NOW AVAILABLE. FOR THE TREATMENT OF Ph-NEGATIVE RELAPSED/REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

Transcription

1 NOW AVAILABLE FOR THE TREATMENT OF Ph-NEGATIVE RELAPSED/REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) Discover the first and only FDA-approved Bispecific CD19-directed CD3 T-cell Engager In a phase 2, open-label, multicenter, single-arm clinical trial: The primary endpoint was the complete remission/complete remission with partial hematological recovery (CR/CRh*) rate within 2 cycles of treatment with BLINCYTO. Eligible patients were 18 years of age with Philadelphia chromosome-negative relapsed or refractory B-precursor ALL. Relapsed or refractory was defined as relapsed with first remission duration of 12 months in first salvage or relapsed or refractory after first salvage therapy or relapsed within 12 months of allogeneic hematopoietic stem cell transplantation (HSCT), and had 10% blasts in bone marrow. 41.6% (95% CI: ) of R/R ALL evaluable patients achieved a CR/CRh* (n=77/185) % (95% CI: ) with CR/CRh* also had an MRD response (defned as MRD by PCR < 1 x 10-4 ) (n=58/77) 1 39% of patients who achieved CR/CRh* went on to receive allogeneic transplant (n=30/77) 1 INDICATION BLINCYTO is indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials. IMPORTANT SAFETY INFORMATION WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended. Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended. Contraindications BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation. Warnings and Precautions Cytokine Release Syndrome (CRS): Life-threatening or fatal CRS occurred in patients receiving BLINCYTO. Infusion reactions have occurred and may be clinically indistinguishable from manifestations of CRS. Closely monitor patients for signs and symptoms of serious events such as pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Interrupt or discontinue BLINCYTO as outlined in the Prescribing Information (PI) _R02_AMG_AAUS_JrnlAd_Blood_Sprd.indd 1-2

2 Neurological Toxicities: Approximately 50% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. Severe, life-threatening, or fatal neurological toxicities occurred in approximately 15% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The median time to onset of any neurological toxicity was 7 days. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO as outlined in the PI. Infections: Approximately 25% of patients receiving BLINCYTO experienced serious infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed. Tumor Lysis Syndrome (TLS): Life-threatening or fatal TLS has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events. Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs. Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered. Elevated Liver Enzymes: Transient elevations in liver enzymes are associated with BLINCYTO treatment. The majority of these events were observed in the setting of CRS. The median time to onset was 15 days. Grade 3 or greater elevations in liver enzymes occurred in 6% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase (GGT), and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN. Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and anti-leukemic chemotherapy. Preparation and administration errors have occurred. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose). Adverse Events The most commonly reported adverse reactions ( 20%) in clinical trials were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), rash (21%), tremor (20%) and constipation (20%). Dosage and Administration Guidelines BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm. It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose). Please see accompanying Brief Summary of Prescribing Information on adjacent pages. R/R=relapsed/refractory; CR=complete remission; CRh*=complete remission with partial hematological recovery; MRD=minimal residual disease Discover the first and only FDA-approved Bispecific CD19-directed CD3 T-cell Engager VISIT BLINCYTO.COM TO LEARN MORE Reference: 1. BLINCYTO (blinatumomab) Prescribing Information, Amgen. BLINCYTO is a trademark of Amgen Inc Amgen Inc. All rights reserved. USA /15 2/5/15 1:58 PM

3 Summary of Prescribing Information BLINCYTO (blinatumomab) for injection, for intravenous use WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES Cytokine Release Syndrome (CRS), which may be lifethreatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended. [See Dosage and Administration (2.3), Warnings and Precautions (5.1)]. Neurological toxicities, which may be severe, lifethreatening, or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended. [See Dosage and Administration (2.3), Warnings and Precautions (5.2)]. 1. INDICATIONS AND USAGE BLINCYTO is indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials [see Clinical Studies (14.1)]. 4. CONTRAINDICATIONS BLINCYTO is contraindicated in patients with known hypersensitivity to blinatumomab or to any component of the product formulation. 5. WARNINGS AND PRECAUTIONS 5.1 Cytokine Release Syndrome Cytokine Release Syndrome (CRS), which may be lifethreatening or fatal, occurred in patients receiving BLINCYTO. Infusion reactions have occurred with the BLINCYTO infusion and may be clinically indistinguishable from manifestations of CRS. Serious adverse events that may be associated with CRS included pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase, increased aspartate aminotransferase, and increased total bilirubin; these events infrequently led to BLINCYTO discontinuation. Life-threatening or fatal CRS was infrequently reported in patients receiving BLINCYTO. In some cases, disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/ macrophage activation syndrome (HLH/MAS) have been reported in the setting of CRS. Patients should be closely monitored for signs or symptoms of these events. Management of these events may require either temporary interruption or discontinuation of BLINCYTO [see Dosage and Administration (2.3)]. 5.2 Neurological Toxicities In patients receiving BLINCYTO in clinical trials, neurological toxicities have occurred in approximately 50% of patients. The median time to onset of any neurological toxicity was 7 days. Grade 3 or higher (severe, lifethreatening, or fatal) neurological toxicities following initiation of BLINCYTO administration occurred in approximately 15% of patients and included encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The majority of events resolved following interruption of BLINCYTO, but some resulted in treatment discontinuation. Monitor patients receiving BLINCYTO for signs and symptoms of neurological toxicities, and interrupt or discontinue BLINCYTO as recommended [see Dosage and Administration (2.3)]. 5.3 Infections In patients receiving BLINCYTO in clinical trials, serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections were observed in approximately 25% of patients, some of which were life-threatening or fatal. As appropriate, administer prophylactic antibiotics and employ surveillance testing during treatment with BLINCYTO. Monitor patients for signs and symptoms of infection and treat appropriately. 5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS), which may be life-threatening or fatal, has been observed in patients receiving BLINCYTO. Appropriate prophylactic measures, including pretreatment nontoxic cytoreduction and ontreatment hydration, should be used for the prevention of TLS during BLINCYTO treatment. Monitor for signs or symptoms of TLS. Management of these events may require either temporary interruption or discontinuation of BLINCYTO [see Dosage and Administration (2.3)]. 5.5 Neutropenia and Febrile Neutropenia Neutropenia and febrile neutropenia, including lifethreatening cases, have been observed in patients receiving BLINCYTO. Monitor laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion. Interrupt BLINCYTO if prolonged neutropenia occurs. 5.6 Effects on Ability to Drive and Use Machines Due to the potential for neurologic events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness [see Warnings and Precautions (5.2)]. Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered. 5.7 Elevated Liver Enzymes Treatment with BLINCYTO was associated with transient elevations in liver enzymes. Although the majority of these events were observed in the setting of CRS, some were observed outside of this setting. For these events, the median time to onset was 15 days. In patients receiving BLINCYTO in clinical trials, Grade 3 or greater elevations in liver enzymes occurred in approximately 6% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and total blood bilirubin prior to the start of and during BLINCYTO treatment. Interrupt BLINCYTO if the transaminases rise to greater than 5 times the upper limit of normal or if bilirubin rises to more than 3 times the upper limit of normal. 5.8 Leukoencephalopathy Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients with prior treatment with cranial irradiation and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown. 5.9 Preparation and Administration Errors Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration strictly to minimize medication errors (including underdose and overdose) [see Dosage and Administration (2.2) and (2.4)]. 6. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Cytokine Release Syndrome [see Warnings and Precautions (5.1)] Neurological Toxicities [see Warnings and Precautions (5.2)] Infections [see Warnings and Precautions (5.3)] Tumor Lysis Syndrome [see Warnings and Precautions (5.4)] Neutropenia and Febrile Neutropenia [see Warnings and Precautions (5.5)] Effects on Ability to Drive and Use Machines [see Warnings and Precautions (5.6)] Elevated Liver Enzymes [see Warnings and Precautions (5.7)] Leukoencephalopathy [see Warnings and Precautions (5.8)] Preparation and Administration Errors [see Warnings and Precautions (5.9)] 6.1 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 safety data described in this section reflect exposure to BLINCYTO in clinical trials in which 212 patients with relapsed or refractory ALL received up to 28 mcg/day. All patients received at least one dose of BLINCYTO. The median age of the study population was 37 years (range: 18 to 79 years), 63% were male, 79% were White, 3% were Asian, and 3% were Black or African American. The most common adverse reactions ( 20%) were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), and constipation (20%). Serious adverse reactions were reported in 65% of patients. The most common serious adverse reactions ( 2%) included febrile neutropenia, pyrexia, pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, infection, overdose, confusion, Staphylococcal bacteremia, and headache. Adverse reactions of Grade 3 or higher were reported in 80% of patients. Discontinuation of therapy due to adverse reactions occurred in 18% of patients treated with BLINCYTO. The adverse reactions reported most frequently as the reason for discontinuation of treatment included encephalopathy and sepsis. Fatal adverse events occurred in 15% of patients. The majority of these events were infections. No fatal adverse events occurred on treatment among patients in remission. The adverse reactions with 10% incidence for any grade or 5% incidence for Grade 3 or higher are summarized in Table 2. Table 2. Adverse Reactions With 10% Incidence for Any Grade or 5% Incidence for Grade 3 or higher (N = 212) Adverse Reaction Any Grade 1 Blood and lymphatic system disorders Febrile neutropenia Anemia Neutropenia Thrombocytopenia 11 8 Leukopenia 9 8 Gastrointestinal disorders Nausea 25 0 Constipation 20 < 1 Diarrhea Abdominal pain 15 2 Vomiting 13 0 General disorders and administration site conditions Pyrexia 62 7 Peripheral edema 25 < 1 Fatigue 17 1 Chills 15 0 Chest pain 11 1 Grade 3 or higher _R02_AMG_AAUS_JrnlAd_Blood_Sprd.indd 3-4

