may produce increased depressant effects (e.g., hypoventilation, hypotension, and profound sedation). Concomitant use with inhibitors of the cytochrome P45 3A4 (CYP3A4) isoform (e.g., erythromycin, ketoconazole, and certain protease inhibitors) may increase fentanyl levels, resulting in increased depressant effects [see Drug Interactions (7)]. Patients on concomitant CNS depressants must be monitored for a change in opioid effects. Consideration should be given to adjusting the dose of ONSOLIS if warranted. Effects on Ability to Drive and Use Machines Opioid analgesics impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Warn patients taking ONSOLIS of these dangers and counsel them accordingly. Chronic Pulmonary Disease Because potent opioids can cause respiratory depression, titrate ONSOLIS with caution in patients with chronic obstructive pulmonary disease or pre-existing medical conditions predisposing them to hypoventilation. In such patients, even normal therapeutic doses of ONSOLIS may further decrease respiratory drive to the point of respiratory failure. Head Injuries and Increased Intracranial Pressure Administer ONSOLIS with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO 2 retention such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury and should be used only if clinically warranted. Cardiac Disease Intravenous fentanyl may produce bradycardia. Therefore, use ONSOLIS with caution in patients with bradyarrhythmias. MAO Inhibitors ONSOLIS is not recommended for use in patients who have received MAO inhibitors within 14 days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. ADVERSE REACTIONS Clinical Studies Experience The safety of ONSOLIS has been evaluated in 36 opioid tolerant patients with breakthrough cancer pain in the efficacy study and an open-label safety study. The mean duration of therapy was 115 days, with 32 patients treated for more than 1 year. The adverse reactions seen with ONSOLIS are typical opioid side effects in a population with cancer. Frequently, opioid-associated adverse reactions will cease or decrease in intensity with continued use of ONSOLIS. Expect opioid side effects and manage them accordingly. The most serious adverse reactions associated with all opioids including ONSOLIS are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. Follow all patients for symptoms of respiratory depression. Because the clinical trials of ONSOLIS were designed to evaluate safety and efficacy in treating patients with breakthrough pain associated with cancer, all patients were also taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone or transdermal fentanyl, for their persistent cancer pain. The adverse event data presented here reflect the actual percentage of patients experiencing each adverse event among patients who received ONSOLIS for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain. There has been no attempt to correct for concomitant use of other opioids, duration of ONSOLIS therapy, or cancer-related symptoms. Adverse reactions are included regardless of severity. Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Table 1 lists, by maximum dose received, adverse reactions with an overall frequency of 5% or greater that occurred during titration. The ability to assign a dose-response relationship to these adverse reactions is limited by the titration schedules used in these studies. Adverse reactions are listed in descending order of frequency within each body system. Table 1 Adverse Reactions Which Occurred During Titration at a Frequency of 5% System Organ Class, Preferred Term, n (%) 2 (N=33) Gastrointestinal Disorders 4 (N=257) ONSOLIS Dose (mcg) 6 (N=27) 8 (N=138) 12 (N=79) >12 (N=9) Total (N=36) Nausea 16 (5) 12 (5) 6 (3) 5 (4) 4 (5) 42 (14) Vomiting 7 (2) 9 (4) 8 (4) 2 (1) 26 (8) Nervous System Disorders Dizziness 5 (2) 5 (2) 6 (3) 2 (1) 4 (5) 22 (7) Somnolence 6 (2) 2 (1) 4 (2) 2 (1) 4 (5) 1 (11) 17 (6) Table 2 lists, by successful dose, adverse reactions with an overall frequency of 5% that occurred during long-term treatment (i.e., the double-blind or open-label maintenance periods). Table 2 Adverse Reactions Which Occurred During Long-Term Treatment at a Frequency of 5% System Organ Class, Preferred Term, n (%) 2 (N=23) 4 (N=59) 6 (N=79) ONSOLIS Dose (mcg) 8 (N=91) 12 (N=81) >12 (N=28) Total (N=213) Gastrointestinal Nausea 2 (9) 6 (1) 8 (1) 12 (13) 26 (32) 4 (14) 56 (26) Vomiting 1 (4) 5 (8) 9 (11) 8 (9) 23 (28) 3 (11) 45 (21) Constipation 2 (9) 4 (7) 4 (5) 4 (4) 6 (7) 4 (14) 23 (11) Diarrhea 1 (4) 1 (2) 4 (5) 4 (4) 1 (12) 19 (9) Dry mouth 1 (4) 4 (7) 3 (4) 2 (2) 3 (4) 1 (4) 14 (7) Abdominal pain 3 (4) 1 (1) 7 (9) 1 (4) 11 (5) General/administration site Asthenia 6 (1) 3 (4) 8 (9) 7 (9) 4 (14) 28 (13) Fatigue 2 (9) 6 (1) 1 (1) 7 (8) 7 (9) 3 (11) 25 (12) Investigations Weight decreased 3 (13) 2 (3) 5 (5) 5 (6) 1 (4) 15 (7) Metabolism/nutrition Dehydration 1 (4) 4 (7) 6 (8) 5 (5) 1 (12) 3 (11) 28 (13) Decreased appetite 4 (7) 4 (5) 6 (7) 2 (2) 2 (7) 18 (8) Anorexia 2 (9) 1 (2) 3 (4) 4 (4) 6 (7) 1 (4) 17 (8) Nervous system Dizziness 2 (9) 4 (7) 2 (3) 3 (3) 1 (12) 2 (7) 23 (11) Headache 2 (9) 1 (2) 3 (4) 9 (1) 7 (9) 2 (9) Somnolence 2 (9) 4 (5) 2 (2) 3 (4) 3 (11) 14 (7) Psychiatric Confusional state 1 (4) 4 (5) 4 (4) 6 (7) 4 (14) 18 (8) Depression 3 (5) 1 (1) 4 (4) 7 (9) 3 (11) 18 (8) Insomnia 2 (3) 2 (3) 3 (3) 4 (5) 2 (7) 12 (6) Anxiety 1 (4) 1 (2) 2 (3) 3 (3) 3 (4) 1 (4) 11 (5) Respiratory Dyspnea 3 (13) 4 (7) 3 (4) 8 (9) 6 (7) 3 (11) 26 (12) Cough 1 (4) 3 (4) 5 (5) 6 (7) 1 (4) 15 (7) Vascular Hypotension 3 (5) 3 (4) 1 (1) 3 (4) 1 (4) 11 (5) In a mucositis study, a group of patients (n=7) with Grade 1 oral mucositis and a matched group of control patients (n=7) without oral mucositis were included in a clinical trial designed to support the safety of ONSOLIS. The adverse event profile was similar in both subsets of patients. There was no evidence that ONSOLIS caused or worsened oral mucosal irritation or pain in either study group. The duration of exposure to ONSOLIS varied greatly, and included open-label and double-blind studies. The adverse reactions listed below represent those that were reported by 1% of patients from two clinical trials (the titration and post-titration periods) while receiving ONSOLIS. Events are classified by system organ class. Cardiac disorders: tachycardia Eye disorders: vision blurred, diplopia Gastrointestinal disorders: nausea, vomiting, constipation, diarrhea, dry mouth, abdominal pain, dyspepsia, dysphagia, abdominal distension, intestinal obstruction, flatulence General disorders and administration site conditions: asthenia, fatigue, malaise Injury, poisoning and procedural complications: fall, contusion Investigations: weight decreased, blood pressure increased Metabolism and nutrition disorders: dehydration, decreased appetite, anorexia Nervous system disorders: dizziness, somnolence, headache, lethargy, amnesia, sedation Psychiatric disorders: confusional state, depression, insomnia, anxiety, hallucination, agitation, mental status changes Renal and urinary disorders: urinary retention Respiratory, thoracic and mediastinal disorders: dyspnea, cough Skin and subcutaneous tissue disorders: pruritus, rash Vascular disorders: hypotension, hot flush, deep vein thrombosis, hypertension DRUG INTERACTIONS Fentanyl is metabolized mainly via the human CYP3A4 isoenzyme system; therefore potential interactions may occur when ONSOLIS is given concurrently with agents that affect CYP3A4 activity. The concomitant use of ONSOLIS with CYP3A4 inhibitors (e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, telithromycin, aprepitant, diltiazem, erythromycin, fluconazole, grapefruit juice, verapamil, or cimetidine) may result in a potentially dangerous increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving ONSOLIS who begin therapy with, or increase the dose of, CYP3A4 inhibitors should be carefully monitored for signs of opioid toxicity over an extended period of time. Dosage increase should be done conservatively [see Warnings and Precautions (5.4)]. The concomitant use of ONSOLIS with CYP3A4 inducers (e.g., barbiturates, carbamazepine, efavirenz, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John s wort, or troglitazone) may result in a decrease in fentanyl plasma concentrations, which could decrease the efficacy of ONSOLIS. Patients receiving ONSOLIS who stop therapy with, or decrease the dose of, CYP3A4 inducers should be monitored for signs of decreased ONSOLIS activity and the dose of ONSOLIS should be adjusted accordingly.

7 USE IN SPECIFIC POPULATIONS Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. ONSOLIS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported. Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures in newborn infants characteristic of neonatal abstinence syndrome. In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. Fentanyl is embryocidal in rats as evidenced by increased resorptions in pregnant rats at doses of 3 mcg/ kg IV or 16 mcg/kg SC. Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for ONSOLIS. Fentanyl citrate was not teratogenic when administered to pregnant animals. In published studies, pregnant rats were treated with fentanyl (1, 1, or 5 mcg/kg/day) via implanted microosmotic minipumps from Day 7 to 21 of their 21 day gestation period. Fentanyl was not teratogenic at doses up to 5 mcg/kg/day [approximately 3-times the maximum recommended human dose (MRHD) of 12 mcg for ONSOLIS per breakthrough cancer pain episode]. Intravenous administration of fentanyl (1 or 3 mcg/kg) to pregnant female rats from gestation Day 6 to 18, was embryo or fetal toxic, and caused a slightly increased mean delivery time in the 3 mcg/kg/day group, but was not teratogenic Labor and Delivery Fentanyl readily passes across the placenta to the fetus; therefore, use of ONSOLIS during labor and delivery is not recommended. Nursing Mothers Fentanyl is excreted in human milk; therefore, ONSOLIS should not be used in nursing women because of the possibility of sedation and/or respiratory depression in their infants. Symptoms of opioid withdrawal may occur in infants at the cessation of nursing by women using ONSOLIS. Pediatric Use Safety and efficacy in pediatric patients below the age of 18 years have not been established. Geriatric Use Of the 36 opioid tolerant patients with breakthrough cancer pain in clinical studies of ONSOLIS, 98 (32.%) were 65 years of age and older. There was no difference in the median titrated dose in patients aged 65 years and older compared to those <65 years. No clinically meaningful difference was noted in the safety profile of the group 65 years of age and older as compared to younger patients in ONSOLIS clinical trials. Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously compared with the younger population. Therefore, exercise caution when individually titrating ONSOLIS in elderly patients to provide adequate efficacy while minimizing risk. Patients with Renal or Hepatic Impairment Insufficient information exists to make recommendations regarding the use of ONSOLIS in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via the human CYP3A4 isoenzyme system and the inactive metabolite is mostly eliminated in urine. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl. It is recommended that ONSOLIS be titrated to clinical effect for all patients with special care taken in patients with severe renal or hepatic disease. Gender Both male and female opioid tolerant patients with cancer were studied for the treatment of breakthrough cancer pain. No clinically relevant gender differences were noted either in dosage requirement or in observed adverse reactions. DRUG ABUSE AND DEPENDENCE Controlled Substance Fentanyl is a Schedule II controlled substance that can produce drug dependence of the morphine type. ONSOLIS may be subject to misuse, abuse and addiction. Abuse and Addiction Manage the handling of ONSOLIS to minimize the risk of abuse, including restriction of access and accounting procedures as appropriate to the clinical setting and as required by law [see How Supplied (16.3) and Storage and Handling (16.1)]. Concerns about abuse and addiction should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. Drug-seeking behavior is very common in addicts and drug abusers. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of addiction and is characterized by misuse for nonmedical purposes, often in combination with other psychoactive substances. Since ONSOLIS may be abused for non-medical use, careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of patients, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse of this product. Dependence Guide the administration of ONSOLIS by the response of the patient. Physical dependence is not ordinarily a concern when one is treating a patient with chronic cancer pain, and fear of tolerance and physical dependence should not deter using doses that adequately relieve the pain. Opioid analgesics may cause physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, buprenorphine, nalbuphine). Physical dependence usually does not occur to a clinically significant degree until after several weeks of continued opioid usage. Tolerance, in which increasingly larger doses are required in order to produce the same degree of analgesia, is initially manifested by a shortened duration of analgesic effect, and subsequently, by decreases in the intensity of analgesia. OVERDOSAGE Clinical Presentation The manifestations of ONSOLIS overdosage are expected to be similar in nature to intravenous fentanyl and other opioids, and are an extension of its pharmacological actions with the most serious significant effect being hypoventilation [see Clinical Pharmacology Pharmacodynamics (12.2)]. Immediate Management Immediate management of opioid overdose includes removal of the ONSOLIS film, if still in the mouth, ensuring a patent airway, physical and verbal stimulation of the patient, and assessment of level of consciousness, ventilatory and circulatory status. Treatment of Overdosage (Accidental Ingestion) in the Opioid NON-Tolerant Person Provide ventilatory support, obtain intravenous access, and employ naloxone or other opioid antagonists as clinically indicated. The duration of respiratory depression following overdose may be longer than the effects of the opioid antagonist s action (e.g., the half-life of naloxone ranges from 3 to 81 minutes) and repeated administration may be necessary. Consult the package insert of the individual opioid antagonist for details about such use. Treatment of Overdose in Opioid Tolerant Patients Provide ventilatory support and obtain intravenous access as clinically indicated. Judicious use of naloxone or another opioid antagonist may be warranted in some instances, but it is associated with the risk of precipitating an acute withdrawal syndrome. General Considerations for Overdose Management of severe ONSOLIS overdose includes: securing a patent airway, assisting or controlling ventilation, establishing intravenous access, and GI decontamination by lavage and/or activated charcoal, once the patient s airway is secure. In the presence of hypoventilation or apnea, assist or control ventilation, and administer oxygen as indicated. Although muscle rigidity interfering with respiration has not been seen following the use of ONSOLIS, this is possible with fentanyl and other opioids. If it occurs, manage by the use of assisted or controlled ventilation, by the administration of an opioid antagonist, and, as a final alternative, by the administration of a neuromuscular blocking agent. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of fentanyl. Fentanyl citrate was not mutagenic in the in vitro Ames reverse mutation assay in S. typhimurium or E. coli or the mouse lymphoma mutagenesis assay, and was not clastogenic in the in vivo mouse micronucleus assay. Fentanyl has been shown to impair fertility in rats at doses of 3 mcg/kg IV and 16 mcg/kg subcutaneously. Conversion to the human equivalent doses indicates that this is within the range of the human recommended dosing for ONSOLIS. PATIENT COUNSELING INFORmATION See Medication Guide (17.3) for specific patient instructions. Patient/Caregiver Instructions Patients will need to be enrolled in the FOCUS Program to receive ONSOLIS. The patient will receive their prescription via a traceable courier (with proof of delivery and adult signature required). The patient will receive a counseling call at the time of the first prescription to verify that they are opioid tolerant and discuss how to use the drug. Provide patients and their caregivers with a Medication Guide for ONSOLIS (17.3). Patients and their caregivers must be instructed that ONSOLIS contains medicine in an amount which can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. Patients and their caregivers must be instructed to keep ONSOLIS out of the reach of children. Patients and members of their household must be instructed to dispose of any unneeded films remaining from a prescription as soon as possible [see How Supplied (16.3) and Storage and Handling (16.1)]. Physicians and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure. Disposal of Unneeded ONSOLIS Films Patients and members of their household must be instructed on the safe disposal of any unneeded films remaining from a prescription as soon as they are no longer needed. To dispose of the unneeded ONSOLIS films: 1. Remove the ONSOLIS film from its foil package. 2. Drop the ONSOLIS film into the toilet. 3. Repeat steps 1 and 2 for each ONSOLIS film. Flush the toilet after all unneeded films have been put into the toilet. Do not flush the ONSOLIS foil packages or cartons down the toilet [see How Supplied (16.3) and Storage and Handling (16.1)]. Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of ONSOLIS are provided in the Medication Guide (17.3). Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered. In the event that a caregiver requires additional assistance in disposing of excess unneeded films that remain in the home after a patient has expired, instruct them to call Meda Pharmaceuticals Inc. at or seek assistance from their local Drug Enforcement Agency (DEA) office. MEDA Pharmaceuticals MEDA Pharmaceuticals Inc. Somerset, NJ 8873 ONSOLIS is a registered trademark of Meda Pharmaceuticals Inc

8 29 Genentech USA, Inc. All rights reserved Printed in USA.

9 A deeper exploration uncovering new opportunities in oncology At Genentech BioOncology, we re leading the fi ght against cancer with innovative science. We believe that great science and the right people can lead to significant advances in cancer treatment. Dedicated scientists Our researchers are dedicated to defi ning the molecular basis of cancer and developing groundbreaking treatments. Gold standard clinical development We identify biomarkers and develop companion diagnostics wherever possible, with the goal of matching each patient with the most appropriate therapy. A commitment to patients We actively pursue ways to ensure patient access to therapeutics through a variety of patient support programs so healthcare providers can remain focused on patient care. Our goal is to fundamentally change the way cancer is treated not just with incremental advances, but with new standards of care.

