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RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information. counts prior to each Rituxan course. During treatment with Rituxan and chemotherapy, obtain CBC and platelet counts at weekly to monthly intervals and more frequently in WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), patients who develop cytopenias. [See Adverse Reactions]. s The duration of cytopenias SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL caused by Rituxan can extend months beyond the treatment period. ADVERSE LEUKOENCEPHALOPATHY (PML) REACTIONS The most common adverse reactions of Rituxan (incidence ≥25%) Infusion Reactions: Rituxan administration can result in serious, including observed in clinical trials of patients with NHL were infusion reactions, fever, fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have lymphopenia, chills, infection, and asthenia. The most common adverse reactions of occurred. Approximately 80% of fatal infusion reactions occurred in Rituxan (incidence ≥25%) observed in clinical trials of patients with CLL were: infusion association with the first infusion. Carefully monitor patients during reactions and neutropenia. Clinical Trials Experience in Lymphoid Malignancies infusions. Discontinue Rituxan infusion and provide medical treatment for Because clinical trials are conducted under widely varying conditions, adverse reaction Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse rates observed in the clinical trials of a drug cannot be directly compared to rates in the Reactions]. s Tumor Lysis Syndrome (TLS): Acute renal failure requiring clinical trials of another drug and may not reflect the rates observed in practice. The data dialysis with instances of fatal outcome can occur in the setting of TLS described below reflect exposure to Rituxan in 2282 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan active-controlled trials (n = 356 and n = 1926). The population included 679 patients [see Warnings and Precautions, Adverse Reactions]. s Severe Mucocutaneous with low-grade follicular lymphoma, 927 patients with DLBCL, and 676 patients with Reactions: Severe, including fatal, mucocutaneous reactions can occur in CLL. Most NHL patients received Rituxan as infusion of 375 mg/m2 per infusion, given as patients receiving Rituxan [see Warnings and Precautions, Adverse a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 Reactions]. s Progressive Multifocal Leukoencephalopathy (PML): JC virus doses, or following chemotherapy for up to 16 doses. CLL patients received Rituxan 375 infection resulting in PML and death can occur in patients receiving Rituxan mg/m2 as an initial infusion followed by 500 mg/m2 for up to 5 doses, in combination with [see Warnings and Precautions, Adverse Reactions]. s fludarabine and cyclophosphamide. Seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of Rituxan-based therapy. Infusion INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) is Reactionss In the majority of patients with NHL, infusion reactions consisting of fever, indicated for the treatment of patients with: Relapsed or refractory, low-grade or chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after beginning the first infusion and resolved with slowing or interruption of the Rituxan first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. saline). The incidence of infusion reactions was highest during the first infusion (77%) Chronic Lymphocytic Leukemia (CLL) Rituxan® (rituximab) is indicated, in and decreased with each subsequent infusion. [See Boxed Warning, Warnings and combination with fludarabine and cyclophosphamide (FC), for the treatment of patients Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, with previously untreated and previously treated CD20-positive CLL. Limitations of use occurred in less than 5% of patients with NHL in the single-arm studies. The overall Rituxan is not recommended for use in patients with severe, active infections. incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan including fatal, infusion reactions. Severe reactions typically occurred during the first was administered following chemotherapy for the treatment of follicular or low-grade infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and NHL, the rate of infection was higher among patients who received Rituxan. In diffuse sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, large B-cell lymphoma patients, viral infections occurred more frequently in those who pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, received Rituxan. Cytopenias and hypogammaglobulinemiaa In patients with NHL ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in patients with an antihistamine and acetaminophen prior to dosing. Institute medical 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia reactions as needed. Depending on the severity of the infusion reaction and the required was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). interventions, temporarily or permanently discontinue Rituxan. Resume infusion at a A single occurrence of transient aplastic anemia (pure red cell aplasia) and two minimum 50% reduction in rate after symptoms have resolved. Closely monitor the occurrences of hemolytic anemia following Rituxan therapy occurred during the singlefollowing patients: those with pre-existing cardiac or pulmonary conditions, those who arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in experienced prior cardiopulmonary adverse reactions, and those with high numbers of 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% circulating malignant cells (≥25,000/mm3). [See Boxed Warning, Warnings and of these patients. Relapsed or Refractory, Low-Grade NHL Adverse reactions in Table 1 Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Acute renal failure, occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. [See some fatal, can occur within 12–24 hours after the first infusion of Rituxan in patients Clinical Studies.] Most patients received Rituxan 375 mg/m2 weekly for 4 doses. with NHL. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden Table 1 confers a greater risk of TLS. Administer aggressive intravenous hydration and anti- Incidence of Adverse Reactions in ≥5% of Patients with Relapsed or Refractory, Lowhyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, Grade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b monitor renal function and fluid balance, and administer supportive care, including dialysis as All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous Any Adverse Events 99 57 Respiratory p y System y 38 4 reactions, some with fatal outcome, can occur in patients treated with Rituxan. These Bodyy as a Whole 86 10 Increased Cough 13 1 Fever 53 1 Rhinitis 12 1 reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid Chills 33 3 Bronchospasm 8 1 dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these Infection 31 4 Dyspnea 7 1 Asthenia 26 1 Sinusitis 6 0 reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan Headache 19 1 Metabolic and Nutritional in patients who experience a severe mucocutaneous reaction. The safety of Abdominal Pain 14 1 Disorders 38 3 Pain 12 1 Angioedema 11 1 readministration of Rituxan to patients with severe mucocutaneous reactions has not Back Pain 10 1 Hyperglycemia 9 1 been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Throat Irritation 9 0 Peripheral Edema 8 0 5 0 LDH Increase 7 0 Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur HemeFlushing and Lymphatic y p System y 67 48 Digestive g System y 37 2 in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases. Lymphopenia 48 40 Nausea 23 1 Leukopenia 14 4 Diarrhea 10 1 The majority of patients with hematologic malignancies diagnosed with PML received Neutropenia 14 6 Vomiting 10 1 Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell Thrombocytopenia 12 2 Nervous System y 32 1 Anemia 8 3 Dizziness 10 1 transplant. The patients with autoimmune diseases had prior or concurrent Skin and Appendages Anxiety 5 1 pp g 44 2 immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of Night Sweats 15 1 Musculoskeletal System y 26 3 Rash 15 1 Myalgia 10 1 their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting Arthralgia Pruritus 14 1 10 1 with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited Urticaria 8 1 Cardiovascular System y 25 3 Hypotension 10 1 to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Rituxan Hypertension 6 1 and consider discontinuation or reduction of any concomitant chemotherapy or a b immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Adverse reactions observed up to 12 months following Rituxan. Adverse reactions graded for severity Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B virus (HBV) reactivation by NCI-CTC criteria. with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and up to malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was 6 months after Rituxan infusion. Previously Untreated Low-Grade NHLL In Study 4, approximately 4 months after the initiation of Rituxan and approximately one month after patients in the R-CVP arm experienced a higher incidence of infusional toxicity and the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. neutropenia compared to patients in the CVP arm. The following adverse reactions Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone: infection for several months following Rituxan therapy. Discontinue Rituxan and any rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), concomitant chemotherapy in patients who develop viral hepatitis, and institute pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In appropriate treatment including antiviral therapy. Insufficient data exist regarding the Study 5, the following adverse reactions were reported more frequently (≥5%) in safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV patients receiving Rituxan following CVP compared to patients who received no further reactivation. [See Adverse Reactions.] Infections Serious, including fatal, bacterial, therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory fungal, and new or reactivated viral infections can occur during and up to one year neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. following the completion of Rituxan-based therapy. New or reactivated viral infections 10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only West Nile virus, and hepatitis B and C. Discontinue Rituxan for serious infections and Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the Rituxan arm institute appropriate anti-infective therapy. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform compared with those who received no further therapy (4% vs. 1%). [See Clinical Studies.] DLBCLL In Studies 6 and 7, [see Clinical Studies] s the following adverse reactions, cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina. [See regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder administration in patients with NHL. Renal toxicity has occurred in patients who (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed experience tumor lysis syndrome and in patients with NHL administered concomitant safety data collection in these studies was primarily limited to Grade 3 and 4 adverse cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity approved treatment regimen. Monitor closely for signs of renal failure and discontinue determined that supraventricular arrhythmias or tachycardia accounted for most of Rituxan in patients with a rising serum creatinine or oliguria. Bowel Obstruction and the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading following Grade 3 or 4 adverse reactions occurred more frequently among patients in to death, can occur in patients receiving Rituxan in combination with chemotherapy. In the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. postmarketing reports, the mean time to documented gastrointestinal perforation was 6 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and more frequently among patients receiving R-CHOP were viral infection (Study 7), institute appropriate treatment for complaints of abdominal pain. [See Adverse neutropenia (Studies 7 and 8), and anemia (Study 8). CLLL The data below reflect Reactions.] Immunization The safety of immunization with live viral vaccines following exposure to Rituxan in combination with fludarabine and cyclophosphamide in 676 s The age range was Rituxan therapy has not been studied and vaccination with live virus vaccines is not patients with CLL in Study 9 or Study 10 [see Clinical Studies]. recommended. Laboratory Monitoring In patients with lymphoid malignancies, during 30–83 years and 71% were men. Detailed safety data collection in Study 9 was limited treatment with Rituxan monotherapy, obtain complete blood counts (CBC) and platelet to Grade 3 and 4 adverse reactions and serious adverse reactions. Infusion-related adverse reactions were defined by any of the following adverse events occurring during or within 24 hours of the start of infusion: nausea, pyrexia, chills, hypotension, vomiting, and dyspnea. In Study 9, the following Grade 3 and 4 adverse reactions occurred more frequently in R-FC–treated patients compared to FC-treated patients: infusion reactions (9% in R-FC arm), neutropenia (30% vs. 19%), febrile neutropenia (9% vs. 6%), leukopenia (23% vs. 12%), and pancytopenia (3% vs. 1%). In Study 10, the following Grade 3 or 4 adverse reactions occurred more frequently in R-FC–treated patients compared to FC-treated patients: infusion reactions (7% in R-FC arm), neutropenia (49% vs. 44%), febrile neutropenia (15% vs. 12%), thrombocytopenia (11% vs. 9%), hypotension (2% vs. 0%), and hepatitis B (2% vs. <1%). Fifty-nine percent of R-FC–treated patients experienced an infusion reaction of any severity. Immunogenicityy As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, anti-human antichimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in Rituxan-treated patients is unclear. Postmarketing Experience The following adverse reactions have been identified during post-approval use of Rituxan in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic:: prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia. Cardiac:: fatal cardiac failure. Immune/ Autoimmune Events:: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection:: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection. Neoplasia:: disease progression of Kaposi’s sarcoma. Skin:: severe mucocutaneous reactions. Gastrointestinal:: bowel obstruction and perforation. Pulmonary:: fatal bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUG INTERACTIONS Formal drug interaction studies have not been performed with Rituxan. In patients with CLL, Rituxan did not alter systemic exposure to fludarabine or cyclophosphamide. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women. Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’s lymphoma is a serious condition that requires treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Nursing Mothers It is not known whether Rituxan is secreted into human milk. However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from oral ingestion of Rituxan should be weighed against the known benefits of breast-feeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHLL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Chronic Lymphocytic Leukemia Among patients with CLL evaluated in two randomized active-controlled trials, 243 of 676 Rituxan-treated patients (36%) were 65 years of age or older; of these, 100 Rituxan-treated patients (15%) were 70 years of age or older. In exploratory analyses defined by age, there was no observed benefit from the addition of Rituxan to fludarabine and cyclophosphamide among patients 70 years of age or older in Study 9 or in Study 10; there was also no observed benefit from the addition of Rituxan to fludarabine and cyclophosphamide among patients 65 years of age or older in Study 10 [see Clinical Studies]. s Patients 70 years or older received lower dose intensity of fludarabine and cyclophosphamide compared to younger patients, regardless of the addition of Rituxan. In Study 9, the dose intensity of Rituxan was similar in older and younger patients, however in Study 10 older patients received a lower dose intensity of Rituxan. The incidence of Grade 3 and 4 adverse reactions was higher among patients receiving R-FC who were 70 years or older compared to younger patients for neutropenia [44% vs. 31% (Study 9); 56% vs. 39% (Study 10)], febrile neutropenia [16% vs. 6% (Study 9)], anemia [5% vs. 2% (Study 9); 21% vs. 10% (Study 10)], thrombocytopenia [19% vs. 8% (Study 10)], pancytopenia [7% vs. 2% (Study 9); 7% vs. 2% (Study 10)] and infections [30% vs. 14% (Study 10)]. OVERDOSAGE There has been no experience with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have been administered in clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertilityy No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of Rituxan or to determine potential effects on fertility in males or females. PATIENT COUNSELING INFORMATION Patients should be provided the Rituxan Medication Guide and provided an opportunity to read prior to each treatment session. It is important that the patient’s overall health be assessed at each visit and the risks of Rituxan therapy and any questions resulting from the patient’s reading of the Medication Guide be discussed. Rituxan is detectable in serum for up to six months following completion of therapy. Individuals of childbearing potential should use effective contraception during treatment and for 12 months after Rituxan therapy. Revised 02/2010 (4851501) Jointly Marketed by: Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 ©2010 Biogen Idec Inc. and Genentech, Inc. 7140919 February 2010 Brief Summary See package insert for full Prescribing Information. For further product information and current package insert, please visit XYNTHA.com or call Wyeth Pharmaceuticals toll-free at 1-800-934-5556. INDICATIONS AND USAGE Control and Prevention of Bleeding Episodes in Hemophilia A XYNTHA Antihemophilic Factor (Recombinant), Plasma/Albumin-Free is indicated for the control and prevention of bleeding episodes in patients with hemophilia A (congenital factor VIII deficiency or classic hemophilia). XYNTHA does not contain von Willebrand factor, and therefore is not indicated in patients with von Willebrand’s disease. Surgical Prophylaxis in Patients with Hemophilia A XYNTHA Antihemophilic Factor (Recombinant), Plasma/Albumin-Free is indicated for surgical prophylaxis in patients with hemophilia A. Study 2 (surgery) is an open-label, single-arm study of at least 25 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. Twenty-two subjects received at least one dose of XYNTHA, resulting in 766 infusions [see Clinical Studies in full Prescribing Information]. In Study 2, the most frequently reported treatmentemergent adverse reaction was pyrexia (41% of subjects). Other adverse reactions reported in ≥ 5% of subjects were: headache (9%), nausea (9%), diarrhea (5%), vomiting (5%) and asthenia (5%). The adverse reactions reported in either study were considered mild or moderate in severity. Immunogenicity In Study 1, the incidence of FVIII inhibitors to XYNTHA was the primary safety endpoint. Two subjects with inhibitors were observed in 89 subjects (2.2%) who completed ≥ 50 exposure days. These results were consistent with the pre-specified endpoint that no more than 2 inhibitors may be observed in at least 81 subjects. CONTRAINDICATIONS—None. 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%. WARNINGS AND PRECAUTIONS DRUG INTERACTIONS—None known. 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. Anaphylaxis and Severe Hypersensitivity Reactions—Allergic type hypersensitivity reactions are possible. Patients should be informed of the early signs or symptoms of hypersensitivity reactions [including hives (rash with itching), generalized urticaria, tightness of the chest, wheezing, and hypotension] and anaphylaxis. Patients should be advised to discontinue use of the product and contact their physicians if these symptoms occur. Neutralizing Antibodies—The occurrence of neutralizing antibodies (inhibitors) is well known in the treatment of patients with hemophilia A. Inhibitors have been detected in patients receiving factor VIII-containing products. Inhibitors are common in previously untreated patients and have been observed in previously treated patients on factor VIII products. Patients using coagulation factor VIII products, including XYNTHA, should be monitored for the development of factor VIII inhibitors. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a factor VIII inhibitor is present. If detected, inhibitors should be titered in Bethesda Units (BU). Formation of Antibodies to Hamster Protein—XYNTHA contains trace amounts of hamster proteins. Patients treated with this product could develop hypersensitivity to these non-human mammalian proteins. Monitoring: Laboratory Tests—Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm 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 reflect the rates observed in clinical practice. Study 1 is a pivotal phase 3 (safety and efficacy) 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]. In Study 1, the most frequently reported treatment-emergent adverse reaction was headache (24% of subjects). Other adverse reactions reported in ≥ 5% of subjects were: nausea (6%), diarrhea (5%), asthenia (5%) and pyrexia (5%). No subject developed anti-CHO or anti-TN8.2 antibodies. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C - Animal reproduction studies have not been conducted with XYNTHA Antihemophilic Factor (Recombinant), Plasma/Albumin-Free. It is also 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—Pharmacokinetics of XYNTHA was studied in 7 previously treated patients 12-16 years of age. Pharmacokinetic parameters in these patients were similar to those obtained for adults after a dose of 50 IU/kg. For these 7 patients, the mean (± SD) Cmax and AUC∞ were 1.09 ± 0.21 IU/mL and 11.5 ± 5.2 IU·h/mL, respectively. The mean clearance and plasma half-life values were 5.23 ± 2.36 mL/h/ kg and 8.03 ± 2.44 hours (range 3.52 – 10.6 hours), respectively. The mean K-value and in vivo recoveries were 2.18 ± 0.41 IU/dL per IU/kg and 112 ± 23%, respectively. 