4 Table 2 (continued) Immune system disorders Cytokine release syndrome Infections and infestations Other pathogen infections Bacterial infections Fungal infections 15 7 Viral infections 13 4 Pneumonia 9 8 Sepsis 7 6 Investigations Increased alanine aminotransferase Increased aspartate aminotransferase Increased weight 11 0 Metabolism and nutrition disorders Hypokalemia 23 6 Hypomagnesemia 12 0 Hyperglycemia 11 7 Decreased appetite 10 3 Hypophosphatemia 6 5 Musculoskeletal and connective tissue disorders Back pain 14 2 Pain in extremity 12 1 Bone pain 11 3 Arthralgia 10 2 Nervous system disorders Headache 36 3 Tremor Dizziness 14 < 1 Psychiatric disorders Insomnia 15 0 Respiratory, thoracic, and mediastinal disorders Cough 19 0 Dyspnea Skin and subcutaneous tissue disorders Rash Vascular disorders Hypotension 11 2 Hypertension Grading based on NCI Common Terminology Criteria for Adverse Events (CTCAE) version Diarrhea includes the following terms: colitis, diarrhea, enteritis, and neutropenic colitis. 3 Tremor includes the following terms: resting tremor and tremor. 4 Dyspnea includes the following terms: acute respiratory failure, bronchial hyperactivity, bronchospasm, dyspnea, dyspnea exertional, respiratory distress, respiratory failure, and wheezing. 5 Rash includes the following terms: erythema, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, and vesicular rash. Additional important adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were: Blood and lymphatic system disorders: leukocytosis (2%), lymphopenia (1%), Cardiac disorders: tachycardia (8%), General disorders and administration site conditions: edema (5%), Immune system disorders: cytokine storm (1%), Investigations: decreased immunoglobulins (9%), increased blood bilirubin (8%), increased gammaglutamyl-transferase (6%), increased liver enzymes (1%), Metabolism and nutrition disorders: tumor lysis syndrome (4%), hypoalbuminemia (4%), Nervous system disorders: encephalopathy (5%), paresthesia (5%), aphasia (4%), convulsion (2%), memory impairment (2%), cognitive disorder (1%), speech disorder (< 1%), Psychiatric disorders: confusion (7%), disorientation (3%), Vascular disorders: capillary leak syndrome (< 1%). Hypersensitivity reactions related to BLINCYTO treatment were hypersensitivity (1%) and bronchospasm (< 1%). 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of BLINCYTO has been evaluated using either an electrochemiluminescence detection technology (ECL) or an enzyme-linked immunosorbent assay (ELISA) screening immunoassay for the detection of binding anti-blinatumomab antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies. In clinical studies, less than 1% of patients treated with BLINCYTO tested positive for binding anti-blinatumomab antibodies. All patients who tested positive for binding antibodies also tested positive for neutralizing antiblinatumomab antibodies. Anti-blinatumomab antibody formation may affect pharmacokinetics of BLINCYTO. No association was seen between antibody development and development of adverse events. If formation of anti-blinatumomab antibodies with a clinically signifcant effect is suspected, contact Amgen at AMGEN ( ) to discuss antibody testing. The detection of anti-blinatumomab antibody formation is highly dependent on the sensitivity and specifcity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be infuenced 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 blinatumomab with the incidence of antibodies to other products may be misleading. 7. DRUG INTERACTIONS No formal drug interaction studies have been conducted with BLINCYTO. Initiation of BLINCYTO treatment causes transient release of cytokines that may suppress CYP450 enzymes. The highest drug-drug interaction risk is during the first 9 days of the first cycle and the first 2 days of the second cycle in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index. In these patients, monitor for toxicity (eg, warfarin) or drug concentrations (eg, cyclosporine). Adjust the dose of the concomitant drug as needed [see Clinical Pharmacology (12.2 and 12.3)]. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of BLINCYTO in pregnant women. Based on its mechanism of action, BLINCYTO may cause fetal toxicity including B-cell lymphocytopenia when administered to a pregnant woman. BLINCYTO should be used during pregnancy only if the potential beneft justifes the potential risk to the fetus. Animal Data Animal reproduction studies have not been conducted with blinatumomab. In embryo-fetal developmental toxicity studies, a murine surrogate molecule was administered intravenously to pregnant mice during the period of organogenesis. The surrogate molecule crossed the placental barrier and did not cause embryofetal toxicity or teratogenicity. The expected depletions of B and T cells were observed in the pregnant mice, but hematological effects were not assessed in fetuses. 8.3 Lactation It is not known whether blinatumomab 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 blinatumomab, 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. 8.4 Pediatric Use There is limited experience in pediatric patients. BLINCYTO was evaluated in a dose-escalation study of 41 pediatric patients with relapsed or refractory B-precursor ALL. The median age was 6 years (range: 2 to 17 years). BLINCYTO was administered at doses of 5 to 30 mcg/m 2 /day. The recommended phase 2 regimen was 5 mcg/m 2 /day on Days 1-7 and 15 mcg/m 2 /day on Days 8-28 for cycle 1, and 15 mcg/m 2 /day on Days 1-28 for subsequent cycles. At a higher dose, a fatal cardiac failure event occurred in the setting of life-threatening cytokine release syndrome (CRS) [see Warnings and Precautions (5.1)]. The steady-state concentrations of blinatumomab were comparable in adult and pediatric patients at the equivalent dose levels based on body surface area (BSA)-based regimens. 8.5 Geriatric Use Of the total number of patients with relapsed or refractory ALL, approximately 13% were 65 years of age and over. Generally, safety and effcacy were similar between elderly patients ( 65 years of age) and patients less than 65 years of age treated with BLINCYTO. Elderly patients experienced a higher rate of neurological toxicities, including cognitive disorder, encephalopathy, confusion, and serious infections [see Warnings and Precautions (5.2) and (5.3)]. 8.6 Hepatic Impairment No formal pharmacokinetic studies using BLINCYTO have been conducted in patients with hepatic impairment. 8.7 Renal Impairment No formal pharmacokinetic studies using BLINCYTO have been conducted in patients with renal impairment. No dose adjustment is needed for patients with baseline creatinine clearance (CrCL) equal to or greater than 30 ml/min. There is no information available in patients with CrCL less than 30 ml/min or patients on hemodialysis [see Clinical Pharmacology (12.3)]. 10. OVERDOSAGE Overdoses have been observed, including one patient who received 133-fold the recommended therapeutic dose of BLINCYTO delivered over a short duration. Overdoses resulted in adverse reactions which were consistent with the reactions observed at the recommended therapeutic dose and included fever, tremors, and headache. In the event of overdose, interrupt the infusion, monitor the patient for signs of toxicity, and provide supportive care [see Warnings and Precautions (5.9)]. Consider reinitiation of BLINCYTO at the correct therapeutic dose when all toxicities have resolved and no earlier than 12 hours after interruption of the infusion [see Dosage and Administration (2.1)]. This brief summary using 12/3/2014 FDA Approved label. BLINCYTO (blinatumomab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA USA Patent: 2015 Amgen Inc. All rights reserved. 1/15 2/5/15 2:00 PM