10 Updated Labeling FDA Approved Please visit to view full Prescribing Information, or call toll-free Bristol-Myers Squibb Printed in U.S.A. 729US9AB715 6/9

11 For The Fight Against cutaneous T-cell lymphoma (CTCL) TM ONTAKTICAL TREATMENT ONTAK is indicated for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the IL 2 receptor. Please see inside spread for Boxed WARNINGS and additional Important Safety Information. PROVEN PERFORMANCE DENILEUKIN DIFTITOX INCLUDED IN THE MF/SS NCCN GUIDELINES FOR APPROVED INDICATION. 1

12 ONTAK PROVEN PERFORMANCE IN THE FIGHT AGAINST CTCL EXHIBITED SIGNIFICANT EFFICACY STUDY 1: OBJECTIVE RESPONSE RATE (ORR) * ALL STAGES 2 STUDY 2: OVERALL RESPONSE (OR) ALL STAGES 2 STUDY 2: OVERALL RESPONSE ADVANCED STAGES 4 (P=.2) 46% (P=.3) 36% (n=36) 38% (n=24) 37% CR +CCR 11% 23% (n=35) CR +CCR 13% 15% PR II 25% CR +CCR 9% PR II 14% PR II 25% 1% (n=21) PR II 1% 18 mcg/kg/day (n=55) 9 mcg/kg/day (n=45) ORR for all ONTAK patients dosed 18 mcg/kg/day or 9 mcg/kg/day was approximately 42% 3 67% of study patients stage IIA 2 Placebo (n=44) *Adjusted for disease stage and changes in randomization ratios. Logistic regression model adjusting for disease stage and changes in randomization ratios over the course of the study; comparisons relative to placebo. 18 mcg/kg/day dose 95% CI, 21%-54% STUDY 1 STUDY 2 9 mcg/kg/day dose 95% CI, 1%-4% All Stages P =NS 3% OR (CR+CCR+PR) for all stages (95% CI, 18%-41%) 2 Of the patients who responded, one-third were stage 1B (7/21, 33%) 4 63% of study patients IIB 18 mcg/kg/day dose 95% CI, 21%-54% Complete response: clinically and histologically clear of disease. Clinical complete response: no evidence of disease clinically, but histologic clearing not verified. II Partial response: 5% reduction in measured tumor burden. 9 mcg/kg/day dose 95% CI, 1%-4% Stage IIB, III, IVA P =.4 3 IMPORTANT SAFETY INFORMATION Study 2 Design 2,3 : A randomized, double-blind, phase III study evaluating doses of 18 or 9 mcg/kg/day of ONTAK in 71 patients with recurrent or persistent stage IB to IVA CTCL. Serious and fatal infusion reactions have been reported. Administer ONTAK in a facility equipped and staffed for cardiopulmonary resuscitation. Immediately stop and permanently discontinue ONTAK for serious infusion reactions. Capillary leak syndrome resulting in death has been reported. Monitor weight, edema, blood pressure and serum albumin levels prior to and during ONTAK treatment. Loss of visual acuity and color vision have been reported. Serious Infusion Reactions Infusion reactions, defined as symptoms occurring within 24 hours of infusion and resolving within 48 hours of the last infusion in that course, were reported in 7.5% of 234 ONTAK-treated patients across 3 clinical studies. Serious infusion reactions were reported in 8.1% of patients. There have been post-marketing reports of infusion reactions resulting in death. For patients completing at least 4 courses of ONTAK treatment in a placebo-controlled trial, the incidence of infusion reactions was lower in the third and fourth cycles as compared to the first and second cycles of ONTAK. Capillary Leak Syndrome Capillary leak syndrome was defined as the occurrence of at least 2 of the following 3 symptoms (hypotension, edema, serum albumin <3. g/dl) at any time during ONTAK therapy. These symptoms were not required to occur simultaneously to be characterized as capillary leak syndrome. As defined, capillary leak syndrome was reported in 32.5% (76/234) of ONTAKtreated patients in clinical studies; one-third required hospitalization or medical intervention to prevent hospitalization.there are post-marketing reports of capillary leak syndrome resulting in death. The onset of symptoms in patients with capillary leak syndrome may be delayed, occurring up to 2 weeks following infusion. Symptoms may persist or worsen after the cessation of ONTAK.

13 SIGNIFICANT PROGRESSION-FREE SURVIVAL DATA STUDY 1: REDUCTION IN RISK OF PROGRESSION OR DEATH: ONTAK VS PLACEBO % reduction in relative risk of disease progression or death Hazard ratio=.27 * (95% CI, ) 58% reduction in relative risk of disease progression or death Hazard ratio=.42 * (95% CI, ) 5 6 P= P= mcg/kg/day 9 mcg/kg/day *A Cox regression analysis stratified for randomization ratio and adjusted for disease stage predicted hazard ratios. Study 1 Design 2,3 : Efficacy and safety of ONTAK were evaluated in a double-blind, placebo-controlled, phase III trial of patients with stage IA to III CD25 (+) CTCL (N=144). Patients were randomized to receive, 9, or 18 mcg/kg/day of ONTAK via IV infusion, days 1-5 of each 21 day cycle, up to 8 cycles. Randomization was stratified by disease stage ( IIA or IIB) to ensure nearly equal distribution of the 3 treatments across both early and advanced stages of disease. MINIMAL MYELOSUPPRESSION ONTAK s side-effect profile shows minimal incidences of drug-related immunosuppression or hematologic toxicity 2,3 Minimal incidences of anemia, leukopenia, or thrombocytopenia PROVEN PERFORMANCE IMPORTANT SAFETY INFORMATION (CONTINUED) Regularly assess patients for weight gain, new onset or worsening edema and hypotension (including orthostatic changes). Monitor serum albumin levels prior to each course of therapy and more often as clinically indicated. Withhold ONTAK for serum albumin levels less than 3 g/dl. Loss of Vision Loss of visual acuity, usually with or without retinal pigment mottling has been reported following administration of ONTAK. Recovery was reported in some of the affected patients; however, most patients reported persistent visual impairment. Hepatobiliary Disorders Increase in ALT/AST from baseline occurred in 84% of ONTAK-treated patients. The majority of these elevations occurred during either the first or second cycle, resolved without medical intervention, and did not require discontinuation of ONTAK. Pregnancy and Lactation ONTAK should be given to a pregnant woman only if clearly needed and should not be used in women who are nursing. Most Common Adverse Reactions In clinical studies (n=234), the most common adverse reactions in ONTAK-treated patients ( 2%) were pyrexia, nausea, fatigue, rigors, vomiting, diarrhea, headache, peripheral edema, cough, dyspnea and pruritus. The most common serious adverse reactions were capillary leak syndrome (11.1%), infusion reactions (8.1%), and visual changes including loss of visual acuity (4%). ONTAK was discontinued in 28.2% (66/234) of patients due to adverse reactions. Please see Brief Summary on reverse including Boxed WARNINGS and additional Important Safety Information. References: 1. Non-Hodgkin s Lymphomas NCCN Clinical Practice Guidelines in Oncology (Version 2.29). 29 National Comprehensive Cancer Network, Inc. http// Accessed October 12, ONTAK [prescribing information]. Woodcliff Lake, NJ: Eisai Inc.; October Data on file. Eisai Inc., Woodcliff Lake, NJ. 4. Olsen E, Duvic M, Frankel A, et al. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol. 21;19(2):

14 Brief Summary of Prescribing Information WARNING: SERIOUS INFUSION REACTIONS, CAPILLARY LEAK SYNDROME AND LOSS OF VISUAL ACUITY. The following adverse reactions have been reported: Serious and fatal infusion reactions. Administer ONTAK in a facility equipped and staffed for cardiopulmonary resuscitation. Immediately stop and permanently discontinue ONTAK for serious infusion reactions. [see Warnings and Precautions]. Capillary leak syndrome resulting in death. Monitor weight, edema, blood pressure and serum albumin levels prior to and during ONTAK treatment. [see Warnings and Precautions]. Loss of visual acuity and color vision. [see Warnings and Precautions]. INDICATIONS AND USAGE ONTAK is indicated for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the IL-2 receptor. [see Warnings and Precautions]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Infusion Reactions: Infusion reactions, defined as symptoms occurring within 24 hours of infusion and resolving within 48 hours of the last infusion in that course, were reported in 7.5% (165/234) of ONTAK-treated patients across 3 clinical studies utilizing the approved doses and schedule. Serious infusion reactions were reported in 8.1% (19/234) of ONTAK-treated patients. There have been post-marketing reports of infusion reactions resulting in death. For patients completing at least 4 courses of ONTAK treatment in Study 1 [see Clinical Studies (14.1)], the incidence of infusion reactions was lower in the 3 rd and 4 th cycles as compared to the 1 st and 2 nd cycles of ONTAK. Resuscitative equipment should be available during ONTAK administration. Immediately stop and permanently discontinue ONTAK for serious infusion reactions. Capillary Leak Syndrome: Capillary leak syndrome was defined as the occurrence of at least 2 of the following 3 symptoms (hypotension, edema, serum albumin <3. g/dl) at any time during ONTAK therapy. These symptoms were not required to occur simultaneously to be characterized as capillary leak syndrome. As defined, capillary leak syndrome was reported in 32.5% (76/234) of ONTAK-treated patients. Among these 76 patients with capillary leak syndrome, one-third required hospitalization or medical intervention to prevent hospitalization. There have been post-marketing reports of capillary leak syndrome resulting in death. The onset of symptoms in patients with capillary leak syndrome may be delayed, occurring up to 2 weeks following infusion. Symptoms may persist or worsen after the cessation of ONTAK. Regularly assess patients for weight gain, new onset or worsening edema, hypotension (including orthostatic changes) and monitor serum albumin levels prior to the initiation of each course of therapy and more often as clinically indicated. Withhold ONTAK for serum albumin levels of less than 3. g/dl [see Warnings and Precautions]. Visual Loss: Loss of visual acuity, usually with loss of color vision, with or without retinal pigment mottling has been reported following administration of ONTAK. Recovery was reported in some of the affected patients; however, most patients reported persistent visual impairment. CD25 Tumor Expression and Evaluation: Confirm that the patient s malignant cells express CD25 prior to administration of ONTAK. A testing service for the assay of CD25 expression in tumor biopsy samples is available. For information on this service call Laboratory Monitoring/Hypoalbuminemia: Monitor serum albumin levels prior to the initiation of each treatment course. Withhold administration of ONTAK if serum albumin levels are less than 3. g/dl. [see Dosage and Administration and Warnings and Precautions]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Infusion Reactions [see Warnings and Precautions] Capillary Leak Syndrome [see Warnings and Precautions] Visual Loss [see Warnings and Precautions] CLINICAL STUDIES EXPERIENCE Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice. Safety data are available for 3 clinical studies in which 234 patients received ONTAK at 9 mcg/kg (n=8) or 18 mcg/kg (n=154) at the recommended schedule. Of these studies, one was placebo-controlled and dose-ranging (Study 1,1 ONTAK-treated patients), one was a dose-comparison of 9 and 18 mcg/kg (Study 2, n=71), and the third was a single-arm study using 18 mcg/kg (n=63); all studies were limited to adult patients with CTCL. The median age of patients across the clinical studies was 6 years (range years) and 36% (n=85) were 65 years of age or older; 55% were men and 85% were Caucasian. Across all 3 studies, the most common adverse reactions in ONTAK-treated patients ( 2%) were pyrexia, nausea, fatigue, rigors, vomiting, diarrhea, headache, peripheral edema, cough, dyspnea, and pruritus. The most common serious adverse reactions were capillary leak syndrome (11.1%), infusion reactions (8.1%), and visual changes including loss of visual acuity (4%). ONTAK was discontinued in 28.2% (66/234) of patients due to adverse reactions. The data described in Table 1 reflect exposure to ONTAK in 1 patients administered as a single agent at the recommended dosing schedule in the randomized placebo-controlled trial (Study 1). The median number of ONTAK cycles was 7 (range 1-1) for the 9 mcg/kg cohort and 6 (range 1-11) for the 18 mcg/kg cohort. The median age of patients was 59 years (range years) and 34% median age of patients was 59 years (range years) and 34% (n=34) were 65 years of age or older; 55% were men and 86% were Caucasian. Table 1: Incidence of Adverse Reactions Occurring in 1% of ONTAK-treated patients (18 mcg/kg group) and at a higher rate than Placebo in Study 1 MedDRA version 6.1 Preferred Term Placebo N=44 n (%) ONTAK 9 mcg/kg N=45 n (%) ONTAK 18 mcg/kg N=55 n (%) Pyrexia 7 (15.9) 22 (48.9) 35 (63.6) Nausea 1 (22.7) 21 (46.7) 33 (6.) Rigors 9 (2.5) 19 (42.2) 26 (47.3) Fatigue 14 (31.8) 21 (46.7) 24 (43.6) Vomiting 3 (6.8) 6 (13.3) 19 (34.5) Headache 8 (18.2) 13 (28.9) 14 (25.5) Table 1: Incidence of Adverse Reactions Occurring in 1% of ONTAK-treated patients (18 mcg/kg group) and at a higher rate than Placebo in Study 1 (cont.) MedDRA version 6.1 Preferred Term Placebo N=44 n (%) ONTAK 9 mcg/kg N=45 n (%) ONTAK 18 mcg/kg N=55 n (%) Edema peripheral 1 (22.7) 9 (2.) 14 (25.5) Diarrhea 4 (9.1) 1 (22.2) 12 (21.8) Anorexia 2 (4.5) 4 (8.9) 11 (2.) Rash 2 (4.5) 11 (24.4) 11 (2.) Myalgia 2 (4.5) 8 (17.8) 11 (2.) Cough 3 (6.8) 9 (2.) 1 (18.2) Pruritus 4 (9.1) 7 (15.6) 1 (18.2) Back pain 1 (2.3) 7 (15.6) 1 (18.2) Asthenia 2 (4.5) 8 (17.8) 1 (18.2) Hypotension 1 (2.3) 3 (6.7) 9 (16.4) Upper respiratory tract infection 5 (11.4) 6 (13.3) 7 (12.7) Dizziness 5 (11.4) 5 (11.1) 7 (12.7) Arthralgia 5 (11.4) 7 (15.6) 7 (12.7) Pain 3 (6.8) 5 (11.1) 7 (12.7) Chest pain 1 (2.3) 2 (4.4) 7 (12.7) Dysgeusia 1 (2.3) () 6 (1.9) Dyspnea 2 (4.5) 6 (13.3) 6 (1.9) Hepatobiliary Disorders: Increase in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) from baseline occurred in 84% of subjects treated with ONTAK (197/234). In the majority of subjects, these enzyme elevations occurred during either the first or the second cycle; enzyme elevation resolved without medical intervention and did not require discontinuation of ONTAK. Immunogenicity: An immune response to denileukin diftitox was assessed using 2 enzyme-linked immunoassays (ELISA). The first assay measured reactivity directed against intact denileukin diftitox calibrated against anti-diphtheria toxin, and the second assay measured reactivity against the IL-2 portion of the protein. An additional in vitro cell-based assay that measured the ability of antibodies in serum to protect a human IL-2R-expressing cell line from toxicity by denileukin diftitox, was used to detect the presence of neutralizing antibodies which inhibited functional activity. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to the intact fusion protein denileukin diftitox. These results are highly dependent on the sensitivity and the specificity of the assays. Additionally, the observed incidence of the antibody positivity may be influenced by several factors, including sample handling, concomitant medication, and underlying disease. For these reasons, the comparison of the incidence of antibodies to denileukin diftitox with the incidence of antibodies to other products may be misleading. In Study 1 [see Clinical Studies], of 95 patients treated with denileukin diftitox, 66% tested positive for antibodies at baseline probably due to a prior exposure to diphtheria toxin or its vaccine. After 1, 2, and 3 courses of treatment, 94%, 99%, and 1% of patients tested positive, respectively. Mean titers of antidenileukin diftitox antibodies were similarly increased in the 9 and 18 mcg/kg/day dose groups after 2 courses of treatment. Meanwhile, pharmacokinetic parameters decreased substantially (Cmax~57%, AUC~8%), and clearance increased 2- to 8- fold. In Study 2 [see Clinical Studies], 131 patients were assessed for binding antibodies. Of these, 51 patients (39%) had antibodies at baseline. Seventy-six percent of patients tested positive after 1 course of treatment and 97% after 3 courses of treatment. Neutralizing antibodies were assessed in 6 patients; 45%, 73%, and 97% had evidence of inhibited functional activity in the cellular assay at baseline and after 1 and 3 courses of treatment, respectively. DRUG INTERACTIONS: No formal drug-drug interaction studies have been conducted with ONTAK. USE IN SPECIFIC POPULATIONS: Pregnancy: It is not known whether ONTAK can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Animal reproduction studies have not been conducted with ONTAK. ONTAK should be given to a pregnant woman only if clearly needed. Nursing Mothers: It is not known whether ONTAK is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ONTAK, a decision should be made whether to discontinue nursing or to discontinue ONTAK, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: Clinical studies of ONTAK did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. OVERDOSAGE: Doses of approximately twice the recommended dose (31 mcg/kg/day) resulted in moderate-to-severe nausea, vomiting, fever, chills, and/or persistent asthenia. PATIENT COUNSELING INFORMATION Advise patients to report: Fever, chills, breathing problems, chest pain, tachycardia, and urticaria following infusion Rapid weight gain, edema, and orthostatic hypotension following infusion. Instruct patients to weigh themselves daily Visual loss, including loss of color vision ONTAK is a registered trademark of Eisai Inc. ONT Eisai Inc. All rights reserved. Printed in USA / November 29.