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 Product as Packaged for Sale - Store XYNTHA 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 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, the product must not be put back into the refrigerator, but must be used immediately or discarded. Do not use XYNTHA 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 the XYNTHA prefilled syringe. During storage, avoid prolonged exposure of XYNTHA to light. Product After Reconstitution - Administer XYNTHA within 3 hours after reconstitution or after removal of the grey rubber tip cap from the XYNTHA prefilled syringe. The reconstituted solution may be stored at room temperature prior to administration. This brief summary is based on the Xyntha® [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free] Prescribing Information W10528C004, revised 04/08, and W10547C002, revised 08/10. Manufactured by Wyeth Pharmaceuticals Inc. 270327-01 Copyright © 2010 Pfizer Inc. Marketed by Pfizer Inc. All rights reserved. September 2010 Available soon in 3000 IU. Additional dosing options in 2011. Visit PfizerHemophilia.com to learn more. COMING SOON—for your hemophilia A patients The only one that’s all-in-one Next-generation purification now in an innovative reconstitution-ready device. Zero transfer step. More convenience. For the first time ever, factor VIII and diluent come preloaded in a single device for your patients. Manufactured by Wyeth Pharmaceuticals Inc. 272199-01 © 2010 Pfizer Inc. All rights reserved. Marketed by Pfizer Inc. Printed in USA/September 2010 DILUENT XYNTHA For illustration of size only. See prescribing information for reconstitution instructions. Indication for XYNTHA XYNTHA Antihemophilic Factor (Recombinant), Plasma/Albumin-Free is indicated for the control and prevention of bleeding episodes in patients with hemophilia A (congenital factor VIII deficiency or classic hemophilia) and for surgical prophylaxis in patients with hemophilia A. XYNTHA does not contain von Willebrand factor and, therefore, is not indicated in von Willebrand’s disease. Important Safety Information for XYNTHA • Anaphylaxis and severe hypersensitivity reactions are possible. Should such reactions occur, treatment with the product should be discontinued, and appropriate treatment should be administered. • Patients using coagulation factor VIII products should be monitored for inhibitors, which have been detected in patients receiving factor VIII-containing products, including XYNTHA. • The most common adverse reaction in study 1 (safety and efficacy study) is headache (24% of subjects) and in study 2 (surgery study) is fever (41% of subjects). The most common adverse reactions (≥5% of subjects) in clinical studies were headache, fever, nausea, diarrhea, vomiting, and weakness. • Patients may develop hypersensitivity to hamster protein, which is present in trace amounts in XYNTHA. • XYNTHA is an injectable medicine administered by intravenous (IV) infusion. Please see brief summary of Prescribing Information. Multiple abnormalities can lead to dysregulated JAK signaling Janus kinase (JAK) pathway signaling is essential for normal hematopoiesis and immune function.1 JAK pathway dysregulation, however, leads to the development of 3 Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs): myelofibrosis (MF), polycythemia vera (PV) and essential thrombocythemia (ET).2 Excessive JAK1 and JAK2 signaling overstimulates signal transducers and activators of transcription (STATs), which activate cell proliferation, survival of malignant cells and increased cytokine production. Manifestations of overactive signaling in MPNs include splenomegaly and constitutional symptoms.3-8 Multiple abnormalities may cause JAK pathway dysregulation, including4: tJAK2 mutations — leading to constitutive activation of JAK2 and increased cell proliferation and survival of malignant cells4 –JAK2 V617F is the most common mutation and results in a constitutively active form of the JAK2 protein4 tI ncreased JAK1 signaling — associated with increased cell proliferation and constitutional symptoms9 tExcess cytokines — leading to overactivation of the JAK signaling pathway and constitutional symptoms4-6 tMPL mutations — leading to constitutive JAK2 signaling and increased megakaryocyte production10 JAK dysregulation is thought to occur in most MPN patients, independent of JAK2V617F mutational status.11 In fact, many MF and ET patients do not have a known mutation.9,11 MF patients also have elevated levels of activated JAK1, which suggests that dysregulated JAK1 and JAK2 signaling is central to the pathogenesis of MF.2,9,12 Regardless of the mechanism of JAK dysregulation, further research on JAK1 and JAK2 mechanisms is providing new insight into their role in MPNs. Visit www.MPNConnect.org/JAKs To learn more about the dysregulated JAK pathway, visit MPNConnect.org/JAKs today and download the JAK Signaling in MPNs video. Other benefits include free educational resources such as an MPN presentation and brochure. Excess myeloid and erythroid cell proliferation as a result of dysregulated JAK-STAT signaling Nucleus DNA Excess STAT activation leads to transcription of genes related to proliferation, cell survival and differentiation Dysregulated JAK signaling— a common link among MF, PV and ET MPL may be mutated and constitutively active JAK2 may be mutated and constitutively active JAK2 STATs Excess cytokines may continuously activate receptors JAK1 Excess JAK activity leads to overactivation of STATs Increased JAK1 signaling References: 1. Pesu M et al. Immunol Rev. 2008;223:132-142. 2. Levine RL et al. Nat Rev Cancer. 2007;7:673-683. 3. Verstovsek S et al. N Engl J Med. 2010;363:1117-1127. 4. Verstovsek S. Hematology Am Soc Hematol Educ Program. 2009:636-642. 5. Holle N et al. Neth J Med. 2010;68:293-298. 