5 NOW JOIN US NOW IN REVEAL Prospective Observational Study of Patients with Polycythemia Vera in US Clinical Practices (NCT ) The REVEAL study is a multicenter, non-interventional, non-randomized, prospective, observational study in an adult population (patients 18 years old) of men and women who have been diagnosed with clinically overt PV. Patients with PV N=2000 Study start Usual Care 36 months End of study SCREENING START OBSERVATION DATA COLLECTION END OBSERVATION Key Inclusion Criteria Age 18 years, diagnosis of polycythemia vera (PV) Willing and able to provide signed informed consent Under the supervision of US physician Key Exclusion Criteria Participation in a blinded study Life expectancy <6 months Diagnosis of MF, PPV-MF, PET-MF Diagnosis of acute myelocytic leukemia (AML) Diagnosis of Myelodysplastic Syndrome To join us as an investigative site in REVEAL: Incyte REVEAL Study Hotline: REVEAL-9 RevealPVStudy.com Info@RevealPVStudy.com Protocol Number INCB-MA-PV-401 sponsored by Incyte Corporation 2015 Incyte Corporation

6 Now recruiting QuANTUM - R Quizartinib Advancement into the Next Generation of Trials for Unmet Needs in AML A Phase III, Open-Label Randomized Study of Quizartinib (AC220) Monotherapy Versus Salvage Chemotherapy in Subjects with FLT3-ITD Positive Acute Myeloid Leukemia Refractory to or Relapsed After First-line Treatment, With or Without Hematopoietic Stem Cell Transplant (HSCT) Patient Population FLT3-ITD positive Refractory to or relapsed within 6 months of first-line AML therapy R A N D O M I Z E D Quizartinib Salvage Chemotherapy (MEC, FLAG- IDA, LoDAC) Patients receiving a HSCT have option to initiate maintenance therapy with quizartinib 2:1 quizartinib vs. salvage chemotherapy (estimated enrollment = 326). Primary Endpoint: Overall survival Scan Here Secondary Endpoints: Event-Free Survival Location: Approximately 117 centers in North America, Europe, Australia ClinicalTrials.gov Identifier: NCT & learn more Quizartinib is an investigational agent and is not approved by the FDA or other regulatory agencies worldwide as a treatment for any indication. Effcacy and safety have not been established. There is no guarantee that quizartinib will become commercially available. For more information about this clinical trial, please visit Daiichi Sankyo, Inc Two Hilton Court Parsippany, NJ Daiichi Sankyo, Inc. All rights reserved. Printed in US 2015 DSON

7 For more information online, visit 729US13BR /13

8 Discover more at BOOTH EXPLORE AT ASCO 2015 Pharmacyclics, Inc Janssen Biotech, Inc /15 PRC To learn more, visit

9 makes all the difference With CancerCare, the difference comes from: Professional oncology social workers Free counseling Education and practical help Up-to-date information CancerCare for Kids For needs that go beyond medical care, refer your patients and their loved ones to CancerCare. CancerCare s free services help people cope with the emotional and practical concerns arising from a cancer diagnosis and are integral to the standard of care for all cancer patients, as recommended by the Institute of Medicine. Help and Hope HOPE (4673)

10 Janssen ibrutinib (Bruton s Tyrosine Kinase (BTK) Inhibitor) Trials* DLBCL and inhl ENROLLING NOW STUDY 1: PHOENIX DBL3001 A study of ibrutinib in combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP) in patients with newly diagnosed non-germinal center B-cell subtype of diffuse large B-cell lymphoma (DLBCL) N=800 KEY ELIGIBILITY CRITERIA Patients 18 years or older, with newly diagnosed, non-gcb DLBCL as determined by central IHC Ann Arbor Stage II-IV R-IPI score of 1 ECOG 0 2 Randomize 1:1 R-CHOP + ibrutinib R-CHOP + Placebo For more information visit: (NCT ). No new sites are being opened; for any questions on the study, please contact Martin Shreeve at MShreeve@its.jnj.com or Kevin Bellew at KBellew2@its.jnj.com. STUDY 2: SELENE FLR3001 BR or R-CHOP + ibrutinib A randomized, double-blind, placebo-controlled phase 3 study of ibrutinib in combination with either Bendamustine and Rituximab (BR) or R-CHOP in subjects with previously treated indolent non- Hodgkin lymphoma (inhl) Randomize 1:1 BR or R-CHOP + Placebo N=400 KEY ELIGIBILITY CRITERIA 18 years of age with histologically confrmed diagnosis of either: a. Follicular lymphoma Grade 1, 2, or 3a, or b. Marginal zone lymphoma (splenic, nodal, or extra-nodal) Relapsed or refractory disease Received at least one prior chemoimmunotherapy regimen containing a CD20 antibody ECOG 0-1 For more information visit: (NCT ). Site selection is ongoing; for any questions on the study, please contact Dr. Esther Rose at ERose10@its.jnj.com, Dr. Jessica Vermeulen at JVermeul@its.jnj.com or Julie Larsen at JLarsen3@its.jnj.com. * The safety and effcacy of the investigational use of this product has not been determined. There is no guarantee that the investigational uses listed will be fled with and/or approved for marketing by any regulatory agency. Janssen Research & Development, LLC

11 THERE S A INSIDE EVERYONE WITH THE POTENTIAL TO TAKE ON MULTIPLE MYELOMA

12 Despite recent advances, multiple myeloma remains a largely incurable disease, with fewer than half of patients surviving f ve years after diagnosis. 1 Natural killer cells are part of the body s f rst line of defense against cancer, but myeloma cells evade and suppress a patient s natural immune response, making further medical advances challenging We need a new approach. Bristol-Myers Squibb is deeply committed to furthering the science behind Immuno-Oncology. Leading the way in Immuno-Oncology research, Bristol-Myers Squibb is investigating the potential of the SLAMF7, KIR, and CD137 pathways to activate the body s own natural killer cells to target myeloma cells. REFERENCES: 1. SEER Stat Fact Sheets: Myeloma, Accessed July 17, 2014; 2. Godfrey J and Benson DM Jr. The role of natural killer cells in immunity against multiple myeloma. Leuk Lymphoma. 2012;53: ; 3. Cheng M, Chen Y, Xiao W et al. NK cell-based immunotherapy for malignant diseases. Cell Molec Immunol. 2013;10: ; 4. Bernal M, Garrido P, Jiménez P et al. Changes in activatory and inhibitory natural killer (NK) receptors may induce progression to multiple myeloma : implications for tumor evasion of T and NK cells. Human Immunol. 2009;70: ; 5. Jinushi M, Vanneman M, Munshi NC et al. MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma. Proc Natl Acad Sci USA. 2008;105: ; 6. Carbone E, Neri P, Mesuraca M et al. HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood. 2005;105: ; 7. von Lilienfeld-Toal M, Frank S, Leyendecker C et al. Reduced immune effector cell NKG2D expression and increased levels of soluble NKG2D ligands in multiple myeloma may not be causally linked. Cancer Immunol Immunother. 2010;59: ; 8. Cook G, Campbell JDM, Carr CE et al. Transforming growth factor beta from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in T lymphocytes. J Leukoc Biol. 1999;66: ; 9. Yu J, Wei M, Becknell B et al. Pro- and anti-infl ammatory cytokine signaling: reciprocal antagonism regulates interferon-gamma production by human natural killer cells. Immunity. 2006;24: ; 10. Nielsen H, Nielsen HJ, Tvede N et al. Immune dysfunction in multiple myeloma. Reduced natural killer cell activity and increased levels of soluble interleukin-2 receptors. APMIS. 1991;99: ; 11. Tinhofer I, Marschitz I, Henn T et al. Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma. Blood. 2000;95: Bristol-Myers Squibb Company. All rights reserved. ONCUS14UB /14