15 In MBC patients who have progressed on an anthracycline and a taxane with or without capecitabine What do you do after the taxane fails? Indications 1 IXEMPRA (ixabepilone) is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine. IXEMPRA is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting Important Safety Information Toxicity in hepatic impairment IXEMPRA (ixabepilone) in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity and neutropeniarelated death In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was greater in patients with hepatic impairment Caution should be used when using IXEMPRA as monotherapy in patients with AST or ALT >5 x ULN. Use of IXEMPRA in patients with AST or ALT >1 x ULN or bilirubin >3 x ULN is not recommended With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent in patients with hepatic impairment Contraindications IXEMPRA is contraindicated in patients: with a known history of a severe (CTC grade 3/4) hypersensitivity reaction to agents containing Cremophor EL or its derivatives such as polyoxyethylated castor oil who have a baseline neutrophil count <15 cells/mm 3 or a platelet count <1, cells/mm 3 Peripheral neuropathy Peripheral neuropathy was common. Patients treated with IXEMPRA (ixabepilone) should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain Neuropathy occurred early during treatment; ~75% of new onset or worsening neuropathy occurred during the first 3 cycles. Patients experiencing new or worsening peripheral neuropathy may require changes in the dose or discontinuation of IXEMPRA Neuropathy was the most frequent cause of treatment discontinuation due to drug toxicity. Caution should be used when treating patients with diabetes mellitus or preexisting peripheral neuropathy Myelosuppression Myelosuppression is dose-dependent and primarily manifested as neutropenia Patients should be monitored for myelosuppression; frequent peripheral blood cell counts are recommended for all patients receiving IXEMPRA Patients who experience severe neutropenia or thrombocytopenia should have their dose reduced. Neutropenia-related deaths occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with IXEMPRA (ixabepilone) in combination with capecitabine. Neutropenia-related death occurred in.4% of 24 patients with IXEMPRA as monotherapy Hypersensitivity reaction Premedicate with an H 1 and an H 2 antagonist approximately 1 hour before IXEMPRA infusion and observe for hypersensitivity reactions (eg, flushing, rash, dyspnea, and bronchospasm) In case of severe hypersensitivity reactions, infusion of IXEMPRA should be stopped and aggressive supportive treatment (eg, epinephrine, corticosteroids) started Patients who experience a hypersensitivity reaction in one cycle of IXEMPRA must be premedicated in subsequent cycles with a corticosteroid in addition to the H 1 and H 2 antagonists, and extension of the infusion time should be considered Pregnancy Women should be advised not to become pregnant when taking IXEMPRA. If this drug is used during pregnancy or the patient becomes pregnant, the patient should be apprised of the potential hazard to the fetus

16 Offer IXEMPRA (ixabepilone) IXEMPRA, a non-taxane chemotherapy, is an FDA-approved option following progression on a taxane and an anthracycline with or without capecitabine Contraindications 1 IXEMPRA is contraindicated in patients: with a known history of a severe (CTC grade 3/4) hypersensitivity reaction to agents containing Cremophor EL or its derivatives such as polyoxyethylated castor oil who have a baseline neutrophil count <15 cells/mm 3 or a platelet count <1, cells/mm 3 in combination with capecitabine, when AST or ALT is >2.5 x ULN or bilirubin is >1 x ULN due to increased risk of toxicity and neutropenia-related death Cardiac adverse reactions Caution should be exercised in patients with a history of cardiac disease. Discontinuation of IXEMPRA (ixabepilone) should be considered in patients who develop cardiac ischemia or impaired cardiac function due to reports of cardiovascular adverse reactions (eg, myocardial ischemia, supraventricular arrhythmia, and ventricular dysfunction). The frequency of cardiac adverse reactions (myocardial ischemia and ventricular dysfunction) was higher in the IXEMPRA in combination with capecitabine (1.9%) than in the capecitabine alone (.3%) treatment group Potential for cognitive impairment from excipients IXEMPRA (ixabepilone) contains dehydrated alcohol USP. Consideration should be given to the possibility of central nervous system and other effects of alcohol Adverse reactions The most common adverse reactions ( 2%) reported by patients receiving IXEMPRA were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The following additional events occurred in 2% in combination treatment: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation. Drug-associated hematologic abnormalities (>4%) include neutropenia, leukopenia, anemia, and thrombocytopenia Cremophor is a registered trademark of BASF AG. AST = aspartate aminotransferase ALT = alanine aminotransferase ULN = upper limit of normal CTC = common terminology criteria Reference: 1. IXEMPRA (ixabepilone) Prescribing Information. Bristol-Myers Squibb; Princeton, NJ. For additional information, please call IXEMPRA ( ) or visit Please see brief summary of full Prescribing Information, including boxed WARNING regarding hepatic impairment, on the following pages. 29 Bristol-Myers Squibb 691US9AB1425 1/9

17 IXEMPRA Kit (ixabepilone) for Injection, for intravenous infusion only Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: TOXICITY IN HEPATIC IMPAIRMENT IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity and neutropenia-related death [see Contraindications and Warnings and Precautions]. INDICATIONS AND USAGE IXEMPRA (ixabepilone) is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting. Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting. IXEMPRA is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine. CONTRAINDICATIONS IXEMPRA is contraindicated in patients with a history of a severe (CTC grade 3/4) hypersensitivity reaction to agents containing Cremophor EL or its derivatives (eg, polyoxyethylated castor oil) [see Warnings and Precautions]. IXEMPRA is contraindicated in patients who have a neutrophil count <15 cells/mm 3 or a platelet count <1, cells/mm 3 [see Warnings and Precautions]. IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN [see Boxed Warning and Warnings and Precautions]. WARNINGS AND PRECAUTIONS Peripheral Neuropathy Peripheral neuropathy was common (see Table 1). Patients treated with IXEMPRA should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. Neuropathy occurred early during treatment; ~75% of new onset or worsening neuropathy occurred during the first 3 cycles. Patients experiencing new or worsening symptoms may require a reduction or delay in the dose of IXEMPRA [see Dosage and Administration (2.2) in Full Prescribing Information]. In clinical studies, peripheral neuropathy was managed through dose reductions, dose delays, and treatment discontinuation. Neuropathy was the most frequent cause of treatment discontinuation due to drug toxicity. In Studies 46 and 81, 8% and 87%, respectively, of patients with peripheral neuropathy who received IXEMPRA had improvement or no worsening of their neuropathy following dose reduction. For patients with grade 3/4 neuropathy in Studies 46 and 81, 76% and 79%, respectively, had documented improvement to baseline or grade 1, twelve weeks after onset. Table 1: Treatment-related Peripheral Neuropathy IXEMPRA with capecitabine IXEMPRA as monotherapy Study 46 Study 81 Peripheral neuropathy (all grades) a,b Peripheral neuropathy (grades 3/4) a,b Discontinuation due to neuropathy Median number of cycles to onset of grade 3/4 neuropathy Median time to improvement of grade 3/4 neuropathy to baseline or to grade 1 67% 23% 21% 4 6. weeks 63% 14% 6% weeks a Sensory and motor neuropathy combined. b 24% and 27% of patients in 46 and 81, respectively, had preexisting neuropathy (grade 1). A pooled analysis of 154 cancer patients treated with IXEMPRA indicated that patients with diabetes mellitus or preexisting peripheral neuropathy may be at increased risk of severe neuropathy. Prior therapy with neurotoxic chemotherapy agents did not predict the development of neuropathy. Patients with moderate to severe neuropathy (grade 2 or greater) were excluded from studies with IXEMPRA. Caution should be used when treating patients with diabetes mellitus or preexisting peripheral neuropathy. Myelosuppression Myelosuppression is dose-dependent and primarily manifested as neutropenia. In clinical studies, grade 4 neutropenia (<5 cells/mm 3 ) occurred in 36% of patients treated with IXEMPRA in combination with capecitabine and 23% of patients treated with IXEMPRA monotherapy. Febrile neutropenia and infection with neutropenia were reported in 5% and 6% of patients treated with IXEMPRA in combination with capecitabine, respectively, and 3% and 5% of patients treated with IXEMPRA as monotherapy, respectively. Neutropeniarelated death occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with IXEMPRA in combination with capecitabine. The rate of neutropenia-related deaths was higher (29%, 5 out of 17) in patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN [see Boxed Warning, Contraindications, and Warnings and Precautions]. Neutropenia-related death occurred in.4% of 24 patients treated with IXEMPRA as monotherapy. No neutropenia-related deaths were reported in 24 patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN treated with IXEMPRA monotherapy. IXEMPRA must not be administered to patients with a neutrophil count <15 cells/mm 3. To monitor for myelosuppression, frequent peripheral blood cell counts are recommended for all patients receiving IXEMPRA. Patients who experience severe neutropenia or thrombocytopenia should have their dose reduced [see Dosage and Administration (2.2) in Full Prescribing Information]. Hepatic Impairment Patients with baseline AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN experienced greater toxicity than patients with baseline AST or ALT 2.5 x ULN or bilirubin 1.5 x ULN when treated with IXEMPRA at 4 mg/m 2 in combination with capecitabine or as monotherapy in breast cancer studies. In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was greater [see Warnings and Precautions]. With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent. The safety and pharmacokinetics of IXEMPRA as monotherapy were evaluated in a dose escalation study in 56 patients with varying degrees of hepatic impairment. Exposure was increased in patients with elevated AST or bilirubin [see Use in Specific Populations]. IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity- and neutropenia-related death [see Boxed Warning, Contraindications, and Warnings and Precautions]. Patients who are treated with IXEMPRA as monotherapy should receive a reduced dose depending on the degree of hepatic impairment [see Dosage and Administration (2.2) in Full Prescribing Information]. Use in patients with AST or ALT >1 x ULN or bilirubin >3 x ULN is not recommended. Limited data are available for patients with AST or ALT >5 x ULN. Caution should be used when treating these patients [see Dosage and Administration (2.2) in Full Prescribing Information]. Hypersensitivity Reactions Patients with a history of a severe hypersensitivity reaction to agents containing Cremophor EL or its derivatives (eg, polyoxyethylated castor oil) should not be treated with IXEMPRA. All patients should be premedicated with an H 1 and an H 2 antagonist approximately 1 hour before IXEMPRA infusion and be observed for hypersensitivity reactions (eg, flushing, rash, dyspnea, and bronchospasm). In case of severe hypersensitivity reactions, infusion of IXEMPRA should be stopped and aggressive supportive treatment (eg, epinephrine, corticosteroids) started. Of the 1323 patients treated with IXEMPRA in clinical studies, 9 patients (1%) had experienced severe hypersensitivity reactions (including anaphylaxis). Three of the 9 patients were able to be retreated. Patients who experience a hypersensitivity reaction in one cycle of IXEMPRA must be premedicated in subsequent cycles with a corticosteroid in addition to the H 1 and H 2 antagonists, and extension of the infusion time should be considered [see Dosage and Administration (2.3) in Full Prescribing Information and Contraindications]. Pregnancy Pregnancy Category D. IXEMPRA may cause fetal harm when administered to pregnant women. There are no adequate and well-controlled studies with IXEMPRA in pregnant women. Women should be advised not to become pregnant when taking IXEMPRA. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Ixabepilone was studied for effects on embryo-fetal development in pregnant rats and rabbits given IV doses of.2,.8, and.3 mg/kg/day and.1,.3,.11, and.3 mg/kg/day, respectively. There were no teratogenic effects. In rats, an increase in resorptions and post-implantation loss and a decrease in the number of live fetuses and fetal weight was observed at the maternally toxic dose of.3 mg/kg/day (approximately one-tenth the human clinical exposure based on AUC). Abnormalities included a reduced ossification of caudal vertebrae, sternebrae, and metacarpals. In rabbits, ixabepilone caused maternal toxicity (death) and embryo-fetal toxicity (resorptions) at.3 mg/kg/day (approximately one-tenth the human clinical dose based on body surface area). No fetuses were available at this dose for evaluation. Cardiac Adverse Reactions The frequency of cardiac adverse reactions (myocardial ischemia and ventricular dysfunction) was higher in the IXEMPRA in combination with capecitabine (1.9%) than in the capecitabine alone (.3%) treatment group. Supraventricular arrhythmias were observed in the combination arm (.5%) and not in the capecitabine alone arm. Caution should be exercised in patients with a history of cardiac disease. Discontinuation of IXEMPRA should be considered in patients who develop cardiac ischemia or impaired cardiac function. Potential for Cognitive Impairment from Excipients Since IXEMPRA contains dehydrated alcohol USP, consideration should be given to the possibility of central nervous system and other effects of alcohol [see Description (11) in Full Prescribing Information]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections. Peripheral neuropathy [see Warnings and Precautions] Myelosuppression [see Warnings and Precautions] Hypersensitivity reactions [see Warnings and Precautions] Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. Unless otherwise specified, assessment of adverse reactions is based on one randomized study (Study 46) and one single-arm study (Study 81). In Study 46, 369 patients with metastatic breast cancer were treated with IXEMPRA 4 mg/m 2 administered intravenously over 3 hours every 21 days, combined with capecitabine 1 mg/m 2 twice daily for 2 weeks followed by a 1-week rest period. Patients treated with capecitabine as monotherapy (n=368) in this study received 125 mg/m 2 twice daily for 2 weeks every 21 days. In Study 81, 126 patients with metastatic or locally advanced breast cancer were treated with IXEMPRA 4 mg/m 2 administered intravenously over 3 hours every 3 weeks. The most common adverse reactions ( 2%) reported by patients receiving IXEMPRA were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The following additional reactions occurred in 2% in combination treatment: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation. The most common hematologic abnormalities (>4%) include neutropenia, leukopenia, anemia, and thrombocytopenia. Table 2 presents nonhematologic adverse reactions reported in 5% or more of patients. Hematologic abnormalities are presented separately in Table 3. Table 2: Nonhematologic Drug-related Adverse Reactions Occurring in at Least 5% of Patients with Metastatic or Locally Advanced Breast Cancer Treated with IXEMPRA (ixabepilone) Study 46 Study 81 System Organ Class a / Preferred Term Infections and Infestations Upper respiratory tract infection b Blood and Lymphatic System Disorders Febrile neutropenia Immune System Disorders Hypersensitivity b Metabolism and Nutrition Disorders Anorexia b Dehydration b Psychiatric Insomnia b Nervous System Disorders Peripheral neuropathy Sensory neuropathy b,e Motor neuropathy b Headache Taste disorder b Dizziness Eye Disorders Lacrimation increased Vascular Disorders Hot flush b Respiratory, Thoracic, and Mediastinal Disorders Dyspnea b Cough b Gastrointestinal Disorders Nausea Vomiting b Stomatitis/mucositis b Diarrhea b Constipation Abdominal pain b Gastroesophageal reflux disease b Skin and Subcutaneous Tissue Disorders Alopecia b Skin rash b Nail disorder b Palmar-plantar erythrodysesthesia syndrome b,f Pruritus Skin exfoliation b Skin hyperpigmentation b IXEMPRA with capecitabine n=369 Total (%) Grade 3/4 (%) 4 c 1 d 3 d 2 <1 d 21 5 d <1 d 1 d 1 3 d 4 d 4 6 d 2 d 1 d 1 d 2 d 18 d <1 d Capecitabine Total (%) < n=368 Grade 3/4 (%) 1 d 1 d <1 d 1 d <1 d 1 2 d 2 3 d 9 <1 d 1 d <1 d 17 d IXEMPRA monotherapy n=126 Total Grade 3/4 (%) (%) d 5 1 d 19 2 d 2 1 d d d d 29 1 d d 16 2 d 13 2 d d d 6 1 d 2 2 (Continued) a System organ class presented as outlined in Guidelines for Preparing Core Clinical Safety Information on Drugs by the Council for International Organizations of Medical Sciences (CIOMS). b A composite of multiple MedDRA Preferred Terms. c NCI CTC grading for febrile neutropenia ranges from Grade 3 to 5. Three patients (1%) experienced Grade 5 (fatal) febrile neutropenia. Other neutropenia-related deaths (9) occurred in the absence of reported febrile neutropenia [see Warnings and Precautions]. d No grade 4 reports. e Peripheral sensory neuropathy (graded with the NCI CTC scale) was defined as the occurrence of any of the following: areflexia, burning sensation, dysesthesia, hyperesthesia, hypoesthesia, hyporeflexia, neuralgia, neuritis, neuropathy, neuropathy peripheral, neurotoxicity, painful response to normal stimuli, paresthesia, pallanesthesia, peripheral sensory neuropathy, polyneuropathy, polyneuropathy toxic and sensorimotor disorder. Peripheral motor neuropathy was defined as the occurrence of any of the following: multifocal motor neuropathy, neuromuscular toxicity, peripheral motor neuropathy, and peripheral sensorimotor neuropathy. f Palmar-plantar erythrodysesthesia (hand-foot syndrome) was graded on a 1-3 severity scale in Study 46.