6. Panteli KE et al. Br J Haematol. 2005;130:709-715. 7. Cervantes F et al. Haematologica. 2009;94:1484-1488. 8. Hsieh P-P et al. Mod Pathol. 2007;20:929-935. 9. Quintás-Cardama A et al. Blood. 2010;115:3109-3117. 10. Pikman Y et al. PLoS Med. 2006;3:1140-1151. 11. Plo I et al. Clin Lymphoma Myeloma. 2009;9(Suppl 3):S329-S339. 12. Delhommeau F et al. Int J Hematol. 2010;91:165-173. ©2010 Incyte Corporation. All rights reserved. 10/10. INCY-00435A. AVASTIN® (bevacizumab) Table 1 NCI-CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control) NCI-CTC Grade 3-4 Events #PEZBTB8IPMF Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra-Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa a Arm 1 *'-1MBDFCP (n = 396) 74% Arm 2 *'-"WBTUJO (n = 392) 87% 7% 5% 5% 10% 8% 8% 2% 5% 1% 1% 12% 9% 3% 3% 25% 2% 34% 4% 31% 14% 37% 21% Central laboratories were collected on Days 1 and 21 of each cycle. AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3. Table 3 NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone) may be influenced by several factors, including sample handling, timing of TBNQMFDPMMFDUJPODPODPNJUBOUNFEJDBUJPOTBOEVOEFSMZJOHEJTFBTF'PSUIFTF reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS Digestive: Intestinal necrosis, mesenteric venous occlusion, anastomotic ulceration Hemic and lymphatic: Pancytopenia Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia #PEZBTB8IPMF Asthenia Headache Pain Cardiovascular Hypertension Digestive Stomatitis Metabolic/Nutrition 8FJHIUMPTT Musculoskeletal Myalgia Respiratory Dyspnea Epistaxis Skin/Appendages Exfoliative dermatitis Urogenital Albuminuria Capecitabine (n = 215) Capecitabine + Avastin (n = 229) 47% 13% 25% 57% 33% 31% 2% 24% 19% 25% 8% 14% 18% 27% Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2. 1% 16% Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in QBUJFOUT SFDFJWJOH CPMVT*'- QMVT "WBTUJO BT DPNQBSFE UP UIF CPMVT*'- QMVT 75% 84% placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who 7% 22% XFSFFOSPMMFEVOUJMFOSPMMNFOUJO"SN'6-7"WBTUJO XBTEJTDPOUJOVFE Table 2 Glioblastoma NCI-CTC Grade 1-4 Adverse Events in Study 1 All adverse events were collected in 163 patients enrolled in Study 7 who either 0DDVSSJOHBU)JHIFS*ODJEFODF<ö>JO*'-"WBTUJOWT*'- received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every Arm 1 Arm 2 Arm 3 *'-1MBDFCP *'-"WBTUJO '6-7"WBTUJO 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. (n = 98) (n = 102) (n = 109) In patients receiving Avastin alone (N=84), the most frequently reported adverse #PEZBTB8IPMF events of any grade were infection (55%), fatigue (45%), headache (37%), Pain 55% 61% 62% hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence Abdominal Pain 55% 61% 50% of Grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), Headache 19% 26% 26% hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related Cardiovascular to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. Hypertension 14% 23% 34% Hypotension 7% 15% 7% In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the Deep Vein Thrombosis 3% 9% 6% incidence of Avastin-related adverse events (Grade 1–4) were bleeding/ Digestive hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension Vomiting 47% 52% 47% (32%), venous thromboembolic event (8%), arterial thromboembolic event Anorexia 30% 43% 35% (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal Constipation 29% 40% 29% perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these Stomatitis 18% 32% 30% 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), Dyspepsia 15% 24% 17% hypertension (5%), venous thromboembolic event (7%), arterial GI Hemorrhage 6% 24% 19% thromboembolic event (3%), wound-healing complications (3%), proteinuria 8FJHIU-PTT (1%), and gastrointestinal perforation (2%). Dry Mouth 2% 7% 4% Metastatic Renal Cell Carcinoma (mRCC) Colitis 1% 6% 1% All grade adverse events were collected in Study 9. Grade 3–5 adverse Hemic/Lymphatic events occurring at a higher incidence (≥ 2%) in 337 patients receiving Thrombocytopenia 0% 5% 5% JOUFSGFSPO BMGB *'/α) plus Avastin compared to 304 patients receiving Nervous *'/α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), Dizziness 20% 26% 19% proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension Respiratory and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, Upper Respiratory Infection 39% 47% 40% small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, Epistaxis 10% 35% 32% gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal Dyspnea 15% 26% 25% hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Voice Alteration 2% 9% 6% Skin/Appendages Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving Alopecia 26% 32% 6% *'/αQMVT"WBTUJODPNQBSFEUPUIF*'/α plus placebo arm are presented in Table 4. Skin Ulcer 1% 6% 6% Table 4 Special Senses NCI-CTC Grades 1−5 Adverse Events in Study 9 Taste Disorder 9% 14% 21% 0DDVSJOHBU)JHIFS*ODJEFODF<ö>JO*'/α"WBTUJOWT*'/α + Placebo) Urogenital Proteinuria 24% 36% 36% 4ZTUFN0SHBO$MBTT *'/α 1MBDFCP *'/α + Avastin Preferred term* (n = 304) (n = 337) Avastin in Combination with FOLFOX4 in Second-line mCRC Gastrointestinal disorders Only Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to Diarrhea 16% 21% treatment were collected in Study 2. The most frequent adverse events (selected General disorders and administration Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events) occurring at site conditions BIJHIFSJODJEFODFö JOQBUJFOUTSFDFJWJOH'0-'09QMVT"WBTUJODPNQBSFEUP 'BUJHVF QBUJFOUTSFDFJWJOH'0-'09BMPOFXFSFGBUJHVFWT EJBSSIFBWT Investigations 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), 