13 Serious Adverse Reactions: Sixty-one patients (47.3%) experienced serious adverse reactions while taking BELEODAQ or within 30 days after their last dose of BELEODAQ. The most common serious adverse reactions (> 2%) were pneumonia, pyrexia, infection, anemia, increased creatinine, thrombocytopenia, and multi-organ failure. One treatment-related death associated with hepatic failure was reported in the trial. One patient with baseline hyperuricemia and bulky disease experienced Grade 4 tumor lysis syndrome during the first cycle of treatment and died due to multi-organ failure. A treatment-related death from ventricular fibrillation was reported in another monotherapy clinical trial with BELEODAQ. ECG analysis did not identify QTc prolongation. Discontinuations due to Adverse Reactions: Twenty-five patients (19.4%) discontinued treatment with BELEODAQ due to adverse reactions. The adverse reactions reported most frequently as the reason for discontinuation of treatment included anemia, febrile neutropenia, fatigue, and multi-organ failure. Dosage Modifications due to Adverse Reactions: In the trial, dosage adjustments due to adverse reactions occurred in 12% of BELEODAQ-treated patients. DRUG INTERACTIONS: UGT1A1 Inhibitors: Belinostat is primarily metabolized by UGT1A1. Avoid concomitant administration of BELEODAQ with strong inhibitors of UGT1A1. Warfarin: Co-administration of BELEODAQ and warfarin resulted in no clinically relevant increase in plasma exposure of either R-warfarin or S-warfarin that would require a dose adjustment. USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category D. Risk Summary: BELEODAQ may cause teratogenicity and/or embryo-fetal lethality because it is a genotoxic drug and targets actively dividing cells. Women should avoid pregnancy while receiving BELEODAQ. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of potential hazard to the fetus. Animal Data: No reproductive and developmental animal toxicology studies have been conducted with belinostat. Nursing Mothers: It is not known whether belinostat 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 BELEODAQ, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. Pediatric Use: Pediatric patients were not included in clinical trials. The safety and effectiveness of BELEODAQ in pediatric patients have not been established. Geriatric Use: In the single-arm trial, 48% of patients (n = 62) were 65 years of age and 10% of patients (n=13) were 75 years of age. The median age of the trial population was 63 years. Patients 65 years of age had a higher response rate to BELEODAQ treatment than patients < 65 years of age (36% versus 16%) while no meaningful differences in response rate were observed between patients 75 years of age and those < 75 years of age. No clinically meaningful differences in serious adverse reactions were observed in patients based on age (< 65 years compared with 65 years or < 75 years of age compared with 75 years of age). Use in Patients with Hepatic Impairment: Belinostat is metabolized in the liver and hepatic impairment is expected to increase exposure to belinostat. Patients with moderate and severe hepatic impairment (total bilirubin >1.5 x upper limit of normal (ULN)) were excluded from clinical trials. There is insufficient data to recommend a dose of BELEODAQ in patients with moderate and severe hepatic impairment. Use in Patients with Renal Impairment: Approximately 40% of the belinostat dose is excreted renally, primarily as metabolites. Belinostat exposure is not altered in patients with Creatinine Clearance (CLcr) > 39 ml/min. There is insufficient data to recommend a dose of BELEODAQ in patients with CLcr 39 ml/min OVERDOSAGE: No specific information is available on the treatment of overdosage of BELEODAQ. There is no antidote for BELEODAQ and it is not known if BELEODAQ is dialyzable. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. The elimination half-life of belinostat is 1.1 hours. PATIENT COUNSELING INFORMATON: Physicians should discuss the FDA approved Patient Information Leaflet with patients prior to treatment with BELEODAQ. Instruct patients to read the Patient Information Leaflet carefully. DOSAGE AND ADMINISTRATION: Dosing Information: The recommended dosage of BELEODAQ is 1,000 mg/ m 2 administered over 30 minutes by intravenous infusion once daily on Days 1-5 of a 21-day cycle. Cycles can be repeated every 21 days until disease progression or unacceptable toxicity. Dosage Modification for Hematologic and Non-Hematologic Toxicities: Table 1 displays the recommended BELEODAQ dosage modifications for hematologic and non-hematologic toxicities. Base dosage adjustments for thrombocytopenia and neutropenia on platelet and absolute neutrophil nadir (lowest value) counts in the preceding cycle of therapy. Absolute neutrophil count (ANC) should be greater than or equal to 1.0 x 10 9 /L and the platelet count should be greater than or equal to 50 x 10 9 /L prior to the start of each cycle and prior to resuming treatment following toxicity. Resume subsequent treatment with BELEODAQ according to the guidelines described in Table 1 below. Discontinue BELEODAQ in patients who have recurrent ANC nadirs less than 0.5 x 10 9 /L and/or recurrent platelet count nadirs less than 25 x 10 9 /L after two dosage reductions. Other toxicities must be NCI-CTCAE Grade 2 or less prior to re-treatment. Monitor complete blood counts at baseline and weekly. Perform serum chemistry tests, including renal and hepatic functions prior to the start of the first dose of each cycle. Table 1: Dosage Modifications for Hematologic and Non-Hematologic Toxicities Dosage Modifications due to Hematologic Toxicities Platelet count 25 x 10 9 /L and nadir ANC 0.5 x 10 9 /L Nadir ANC < 0.5 x 10 9 /L (any platelet count) Platelet count < 25 x 10 9 /L (any nadir ANC) Dosage Modifications due to Non-Hematologic Toxicities Any CTCAE Grade 3 or 4 adverse reaction a Recurrence of CTCAE Grade 3 or 4 adverse reaction after two dosage reductions Dosage Modification No Change Decrease dosage by 25% (750 mg/m 2 ) Decrease dosage by 25% (750 mg/m 2 ) Discontinue BELEODAQ a For nausea, vomiting, and diarrhea, only dose modify if the duration is greater than 7 days with supportive management Patients with Reduced UGT1A1 Activity: Reduce the starting dose of BELEODAQ to 750 mg/m 2 in patients known to be homozygous for the UGT1A1*28 allele. Preparation and Administration Precautions: As with other potentially cytotoxic anticancer agents, exercise care in the handling and preparation of solutions prepared with BELEODAQ. Manufactured for: Spectrum Pharmaceuticals, Inc. Irvine, CA Beleodaq is a trademark of Spectrum Pharmaceuticals, Inc. All rights are reserved. U.S. Patent: 6,888,027

14 When faced with overactive signaling... Indications and Usage Jakafi is indicated for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. Important Safety Information Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi Jakafi is a registered trademark of Incyte Corporation. 2015, Incyte Corporation. All rights reserved. RUX /15 Severe neutropenia (ANC <0.5 X 10 9 /L) was generally reversible by withholding Jakafi until recovery Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly Tuberculosis (TB) infection has been reported. Observe patients taking Jakafi for signs and symptoms of active TB and manage promptly. Prior to initiating Jakafi, evaluate patients for TB risk factors and test those at higher risk for latent infection. Consult a physician with expertise in the treatment of TB before starting Jakafi in patients with evidence of active or latent TB. Continuation of Jakafi during treatment of active TB should be based on the overall risk-benefit determination Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate Advise patients about early signs and symptoms of herpes zoster and to seek early treatment

15 Inhibit the JAK pathway * in polycythemia vera not controlled with hydroxyurea 1-3 Jakafi (ruxolitinib) is the first and only FDA-approved treatment for patients who have had an inadequate response to or are intolerant of hydroxyurea 3 Jakafi demonstrated superior results in a phase 3 trial vs best available therapy 3,4 * Ruxolitinib, a kinase inhibitor, inhibits JAK1 and JAK2 (Janus-associated kinases 1 and 2), which mediate the signaling of cytokines and growth factors important for hematopoiesis and immune function. 3 A randomized, open-label, active-controlled phase 3 trial comparing Jakafi with best available therapy (BAT) in 222 patients. Best available therapy included hydroxyurea (60%), interferon/pegylated interferon (12%), anagrelide (7%), pipobroman (2%), lenalidomide/thalidomide (5%), and observation (15%). Patients had been diagnosed with polycythemia vera for at least 24 weeks, had an inadequate response to or were intolerant of hydroxyurea, required phlebotomy, and exhibited splenomegaly. The primary end point was the proportion of subjects achieving a response at week 32, with response defined as having achieved both hematocrit (Hct) control (the absence of phlebotomy eligibility beginning at the week 8 visit and continuing through week 32) and spleen volume reduction (a 35% reduction from baseline in spleen volume at week 32). Phlebotomy eligibility was defined as Hct >45% that is 3 percentage points higher than baseline or Hct >48% (lower value). 3,4 Primary Response at Week 32 3,4 Patients Composite Primary End Point P < % a (n = 23) 1% b (n = 1) Hct Control + Spleen Volume Reduction a 95% CI, 14%-30% b 95% CI, 0%-5% 60% (n = 66) Individual Components of Primary End Point 20% (n = 22) Hct Control Without Phlebotomy Jakaf (n = 110) BAT (n = 112) 38% (n = 42) 1% (n = 1) 35% Spleen Volume Reduction When discontinuing Jakafi, myeloproliferative neoplasmrelated symptoms may return within one week. After discontinuation, some patients with myelofibrosis have experienced fever, respiratory distress, hypotension, DIC, or multi organ failure. If any of these occur after discontinuation or while tapering Jakafi, evaluate and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi without consulting their physician. When discontinuing or interrupting Jakafi for reasons other than thrombocytopenia or neutropenia, consider gradual tapering rather than abrupt discontinuation Non melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred. Perform periodic skin examinations The three most frequent non-hematologic adverse reactions (incidence >10%) were bruising, dizziness and headache A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or fluconazole or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast-feed Please see Brief Summary of Full Prescribing Information for Jakafi on the following pages. References: 1. Rampal R et al. Blood. 2014;123(22):e123-e Keohane C et al. Biologics. 2013;7: Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation. 4. Vannucchi AM et al. N Engl J Med. 2015;372(5): Review the clinical trial data at