18 Table 2: Nonhematologic Drug-related Adverse Reactions Occurring in at Least 5% of Patients (Continued) with Metastatic or Locally Advanced Breast Cancer Treated with IXEMPRA (ixabepilone) Study 46 Study 81 IXEMPRA with Capecitabine IXEMPRA capecitabine monotherapy n=369 n=368 n=126 System Organ Class a / Total Grade 3/4 Total Grade 3/4 Total Grade 3/4 Preferred Term (%) (%) (%) (%) (%) (%) Musculoskeletal, Connective Tissue, and Bone Disorders Myalgia/arthralgia b 39 8 d 5 <1 d 49 8 d Musculoskeletal pain b 23 2 d d General Disorders and Administrative Site Conditions Fatigue/asthenia b Edema b 8 5 <1 d 9 1 d Pyrexia 1 1 d d Pain b 9 1 d d Chest pain b 4 1 d <1 5 1 d Investigations Weight decreased a System organ class presented as outlined in Guidelines for Preparing Core Clinical Safety Information on Drugs by the Council for International Organizations of Medical Sciences (CIOMS). b A composite of multiple MedDRA Preferred Terms. c NCI CTC grading for febrile neutropenia ranges from Grade 3 to 5. Three patients (1%) experienced Grade 5 (fatal) febrile neutropenia. Other neutropenia-related deaths (9) occurred in the absence of reported febrile neutropenia [see Warnings and Precautions]. d No grade 4 reports. e Peripheral sensory neuropathy (graded with the NCI CTC scale) was defined as the occurrence of any of the following: areflexia, burning sensation, dysesthesia, hyperesthesia, hypoesthesia, hyporeflexia, neuralgia, neuritis, neuropathy, neuropathy peripheral, neurotoxicity, painful response to normal stimuli, paresthesia, pallanesthesia, peripheral sensory neuropathy, polyneuropathy, polyneuropathy toxic and sensorimotor disorder. Peripheral motor neuropathy was defined as the occurrence of any of the following: multifocal motor neuropathy, neuromuscular toxicity, peripheral motor neuropathy, and peripheral sensorimotor neuropathy. f Palmar-plantar erythrodysesthesia (hand-foot syndrome) was graded on a 1-3 severity scale in Study 46. Table 3: Hematology Parameter Neutropenia a Leukopenia (WBC) Anemia (Hgb) Thrombocytopenia Hematologic Abnormalities in Patients with Metastatic or Locally Advanced Breast Cancer Treated with IXEMPRA Study 46 Study 81 IXEMPRA with Capecitabine IXEMPRA capecitabine monotherapy n=369 n=368 n=126 Grade 3 (%) Grade 4 (%) Grade 3 (%) Grade 4 (%) Grade 3 Grade 4 (%) (%) a G-CSF (granulocyte colony stimulating factor) or GM-CSF (granulocyte macrophage stimulating factor) was used in 2% and 17% of patients who received IXEMPRA in Study 46 and Study 81, respectively. The following serious adverse reactions were also reported in 1323 patients treated with IXEMPRA as monotherapy or in combination with other therapies in Phase 2 and 3 studies. Infections and Infestations: sepsis, pneumonia, infection, neutropenic infection, urinary tract infection, bacterial infection, enterocolitis, laryngitis, lower respiratory tract infection Blood and Lymphatic System Disorders: coagulopathy, lymphopenia Metabolism and Nutrition Disorders: hyponatremia, metabolic acidosis, hypokalemia, hypovolemia Nervous System Disorders: cognitive disorder, syncope, cerebral hemorrhage, abnormal coordination, lethargy Cardiac Disorders: myocardial infarction, supraventricular arrhythmia, left ventricular dysfunction, angina pectoris, atrial flutter, cardiomyopathy, myocardial ischemia Vascular Disorders: hypotension, thrombosis, embolism, hemorrhage, hypovolemic shock, vasculitis Respiratory, Thoracic, and Mediastinal Disorders: pneumonitis, hypoxia, respiratory failure, acute pulmonary edema, dysphonia, pharyngolaryngeal pain Gastrointestinal Disorders: ileus, colitis, impaired gastric emptying, esophagitis, dysphagia, gastritis, gastrointestinal hemorrhage Hepatobiliary Disorders: acute hepatic failure, jaundice Skin and Subcutaneous Tissue Disorders: erythema multiforme Musculoskeletal, Connective Tissue Disorders, and Bone Disorders: muscular weakness, muscle spasms, trismus Renal and Urinary Disorders: nephrolithiasis, renal failure General Disorders and Administration Site Conditions: chills Investigations: increased transaminases, increased blood alkaline phosphatase, increased gamma-glutamyltransferase DRUG INTERACTIONS Effect of Other Drugs on Ixabepilone Drugs That May Increase Ixabepilone Plasma Concentrations CYP3A4 Inhibitors: Co-administration of ixabepilone with ketoconazole, a potent CYP3A4 inhibitor, increased ixabepilone AUC by 79% compared to ixabepilone treatment alone. If alternative treatment cannot be administered, a dose adjustment should be considered. The effect of mild or moderate inhibitors (eg, erythromycin, fluconazole, or verapamil) on exposure to ixabepilone has not been studied. Therefore, caution should be used when administering mild or moderate CYP3A4 inhibitors during treatment with IXEMPRA, and alternative therapeutic agents that do not inhibit CYP3A4 should be considered. Patients receiving CYP3A4 inhibitors during treatment with IXEMPRA should be monitored closely for acute toxicities (eg, frequent monitoring of peripheral blood counts between cycles of IXEMPRA) [see Dosage and Administration (2.2) in Full Prescribing Information]. Drugs That May Decrease Ixabepilone Plasma Concentrations CYP3A4 Inducers: IXEMPRA is a CYP3A4 substrate. Strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifampicin, rifabutin, and phenobarbital) may decrease ixabepilone concentrations leading to subtherapeutic levels. Therefore, therapeutic agents with low enzyme induction potential should be considered for coadministration with IXEMPRA. St. John s Wort may decrease ixabepilone plasma concentrations unpredictably and should be avoided. Effect of Ixabepilone on Other Drugs Ixabepilone does not inhibit CYP enzymes at relevant clinical concentrations and is not expected to alter the plasma concentrations of other drugs [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Capecitabine In patients with cancer who received ixabepilone (4 mg/m 2 ) in combination with capecitabine (1 mg/m 2 ), ixabepilone C max decreased by 19%, capecitabine C max decreased by 27%, and 5-fluorouracil AUC increased by 14%, as compared to ixabepilone or capecitabine administered separately. The interaction is not clinically significant given that the combination treatment is supported by efficacy data USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [See Warnings and Precautions.] Nursing Mothers It is not known whether ixabepilone is excreted into human milk. Following intravenous administration of radiolabeled ixabepilone to rats on days 7 to 9 postpartum, concentrations of radioactivity in milk were comparable with those in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ixabepilone, a decision must be made whether to discontinue nursing or to discontinue IXEMPRA (ixabepilone) taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of IXEMPRA did not include sufficient numbers of subjects aged sixty-five and over to determine whether they respond differently from younger subjects. Forty-five of 431 patients treated with IXEMPRA in combination with capecitabine were 65 years of age and 3 patients were 75. Overall, the incidence of grade 3/4 adverse reactions were higher in patients 65 years of age versus those <65 years of age (82% versus 68%) including grade 3/4 stomatitis (9% versus 1%), diarrhea (9% versus 6%), palmar-plantar erythrodysesthesia syndrome (27% versus 2%), peripheral neuropathy (24% versus 22%), febrile neutropenia (9% versus 3%), fatigue (16% versus 12%), and asthenia (11% versus 6%). Toxicity-related deaths occurred in 2 (4.7%) of 43 patients 65 years with normal baseline hepatic function or mild impairment. Thirty-two of 24 breast cancer patients treated with IXEMPRA as monotherapy were 65 years of age and 6 patients were 75. No overall differences in safety were observed in these patients compared to those <65 years of age. Hepatic Impairment IXEMPRA was evaluated in 56 patients with mild to severe hepatic impairment defined by bilirubin levels and AST levels. Compared to patients with normal hepatic function (n=17), the area under the curve (AUC -infinity ) of ixabepilone increased by: 22% in patients with a) bilirubin >1 1.5 x ULN or b) AST >ULN but bilirubin <1.5 x ULN; 3% in patients with bilirubin >1.5 3 x ULN and any AST level; and 81% in patients with bilirubin >3 x ULN and any AST level. Doses of 1 and 2 mg/m 2 as monotherapy were tolerated in 17 patients with severe hepatic impairment (bilirubin >3 x ULN). IXEMPRA in combination with capecitabine must not be given to patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN [see Boxed Warning, Contraindications, and Warnings and Precautions]. Dose reduction is recommended when administering IXEMPRA as monotherapy to patients with hepatic impairment [see Dosage and Administration (2.3) in Full Prescribing Information]. Because there is a need for dosage adjustment based upon hepatic function, assessment of hepatic function is recommended before initiation of IXEMPRA and periodically thereafter. Renal Impairment Ixabepilone is minimally excreted via the kidney. No controlled pharmacokinetic studies were conducted with IXEMPRA in patients with renal impairment. IXEMPRA in combination with capecitabine has not been evaluated in patients with calculated creatinine clearance of <5 ml/min. IXEMPRA as monotherapy has not been evaluated in patients with creatinine >1.5 times ULN. In a population pharmacokinetic analysis of IXEMPRA as monotherapy, there was no meaningful effect of mild and moderate renal insufficiency (CrCL >3 ml/min) on the pharmacokinetics of ixabepilone. OVERDOSAGE Experience with overdose of IXEMPRA is limited to isolated cases. The adverse reactions reported in these cases included peripheral neuropathy, fatigue, musculoskeletal pain/myalgia, and gastrointestinal symptoms (nausea, anorexia, diarrhea, abdominal pain, stomatitis). The highest dose mistakenly received was 1 mg/m 2 (total dose 185 mg). There is no known antidote for overdosage of IXEMPRA. In case of overdosage, the patient should be closely monitored and supportive treatment should be administered. Management of overdose should include supportive medical interventions to treat the presenting clinical manifestations. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with ixabepilone have not been conducted. Ixabepilone did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in an in vitro cytogenetic assay using primary human lymphocytes. Ixabepilone was clastogenic (induction of micronuclei) in the in vivo rat micronucleus assay at doses.625 mg/kg/day. There were no effects on male or female rat mating or fertility at doses up to.2 mg/kg/day in both males and females (approximately one-fifteenth the expected human clinical exposure based on AUC). The effect of ixabepilone on human fertility is unknown. However, when rats were given an IV infusion of ixabepilone during breeding and through the first 7 days of gestation, a significant increase in resorptions and pre- and post-implantation loss and a decrease in the number of corpora lutea was observed at.2 mg/kg/day. Testicular atrophy or degeneration was observed in 6-month rat and 9-month dog studies when ixabepilone was given every 21 days at intravenous doses of 6.7 mg/kg (4 mg/m 2 ) in rats (approximately 2.1 times the expected clinical exposure based on AUC) and.5 and.75 mg/kg (1 and 15 mg/m 2 ) in dogs (approximately.2 and.4 times the expected clinical exposure based on AUC). Animal Toxicology Overdose In rats, single intravenous doses of ixabepilone from 6 to 18 mg/m 2 (mean AUC values 8156 ng h/ml) were associated with mortality occurring between 5 and 14 days after dosing, and toxicity was principally manifested in the gastrointestinal, hematopoietic (bone-marrow), lymphatic, peripheral-nervous, and male-reproductive systems. In dogs, a single intravenous dose of 1 mg/m 2 (mean AUC value of 6925 ng h/ml) was markedly toxic, inducing severe gastrointestinal toxicity and death 3 days after dosing. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.6) in Full Prescribing Information Peripheral Neuropathy Patients should be advised to report to their physician any numbness and tingling of the hands or feet [see Warnings and Precautions]. Fever/Neutropenia Patients should be instructed to call their physician if a fever of 1.5 F or greater or other evidence of potential infection such as chills, cough, or burning or pain on urination develops [see Warnings and Precautions]. Hypersensitivity Reactions Patients should be advised to call their physician if they experience urticaria, pruritus, rash, flushing, swelling, dyspnea, chest tightness or other hypersensitivity-related symptoms following an infusion of IXEMPRA [see Warnings and Precautions]. Pregnancy Patients should be advised to use effective contraceptive measures to prevent pregnancy and to avoid nursing during treatment with IXEMPRA [see Warnings and Precautions and Use in Specific Populations]. Cardiac Adverse Reactions Patients should be advised to report to their physician chest pain, difficulty breathing, palpitations or unusual weight gain [see Warnings and Precautions]. IXEMPRA (ixabepilone) for injection Manufactured by: Baxter Oncology GmbH, 3379 Halle/Westfalen, Germany DILUENT for IXEMPRA Manufactured by: Baxter Oncology GmbH, 3379 Halle/Westfalen, Germany Distributed by Bristol-Myers Squibb Company, Princeton, NJ 8543 USA A XG-B1A-1-9 Rev October 29

19 First-line FLT3-mutant AML clinical trial CALGB 163 (Novartis # CPKC412A 231) NOW ENROLLING Rationale FLT3 mutations are common in AML and are associated with poor prognosis* Study Randomized, placebo-controlled study involving > 5 patients with FLT3 mutations Newly diagnosed AML patients < 6 years Addition of oral midostaurin (or placebo) to induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine Includes midostaurin/placebo continuation therapy for up to 12 months Primary endpoint: overall survival PKC412 (Midostaurin) Questions regarding the conduct of the trial should be directed to the CALGB Study Chair: Richard M. Stone, M.D. Dana Farber Cancer Institute rstone@partners.org For more information please refer to: International Participants AMLSG German Austrian Acute Myeloid Leukemia Study Group CETLAM Groupo Cooperativo de Tratamiento de las Leucemias Agudas y Mielodisplasias Brazil United Kingdom Hungary EORTC European Organization for Research and Treatment of Cancer GIMEMA Gruppo Italiano Malattie Ematologiche dell Adulto North American Cooperative Groups OSHO Ostdeutsche Studiengruppe Haematologie und Onkologie PETHEMA Programa Español para el Tratamiento de las Hemopatias Malignas SAL Study Alliance Leukemia *Kottaridis PD, et al. Blood. 21;98: Small D, et al. Hematology Am Soc Hematol Educ Program. 26: Cancer and Leukemia Group B. Midostaurin is investigational. Effi cacy and safety have not been established. There is no guarantee that midostaurin will become commercially available. C-ONC-171

20 ERBITUX (cetuximab): FOR PATIENTS WITH HEAD AND NECK CANCER* ERBITUX + RT: 26% reduction in Risk of Death from SCCHN 1,2 Important Safety Information Including Boxed WARNINGS Infusion Reactions Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1 Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions Most (9%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 28 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last ERBITUX treatment Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy Pulmonary Toxicity Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 157 (<.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed Dermatologic Toxicities In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae Sun exposure may exacerbate these effects ERBITUX Plus Radiation Therapy and Cisplatin The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (1 mg/m 2 ) in patients with locally advanced squamous cell carcinoma of the head and neck Two of 21 patients died, one as a result of pneumonia and one of an unknown cause Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

21 Delivery of planned RT dose No. (%) of Patients ERBITUX + RT RT Alone (n = 211) (n = 213) Adequate delivery per protocol 184 (87.2) 187 (87.8) Inadequate delivery per protocol 27 (12.8) 26 (12.2) No difference in radiation dose delivered between the 2 treatment groups in a randomized trial comparing ERBITUX + RT versus RT alone in patients with locally or regionally advanced SCCHN. 2 ERBITUX + RT (%) RT Alone (%) (n = 28) (n = 212) Grades Grade Grades Grade 1-4 3/ /4 Mucositis/stomatitis Dysphagia Xerostomia Radiation dermatitis The incidences of grades 3/4 xerostomia, mucositis/stomatitis, and radiation dermatitis were more frequent in the ERBITUX plus RT arm *INDICATIONS ERBITUX (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed SCCHN = squamous cell carcinoma of the head and neck; RT = radiation therapy. Electrolyte Depletion Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy Replete electrolytes as necessary Late Radiation Toxicities The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms Pregnancy In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus Adverse Events The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus The most common adverse reactions associated with ERBITUX (incidence 25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=28) versus radiation alone (n=212) (incidence 5%) were acneform rash (87%/1%), radiation dermatitis (86%/9%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy ( 1%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) For more information, please visit or call ERBITUX ( ). References: 1. ERBITUX (cetuximab) Package Insert. ImClone LLC, New York, NY 114 and Bristol-Myers Squibb, Princeton, NJ 8543; July Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 26;354: Data on file, Bristol-Myers Squibb, ERBI 1. 29, ImClone LLC, New York, New York 114, U.S.A. and Bristol-Myers Squibb, Princeton, New Jersey 8543, U.S.A. All rights reserved. ERBITUX is a registered trademark of ImClone LLC. Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent page. 693US9AB1532 7/9

22 ERBITUX (cetuximab) Solution for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 28 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.] INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN) Erbitux (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2 5% of 1373 patients in clinical trials, with fatal outcome in 1 patient. Approximately 9% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 28 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.] Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 157 (<.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76 88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1 17% of patients. Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.] Use of Erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (1 mg/m 2 ) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events. Hypomagnesemia and Electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6 17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary. Epidermal Growth Factor Receptor (EGFR) Expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmdx test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Infusion reactions [See Boxed Warning and Warnings and Precautions.] Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.] Pulmonary toxicity [See Warnings and Precautions.] Dermatologic toxicity [See Warnings and Precautions.] Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions with Erbitux (cetuximab) (incidence 25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across all studies, Erbitux was discontinued in 3 1% of patients because of adverse reactions. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15 21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2 5% of patients; infusion reactions were fatal in 1 patient. Infections: The incidence of infection was variable across studies, ranging from 13 35%. Sepsis occurred in 1 4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 42 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (4 mg/m 2 initial dose, followed by 25 mg/m 2 weekly). Patients received a median of 8 infusions (range 1 11). Table 1: Incidence of Selected Adverse Events ( 1%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=28) (n=212) Body System Grades Grades Grades Grades Preferred Term and and 4 % of Patients Body as a Whole Asthenia Fever Headache 19 <1 8 <1 Infusion Reaction Infection Chills Digestive Nausea Emesis Diarrhea Dyspepsia Metabolic/Nutritional Weight Loss Dehydration Alanine Transaminase, high Aspartate Transaminase, high Alkaline Phosphatase, high 3 33 <1 24 Respiratory Pharyngitis Skin/Appendages Acneform Rash Radiation Dermatitis Application Site Reaction Pruritus Includes cases also reported as infusion reaction. 2 Infusion reaction is defined as any event described at any time during the clinical study as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, chills and fever, or dyspnea. 3 Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from for Erbitux plus Radiation arm; for Radiation alone. 4 Acneform rash is defined as any event described as acne, rash, maculopapular rash, pustular rash, dry skin, or exfoliative dermatitis. The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study. Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

23 Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (4 mg/m 2 initial dose, followed by 25 mg/m 2 weekly). Table 2: Incidence of Selected Adverse Events Occurring in 1% of Patients with Advanced Colorectal Carcinoma 1 Treated with Erbitux Monotherapy Erbitux plus BSC BSC alone (n=288) (n=274) Body System Any Grades Any Grades Preferred Term Grades 2 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation <1 Dry Skin Pruritus Other-Dermatology Nail Changes 21 4 Body as a Whole Fatigue Fever <1 Infusion Reactions Rigors, Chills 13 <1 4 Pain Abdominal Pain Pain-Other Headache Bone Pain Pulmonary Dyspnea Cough Gastrointestinal Constipation Diarrhea Vomiting Stomatitis <1 Other-Gastrointestinal Mouth Dryness 11 4 Infection Infection without neutropenia Neurology Insomnia Confusion Anxiety Depression <1 1 Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls. 2 Adverse events were graded using the NCI CTC, V Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated. BSC = best supportive care The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3 4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%). Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 11) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 2 48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 6 days following the last dose of Erbitux. Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab have not been studied in pediatric populations. Geriatric Use Of the 162 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 28 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older. OVERDOSAGE The maximum single dose of Erbitux administered is 1 mg/m 2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 5% (5/1) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIENT COUNSELING INFORMATION Advise patients: To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux is a registered trademark of ImClone Systems Incorporated. Manufactured by ImClone Systems Incorporated, Branchburg, NJ 8876 Distributed and Marketed by Bristol-Myers Squibb Company, Princeton, NJ 8543 Copyright 29 by ImClone Systems Incorporated and Bristol-Myers Squibb Company. All rights reserved A5 ER-B1A-7-9 Rev July 29