8FJHIUEFDSFBTFE dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), Metabolism and nutrition disorders hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and Anorexia 31% 36% headache (3% vs. 0%). These data are likely to under-estimate the true adverse event Musculoskeletal and connective rates due to the reporting mechanisms used in Study 2. tissue disorders Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Myalgia 14% 19% Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were Back pain 6% 12% collected in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse Nervous system disorders events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin Headache 16% 24% compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue Renal and urinary disorders (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), Proteinuria 3% 20% venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/ Respiratory, thoracic and pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), mediastinal disorders hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Epistaxis 4% 27% Dysphonia 0% 5% Metastatic Breast Cancer (MBC) Vascular disorders Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were Hypertension 9% 28% collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving *Adverse events were encoded using MedDRA, Version 10.1. paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), The following adverse events were reported at a 5-fold greater incidence in the fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs. *'/αQMVT"WBTUJOBSNDPNQBSFEUP*'/α alone and not represented in Table 4: 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs. tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); 0.3%) and proteinuria (3% vs. 0%). gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute 6.2 Immunogenicity incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. As with all therapeutic proteins, there is a potential for immunogenicity. The incidence 'BUBMBEWFSTFSFBDUJPOTPDDVSSFEJO PGQBUJFOUTXIPSFDFJWFEQBDMJUBYFM of antibody development in patients receiving Avastin has not been adequately plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial determined because the assay sensitivity was inadequate to reliably detect lower infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2). titers. Enzyme-linked immunosorbent assays (ELISAs) were performed on sera from Avastin is not approved for use in combination with capecitabine or for use in second approximately 500 patients treated with Avastin, primarily in combination with or third line treatment of MBC. The data below are presented to provide information on chemotherapy. High titer human anti-Avastin antibodies were not detected. the overall safety profile of Avastin in women with breast cancer since Study 6 is the Immunogenicity data are highly dependent on the sensitivity and specificity of only randomized, controlled study in which all adverse events were collected for all the assay. Additionally, the observed incidence of antibody positivity in an assay 7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was BENJOJTUFSFEBTQBSUPGUIF'0-'*3*SFHJNFOXJUIPSXJUIPVU"WBTUJO5IF results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Because of the observed teratogenic effects of known inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).] 8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment. 8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. *O 4UVEZ QBUJFOUT BHFE ö ZFBST SFDFJWJOH"WBTUJO QMVT '0-'09 IBE B greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether the overall adverse events profile was different in the elderly as compared with younger patients. Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients. Manufactured by: Genentech, Inc. %/"8BZ 4PVUI4BO'SBODJTDP$" 94080-4990 7453214 4835706 *OJUJBM64"QQSPWBM'FCSVBSZ $PEF3FWJTJPO%BUF+VMZ © 2009 Genentech, Inc www.IDanemia.com A treatment strategy for anemia Check and address iron deficiency first. • In chronic renal insufficiency patients, iron deficiency is a common yet undertreated cause of anemia.1 • Identifying—and treating—iron deficiency anemia before initiating any other treatment is the optimal strategy in these patients. Reference: 1. Agarwal AK. Practical approach to the diagnosis and treatment of anemia associated with CKD in elderly. J Am Med Dir Assoc. 2006;7:S7-S12. AMAG Pharmaceuticals and the AMAG logo are trademarks of AMAG Pharmaceuticals, Inc. ©2010 AMAG Pharmaceuticals, Inc. DS-0088-0710 ® 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 1-800-813-HOPE (4673) www.cancercare.org FPbleOed top e g Need a m i t lef p o t e d Fa Coming together for the gaucher community Strengths combine in the Patient-Focused Partnership of Pfizer and Protalix Promising commitment • Pfizer and Protalix are committed to discovering novel, lifesaving therapies, including therapies for rare diseases such as Gaucher disease — Pfizer is a leader in research and new drug development, applying science and its global resources to improve health at every stage of life — Protalix is a leader in protein production technology, focusing on the research and development of therapeutic proteins for various diseases, including genetic disorders such as Gaucher disease Providing resources • Now available: GaucherPartners.com/ad1, an online Gaucher resource for you and your patients Visit GaucherPartners.com/ad1, an informative new resource for the Gaucher community NPE00287 ©2010 Pfizer Inc All rights reserved. Printed in USA/November 2010 SAVE THE DATE The American Society of Hematology presents the only official ® 2011 Highlights of ASH in North America