16 BRIEF SUMMARY: For Full Prescribing Information, see package insert. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with Jakaf can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakaf. Platelet transfusions may be necessary [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Patients developing anemia may require blood transfusions and/or dose modifcations of Jakaf. Severe neutropenia (ANC less than 0.5 X 10 9 /L) was generally reversible by withholding Jakaf until recovery [see Adverse Reactions (6.1)]. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting therapy with Jakaf until active serious infections have resolved. Observe patients receiving Jakaf for signs and symptoms of infection and manage promptly. Tuberculosis Tuberculosis infection has been reported in patients receiving Jakaf. Observe patients receiving Jakaf for signs and symptoms of active tuberculosis and manage promptly. Prior to initiating Jakaf, patients should be evaluated for tuberculosis risk factors, and those at higher risk should be tested for latent infection. Risk factors include, but are not limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history of active or latent tuberculosis where an adequate course of treatment cannot be confrmed. For patients with evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting Jakaf. The decision to continue Jakaf during treatment of active tuberculosis should be based on the overall risk-beneft determination. PML Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofbrosis. If PML is suspected, stop Jakaf and evaluate. Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [see Adverse Reactions (6.1)]. Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakaf Following discontinuation of Jakaf, symptoms from myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week. Some patients with myelofbrosis have experienced one or more of the following adverse events after discontinuing Jakaf: fever, respiratory distress, hypotension, DIC, or multi-organ failure. If one or more of these occur after discontinuation of, or while tapering the dose of Jakaf, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of Jakaf. Instruct patients not to interrupt or discontinue Jakaf therapy without consulting their physician. When discontinuing or interrupting therapy with Jakaf for reasons other than thrombocytopenia or neutropenia [see Dosage and Administration (2.5) in Full Prescribing Information], consider tapering the dose of Jakaf gradually rather than discontinuing abruptly. Non-Melanoma Skin Cancer Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred in patients treated with Jakaf. Perform periodic skin examinations. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1)] Risk of Infection [see Warnings and Precautions (5.2)] Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakaf [see Warnings and Precautions (5.3)] Non-Melanoma Skin Cancer [see Warnings and Precautions (5.4)]. 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 refect the rates observed in practice. Clinical Trials Experience in Myelofbrosis The safety of Jakaf was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofbrosis in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakaf of 9.5 months (range 0.5 to 17 months), with 89% of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 10 9 /L) and 20 mg twice daily (pretreatment platelet counts greater than 200 X 10 9 /L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the frst 8 weeks of therapy. In a double-blind, randomized, placebocontrolled study of Jakaf, among the 155 patients treated with Jakaf, the most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2 ]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with Jakaf and 11% of patients treated with placebo. Table 1 presents the most common adverse reactions occurring in patients who received Jakaf in the double-blind, placebo-controlled study during randomized treatment. Table 1: Myelofbrosis: Adverse Reactions Occurring in Patients on Jakaf in the Double-blind, Placebo-controlled Study During Randomized Treatment Adverse Reactions All Grades a Jakaf (N=155) Grade 3 Grade 4 All Grades Placebo (N=151) Grade 3 Grade 4 Bruising b 23 < Dizziness c 18 < Headache Urinary Tract Infections d <1 <1 Weight Gain e 7 <1 0 1 <1 0 Flatulence <1 0 0 Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median time to onset of frst CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (<1%) discontinued treatment because of anemia. In patients receiving Jakaf, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dl below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dl below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakaf and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakaf and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 10 9 /L was 14 days. Platelet transfusions were administered to 5% of patients receiving Jakaf and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in <1% of patients receiving Jakaf and <1% of patients receiving control regimens. Patients with a platelet count of 100 X 10 9 /L to 200 X 10 9 /L before starting Jakaf had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 10 9 /L (17% versus 7%). Neutropenia In the two Phase 3 clinical studies, 1% of patients reduced or stopped Jakaf because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakaf or placebo in the placebocontrolled study. Table 2: Myelofbrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Study a Laboratory Parameter All Grades b Jakaf (N=155) Grade 3 Grade 4 All Grades Placebo (N=151) Grade 3 Grade 4 Thrombocytopenia Anemia Neutropenia <1 1 a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 Additional Data from the Placebo-controlled Study 25% of patients treated with Jakaf and 7% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for Jakaf with 1% Grade 3 and no Grade 4 ALT elevations. 17% of patients treated with Jakaf and 6% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was <1% for Jakaf with no Grade 3 or 4 AST elevations. 17% of patients treated with Jakaf and <1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was <1% for Jakaf with no Grade 3 or 4 cholesterol elevations. Clinical Trial Experience in Polycythemia Vera In a randomized, open-label, active-controlled study, 110 patients with polycythemia vera resistant to or intolerant of hydroxyurea received Jakaf and 111 patients received best available therapy [see Clinical Studies (14.2) in Full Prescribing Information]. The most frequent adverse drug reaction was anemia. Table 3 presents the most frequent non-hematologic treatment emergent adverse events occurring up to Week 32. Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with Jakaf. Table 3: Polycythemia Vera: Treatment Emergent Adverse Events Occurring in 6% of Patients on Jakaf in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment Jakaf (N=110) Best Available Therapy (N=111) Adverse Events All Grades a Grade 3-4 All Grades Grade 3-4 Headache 16 <1 19 <1 Abdominal Pain b 15 <1 15 <1 Diarrhea <1 Dizziness c Fatigue Pruritus 14 < Dyspnea d Muscle Spasms 12 <1 5 0 Nasopharyngitis Constipation Cough Edema e Arthralgia <1 Asthenia Epistaxis Herpes Zoster f 6 <1 0 0 Nausea Herpes Zoster f <1 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes abdominal pain, abdominal pain lower, and abdominal pain upper a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 c includes dizziness and vertigo b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere s Disease, labyrinthitis d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identifed, nitrite urine present e includes weight increased, abnormal weight gain f includes herpes zoster and post-herpetic neuralgia d includes dyspnea and dyspnea exertional e includes edema and peripheral edema f includes herpes zoster and post-herpetic neuralgia Other clinically important treatment emergent adverse events observed in less than 6% of patients treated with Jakaf were: Weight gain, hypertension, and urinary tract infections Clinically relevant laboratory abnormalities are shown in Table 4.

17 Table 4: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment a Laboratory Parameter Hematology All Grades b Jakaf (N=110) Grade 3 Grade 4 All Grades Best Available Therapy (N=111) Grade 3 Grade 4 Anemia 72 <1 < Thrombocytopenia 27 5 < <1 Neutropenia 3 0 <1 10 <1 0 Chemistry Hypercholesterolemia Elevated ALT 25 < Elevated AST <1 0 Hypertriglyceridemia count between 50 X 10 9 /L and 150 X 10 9 /L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and hepatic impairment [see Dosage and Administration (2.4) in Full Prescribing Information]. OVERDOSAGE There is no known antidote for overdoses with Jakaf. Single doses up to 200 mg have been given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment should be given. Hemodialysis is not expected to enhance the elimination of ruxolitinib. Jakaf is a registered trademark of Incyte. All rights reserved. U.S. Patent Nos ; ; ; ; Incyte Corporation. All rights reserved. Issued: December 2014 RUX-1428 a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9. CYP3A4 inhibitors: The C max and AUC of ruxolitinib increased 33% and 91%, respectively following concomitant administration with the strong CYP3A4 inhibitor ketoconazole in healthy subjects. Concomitant administration with mild or moderate CYP3A4 inhibitors did not result in an exposure change requiring intervention [see Pharmacokinetics (12.3) in Full Prescribing Information]. When administering Jakaf with strong CYP3A4 inhibitors, consider dose reduction [see Dosage and Administration (2.3) in Full Prescribing Information]. Fluconazole: The AUC of ruxolitinib is predicted to increase by approximately 100% to 300% following concomitant administration with the combined CYP3A4 and CYP2C9 inhibitor fuconazole at doses of 100 mg to 400 mg once daily, respectively [see Pharmacokinetics (12.3) in Full Prescribing Information]. Avoid the concomitant use of Jakaf with fuconazole doses of greater than 200 mg daily [see Dosage and Administration (2.3) in Full Prescribing Information]. CYP3A4 inducers: The C max and AUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration with the strong CYP3A4 inducer rifampin in healthy subjects. No dose adjustment is recommended; however, monitor patients frequently and adjust the Jakaf dose based on safety and effcacy [see Pharmacokinetics (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Risk Summary There are no adequate and well-controlled studies of Jakaf in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. Jakaf should be used during pregnancy only if the potential beneft justifes the potential risk to the fetus. Animal Data Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse fndings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Jakaf, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Jakaf in pediatric patients have not been established. Geriatric Use Of the total number of myelofbrosis patients in clinical studies with Jakaf, 52% were 65 years of age and older. No overall differences in safety or effectiveness of Jakaf were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakaf (25 mg) were evaluated in a study in healthy subjects [CrCl ml/min (N=8)] and in subjects with mild [CrCl ml/min (N=8)], moderate [CrCl ml/min (N=8)], or severe renal impairment [CrCl ml/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pstat3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakaf to patients with myelofbrosis and moderate (CrCl ml/min) or severe renal impairment (CrCl ml/min) with a platelet count between 50 X 10 9 /L and 150 X 10 9 /L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and moderate (CrCl ml/min) or severe renal impairment (CrCl ml/min). In all patients with end stage renal disease on dialysis, a dose reduction is recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakaf (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls ( hours versus 2.8 hours). The change in the pharmacodynamic marker, pstat3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakaf to patients with myelofbrosis and any degree of hepatic impairment and with a platelet