24 For previously untreated diffuse large B-cell, CD2-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens When planning a treatment course for DLBCL Take the essential path toward improved survival RITUXAN+CHOP is proven to prolong survival in DLBCL Cumulative Proportion Surviving % INCREASE in 7-year OS in GELA* trial 1,2 R-CHOP (n=22) CHOP (n=197) p = Years At 7 years, 8 cycles of RITUXAN+ CHOP increased overall survival (OS) from 36% to 53% compared with CHOP alone 1 At 5 years, 8 cycles of RITUXAN+ CHOP increased OS from 46% to 58% compared with CHOP alone 5 BOXED WARNINGS and Additional Important Safety Information The most important serious adverse reactions of RITUXAN are fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of RITUXAN (incidence 25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. 5 RITUXAN in Combination with CHOP Chemotherapy for DLBCL: The following adverse reactions, regardless of severity, were reported more frequently ( 5%) in patients age 6 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs 46%), lung disorder (31% vs 24%), cardiac disorder (29% vs 21%), and chills (13% vs 4%). In the GELA LNH 98-5 study, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs 1.% for CHOP). 5 The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs 7%) and lung disorder (6% vs 3%). Other Grade 3 or 4 adverse reactions reported more frequently among patients receiving R-CHOP were viral infection (GELA LNH 98-5 study), neutropenia (GELA LNH 98-5 and MInT studies), and anemia (MInT study). 5 Please see brief summary of prescribing information on adjacent page. Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion. *GELA (Groupe d Etude des Lymphomes de l Adulte) LNH 98-5 trial: A Phase III trial of 399 previously untreated elderly (age 6 years) DLBCL patients. 3,4 CHOP: Cyclophosphamide, doxorubicin, vincristine, and prednisone. References: 1. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. J Clin Oncol. 27;25(suppl 18S):443s. Abstract Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. Paper presented at: 43rd American Society of Clinical Oncology Annual Meeting; June 1-5, 27; Chicago, Ill. Abstract Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large- B-cell lymphoma. N Engl J Med. 22;346: Data on file, Genentech, Inc. 5. RITUXAN (Rituximab) full prescribing information, Genentech, Inc., Genentech, Inc., and Biogen Idec Inc. All rights reserved. 3 Printed in USA on Recycled Paper April 28 PROVE N. POWE R FU L.

25 RITUXAN (Rituximab) Brief summary Please consult full prescribing information. WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) Infusion Reactions: Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 8% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse Reactions]. Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-hodgkin s lymphoma (NHL) patients with Rituxan [see Warnings and Precautions, Adverse Reactions]. Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions]. Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions]. INDICATIONS AND USAGE Non-Hodgkin s Lymphoma (NHL) Rituxan (rituximab) is indicated for the treatment of patients with: Relapsed or refractory, low-grade or follicular, CD2-positive, B-cell NHL as a single agent; Previously untreated follicular, CD2-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing (including stable disease), low-grade, CD2- positive B-cell NHL, as a single agent, after first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD2-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 3 12 minutes. Rituxan-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, or anaphylactoid events. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, consider resumption of the infusion at a minimum 5% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with preexisting cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells ( 25,/mm 3 ). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can occur within hours after the first infusion. Fatal TLS cases have occurred after administration of Rituxan. A high number of circulating malignant cells ( 25,/mm 3 ) or high tumor burden confers a greater risk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1 13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B Virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of Rituxan and approximately one month after the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several months following Rituxan therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who develop viral hepatitis, and institute appropriate treatment including antiviral therapy. Insufficient data exist regarding the safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions.] Other Viral Infections The following additional serious viral infections, either new, reactivated, or exacerbated, have been identified in clinical studies or postmarketing reports. The majority of patients received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections occurred as late as one year following discontinuation of Rituxan and have resulted in death. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with hematologic malignancies. Renal toxicity has occurred in patients with high numbers of circulating malignant cells ( 25,/mm 3 ) or high tumor burden who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an approved treatment regimen. Use extreme caution if this non-approved combination is used in clinical trials and monitor closely for signs of renal failure. Consider discontinuation of Rituxan for patients with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1 77) days in patients with NHL. Perform a thorough diagnostic evaluation and institute appropriate treatment for complaints of abdominal pain, especially early in the course of Rituxan therapy. [See Adverse Reactions.] Immunization The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live virus vaccines is not recommended. For NHL patients, the benefits of primary or booster vaccinations should be weighted against the risks of delay in initiation of Rituxan therapy. Laboratory Monitoring Because Rituxan binds to all CD2- positive B lymphocytes (malignant and non-malignant), obtain complete blood counts (CBC) and platelet counts at regular intervals during Rituxan therapy and more frequently in patients who develop cytopenias [see Adverse Reactions]. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period. ADVERSE REACTIONSThe most common adverse reactions of Rituxan (incidence 25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. The most important serious adverse reactions of Rituxan are infusion reactions, tumor lysis syndrome, mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML, other viral infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation. Clinical Trials Experience Non-Hodgkin s Lymphoma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to Rituxan in 166 patients, with exposures ranging from a single infusion up to 6 8 months. Rituxan was studied in both single-agent and active-controlled trials (n = 356 and n = 125). These data were obtained in adults with low-grade, follicular, or DLBCL NHL. Most patients received Rituxan as an infusion of 375 mg/m 2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 3 to 12 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 1%, unknown 6%, and fungal 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (4%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, days) and of neutropenia was 13 days (range, days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in 7% to 8% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. Single-Agent Rituxan Adverse reactions in Table 1 occurred in 356 patients with relapsed or refractory, lowgrade or follicular, CD2-positive, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. Most patients received Rituxan 375 mg/m 2 weekly for 4 doses. Table 1 Incidence of Adverse Events in 5% of Patients with Relapsed or Refractory, Low- Grade or Follicular NHL, Receiving Single-agent Rituxan (N = 356) a,b All Grades (%) Grade 3 and 4 (%) Any Adverse Events Body as a Whole 86 1 Fever 53 1 Chills 33 3 Infection 31 4 Asthenia 26 1 Headache 19 1 Abdominal Pain 14 1 Pain 12 1 Back Pain 1 1 Throat Irritation 9 Flushing 5 Heme and Lymphatic System Lymphopenia 48 4 Leukopenia 14 4 Neutropenia 14 6 Thrombocytopenia 12 2 Anemia 8 3 Skin and Appendages 44 2 Night Sweats 15 1 Rash 15 1 Pruritus 14 1 Urticaria 8 1 All Grades (%) Grade 3 and 4 (%) 38 4 Respiratory System Increased Cough 13 1 Rhinitis 12 1 Bronchospasm 8 1 Dyspnea 7 1 Sinusitis 6 Metabolic and Nutritional Disorders 38 3 Angioedema 11 1 Hyperglycemia 9 1 Peripheral Edema 8 LDH Increase 7 Digestive System 37 2 Nausea 23 1 Diarrhea 1 1 Vomiting 1 1 Nervous System 32 1 Dizziness 1 1 Anxiety 5 1 Musculoskeletal System 26 3 Myalgia 1 1 Arthralgia 1 1 Cardiovascular System 25 3 Hypotension 1 1 Hypertension 6 1 a Adverse reactions observed up to 12 months following Rituxan. b Adverse reactions graded for severity by NCI-CTC criteria. In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and up to 6 months after Rituxan infusion. Rituxan in Combination With Chemotherapy Adverse reactions information below is based on 125 patients who received Rituxan in combination with chemotherapy or following chemotherapy. Rituxan in Combination With Chemotherapy for Low-Grade NHL In Study 4, patients in the R-CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently ( 5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (1% vs. 2%), pruritus (1% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactions were reported more frequently ( 5%) in patients receiving Rituxan following CVP compared to patients who received no further therapy: fatigue (39% vs. 14%), anemia (35% vs. 2%), peripheral sensory neuropathy (3% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. 1%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently ( 2%) in the Rituxan arm compared with those who received no further therapy (4% vs. 1%). Rituxan in Combination With Chemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions, regardless of severity, were reported more frequently ( 5%) in patients age 6 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.% for CHOP). The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia (Study 8). Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, antihuman anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in rituximab treated patients is unclear. Postmarketing Experience The following adverse reactions have been identified during postapproval use of Rituxan in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic: prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom s macroglobulinemia. Cardiac: fatal cardiac failure. Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection. Neoplasia: disease progression of Kaposi s sarcoma. Skin: severe mucocutaneous reactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatal bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUG INTERACTIONS Formal drug interaction studies have not been performed with Rituxan. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women. Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin s lymphoma is a serious condition that requires treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Nursing Mothers It is not known whether Rituxan is secreted into human milk. However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from oral ingestion of Rituxan should be weighed against the known benefits of breastfeeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, activecontrolled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin s Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD2-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. OVERDOSAGE There has been no experience with overdosage in human clinical trials. Single doses of up to 5 mg/m 2 have been given in dose-escalation clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility No long term animal studies have been performed to establish the carcinogenic or mutagenic potential of Rituxan or to determine potential effects on fertility in males or females. PATIENT COUNSELING INFORMATION Patients should be provided the Rituxan Medication Guide and provided an opportunity to read prior to each treatment session. Because caution should be exercised in administering Rituxan to patients with active infections, it is important that the patient s overall health be assessed at each visit and any questions resulting from the patient s reading of the Medication Guide be discussed. Rituxan is detectable in serum for up to six months following completion of therapy. Individuals of childbearing potential should use effective contraception during treatment and for 12 months after Rituxan therapy. Revised 9/28 (483555) Jointly Marketed by: Biogen Idec Inc. 52 Research Place San Diego, CA Genentech USA, Inc. 1 DNA Way South San Francisco, CA Biogen Idec Inc. and Genentech, Inc October 28

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27 Indications and Important Safety Information for ALIMTA Indications ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. ALIMTA is indicated as a single agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy. Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. Important Safety Information Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy. Contraindication: ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation. Warnings and Precautions: Patients must be instructed to take folic acid and vitamin B 12 with ALIMTA as a prophylaxis to reduce treatment-related hematologic and GI toxicities. Pretreatment with dexamethasone or its equivalent has been reported to reduce the incidence and severity of skin rash. ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities. ALIMTA should not be administered to patients with a creatinine clearance <45 ml/min. One patient with severe renal impairment (creatinine clearance 19 ml/min) who did not receive folic acid and vitamin B 12 died of drug-related toxicity following administration of ALIMTA alone. Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicities. Patients should not begin a new cycle of treatment unless the ANC is 15 cells/mm 3, the platelet count is 1, cells/mm 3, and creatinine clearance is 45 ml/min. Pregnancy Category D ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration. Drug Interactions: Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. See Warnings and Precautions for specific information regarding ibuprofen administration. ALIMTA is a registered trademark of Eli Lilly and Company. PM PRINTED IN USA 29, Lilly USA, LLC. ALL RIGHTS RESERVED.

28 Histology Matters with ALIMTA because EXTENDED SURVIVAL MATTERS. Approved for the 1st-line treatment of advanced nonsquamous NSCLC and now approved for the maintenance treatment of advanced nonsquamous NSCLC. ALIMTA is not indicated for the treatment of patients with squamous cell NSCLC. Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy. Within the ALIMTA maintenance trial design, ALIMTA/cisplatin was not included as an induction therapy. For more information, visit Use in Specific Patient Populations: It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother. The safety and effectiveness of ALIMTA in pediatric patients have not been established. Dose adjustments may be necessary in patients with hepatic insufficiency. Dosage and Administration Guidelines: Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information. Abbreviated Adverse Reactions (% incidence) for NSCLC 1st-line: The most severe adverse reactions (Grades 3/4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (15 vs 27); leukopenia (5 vs 8); thrombocytopenia (4 vs 13); anemia (6 vs 1); fatigue (7 vs 5); nausea (7 vs 4); vomiting (6 vs 6); anorexia (2 vs 1); and creatinine elevation (1 vs 1). Common adverse reactions (all Grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56 vs 53); fatigue (43 vs 45); vomiting (4 vs 36); anemia (33 vs 46); neutropenia (29 vs 38); anorexia (27 vs 24); constipation (21 vs 2); leukopenia (18 vs 21); stomatitis/pharyngitis (14 vs 12); alopecia (12 vs 21); diarrhea (12 vs 13); thrombocytopenia (1 vs 27); neuropathy/sensory (9 vs 12); taste disturbance (8 vs 9); rash/desquamation (7 vs 8); and dyspepsia/heartburn (5 vs 6). Abbreviated Adverse Reactions (% incidence) for NSCLC Maintenance: The most severe adverse reactions (Grades 3/4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NSCLC) were anemia (3 vs 1); neutropenia (3 vs ); leukopenia (2 vs 1); fatigue (5 vs 1); nausea (1 vs 1); anorexia (2 vs ); mucositis/stomatitis (1 vs ); diarrhea (1 vs ); infection (2 vs ); neuropathy-sensory (1 vs ). Common adverse reactions (all Grades) with ALIMTA as a single agent versus placebo, respectively, were anemia (15 vs 6); neutropenia (6 vs ); leukopenia (6 vs 1); increased ALT (1 vs 4); increased AST (8 vs 4); fatigue (25 vs 11); nausea (19 vs 6); anorexia (19 vs 5); vomiting (9 vs 1); mucositis/stomatitis (7 vs 2); diarrhea (5 vs 3); infection (5 vs 2); neuropathy-sensory (9 vs 4); and rash/desquamation (1 vs 3). Abbreviated Adverse Reactions (% incidence) for NSCLC 2nd-line: The most severe adverse reactions (Grades 3/4) with ALIMTA as a single agent versus docetaxel, respectively, for the 2nd-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (5 vs 4); leukopenia (4 vs 27); thrombocytopenia (2 vs ); anemia (4 vs 4); fatigue (5 vs 5); nausea (3 vs 2); anorexia (2 vs 3); vomiting (2 vs 1); increased ALT (2 vs ); increased AST (1 vs ); and stomatitis/pharyngitis (1 vs 1). Common adverse reactions (all Grades) with ALIMTA as a single agent versus docetaxel, respectively, were fatigue (34 vs 36); nausea (31 vs 17); anorexia (22 vs 24); anemia (19 vs 22); vomiting (16 vs 12); stomatitis/pharyngitis (15 vs 17); rash (14 vs 6); diarrhea (13 vs 24); leukopenia (12 vs 34); and neutropenia (11 vs 45). For additional safety and dosing guidelines, please see brief summary of Prescribing Information on adjacent page.

29 ALIMTA (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information. 1 INDICATIONS AND USAGE 1.1 Nonsquamous Non-Small Cell Lung Cancer Combination with Cisplatin ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. 1.2 Nonsquamous Non-Small Cell Lung Cancer Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. 1.3 Nonsquamous Non-Small Cell Lung Cancer After Prior Chemotherapy ALIMTA is indicated as a single agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy. 1.4 Mesothelioma ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. 1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. [see Clinical Studies (14.1, 14.2, and 14.3)] 2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin Nonsquamous Non-Small Cell Lung Cancer and Malignant Pleural Mesothelioma The recommended dose of ALIMTA is 5 mg/m 2 administered as an intravenous infusion over 1 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m 2 infused over 2 hours beginning approximately 3 minutes after the end of ALIMTA administration. Patients should receive appropriate hydration prior to and/or after receiving cisplatin. See cisplatin package insert for more information. 2.2 Single-Agent Use Nonsquamous Non-Small Cell Lung Cancer The recommended dose of ALIMTA is 5 mg/m 2 administered as an intravenous infusion over 1 minutes on Day 1 of each 21-day cycle. 2.3 Premedication Regimen Vitamin Supplementation To reduce toxicity, patients treated with ALIMTA must be instructed to take a low-dose oral folic acid preparation or multivitamin with folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose of ALIMTA; and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA. Patients must also receive one (1) intramuscular injection of vitamin B 12 during the week preceding the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B 12 injections may be given the same day as ALIMTA. In clinical trials, the dose of folic acid studied ranged from 35 to 1 mcg, and the dose of vitamin B 12 was 1 mcg. The most commonly used dose of oral folic acid in clinical trials was 4 mcg [see Warnings and Precautions (5.1)]. Corticosteroid Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)]. 2.4 Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is 15 cells/mm 3, the platelet count is 1, cells/ mm 3, and creatinine clearance is 45 ml/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)]. Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin. Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin Hematologic Toxicities Nadir ANC <5/mm 3 and nadir platelets 5,/mm 3 75% of previous dose (pemetrexed and cisplatin) Nadir platelets <5,/mm 3 without bleeding 75% of previous dose regardless of nadir ANC (pemetrexed and cisplatin) Nadir platelets <5,/mm 3 with bleeding a, regardless 5% of previous dose of nadir ANC (pemetrexed and cisplatin) a These criteria meet the CTC version 2. (NCI 1998) definition of CTC Grade 2 bleeding. If patients develop nonhematologic toxicities (excluding neurotoxicity) Grade 3, treatment should be withheld until resolution to less than or equal to the patient s pre-therapy value. Treatment should be resumed according to guidelines in Table 2. Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin Nonhematologic Toxicities a,b Dose of ALIMTA Dose of Cisplatin (mg/m 2 ) (mg/m 2 ) Any Grade 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous dose Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea 75% of previous dose 75% of previous dose Grade 3 or 4 mucositis 5% of previous dose 1% of previous dose a NCI Common Toxicity Criteria (CTC). b Excluding neurotoxicity (see Table 3). In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced. Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin Neurotoxicity Dose of ALIMTA Dose of Cisplatin CTC Grade (mg/m 2 ) (mg/m 2 ) -1 1% of previous dose 1% of previous dose 2 1% of previous dose 5% of previous dose Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed. Renally Impaired Patients In clinical studies, patients with creatinine clearance 45 ml/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 ml/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. 3 DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 1 mg or 5 mg pemetrexed. 4 CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation. 5 WARNINGS AND PRECAUTIONS 5.1 Premedication Regimen Need for Folate and Vitamin B 12 Supplementation Patients treated with ALIMTA must be instructed to take folic acid and vitamin B 12 as a prophylactic measure to reduce treatment-related hematologic and GI toxicity [see Dosage and Administration (2.3)]. In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B 12 was administered. Corticosteroid Supplementation Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction [see Dosage and Administration (2.3)]. 5.2 Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)]. 5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance 45 ml/min. Insufficient numbers of patients have been studied with creatinine clearance <45 ml/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 ml/min [see Dosage and Administration (2.4)]. One patient with severe renal impairment (creatinine clearance 19 ml/min) who did not receive folic acid and vitamin B 12 died of drug-related toxicity following administration of ALIMTA alone. 5.4 Use with Non-Steroidal Anti-Inflammatory Drugs with Mild to Moderate Renal Insufficiency Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min). Other NSAIDs should also be used with caution [see Drug Interactions (7.1)]. 5.5 Required Laboratory Monitoring Patients should not begin a new cycle of treatment unless the ANC is 15 cells/mm 3, the platelet count is 1, cells/mm 3, and creatinine clearance is 45 ml/min [see Dosage and Administration (2.4)]. ALIMTA (pemetrexed for injection) PV 526 AMP ALIMTA (pemetrexed for injection) PV 526 AMP