International International in China Dallas, TX* January 21-22 Vancouver, Canada January 21-22 Beijing, China** April 2-3 in Latin America San Francisco, CA January 28-29 Washington, DC January 28-29 Punta del Este, Uruguay+ April 29-30 Please note: AMA PRA Category 1 Credits™ will not be available for international meetings. New York, NY February 4-5 San Diego, CA February 4-5 www.hematology.org/highlights * Simultaneous translation into Spanish available in Dallas, TX. ** Simultaneous translation into Chinese available in Beijing, China. + Simultaneous translation into Spanish and Portuguese available in Punta del Este, Uruguay. NOW ENROLLING PATIENTS WITH POLYCYTHEMIA VERA Randomized Study of Efficacy and Safety in Polycythemia Vera with JAK Inhibitor INCB018424 Versus Best Available Care A PHASE III STUDY INVESTIGATING INCB018424 — AN ORAL JAK1 AND JAK2 INHIBITOR The RESPONSE trial is a global, randomized, open-label, multicenter, phase III study of the oral JAK1 and JAK2 inhibitor INCB018424 in patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea. RESPONSE is sponsored by both Incyte and Novartis. Primary endpoint Composite endpoint of phlebotomy independence and spleen volume reduction at Week 32 Secondary endpoints s Proportion of patients who maintain the primary endpoint response for ≥48 weeks s Proportion of patients achieving complete hematologic remission at 32 weeks Patients with PV (N≈300) INCB018424 (oral) 10 mg bid Randomized 1:1 Best available therapy as selected by physician*† The treatment duration for the study will be 80 weeks. Physician’s choice: hydroxyurea, interferon, anagrelide, pipobroman, IMIDs, or observation. Patients randomized to best available therapy may be eligible to cross over to INCB018424. * † If you have a PV patient who is at least 18 years of age and who meets the following criteria, he/she may be eligible for enrollment in RESPONSE: s Resistant to or intolerant of hydroxyurea s Phlebotomy requirement due to inadequate hematocrit control at least once every 3 months s Palpable splenomegaly ≥5 cm below the costal margin s Elevated white blood cell and/or platelet counts To enroll a US patient in RESPONSE or to find out more about this trial, please call 1-877-4-PV- TRIAL or visit www.responsetrial.com. © 2010 Incyte Corporation. 09/10. INCY-00450. INCB018424 is an investigational compound. 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NOW IN THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) DRIVING BETTER OUTCOMES RITUXAN+FC improved median PFS in first-line and previously treated CLL1,2 In relapsed/refractory* CLL 2.1-year follow-up In first-line CLL 1.7-year follow-up 39.8 months R-FC vs 26.7 months 31.5 months R-FC FC 8.3 vs 21.7 months FC 5.0 month month improvement in median improvement in median PFS PFS CLL8 TRIAL (N=817) REACH TRIAL (N=552) RITUXAN-NAIVE PATIENTS In the CLL8 trial2 RITUXAN+FC more than doubled CR in first-line CLL compared with FC alone (36% vs 17%; p<0.0001) In the REACH trial 2 Patients who responded to RITUXAN+FC (n=167) maintained their responses for nearly 2 years longer (48 months vs 27 months; p=0.0294) than those treated with FC alone (n=134) Treatment considerations These trials were not designed or powered to detect a significant difference in PFS by age category. However, exploratory analyses defined by age suggest no observed benefit with the addition of RITUXAN to FC chemotherapy in previously untreated CLL patients 70 years of age or older and in previously treated CLL patients 65 years of age or older.1 *In the REACH trial, patients had received 1 prior therapy. Patients who had previously received RITUXAN or both fludarabine and cyclophosphamide, either sequentially or in combination, were excluded from the trial, as were fludarabine-refractory patients; alkylator-refractory patients were permitted.2 R=RITUXAN; FC=fludarabine and cyclophosphamide; PFS=progression-free survival; CR=complete response. Indication RITUXAN® (Rituximab) is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL. RITUXAN is not recommended for use in patients with severe, active infections. BOXED WARNINGS RITUXAN administration can result in serious, including fatal, adverse reactions. These include infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy (PML) Warnings and Precautions RITUXAN can also result in serious, including fatal, adverse reactions. These include hepatitis B reactivation with fulminant hepatitis and hepatic failure resulting in death; other infections, including bacterial, fungal, new or reactivated viral infections; cardiovascular events; severe, including fatal, renal toxicity; and abdominal pain, bowel obstruction and perforation, in some cases leading to death Additional Important Safety Information The most common adverse reactions of RITUXAN (incidence ≥25%) observed in clinical trials of patients with CLL were infusion reactions and neutropenia. Most patients treated with R-FC experienced at least one Grade 3 or 4 adverse reaction. The most frequently reported Grade 3 or 4 adverse reaction was neutropenia In clinical trials, CLL patients 70 years of age or older who received R-FC had more Grade 3 and 4 adverse reactions compared with younger CLL patients who received the same treatment For additional safety information, please see following page for brief summary of full prescribing information, including BOXED WARNINGS. Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion. References: 1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2010. 2. Data on file, Genentech, Inc. ©2010 Genentech USA, Inc., and Biogen Idec Inc. All rights reserved. 10021501 May 2010