18 INDICATION FOR XYNTHA Xyntha Antihemophilic Factor (Recombinant) is indicated in adults and children with hemophilia A (congenital factor VIII deficiency or classic hemophilia) for control and prevention of bleeding episodes and for perioperative management. XYNTHA does not contain von Willebrand factor and, therefore, is not indicated in von Willebrand s disease. IMPORTANT SAFETY INFORMATION FOR XYNTHA Do not use in patients who have manifested lifethreatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including hamster proteins. Allergic-type hypersensitivity reactions, including anaphylaxis, are possible with XYNTHA. Inform patients of the early signs or symptoms of hypersensitivity reactions (including hives, generalized urticaria, chest tightness, wheezing, and hypotension) and anaphylaxis. Discontinue XYNTHA if hypersensitivity symptoms occur and administer appropriate emergency treatment. XYNTHA contains trace amounts of hamster proteins. Patients may develop hypersensitivity to these proteins. Inhibitors have been reported following administration of XYNTHA. Monitor patients for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Clinical response to XYNTHA may vary. If bleeding is not controlled with the recommended dose of factor, determine the plasma level and administer a dose of XYNTHA sufcient to achieve clinical response. If the factor level does not increase or there is no response, suspect an inhibitor and perform appropriate testing.

19 XYNTHA SOLOFUSE Efcacy and reconstitution convenience together XYNTHA SOLOFUSE is factor VIII with proven efcacy and easy, all-in-one reconstitution XYNTHA Antihemophilic Factor (Recombinant), successfully controlled and prevented bleeds with 1 or 2 infusions administered prior to initiation or during regular treatment % of bleeds were treated successfully on demand with 1 or 2 infusions* The median annualized bleed rate for all bleeding episodes was 1.9 (3.9 mean) and 45.7% of subjects had no bleeding episodes during regular treatment 1 XYNTHA SOLOFUSE Available in a wide range of doses IU 500 IU 1000 IU 2000 IU 3000 IU Start your patients on XYNTHA SOLOFUSE visit Across all studies, the most common adverse reactions ( 10%) with XYNTHA in previously treated adult and pediatric patients were headache (26% of subjects), arthralgia (25%), fever (21%), and cough (11%). Other adverse reactions reported in 5% of subjects were diarrhea, vomiting, weakness, and nausea. XYNTHA is an injectable medicine administered by intravenous (IV) infusion. Patients should be advised that local irritation may occur when infusing XYNTHA after reconstitution in XYNTHA SOLOFUSE. You are encouraged to report negative side efects of prescription drugs to the FDA. Visit or call FDA Please see brief summary of Full Prescribing Information on next page. RUS Pfizer Inc. All rights reserved. REFERENCES: 1. XYNTHA SOLOFUSE Antihemophilic Factor (Recombinant) [Prescribing Information]. Philadelphia, PA: Wyeth Pharmaceuticals Inc; October Recht M, Nemes L, Matysiak M, et al. Clinical evaluation of moroctocog alfa (AF-CC), a new generation of B-domain deleted recombinant factor VIII (BDDrFVIII) for treatment of haemophilia A: demonstration of safety, efcacy, and pharmacokinetic equivalence to full-length recombinant factor VIII. Haemophilia. 2009;15(4): * Results reported here for 53 patients (187 bleeding episodes) who received 282 infusions of XYNTHA (median dose 30.6 IU/kg) over 6 months. 1,2 Printed in USA/April 2015