30 5.6 Pregnancy Category D Based on its mechanism of action, ALIMTA can cause fetal harm when administered to Incidence 1% to 5% Body as a Whole febrile neutropenia, infection, pyrexia a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. [see Use in Specific Populations (8.1)] General Disorders dehydration Metabolism and Nutrition increased AST, increased ALT Renal creatinine clearance decrease, renal failure Special Senses conjunctivitis Incidence Less than 1% Cardiovascular arrhythmia General Disorders chest pain 5.7 Third Space Fluid Metabolism and Nutrition increased GGT The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is Neurology motor neuropathy unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration. Non-Small Cell Lung Cancer (NSCLC) - Maintenance Table 5 provides the frequency and severity of adverse reactions that have been 6 ADVERSE REACTIONS reported in >5% of 438 patients with NSCLC who received ALIMTA and 218 patients with NSCLC who received placebo. All patients received study therapy immediately following 6.1 Clinical Trials Experience 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in Because clinical trials are conducted under widely varying conditions, adverse both study arms were fully supplemented with folic acid and vitamin B 12. reactions rates cannot be directly compared to rates in other clinical trials and may not reflect Table 5: Adverse Reactions in Patients Receiving ALIMTA versus Placebo in NSCLC the rates observed in clinical practice. ALIMTA Placebo In clinical trials, the most common adverse reactions (incidence 2%) during therapy Reaction with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common (N=438) (N=218) All Grades Grade 3-4 All Grades Grade 3-4 adverse reactions (incidence 2%) during therapy with ALIMTA when used in combination Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. All Adverse Reactions Non-Small Cell Lung Cancer (NSCLC) Combination with Cisplatin Table 4 provides the frequency and severity of adverse reactions that have been Laboratory Hematologic reported in >5% of 839 patients with NSCLC who were randomized to study and received Anemia ALIMTA plus cisplatin and 83 patients with NSCLC who were randomized to study and Neutropenia 6 3 received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for Leukopenia locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B 12. Hepatic Increased ALT 1 4 Table 4: Adverse Reactions in Fully Supplemented Increased AST 8 4 Patients Receiving ALIMTA plus Cisplatin in NSCLC a Clinical ALIMTA/cisplatin Gemcitabine/cisplatin Constitutional Symptoms Reaction b (N=839) (N=83) Fatigue All Grades Grade 3-4 All Grades Grade 3-4 Gastrointestinal Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Nausea All Adverse Reactions Anorexia Vomiting 9 1 Laboratory Mucositis/stomatitis Hematologic Diarrhea Anemia Neutropenia Infection Leukopenia Neurology Thrombocytopenia Neuropathy-sensory Renal Creatinine elevation Dermatology/Skin Rash/Desquamation 1 3 a Clinical For the purpose of this table a cut off of 5% was used for inclusion of all events where the Constitutional Symptoms reporter considered a possible relationship to ALIMTA. b Fatigue Refer to NCI CTCAE Criteria version 3. for each Grade of toxicity. Gastrointestinal Nausea No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients based on age, gender, ethnic origin, or histology except a higher incidence of Grade 3/4 Vomiting fatigue for Caucasian patients compared to non-caucasian patients (6.5% versus.6%). Anorexia Safety was assessed by exposure for patients who received at least one dose of Constipation ALIMTA (N=438). The incidence of adverse reactions was evaluated for patients who received Stomatitis/Pharyngitis cycles of ALIMTA, and compared to patients who received >6 cycles of ALIMTA. Increases Diarrhea in adverse reactions (all grades) were observed with longer exposure; however no clinically Dyspepsia/Heartburn 5 6 relevant differences in Grade 3/4 adverse reactions were seen. Neurology Neuropathy-sensory Consistent with the higher incidence of anemia (all grades) on the ALIMTA arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and Taste disturbance 8 c 9 c darbepoetin) were higher in the ALIMTA arm compared to the placebo arm (transfusions Dermatology/Skin Alopecia 12 c 21 1 c 9.5% versus 3.2%, ESAs 5.9% versus 1.8%). The following additional adverse reactions were observed in patients with non-small Rash/Desquamation cell lung cancer who received ALIMTA. a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2. for each Grade of toxicity. Incidence 1% to 5% Dermatology/Skin alopecia, pruritis/itching Gastrointestinal constipation c According to NCI CTC Criteria version 2., this adverse event term should only be reported General Disorders edema, fever (in the absence of neutropenia) as Grade 1 or 2. Hematologic thrombocytopenia No clinically relevant differences in adverse reactions were seen in patients based on histology. In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm. The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin. Renal decreased creatinine clearance, increased creatinine, decreased glomerular filtration rate Special Senses ocular surface disease (including conjunctivitis), increased lacrimation Incidence Less than 1% Cardiovascular supraventricular arrhythmia Dermatology/Skin erythema multiforme ALIMTA (pemetrexed for injection) PV 526 AMP ALIMTA (pemetrexed for injection) PV 526 AMP

31 General Disorders febrile neutropenia, allergic reaction/hypersensitivity Neurology motor neuropathy Renal renal failure Non-Small Cell Lung Cancer (NSCLC) After Prior Chemotherapy Table 6 provides the frequency and severity of adverse reactions that have been reported in >5% of 265 patients randomly assigned to receive single-agent ALIMTA with folic acid and vitamin B 12 supplementation and 276 patients randomly assigned to receive singleagent docetaxel. All patients were diagnosed with locally advanced or metastatic NSCLC and received prior chemotherapy. Table 6: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA versus Docetaxel in NSCLC a ALIMTA Docetaxel Reaction b (N=265) (N=276) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Laboratory Hematologic Anemia Leukopenia Neutropenia Thrombocytopenia Hepatic Increased ALT Increased AST Clinical Gastrointestinal Nausea Anorexia Vomiting Stomatitis/Pharyngitis Diarrhea Constipation 6 4 Constitutional Symptoms Fatigue Fever 8 8 Dermatology/Skin Rash/Desquamation 14 6 Pruritis 7 2 Alopecia 6 1 c 38 2 c a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria for lab values for each Grade of toxicity (version 2.). c According to NCI CTC Criteria version 2., this adverse event term should only be reported as Grade 1 or 2. No clinically relevant differences in adverse reactions were seen in patients based on histology. Clinically relevant adverse reactions occurring in <5% of patients that received ALIMTA treatment but >5% of patients that received docetaxel include CTC Grade 3/4 febrile neutropenia (1.9% ALIMTA, 12.7% docetaxel). The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA. Incidence 1% to 5% Body as a Whole abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection Dermatology/Skin erythema multiforme Neurology motor neuropathy, sensory neuropathy Renal increased creatinine Incidence Less than 1% Cardiovascular supraventricular arrhythmias Malignant Pleural Mesothelioma (MPM) Table 7 provides the frequency and severity of adverse reactions that have been reported in >5% of 168 patients with mesothelioma who were randomly assigned to receive cisplatin and ALIMTA and 163 patients with mesothelioma randomly assigned to receive single-agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and vitamin B 12. Table 7: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPM a Table 7 continued here. Table 7: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPM a Reaction b ALIMTA/cisplatin (N=168) Cisplatin (N=163) All Grades Toxicity (%) Grade 3-4 Toxicity (%) All Grades Toxicity (%) Grade 3-4 Toxicity (%) Laboratory Hematologic (cont.) Thrombocytopenia Renal Creatinine elevation Creatinine clearance decreased Clinical Eye Disorder Conjunctivitis 5 1 Gastrointestinal Nausea Vomiting Stomatitis/Pharyngitis Anorexia Diarrhea Constipation Dyspepsia Constitutional Symptoms Fatigue Metabolism and Nutrition Dehydration Neurology Neuropathy-sensory Taste Disturbance 1 8 c c Dermatology/Skin Rash Alopecia c 5 6 c a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2. for each Grade of toxicity except the term creatinine clearance decreased which is derived from the CTC term renal/genitourinary-other. c According to NCI CTC Criteria version 2., this adverse event term should only be reported as Grade 1 or 2. The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned to receive ALIMTA plus cisplatin. Incidence 1% to 5% Body as a Whole febrile neutropenia, infection, pyrexia Dermatology/Skin urticaria General Disorders chest pain Metabolism and Nutrition increased AST, increased ALT, increased GGT Renal renal failure Incidence Less than 1% Cardiovascular arrhythmia Neurology motor neuropathy Effects of Vitamin Supplementations Table 8 compares the incidence (percentage of patients) of CTC Grade 3/4 toxicities in patients who received vitamin supplementation with daily folic acid and vitamin B 12 from the time of enrollment in the study (fully supplemented) with the incidence in patients who never received vitamin supplementation (never supplemented) during the study in the ALIMTA plus cisplatin arm. Table 8: Selected Grade 3/4 Adverse Events Comparing Fully Supplemented versus Never Supplemented Patients in the ALIMTA plus Cisplatin arm (% incidence) Fully Supplemented Never Supplemented Patients Patients Adverse Event a (%) (N=168) (N=32) Neutropenia/granulocytopenia Thrombocytopenia 5 9 Vomiting Febrile neutropenia 1 9 Infection with Grade 3/4 neutropenia 6 Diarrhea 4 9 a Refer to NCI CTC criteria for lab and non-laboratory values for each grade of toxicity (Version 2.). The following adverse events were greater in the fully supplemented group compared to the never supplemented group: hypertension (11%, 3%), chest pain (8%, 6%), and thrombosis/embolism (6%, 3%). Subpopulations No relevant effect for ALIMTA safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%). 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of ALIMTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have occurred with ALIMTA when used as a single-agent and in combination therapies. Gastrointestinal colitis General Disorders and Administration Site Conditions edema ALIMTA/cisplatin Cisplatin Reaction b (N=168) (N=163) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Laboratory Hematologic Neutropenia Leukopenia Anemia Table 7 continued in next column. ALIMTA (pemetrexed for injection) PV 526 AMP ALIMTA (pemetrexed for injection) PV 526 AMP

32 Injury, poisoning, and procedural complications Radiation recall has been reported in patients who have previously received radiotherapy Respiratory interstitial pneumonitis 7 DRUG INTERACTIONS 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ibuprofen Although ibuprofen (4 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance 8 ml/min). Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min) [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Other NSAIDs Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. 7.2 Nephrotoxic Drugs ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects Pregnancy Category D [see Warnings and Precautions (5.6)] Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m 2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m 2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA. 8.3 Nursing Mothers It is not known whether ALIMTA or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother. 8.4 Pediatric Use The safety and effectiveness of ALIMTA in pediatric patients have not been established. 8.5 Geriatric Use ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)]. In the initial treatment non-small cell lung cancer clinical trial, 37.7% of patients treated with ALIMTA plus cisplatin were 65 years and Grade 3/4 neutropenia was greater as compared to patients <65 years (19.9% versus 12.2%). For patients <65 years, the HR for overall survival was.96 (95% CI:.83, 1.1) and for patients 65 years the HR was.88 (95% CI:.74, 1.6) in the intent-to-treat population. In the maintenance non-small cell lung cancer trial, 33.3% of patients treated with ALIMTA were 65 years and no differences were seen in Grade 3/4 adverse reactions as compared to patients <65 years. For patients <65 years, the HR for overall survival was.74 (95% CI:.58,.93) and for patients 65 years the HR was.88 (95% CI:.65, 1.21) in the intent-to-treat population. In the non-small cell lung cancer trial after prior chemotherapy, 29.7% patients treated with ALIMTA were 65 years and Grade 3/4 hypertension was greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was.95 (95% CI:.76, 1.19), and for patients 65 years the HR was 1.15 (95% CI:.79, 1.68) in the intent-to-treat population. The mesothelioma trial included 36.7% patients treated with ALIMTA plus cisplatin that were 65 years, and Grade 3/4 fatigue, leukopenia, neutropenia, and thrombocytopenia were greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was.71 (95% CI:.53,.96) and for patients 65 years, the HR was.85 (95% CI:.59, 1.22) in the intent-to-treat population. 8.6 Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA are provided in Table 2 [see Dosage and Administration (2.4)]. 8.7 Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment. 8.8 Gender In the initial treatment non-small cell lung cancer trial, 7% of patients were males and 3% females. For males the HR for overall survival was.97 (95% CI:.85, 1.1) and for females the HR was.86 (95% CI:.7, 1.6) in the intent-to-treat population. In the maintenance non-small cell lung cancer trial, 73% of patients were males and 27% females. For males the HR for overall survival was.78 (95% CI:.63,.96) and for females the HR was.83 (95% CI:.56, 1.21) in the intent-to-treat population. In the non-small cell lung cancer trial after prior chemotherapy, 72% of patients were males and 28% females. For males the HR for overall survival was.95 (95% CI:.76, 1.19) and for females the HR was 1.28 (95% CI:.86, 1.91) in the intent-to-treat population. In the mesothelioma trial, 82% of patients were males and 18% females. For males the HR for overall survival was.85 (95% CI:.66, 1.9) and for females the HR was.48 (95% CI:.27,.85) in the intent-to-treat population. 8.9 Race In the initial treatment non-small cell lung cancer trial, 78% of patients were Caucasians, 13% East/Southeast Asians, and 9% others. For Caucasians, the HR for overall survival was.92 (95% CI:.82, 1.4), for East/Southeast Asians the HR was.86 (95% CI:.61, 1.21), and for others the HR was 1.24 (95% CI:.84, 1.84) in the intent-to-treat population. In the maintenance non-small cell lung cancer trial, 65% of patients were Caucasians, 23% East Asian, and 12% others. For Caucasians the HR for overall survival was.77 (95% CI:.62,.97), for East Asians was 1.5 (95% CI:.7, 1.59) and for others the HR was.46 (95% CI:.26,.79) in the intent-to-treat population. In the non-small cell lung cancer trial after prior chemotherapy, 71% of patients were Caucasians and 29% others. For Caucasians the HR for overall survival was.91 (95% CI:.73, 1.15) and for others the HR was 1.27 (95% CI:.87, 1.87) in the intent-to-treat population. In the mesothelioma trial, 92% of patients were Caucasians and 8% others. For Caucasians, the HR for overall survival was.77 (95% CI:.61,.97) and for others the HR was.86 (95% CI:.39, 1.9) in the intent-to-treat population. 1 OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting 3 days, CTC Grade 4 neutropenia lasting 3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 1 mg/m 2, intravenously once, followed by leucovorin, 5 mg/m 2, intravenously every 6 hours for 8 days. The ability of ALIMTA to be dialyzed is unknown. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m 2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling. Patients should be instructed to read the patient package insert carefully Need for Folic Acid and Vitamin B 12 Patients treated with ALIMTA must be instructed to take folic acid and vitamin B 12 as a prophylactic measure to reduce treatment-related hematologic and gastrointestinal toxicity [see Dosage and Administration (2.3)] Low Blood Cell Counts Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of anemia occur Gastrointestinal Effects Patients should be instructed to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear Concomitant Medications Patients should be instructed to inform the physician if they are taking any concomitant prescription or over-the-counter medications including those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)] FDA-Approved Patient Labeling Patients should be instructed to read the patient package insert carefully. To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-8- LillyRx ( ) or FDA at 1-8-FDA-188, or Literature revised July 2, 29 Eli Lilly and Company Indianapolis, IN 46285, USA Copyright 24, 29, Eli Lilly and Company. All rights reserved. PV 526 AMP PRINTED IN USA ALIMTA (pemetrexed for injection) PV 526 AMP ALIMTA (pemetrexed for injection) PV 526 AMP

33 For Neuroendocrine Tumors (NETs), Is watch and wait out of date? NETs are a group of malignancies that originate from neuroendocrine cells throughout the body. Some of these tumors can be aggressive 1 : The 5-year survival rate of well- and moderately differentiated NETs with distant metastases is 35%, which is similar to the 5-year survival rate for prostate cancer with distant metastases (31%) and breast cancer with distant metastases (23%) 1-3 For poorly differentiated NETs with distant metastases, the 5-year survival rate is 4% 1 Distant metastases are present at diagnosis in 21% of patients with well-differentiated, 3% of patients with moderately differentiated, and 5% of patients with poorly/undifferentiated NETs 1 The most common cause of death in patients with NETs is organ failure 1 Even small gastrointestinal and pancreatic NETs (<2 cm) can be aggressive and metastasize 4-6 Considering these data, should we manage NETs more actively? References: 1. Yao JC, Hassan M, Phan A, et al. One hundred years after carcinoid : epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 28;26(18): National Cancer Institute. Surveillance Epidemiology and End Results (SEER) Stat Fact Sheets: Cancer of the Prostate. Available at: Accessed September 18, National Cancer Institute. Surveillance Epidemiology and End Results (SEER) Stat Fact Sheets: Cancer of the Breast. Available at: Accessed September 18, Alexiev BA, Drachenberg CB, Papadimitriou JC. Endocrine tumors of the gastrointestinal tract and pancreas: grading, tumor size and proliferation index do not predict malignant behavior. Diagn Pathol. 27;2: Soga J. Early-stage carcinoids of the gastrointestinal tract: an analysis of 1914 reported cases. Cancer. 25;13(8): Mullen JT, Wang H, Yao JC, et al. Carcinoid tumors of the duodenum. Surgery. 25;138(6): An educational message from Novartis Pharmaceuticals Corporation East Hanover, NJ 7936 Novartis 29 September 29 C-NET-12

34 Avid golfer. Adenocarcinoma survivor. Tarceva patient. Wilma Bateman, Tarceva NSCLC patient After raising six children, Wilma thought that perfecting her golf swing was the biggest challenge she had yet to face. Then she found out she had NSCLC. But with the help of Tarceva, she s still taking on life s challenges and still swinging. Please see important safety information and brief summary of full prescribing information on adjacent pages. Indication and usage in second-line advanced NSCLC Tarceva monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. Results from two multicenter, placebo-controlled, randomized, Phase III trials conducted in first-line patients with locally advanced or metastatic NSCLC showed no clinical benefit with the concurrent administration of Tarceva with platinum-based chemotherapy, and its use is not recommended in that setting. Results not typical.