20 Brief Summary See package insert for full Prescribing Information. For further product information and current package insert, please visit XYNTHA.com or call Pfzer Inc toll-free at INDICATIONS AND USAGE Control and Prevention of Bleeding Episodes in Patients with Hemophilia A XYNTHA Antihemophilic Factor (Recombinant) is indicated in adults and children with hemophilia A (congenital factor VIII defciency or classic hemophilia) for control and prevention of bleeding episodes. XYNTHA does not contain von Willebrand factor, and therefore is not indicated in patients with von Willebrand s disease. Perioperative Management in Patients with Hemophilia A XYNTHA Antihemophilic Factor (Recombinant) is indicated in adults and children with hemophilia A for perioperative management. DOSAGE FORMS AND STRENGTHS XYNTHA is supplied as a white to off-white freeze-dried powder in the following dosages: 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU. CONTRAINDICATIONS Do not use in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including hamster proteins. WARNINGS AND PRECAUTIONS General The clinical response to XYNTHA may vary. If bleeding is not controlled with the recommended dose, the plasma level of factor VIII should be determined and a suffcient dose of XYNTHA should be administered to achieve a satisfactory clinical response. If the patient s plasma factor VIII level fails to increase as expected or if bleeding is not controlled after the expected dose, the presence of an inhibitor (neutralizing antibodies) should be suspected and appropriate testing performed. Hypersensitivity Reactions Allergic type hypersensitivity reactions, including anaphylaxis, are possible with XYNTHA. Inform patients of the early signs or symptoms of hypersensitivity reactions (including hives [rash with itching], generalized urticaria, chest tightness, wheezing, and hypotension) and anaphylaxis. Discontinue XYNTHA if hypersensitivity symptoms occur and administer appropriate emergency treatment. Formation of Antibodies to Hamster Protein XYNTHA contains trace amounts of hamster proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. Neutralizing Antibodies Inhibitors have been reported following administration of XYNTHA. Monitor patients for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures factor VIII inhibitor concentration to determine if a factor VIII inhibitor is present. Monitoring: Laboratory Tests Monitor plasma factor VIII activity levels by the one-stage clotting assay to confrm that adequate factor VIII levels have been achieved and are maintained, when clinically indicated [see Dosage and Administration in full Prescribing Information]. It is recommended that individual factor VIII values for recovery and, if clinically indicated, other pharmacokinetic characteristics be used to guide dosing and administration. Monitor for development of factor VIII inhibitors. Perform assay to determine if factor VIII inhibitor is present when expected factor VIII activity plasma levels are not attained, or when bleeding is not controlled with the expected dose of XYNTHA. Use Bethesda Units (BU) to titer inhibitors. 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 refect the rates observed in clinical practice. XYNTHA was evaluated in fve clinical studies (N=155), four completed studies with adult and pediatric PTPs and one ongoing study in pediatric PTPs <6 years of age. Study 1 is a pivotal phase 3 (safety and effcacy) study in which previously treated patients (PTPs) with hemophilia A received XYNTHA for routine prophylaxis and on-demand treatment, 94 subjects received at least one dose of XYNTHA, resulting in a total of 6,775 infusions [see Clinical Studies in full Prescribing Information]. Study 2 (surgery) is an open-label, single-arm study of 30 evaluable PTPs with severe or moderately severe hemophilia A (factor VIII activity in plasma [FVIII:C] 2%) who required elective major surgery and were planned to receive XYNTHA replacement therapy for at least 6 days post-surgery. All subjects received at least one dose of XYNTHA, resulting in 1,161 infusions [see Clinical Studies in full Prescribing Information]. Across all studies, safety was evaluated in 48 previously treated pediatric patients <16 years of age (28 children, <6 years of age and 20 adolescents, 12 to <16 years of age). A total of 7,150 infusions of XYNTHA were administered with a median dose per infusion of 29 IU/kg (min, max: 9,108 IU/kg). Across all studies, the most common adverse reactions ( 10%) with XYNTHA in adult and pediatric PTPs were headache (26% of subjects), arthralgia (25%), pyrexia (21%), cough (11%). Other adverse reactions reported in 5% of subjects were: diarrhea (8%), vomiting (7%), asthenia (7%), and nausea (6%). Immunogenicity There is a potential for immunogenicity with therapeutic proteins. The development of factor VIII inhibitors with XYNTHA was evaluated in 144 adult and pediatric PTPs with at least 50 EDs. Laboratory-based assessments for FVIII inhibitor (partial Nijmegen modifcation of the Bethesda inhibitor assay) were conducted in the clinical studies. The criterion for a positive FVIII test result was 0.6 BU/mL. Across all studies, 3 subjects developed factor VIII inhibitors (2.1%). The clinical studies for XYNTHA examined 124 subjects (94 for bleeding and 30 for surgery) who had previously been treated with factor VIII (PTPs). In the safety and effcacy study, two subjects with inhibitors were observed in 89 subjects (2.2%) who completed 50 exposure days. In a Bayesian statistical analysis, results from this study were used to update PTP results from a prior supporting study using XYNTHA manufactured at the initial facility, where one de novo and two recurrent inhibitors were observed in 110 subjects, and the experience with predecessor product (1 inhibitor in 113 subjects). This Bayesian analysis indicates that the population (true) inhibitor rate for XYNTHA, the estimate of the 95% upper limit of the true inhibitor rate, was 4.17%. None of the PTPs developed anti-cho (Chinese hamster ovary) or anti-tn8.2 antibodies. One PTP developed anti-fviii antibodies, but this subject did not develop an inhibitor. In the surgery study, one low titer persistent inhibitor and one transient false-positive inhibitor were reported. In this study, one surgical subject developed anti-cho cell antibodies with no associated allergic reaction. One subject developed anti-fviii antibodies, but this subject did not develop an inhibitor. Across all studies, safety was evaluated in 40 previously treated pediatric patients <16 years of age with at least 50 EDs (25 children, <6 years of age and 15 adolescents, 12 to <16 years of age). Of these, one pediatric subject developed an inhibitor. DRUG INTERACTIONS None known. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C - Animal reproduction studies have not been conducted with XYNTHA. It is not known whether XYNTHA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. XYNTHA should be given to a pregnant woman only if clinically indicated. Labor and Delivery There is no information available on the effect of factor VIII replacement therapy on labor and delivery. XYNTHA should be used only if clinically indicated. Nursing Mothers It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if XYNTHA is administered to nursing mothers. XYNTHA should be given to nursing mothers only if clinically indicated. Pediatric Use In comparison to the pharmacokinetic parameters reported in adults, children have shorter half-lives, larger volumes of distribution and lower recovery of factor VIII after XYNTHA administration. The clearance (based on per kg body weight) is approximately 40% higher in children. Higher or more frequent doses may be required to account for the observed differences in pharmacokinetic parameters [see Clinical Pharmacology in full Prescribing Information]. In the completed open label safety and effcacy study of XYNTHA (n=94), 17 adolescent subjects 12 to <16 years of age with severe or moderately severe hemophilia A (FVIII:C 2%), who were previously treated with at least 150 EDs to FVIII products, received XYNTHA for ondemand and follow-up treatment. The median dose per infusion was 47 IU/kg (min-max: 24-74) and the median exposure per subject was 6 days (min-max: 1-26). Additional data are available from a safety and effcacy study of XYNTHA in children <6 years of age with moderately severe or severe hemophilia A (FVIII:C 2%) and with at least 20 prior EDs to FVIII products. In this study subjects received XYNTHA for on-demand and follow-up treatment of bleeding episodes. The median dose per infusion was 28 IU/kg and the median exposure per subject was 16 days. Geriatric Use Clinical studies of XYNTHA did not include subjects aged 65 and over. In general, dose selection for an elderly patient should be individualized. STORAGE AND HANDLING XYNTHA Vials Product as Packaged for Sale - Store XYNTHA vials under refrigeration at a temperature of 2 to 8 C (36 to 46 F) for up to 36 months from the date of manufacture until the expiration date stated on the label. XYNTHA vials may also be stored at room temperature not to exceed 25 C (77 F) for up to 3 months, until the expiration date. After room temperature storage, XYNTHA vials can be returned to the refrigerator until the expiration date. Do not store XYNTHA vials at room temperature and return it to the refrigerator more than once. The starting date at room temperature storage should be clearly recorded. The patient should write in the space provided on the outer carton. At the end of the 3-month period, the product must be used immediately, discarded, or returned to refrigerated storage. The diluent syringe may be stored at 2 to 25 C (36 to 77 F). XYNTHA Solofuse Product as Packaged for Sale - Store XYNTHA Solofuse under refrigeration at a temperature of 2 to 8 C (36 to 46 F) for up to 36 months from the date of manufacture until the expiration date stated on the label. Within the expiration date, XYNTHA Solofuse may also be stored at room temperature not to exceed 25 C (77 F) for up to 3 months. The starting date at room temperature storage should be clearly recorded in the space provided on the outer carton. At the end of the 3-month period, XYNTHA Solofuse must not be put back into the refrigerator, but must be used immediately or discarded. Do not use XYNTHA Solofuse after the expiration date stated on the label or after 3 months when stored at room temperature, whichever is earlier. Do not freeze, to prevent damage to XYNTHA Solofuse. During storage, avoid prolonged exposure of XYNTHA Solofuse to light. Product After Reconstitution - Administer XYNTHA within 3 hours after reconstitution or after removal of the grey rubber tip cap from XYNTHA Solofuse. The reconstituted solution may be stored at room temperature prior to administration. This brief summary is based on the Xyntha [Antihemophilic Factor (Recombinant)] Prescribing Information LAB , revised 10/14, and LAB , revised 10/14. RUS Pfizer Inc. All rights reserved. April 2015

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22 Brief Summary of Full Prescribing Information InjectaFer (ferric carboxymaltose injection) rx Only InDIcatIOnS and USaGe: Injectafer (ferric carboxymaltose injection) is an iron replacement product indicated for the treatment of iron defciency anemia in adult patients: who have intolerance to oral iron or who have had unsatisfactory response to oral iron, who have non-dialysis dependent chronic kidney disease. DOSaGe and administration: For patients weighing 50 kg (110 lb) or more: Give Injectafer in two doses separated by at least 7 days. Give each dose as 750 mg for a total cumulative dose not to exceed 1500 mg of iron per course. For patients weighing less than 50 kg (110 lb): Give Injectafer in two doses separated by at least 7 days. Give each dose as 15 mg/kg body weight for a total cumulative dose not to exceed 1500 mg of iron per course. Injectafer treatment may be repeated if iron defciency anemia reoccurs. Administer Injectafer intravenously, either as an undiluted slow intravenous push or by infusion. When administering as a slow intravenous push, give at the rate of approximately 100 mg (2 ml) per minute. When administered via infusion, dilute up to 750 mg of iron in no more than 250 ml of sterile 0.9% sodium chloride injection, USP, such that the concentration of the infusion is not less than 2 mg of iron per ml and administer over at least 15 minutes. Inspect parenteral drug products visually for the absence of particulate matter and discoloration prior to administration. The product contains no preservatives. Injectafer is a single-use vial. Discard unused portion. Avoid extravasation of Injectafer since brown discoloration of the extravasation site may be long lasting. Monitor for extravasation. If extravasation occurs, discontinue the Injectafer administration at that site. DOSaGe FOrMS and StrenGtHS: Single-use vials containing 50 mg elemental iron per ml in the following presentation: 750 mg iron/15 ml contraindications: Hypersensitivity to Injectafer or any of its inactive components. WarnInGS and PrecaUtIOnS Hypersensitivity reactions: Serious hypersensitivity reactions, including anaphylactictype reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Injectafer. Patients may present with shock, clinically signifcant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after Injectafer administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Injectafer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving Injectafer. Other serious or severe adverse reactions potentially associated with hypersensitivity which included, but not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects. Hypertension: In clinical studies, hypertension was reported in 3.8% (67/1775) of subjects in clinical trials 1 and 2. Transient elevations in systolic blood pressure, sometimes occurring with facial fushing, dizziness, or nausea were observed in 6% (106/1775) of subjects in these two clinical trials. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each Injectafer administration. Laboratory test alterations: In the 24 hours following administration of Injectafer, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in Injectafer. adverse reactions adverse reactions in clinical trials: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not refect the rates observed in clinical practice. In two randomized clinical studies, a total of 1775 patients were exposed to Injectafer 15 mg/kg body weight up to a maximum single dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative dose of 1500 mg of iron. Adverse reactions reported by 1% of treated patients are shown in the following table. Table 1. Adverse reactions reported in 1% of Study Patients in Clinical Trials 1 and 2 Term Nausea Hypertension Flushing/Hot Flush Blood Phosphorus Decrease Dizziness Vomiting Injection Site Discoloration Headache Alanine Aminotransferase Increase Dysgeusia Hypotension Constipation Injectafer (N=1775) % Pooled Comparators a (N=1783) % a Includes oral iron and all formulations of IV iron other than Injectafer Oral iron (N=253) % Transient decreases in laboratory blood phosphorus levels (< 2 mg/dl) have been observed in 27% (440/1638) of patients in clinical trials. adverse reactions from Post-marketing experience: The following serious adverse reactions have been most commonly reported from the post-marketing spontaneous reports with Injectafer : urticaria, dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, arthralgia, and syncope. One case of hypophosphatemic osteomalacia was reported in a subject who received 500 mg of Injectafer every 2 weeks for a total of 16 weeks. Partial recovery followed discontinuation of Injectafer. DrUG InteractIOnS: Formal drug interaction studies have not been performed with Injectafer. USe In SPecIFIc POPULatIOnS Pregnancy Pregnancy Category C: Adequate and well controlled studies in pregnant women have not been conducted. Injectafer should be used during pregnancy only if the potential beneft justifes the potential risk to the fetus. nursing Mothers: A study to determine iron concentrations in breast milk after administration of Injectafer (n=11) or oral ferrous sulfate (n=14) was conducted in 25 lactating women with postpartum iron defciency anemia. Mean breast milk iron levels were higher in lactating women receiving Injectafer than in lactating women receiving oral ferrous sulfate. Pediatric Use: Safety and effectiveness has not been established in pediatric patients. Geriatric Use: Of the 1775 subjects in clinical studies of Injectafer, 50% were 65 years and over, while 25% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identifed differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. OVerDOSaGe: Excessive dosages of Injectafer may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. A patient who received Injectafer 18,000 mg over 6 months developed hemosiderosis with multiple joint disorder, walking disability and asthenia. Hypophosphatemic osteomalacia was reported in a patient who received Injectafer 4000 mg over 4 months. Partial recovery followed discontinuation of Injectafer. DeScrIPtIOn: Ferric carboxymaltose, an iron replacement product, is an iron carbohydrate complex with the chemical name of polynuclear iron (III) hydroxide 4(R)-(poly-(1 4)-O-α-D-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate. It has a relative molecular weight of approximately 150,000 Da. Injectafer (ferric carboxymaltose injection) is a dark brown, sterile, aqueous, isotonic colloidal solution for intravenous injection. Each ml contains 50 mg iron as ferric carboxymaltose in water for injection. Sodium hydroxide and/or hydrochloric acid may have been added to adjust the ph to The vial closure is not made with natural rubber latex. clinical PHarMacOLOGY Mechanism of action: Ferric carboxymaltose is a colloidal iron (III) hydroxide in complex with carboxymaltose, a carbohydrate polymer that releases iron. Pharmacodynamics: Using positron emission tomography (PET) it was demonstrated that red cell uptake of 59 Fe and 52 Fe from Injectafer ranged from 61% to 99%. In patients with iron defciency, red cell uptake of radio-labeled iron ranged from 91% to 99% after 24 days Injectafer dose. In patients with renal anemia red cell uptake of radio-labeled iron ranged from 61% to 84% after 24 days Injectafer dose. Pharmacokinetics: After administration of a single dose of Injectafer of 100 to 1000 mg of iron in iron defcient patients, maximum iron levels of 37 µg/ml to 333 µg/ml were obtained respectively after 15 minutes to 1.21 hours post dose. The volume of distribution was estimated to be 3 L. The iron injected or infused was rapidly cleared from the plasma, the terminal half life ranged from 7 to 12 hours. Renal elimination of iron was negligible. nonclinical toxicology carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenicity studies have not been performed with ferric carboxymaltose. Ferric carboxymaltose was not genotoxic in the following genetic toxicology studies: in vitro microbial mutagenesis (Ames) assay, in vitro chromosome aberration test in human lymphocytes, in vitro mammalian cell mutation assay in mouse lymphoma L5178Y/TK+/- cells, in vivo mouse micronucleus test at single intravenous doses up to 500 mg/kg. In a combined male and female fertility study, ferric carboxymaltose was administered intravenously over one hour to male and female rats at iron doses of up to 30 mg/kg. Animals were dosed 3 times per week (on Days 0, 3, and 7). There was no effect on mating function, fertility or early embryonic development. The dose of 30 mg/kg in animals is approximately 40% of the human dose of 750 mg based on body surface area. clinical StUDIeS: The safety and effcacy of Injectafer for treatment of iron defciency anemia were evaluated in two randomized, open-label, controlled clinical trials (Trial 1 and Trial 2). In these two trials, Injectafer was administered at dose of 15 mg/kg body weight up to a maximum single dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative dose of 1500 mg of iron. PatIent counseling InFOrMatIOn Question patients regarding any prior history of reactions to parenteral iron products. Advise patients of the risks associated with Injectafer. Advise patients to report any signs and symptoms of hypersensitivity that may develop during and following Injectafer administration, such as rash, itching, dizziness, lightheadedness, swelling and breathing problems. Injectafer is manufactured under license from Vifor (International) Inc, Switzerland. IN0650BS Iss. 7/2013

23 Transform your patients iron therapy experience with Injectafer (ferric carboxymaltose injection) Indication Injectafer is indicated for the treatment of iron defciency anemia in adult patients - who have intolerance to oral iron or have had unsatisfactory response to oral iron or - who have non-dialysis dependent chronic kidney disease The frst non-dextran IV iron for iron defciency anemia of various etiologies Safety Patients with previous drug allergies were included in clinical trials Safety profle comparable to Venofer (iron sucrose injection, USP) 1 More Iron. Fewer Infusions. Highest FDA-approved single dose of IV iron, up to 750 mg* Two administration options - infusion over at least 15 minutes or slow push injection over at least 7.5 minutes IMPORTANT SAFETY INFORMATION INDICATIONS/CONTRAINDICATIONS Injectafer (ferric carboxymaltose injection) is an iron replacement product indicated for the treatment of iron defciency anemia in adult patients who have intolerance to oral iron or have had unsatisfactory response to oral iron, and in adult patients with non-dialysis dependent chronic kidney disease. Injectafer is contraindicated in patients with hypersensitivity to Injectafer or any of its inactive components. WARNINGS AND PRECAUTIONS Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Injectafer. Patients may present with shock, clinically signifcant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after Injectafer administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Injectafer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. In clinical trials, serious anaphylactic/ anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving Injectafer. Other serious or severe adverse reactions potentially associated with hypersensitivity which included, but were not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects. In clinical studies, hypertension was reported in 3.8% (67/1775) of subjects. Transient elevations in systolic blood pressure, sometimes occurring with facial fushing, dizziness, or nausea were observed in 6% (106/1775) of subjects. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each Injectafer administration. In the 24 hours following administration of Injectafer, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in Injectafer. ADVERSE REACTIONS In two randomized clinical studies, a total of 1775 patients were exposed to Injectafer, 15 mg/kg of body weight, up to a single maximum dose of 750 mg of iron on two occasions, separated by at least 7 days, up to a cumulative dose of 1500 mg of iron. Adverse reactions reported by 2% of Injectafer -treated patients were nausea (7.2%); hypertension (3.8%); fushing/hot fush (3.6%); blood phosphorus decrease (2.1%); and dizziness (2.0%). The following serious adverse reactions have been most commonly reported from the postmarketing spontaneous reports: urticaria, dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, arthralgia, and syncope. * For patients weighing 50 kg (110 lb) or more, give each dose as 750 mg. For patients weighing less than 50 kg (110 lb), give each dose as 15 mg/kg body weight. When administered via infusion, dilute up to 750 mg of iron in no more than 250mL of sterile 0.9% sodium chloride injection, USP, such that the concentration of the infusion is not <2 mg of iron per ml and administer over at least 15 minutes. When administering as a slow intravenous push, give at the rate of approximately 100 mg (2 ml) per minute. References 1. Onken JE, Bregman DB, Harrington RA, et. al. Ferric carboxymaltose in patients with iron-defciency anemia and impaired renal function: the REPAIR-IDA trial. Nephrol Dial Transplant doi:10:1093/ndt/gft251 Please see Brief Summary of Full Prescribing Information on the following page. J code: J1439 (Efective 1/1/15) IV IRON REIMBURSEMENT HOTLINE: IV-IRON Injectafer is manufactured under license from Vifor (International, Inc.) Switzerland American Regent, Inc. FCM123 Rev. 11/2014