35 Tarceva may make positive outcomes possible in select patients Second-line NSCLC survival based on a retrospective, exploratory subset analysis of BR.21: Squamous-cell histology * Tarceva more than doubled median survival vs placebo in patients with PS /1, squamous-cell histology (1. months vs 4.2 months, respectively; HR=.46; 95% CI= ). 1 Female with adenocarcinoma * Tarceva tripled median survival vs placebo in female patients with adenocarcinoma (11.75 months vs 3.91 months, respectively; HR=.41; 95% CI= ). 1 Median survival Median survival Tarceva (n=38) Placebo (n=24) 4.2 months 1. months P= Months Tarceva (n=5) Placebo (n=26) 3.91 months months P=.15 Never smoker * Tarceva tripled median survival vs placebo in never smokers (13.37 months vs 4.32 months, respectively; HR=.27; 95% CI= ). 1 Median survival Months Tarceva (n=51) Placebo (n=2) 4.32 months P< months BR.21 unselected NSCLC patients Median survival was lengthened in unselected patients in a phase III NSCLC trial vs placebo (6.7 months vs 4.7 months, respectively; HR=.73; 95% CI= ). 2 Overall survival was prolonged by 37% (HR=.73; P<.1). 2 One-year survival rate increased by 45% (31.2% vs 21.5%). 2 Median survival Months Tarceva (n=488) Placebo (n=243) * The data presented cannot be extrapolated to patients outside the identifi ed subsets. The safety profiles of the patients in the identified subsets are unknown. 4.7 months 6.7 months P< Months Share your stories Encourage your patients to share their stories by calling or ing shareyourstories@gene.com. References: 1. Data on fi le, OSI Pharmaceuticals Inc. 2. Tarceva [package insert]. Melville, NY: OSI Pharmaceuticals Inc; 29. TARCEVA, its logo mark and are trademarks of OSI Pharmaceuticals, Inc., Melville, NY 11747, USA. 29 Genentech USA, Inc. All rights reserved. 8/

36 First-line pancreatic cancer In the pivotal phase III trial evaluating Tarceva plus gemcitabine vs placebo plus gemcitabine, the Tarceva combination signifi cantly improved: - Overall survival outcomes by 23% vs gemcitabine alone (HR=.81; 95% CI= ; P=.28) 2 - One-year survival (23.8% with Tarceva plus gemcitabine vs 19.4% with gemcitabine alone) 2 - Median survival (6.4 months with Tarceva plus gemcitabine vs 6. months with gemcitabine alone) 2 Indications and usage Second-line advanced NSCLC Tarceva monotherapy is indicated for the treatment of patients with Percentage of patients alive at one year 25% 2% 15% 1% 5% % CELEBRATING YEARS 23.8% Tarceva + gemcitabine (n=261) 1-year survival 19.4% Gemcitabine (n=26) locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. Results from two multicenter, placebo-controlled, randomized, Phase III trials conducted in first-line patients with locally advanced or metastatic NSCLC showed no clinical benefit with the concurrent administration of Tarceva with platinum-based chemotherapy, and its use is not recommended in that setting. First-line advanced pancreatic cancer Tarceva in combination with gemcitabine is indicated for first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer. Important safety information There have been infrequent reports of serious Interstitial Lung Disease (ILD)-like events, including fatalities, in patients receiving Tarceva for treatment of NSCLC, pancreatic cancer or other advanced solid tumors. Cases of hepatic failure, hepatorenal syndrome, acute renal failure (all including fatalities), and renal insuffi ciency have been reported during use of Tarceva. Gastrointestinal perforation (including fatalities) has been reported in patients receiving Tarceva. Bullous, blistering and exfoliative skin conditions have been reported including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, which in some cases were fatal. In the pancreatic cancer trial, other serious adverse reactions associated with Tarceva plus gemcitabine and which may have included fatalities, were myocardial infarction/ischemia, cerebrovascular accident and microangiopathic hemolytic anemia with thrombocytopenia. Corneal perforation and ulceration have been reported during use of Tarceva. When receiving Tarceva therapy, women should be advised against becoming pregnant or breastfeeding. Tarceva is pregnancy category D. The most common adverse reactions in patients with NSCLC receiving Tarceva monotherapy 15 mg were rash and diarrhea. The most common adverse reactions in patients with pancreatic cancer receiving Tarceva 1 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. tablets Please see brief summary of full prescribing information on adjacent page. POSSIBILITIES Proven to prolong survival

37 TARCEVA (erlotinib) TABLETS BRIEF SUMMARY Please see the Tarceva package insert for full prescribing information. INDICATIONS AND USAGE Non-Small Cell Lung Cancer (NSCLC) TARCEVA monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen [see Clinical Studies (14.1)]. Results from two, multicenter, placebo-controlled, randomized, Phase 3 trials conducted in first-line patients with locally advanced or metastatic NSCLC showed no clinical benefit with the concurrent administration of TARCEVA with platinum-based chemotherapy [carboplatin and paclitaxel or gemcitabine and cisplatin] and its use is not recommended in that setting [see Clinical Studies (14.2)]. Pancreatic Cancer TARCEVA in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer [see Clinical Studies (14.3)]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Pulmonary Toxicity There have been infrequent reports of serious Interstitial Lung Disease (ILD)-like events, including fatalities, in patients receiving TARCEVA for treatment of NSCLC, pancreatic cancer or other advanced solid tumors. In the randomized single-agent NSCLC study [see Clinical Studies (14.1)], the incidence of ILD-like events (.8%) was the same in both the placebo and TARCEVA groups. In the pancreatic cancer study in combination with gemcitabine [see Clinical Studies (14.3)], the incidence of ILD-like events was 2.5% in the TARCEVA plus gemcitabine group vs..4% in the placebo plus gemcitabine group. The overall incidence of ILD-like events in approximately 49 TARCEVA-treated patients from all studies (including uncontrolled studies and studies with concurrent chemotherapy) was approximately.7%. Reported diagnoses in patients suspected of having ILD-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, Acute Respiratory Distress Syndrome and lung infiltration. Symptoms started from 5 days to more than 9 months (median 39 days) after initiating TARCEVA therapy. In the lung cancer trials most of the cases were associated with confounding or contributing factors such as concomitant/prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary infections. In the event of an acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever, TARCEVA therapy should be interrupted pending diagnostic evaluation. If ILD is diagnosed, TARCEVA should be discontinued and appropriate treatment instituted as needed [see Dosage and Administration (2.3)]. Renal Failure Cases of hepatorenal syndrome, acute renal failure (including fatalities), and renal insufficiency have been reported. Some were secondary to baseline hepatic impairment while others were associated with severe dehydration due to diarrhea, vomiting, and/or anorexia or concurrent chemotherapy use. In the event of dehydration, particularly in patients with contributing risk factors for renal failure (eg, pre-existing renal disease, medical conditions or medications that may lead to renal disease, or other predisposing conditions including advanced age), TARCEVA therapy should be interrupted and appropriate measures should be taken to intensively rehydrate the patient. Periodic monitoring of renal function and serum electrolytes is recommended in patients at risk of dehydration [see Adverse Reactions (6.3) and Dosage and Administration (2.3)]. Hepatotoxicity Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported during use of TARCEVA, particularly in patients with baseline hepatic impairment. Therefore, periodic liver function testing (transaminases, bilirubin, and alkaline phosphatase) is recommended. In the setting of worsening liver function tests, dose interruption and/or dose reduction with frequent liver function test monitoring should be considered. TARCEVA dosing should be interrupted or discontinued if total bilirubin is > 3 x ULN and/or transaminases are > 5 x ULN in the setting of normal pretreatment values [see Adverse Reactions (6.3) and Dosage and Administration (2.3)]. Patients with Hepatic Impairment In a pharmacokinetic study in patients with moderate hepatic impairment (Child-Pugh B) associated with significant liver tumor burden, 1 out of 15 patients died on treatment or within 3 days of the last TARCEVA dose. One patient died from hepatorenal syndrome, 1 patient died from rapidly progressing liver failure and the remaining 8 patients died from progressive disease. Six out of the 1 patients who died had baseline total bilirubin > 3 x ULN suggesting severe hepatic impairment. Treatment with TARCEVA should be used with extra caution in patients with total bilirubin > 3 x ULN. Patients with hepatic impairment (total bilirubin > ULN or Child-Pugh A, B and C) should be closely monitored during therapy with TARCEVA. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe such as doubling of total bilirubin and/or tripling of transaminases in the setting of pretreatment values outside normal range [see Clinical Pharmacology (12.3) and Dosage and Administration (2.3)]. Gastrointestinal Perforation Gastrointestinal perforation (including fatalities) has been reported in patients receiving TARCEVA. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease are at increased risk. [see Adverse Reactions (6.3)]. Permanently discontinue TARCEVA in patients who develop gastrointestinal perforation. Bullous and Exfoliative Skin Disorders Bullous, blistering and exfoliative skin conditions have been reported including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, which in some cases were fatal [see Adverse Reactions (6.3)]. Interrupt or discontinue TARCEVA treatment if the patient develops severe bullous, blistering or exfoliating conditions. Myocardial infarction/ischemia In the pancreatic carcinoma trial, six patients (incidence of 2.3%) in the TARCEVA/ gemcitabine group developed myocardial infarction/ischemia. One of these patients died due to myocardial infarction. In comparison, 3 patients in the placebo/gemcitabine group developed myocardial infarction (incidence 1.2%) and one died due to myocardial infarction. Cerebrovascular accident In the pancreatic carcinoma trial, six patients in the TARCEVA/gemcitabine group developed cerebrovascular accidents (incidence: 2.3%). One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo/gemcitabine group there were no cerebrovascular accidents. Microangiopathic Hemolytic Anemia with Thrombocytopenia In the pancreatic carcinoma trial, two patients in the TARCEVA/gemcitabine group developed microangiopathic hemolytic anemia with thrombocytopenia (incidence:.8%). Both patients received TARCEVA and gemcitabine concurrently. In comparison, in the placebo/gemcitabine group there were no cases of microangiopathic hemolytic anemia with thrombocytopenia. Ocular Disorders Corneal perforation and ulceration have been reported during use of TARCEVA. Other ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis have been observed with TARCEVA treatment and are known risk factors for corneal ulceration/perforation [see Adverse Reactions (6.3)]. Interrupt or discontinue TARCEVA therapy if patients present with acute/worsening ocular disorders such as eye pain. Use in Pregnancy Pregnancy Category D Women of childbearing potential should avoid becoming pregnant while being treated with TARCEVA. Erlotinib administered to rabbits during organogenesis at doses that result in plasma drug concentrations of approximately 3 times those in humans (AUCs at 15 mg daily dose) was associated with embryo/fetal lethality and abortion. When erlotinib was administered to female rats prior to mating and through the first week of pregnancy, at doses.3 or.7 times the clinical dose of 15 mg, on a mg/m 2 basis, there was an increase in early resorptions that resulted in a decrease in the number of live fetuses. [see Use in Specific Populations (8.1)]. Elevated International Normalized Ratio and Potential Bleeding International Normalized Ratio (INR) elevations and infrequent reports of bleeding events including gastrointestinal and non-gastrointestinal bleedings have been reported in clinical studies, some associated with concomitant warfarin administration. Patients taking warfarin or other coumarin-derivative anticoagulants should be monitored regularly for changes in prothrombin time or INR. [see Adverse Reactions (6.3)]. ADVERSE REACTIONS Non-Small Cell Lung Cancer Adverse reactions, regardless of causality, that occurred in at least 1% of patients treated with single-agent TARCEVA at 15 mg and at least 3% more often than in the placebo group in the randomized trial of patients with NSCLC are summarized by NCI-CTC (version 2.) Grade in Table 1. The most common adverse reactions in patients receiving single-agent TARCEVA 15 mg were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 9% and 6%, respectively, in TARCEVA-treated patients. Rash and diarrhea each resulted in study discontinuation in 1% of TARCEVA-treated patients. Six percent and 1% of patients needed dose reduction for rash and diarrhea, respectively. The median time to onset of rash was 8 days, and the median time to onset of diarrhea was 12 days. Table 1: Adverse Reactions Occurring More Frequently ( 3%) in the Single-agent TARCEVA Group than in the Placebo Group and in 1% of Patients in the TARCEVA Group. TARCEVA 15 mg N = 485 Any Grade Grade Grade 3 4 Any Grade Placebo N = 242 Grade 3 Grade 4 NCI-CTC Grade MedDRA Preferred Term % % % % % % Rash 75 8 < 1 17 Diarrhea 54 6 < 1 18 < 1 Anorexia < 1 Fatigue Dyspnea Cough Nausea Infection Vomiting 23 2 < Stomatitis 17 < 1 3 Pruritus 13 < 1 5 Dry skin 12 4 Conjunctivitis 12 < 1 2 < 1 Keratoconjunctivitis 12 3 sicca Abdominal pain 11 2 < < 1 Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) were observed in patients receiving single-agent TARCEVA 15 mg. These elevations were mainly transient or associated with liver metastases. Grade 2 (> x ULN) ALT elevations occurred in 4% and < 1% of TARCEVA and placebo treated patients, respectively. Grade 3 (> x ULN) elevations were not observed in TARCEVA-treated patients. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe. [see Dosage and Administration (2.3)]. Pancreatic Cancer Adverse reactions, regardless of causality, that occurred in at least 1% of patients treated with TARCEVA 1 mg plus gemcitabine in the randomized trial of patients with pancreatic cancer are summarized by NCI-CTC (version 2.) Grade in Table 2. The most common adverse reactions in pancreatic cancer patients receiving TARCEVA 1 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. In the TARCEVA plus gemcitabine arm, Grade 3/4 rash and diarrhea were each reported in 5% of TARCEVA plus gemcitabine-treated patients. The median time to onset of rash and diarrhea was 1 days and 15 days, respectively. Rash and diarrhea each resulted in dose reductions in 2% of patients, and resulted in study discontinuation in up to 1% of patients receiving TARCEVA plus gemcitabine. The 15 mg cohort was associated with a higher rate of certain class-specific adverse reactions including rash and required more frequent dose reduction or interruption. Table 2: Adverse Reactions Occurring in 1% of TARCEVA-treated Pancreatic Cancer Patients: 1 mg cohort TARCEVA + Gemcitabine 1 mg/m 2 IV N = 259 Any Grade Grade 3 Grade 4 Placebo + Gemcitabine 1 mg/m 2 IV N = 256 Any Grade Grade 3 Grade 4 NCI-CTC Grade MedDRA Preferred Term % % % % % % Fatigue Rash Nausea Anorexia 52 6 < < 1 Diarrhea 48 5 < Abdominal pain 46 9 < < 1 Vomiting 42 7 < < 1 Weight decreased < 1 Infection* Edema 37 3 < < 1 Pyrexia Constipation Bone pain 25 4 < Dyspnea 24 5 < Stomatitis 22 < 1 12 Myalgia < 1 Depression < 1 Dyspepsia 17 < 1 13 < 1 Cough Dizziness 15 < 1 13 < 1 Headache 15 < 1 1 Insomnia 15 < 1 16 < 1 Alopecia Anxiety < 1 Neuropathy 13 1 < 1 1 < 1 Flatulence 13 9 < 1 Rigors 12 9 *Includes all MedDRA preferred terms in the Infections and Infestations System Organ Class. In the pancreatic carcinoma trial, 1 patients in the TARCEVA/gemcitabine group developed deep venous thrombosis (incidence: 3.9%). In comparison, 3 patients in the placebo/gemcitabine group developed deep venous thrombosis (incidence 1.2%). The overall incidence of grade 3 or 4 thrombotic events, including deep venous thrombosis, was similar in the two treatment arms: 11% for TARCEVA plus gemcitabine and 9% for placebo plus gemcitabine. No differences in Grade 3 or Grade 4 hematologic laboratory toxicities were detected between the TARCEVA plus gemcitabine group compared to the placebo plus gemcitabine group. Severe adverse reactions ( grade 3 NCI-CTC) in the TARCEVA plus gemcitabine group with incidences < 5% included syncope, arrhythmias, ileus, pancreatitis, hemolytic anemia including microangiopathic hemolytic anemia with thrombocytopenia, myocardial infarction/ischemia, cerebrovascular accidents including cerebral hemorrhage, and renal insufficiency [see Warnings and Precautions (5)]. Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) have been observed following the administration of TARCEVA plus gemcitabine in patients with pancreatic cancer. Table 3 displays the most severe NCI-CTC grade of liver function abnormalities that developed. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe [see Dosage and Administration (2.3)]. Table 3: Liver Function Test Abnormalities (most severe NCI-CTC grade) in Pancreatic Cancer Patients: 1 mg Cohort TARCEVA + Gemcitabine 1 mg/m 2 IV N = 259 Grade Grade Grade Placebo + Gemcitabine 1 mg/m 2 IV N = 256 Grade Grade Grade NCI-CTC Grade Bilirubin 17% 1% < 1% 11% 1% 3% ALT 31% 13% < 1% 22% 9% % AST 24% 1% < 1% 19% 9% % NSCLC and Pancreatic Cancer Indications Gastrointestinal Disorders Gastrointestinal perforations have been reported in patients in clinical studies and during post-marketing use of TARCEVA [see Warnings and Precautions (5.5)]. During the NSCLC and the combination pancreatic cancer trials, infrequent cases of gastrointestinal bleeding have been reported, some associated with concomitant warfarin or NSAID administration. [see Warnings and Precautions (5.12)]. These adverse reactions were reported as peptic ulcer bleeding (gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis. Renal Disorders Cases of acute renal failure or renal insufficiency, including fatalities, with or without hypokalemia have been reported. [see Warnings and Precautions (5.2)]. Hepatic Disorders Hepatic failure has been reported in patients treated with single-agent TARCEVA or TARCEVA combined with chemotherapy in clinical studies and during post-marketing use of TARCEVA [see Warnings and Precautions (5.3)]; it is not possible to reliably estimate the frequency or establish a causal relationship to TARCEVA treatment. Ocular Disorders Corneal ulcerations or perforations have been reported in patients receiving TARCEVA treatment. Abnormal eyelash growth including in-growing eyelashes, excessive growth and thickening of the eyelashes have been reported [see Warnings and Precautions (5.1)] and are risk factors for corneal ulceration/perforation. NCI-CTC Grade 3 conjunctivitis and keratitis have been reported infrequently in patients receiving TARCEVA therapy in the NSCLC and pancreatic cancer clinical trials. [see Patient Counseling Information (17)] Skin, Hair and Nail Disorders Bullous, blistering and exfoliative skin conditions have been reported, including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis [see Warnings and Precautions (5.6)]. In patients who develop skin rash, the appearance of the rash is typically erythematous and maculopapular and it may resemble acne with follicular pustules, but is histopathologically different. This skin reaction commonly occurs on the face, upper chest and back, but may be more generalized or severe (NCI-CTC Grade 3 or 4) with desquamation. Skin reactions may occur or worsen in sun exposed areas; therefore, the use of sunscreen or avoidance of sun exposure is recommended. Associated symptoms may include itching, tenderness and/or burning. Also, hyperpigmentation or dry skin with or without digital skin fissures may occur. Hair and nail disorders including alopecia, hirsutism, eyelash/eyebrow (see above) changes, paronychia and brittle and loose nails have been reported in clinical trials and during post-marketing use of TARCEVA. Other Disorders Epistaxis has been reported in both the single-agent NSCLC and the pancreatic cancer clinical trials. In general, no notable differences in the safety of TARCEVA monotherapy or in combination with gemcitabine could be discerned between females or males and between patients younger or older than the age of 65 years [see Use in Specific Populations (8.4, 8.5 and 8.6)]. The safety of TARCEVA appears similar in Caucasian and Asian patients. DRUG INTERACTIONS Erlotinib is metabolized predominantly by CYP3A4, and inhibitors of CYP3A4 would be expected to increase exposure. Co-treatment with the potent CYP3A4 inhibitor ketoconazole increases erlotinib AUC by 2/3. When TARCEVA was co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2, the erlotinib exposure [AUC] and maximum concentration [Cmax] increased by 39% and 17% respectively. Caution should be used when administering or taking TARCEVA with ketoconazole and other strong CYP3A4 inhibitors such as, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole and grapefruit or grapefruit juice. [see Dosage and Administration (2.3)]. Pre-treatment with the CYP3A4 inducer rifampicin for 7 days prior to TARCEVA decreased erlotinib AUC by about 2/3 to 4/5, which is equivalent to a dose of about 3 to 5 mg in NSCLC patients. In a separate study, treatment with rifampicin for 11 days, with co-administration of a single 45 mg dose of TARCEVA on day 8 resulted in a mean erlotinib exposure (AUC) that was 57.6% of that observed following a single 15 mg TARCEVA dose in the absence of rifampicin treatment [see Dose Modifications (2.3)]. Use of alternative treatments lacking CYP3A4 inducing activity is strongly recommended. If an alternative treatment is unavailable, adjusting the starting dose should be considered. If the TARCEVA dose is adjusted upward, the dose will need to be reduced immediately to the indicated starting dose upon discontinuation of rifampicin or other inducers. Other CYP3A4 inducers include, but are not limited to, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital and St. John s Wort [see Dosage and Administration (2.3)]. Cigarette smoking has been shown to reduce erlotinib AUC. Patients should be advised to stop smoking; however, if they continue to smoke, a cautious increase in the dose of TARCEVA, not exceeding 3 mg may be considered, while monitoring the patient s safety. If the TARCEVA dose is adjusted upward, the dose should be reduced immediately to the indicated starting dose upon cessation of smoking. [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Pretreatment and co-administration of TARCEVA decreased the AUC of CYP3A4 substrate, midazolam, by 24%. The mechanism is not clear. In a study, there were no significant effects of gemcitabine on the pharmacokinetics of erlotinib nor were there significant effects of erlotinib on the pharmacokinetics of gemcitabine. Drugs that alter the ph of the upper GI tract may alter the solubility of erlotinib and reduce its bioavailability. Co-administration of TARCEVA with omeprazole, a proton pump inhibitor, decreased the erlotinib AUC by 46%. Increasing the dose of TARCEVA when co-administered with such agents is not likely to compensate for the loss of exposure. Since proton pump inhibitors affect ph of the upper GI tract for an extended period, separation of doses may not eliminate the interaction. The concomitant use of proton pump inhibitors with TARCEVA should be avoided if possible. The use of antacids may be considered in place of histamine 2 receptor blockers (H 2 blockers) or proton pump inhibitors in patients receiving TARCEVA. However, no clinical study has been conducted to evaluate the effect of antacids on erlotinib pharmacokinetics. If an antacid is necessary, the antacid dose and the TARCEVA dose should be separated by several hours [see Clinical Pharmacology (12.3)]. Manufactured for: OSI Pharmaceuticals Inc., Melville, NY Manufactured by: Schwarz Pharma Manufacturing, Seymour, IN Distributed by: Genentech USA, Inc. 1 DNA Way, South San Francisco, CA For further information please call TARCEVA ( ) or visit TARCEVA and Melville, NY, 11747, USA. 29 OSI Pharmaceuticals, Inc., and Genentech, Inc. All rights reserved. Rev. 5/ (75667) are trademarks of OSI Pharmaceuticals, Inc.,

38 ADVERTISEMENT Breakthrough cancer pain A Closer Look at Identifying the Problem Cancer pain is a serious healthcare problem A number of studies conducted over the past 2 to 25 years have demonstrated that pain is undertreated in nearly half of patients with cancer. 1-5 Recently, the Global Results Presentation conducted by European Pain in Cancer (EPIC) reported that many patients with cancer experience moderate-to-severe pain every day. Pain so severe, it is often described as intolerable. 4 This type of cancer pain can be enduring and relentless. 5 In addition to its severity, cancer pain is common throughout the entire course of disease. About a third of cancer patients experience pain at diagnosis, more than half experience pain during active treatment, and the majority experience pain with advanced disease. 6 Relatively low utilization rates of opioids have been reported among patients with metastatic cancer in their final year of life. Although published clinical guidelines recommend the use of opioids in this setting, this suggests that for many patients with advanced cancer, pain may be suboptimally treated. 5 Cancer pain is one of the most feared consequences of cancer. Pain is believed to be part of having cancer. 4 Although family members are supportive, they cannot fully comprehend the intensity of the pain or the patient s suffering. 4 Untreated or undertreated pain has a profound impact on emotional distress. 3 Patients with pain have an increased incidence of psychological factors (ie, depression and anxiety), which intensify the pain experience, and patients with cancer pain who present with psychiatric symptoms might actually be showing symptoms of uncontrolled pain. 3 Unrelieved, cancer pain destroys quality of life. 4 It adversely affects psychological and physical well-being. 7 Pain interferes with functioning, forces some patients to stop working, interferes with thinking or concentration, requires patients to rely heavily on other people, and prevents patients from caring for themselves or others. 4 Patients who experience persistent pain report a significant reduction in their ability to sleep, perform daily activities, engage in relationships with others, and enjoy life. 5 Pain also affects the family s ability to provide appropriate support. 2 According to the National Cancer Institute, there is a low priority given to cancer pain treatment. 8 Physicians are trained to focus on prolonging life and achieving a cure, rather than assessing pain 8 or alleviating suffering. 3

39 A D V E R T I S E M E N T Pain Intensity Recognizing breakthrough cancer pain In basic terms, many patients with cancer experience 2 types of cancer pain: persistent pain and breakthrough pain. Persistent pain is chronic, constant, and continuous requiring around-the-clock (baseline) medication. Breakthrough pain is pain that breaks through the baseline pain medication and is described as moderate to severe. Breakthrough cancer pain is different from persistent cancer pain. Breakthrough pain maybe episodic, spontaneous, or provoked, and it is often difficult to treat. 6 Its onset, duration, and frequency differ as well. 6 As such, it requires different medication 9,1 and a treatment strategy tailored for the individual patient. 9 Breakthrough Cancer Pain 9,11,12 AROUND-THE-CLOCK OPIOID MEDICATION PERSISTENT CANCER PAIN Artist s rendering derived from Fishbain DA. Am J Manag Care. 28;14(5 suppl 1):S123-S128; Portenoy RK, et al. Pain. 199;41: ; Shoemaker SA, et al. Poster presented at the 25th Annual Meeting of the American Academy of Pain Medicine. Honolulu, HI; January 28-31, 29 Although there is no unanimous agreement on the definition of the term breakthrough cancer pain, it is often described as transient worsening of ongoing, steady, or persistent pain in cancer patients. 6 In addition, the onset, duration, frequency, and intensity of breakthrough cancer pain differ widely from episode-to-episode and from patient-to-patient, making it difficult to generalize or characterize. 5 Nearly half of breakthrough cancer pain episodes have a sudden or intense onset. 6 The duration of these episodes varies from 15 minutes to hours. The frequency of breakthrough cancer pain episodes ranges from 4 to 7 per day and pain intensity may differ between episodes. 6 Time In a number of studies, 5% to 7% of cancer patients with pain have breakthrough cancer pain. 6 More importantly, in a recent study of patients using prescription analgesia, 64% report their medicine is not adequate to control their pain. 4 Breakthrough cancer pain must be identified in order to treat it appropriately Many healthcare professionals recognize the fact that cancer pain and breakthrough cancer pain in particular are serious healthcare problems. To help identify breakthrough cancer pain, it is critically important to start the conversation with the patient and fully understand the patient s needs before an individualized treatment regimen for relief can begin. Next in the Series: Closing the Gap by Opening the Dialogue References: 1. Cleeland CS. The impact of pain on the patient with cancer. Cancer. 1984;54 (11 suppl): Levin DN, Cleeland CS, Dar R. Public attitudes toward cancer pain. Cancer. 1985;56: Breitbart W. Psychiatric management of cancer pain. Cancer. 1989;63(11 suppl): European Pain in Cancer (EPIC) Global Results Presentation. EPIC Steering Group Presentation. July Final%2Results%2Presentation.ppt. Accessed July 2, Berger A, Dukes E, Smith M, et al. Use of oral and transdermal opioids among patients with metastatic cancer during the last year of life. J Pain Symptom Manage. 23;26(2): Svendsen KB, Andersen S, Arnason S, et al. Breakthrough pain in malignant and non-malignant diseases: a review of prevalence, characteristics and mechanisms. Eur J Pain. 25;9(2): Ferrell BR, Wisdom C, Wenzl C. Quality of life as an outcome variable in the management of cancer pain. Cancer. 1989;63(11 suppl): National Cancer Institute. supportivecare/pain/healthprofessional/page2. Accessed March 25, Fishbain DA. Pharmacotherapeutic management of breakthrough pain in patients with chronic persistent pain. Am J Manag Care. 28;14(5 suppl 1): S123-S Palos GR, Ashing-Giwa KT. The importance of community and culture in the comprehensive management of pain. Pain Practitioner. 27;17(2): Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain. 199;41: Shoemaker SA, Bruns D, Portenoy RK. Characteristics and impact of breakthrough pain (BTP) in noncancer- and cancer-related chronic pain managed by clinicians who are not pain specialists. Poster presented at the 25th Annual Meeting of the American Academy of Pain Medicine. Honolulu, HI; January 28-31, MEDA Pharmaceuticals Inc. All rights reserved. Printed in the USA. 7/9 BEM912

40 REgiSTER NOW! The Westin Diplomat 3555 South Ocean Drive Hollywood, Florida NCCN21 NCCN 15 th Annual Conference: CliniCal PraCtiCe Guidelines & Quality CanCer Care Highlights include*: nccn CliniCal PraCtiCe Guidelines in OnCOlOGy update sessions: Acute Myeloid Leukemia Breast Cancer Cervical Cancer Colon Cancer Esophageal Cancer New NCCN Guidelines: Mesothelioma Multiple Myeloma Non-Small Cell Lung Cancer Occult Primary Prostate Cancer special sessions: Central Nervous System (CNS) Metastases HPV and the Risk of Cancer New Advances in Molecular Diagnostics and Cancer Overview of Adolescent/Young Adult (AYA) Oncology nccn task FOrCe reports: NCCN Task Force Report: Gastrointestinal Stromal Tumors (GIST) NCCN Task Force Report: Specialty Pharmacy in Oncology Impact on Patient Care and Practice NCCN Task Force Report: Transfusions and Iron Overload in Myelodysplastic Syndromes ROuNDTABLE DISCuSSIONS: Cancer Care at the End of Life: When is Enough, Enough? Clinical and Economic Issues Impacting Cancer Care Delivery SuNDAY BRuNCH WITH THE ExPERTS: Management of Adverse Events March 1 14 REGISTER NOW! 21 NCCN Pharmacy Program: Best Practices in Oncology Pharmacy Management Wednesday, March 1, 21 NCCN Reimbursement Resource Room Learn about reimbursement help and services available For more information on how to participate, contact C. Lyn Fitzgerald at or fitzgerald@nccn.org Exhibit Opportunities Available For more information, contact Jennifer Tredwell at or tredwell@nccn.org *Subject to Change AC-N Visit NCCN.org to register or to view more information for these educational programs.

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45 SuBSCrIBe TODAy! NCCN Drugs & Biologics Compendium an authoritative resource in coverage policy decisions Officially Recognized by CMS and UnitedHealthcare The NCCN Drugs & Biologics Compendium lists appropriate uses of agents as derived from the NCCN Clinical Practice Guidelines in Oncology. The uses identified are based upon evaluation of evidence from scientific literature integrated with expert judgment in an evidencebased process. Indicated uses are categorized in a systematic approach that describes the type of evidence available for and the degree of consensus underlying each recommendation. All recommendations (at all category levels) in the NCCN Compendium constitute appropriate, medicallynecessary care. The NCCN Compendium lists both FDAapproved uses and appropriate uses beyond the FDA-approved label. The NCCN Compendium neither represents an all-inclusive listing of every drug and biologic nor every appropriate use and indication for drugs and biologics. Any clinician seeking to apply or consult the NCCN Compendium is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient s care or treatment. Visit NCCN.org to subscribe to the NCCN Drugs & Biologics Compendium DBC-N DBC-N-117-5

46 c h e m o t h e r a p y In NSCLC, It s Only Half The Story. While chemotherapy remains a standard of care for advanced non-small cell lung cancer (NSCLC), new avenues of research continue to be investigated. Alternatives to cytotoxic chemotherapy for NSCLC have been incorporated into treatment strategies; however, there is still a need for additional treatment options for many patients. 1 Bristol-Myers Squibb has a history of successfully achieving important milestones in the research of NSCLC. Bristol-Myers Squibb and ImClone Systems are working together on the development of an investigational biologic treatment that may have the potential to better serve the needs of such patients. Together, we can make a difference. Reference: 1. Ettinger DS, Akerley W, Bepler G, et al. Non-small cell lung cancer. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. v Available at: Accessed March 7, ImClone Systems Incorporated, New York, New York 114, U.S.A. and Bristol-Myers Squibb Company, Princeton, New Jersey 8543, U.S.A. All rights reserved. 693US9AB362 3/9 I N N O V A T O R S I N N S C L C T H E R A P Y

47 CME/CE Available NeW FRee educational PROGRAM FROM NCCN! NCCN Guidelines Update Webinar Series NCCN has created a new educational initiative designed to quickly communicate updates to the NCCN Clinical Practice Guidelines in Oncology via online webinars. NCCN recognizes the need for education based on the NCCN Guidelines given the rapidly changing scientific and clinical environment. Hosted by a faculty member from the corresponding NCCN Guidelines Panel, the NCCN Guidelines Update Webinar Series provides participants with an inside look at recent NCCN Guidelines updates. The program includes a live Q&A session. Multiple webinars will be scheduled at varying times to provide clinicians with a variety of opportunities to participate. There is no registration fee for these programs and the online format allows for a convenient learning platform with no associated travel fees. Participate in live Q&A NCCN is in the process of scheduling several upcoming webinars. Please check NCCN.org for the most up-to-date schedule. Please contact NCCN (6226) or visit NCCN.org for more information on these educational programs. GlWeB-N-4-119

48 For more information about GEMZAR, please see your Lilly sales professional or visit GEMZAR.com. GEMZAR is a registered trademark of Eli Lilly and Company. GC PRINTED IN USA 29, Lilly USA, LLC. ALL RIGHTS RESERVED.