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Background Brentuximab vedotin (BV) is a novel antibody drug conjugate consisting of an anti- CD30 IgG1 antibody, cAC10, linked to monomethylauristatin E, a potent inhibitor of microtubule polymerization. It is approved for treatment of relapsed classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) in the US (FDA; 8/2011) and Europe (EMA; 10/2012). Peripheral neuropathy was the most frequent treatment-related adverse event (AE) in phase II trials, and the most common Grade 3 or higher toxicity apart from cytopenias. Although abdominal pain has been observed in up to 25% of all patients, pancreatitis is a previously unrecognized AE. We now report 8 cases of BV-associated pancreatitis, 2 of them fatal. Methods Following a grade 5 AE from pancreatitis in a patient receiving single-agent BV on an ongoing clinical trial ([NCT01476410][1]), collaborating investigators examined their collective cases of pancreatitis associated with BV. Lymphoma specialists at other centers were solicited for additional events. IRB or Ethics Committee approval as required was obtained in all cases. AE's reported to the FDA Adverse Event Report Systems (FAERS) from 6/2011-7/2013 were also examined. Data was collected and analyzed through the Research on Adverse Drug Events and Reports Project. Immunohistochemical staining with the anti-CD30 antibody BER-H2 (DAKO) was performed on residual normal pancreas from one of the fatal cases and normal control pancreas. Results Eight cases of BV-associated pancreatitis were identified by collaborators, and one additional report with limited information was listed in FAERS. Demographic, treatment and AE information for the eight complete cases is detailed in [Table 1][2]. In all cases, BV was administered as a single agent. In seven cases, the dosing was 1.8 mg/kg every 21 days with a maximum of 180 mg; in one case, BV was administered weekly at 1.2 mg/kg (days 1,8,15, q 28). Two patients were retreated with BV after resolution of pancreatitis; one had no further evidence of pancreatitis and proceeded to a stem cell transplant, whereas the other patient, having recovered from Grade 4 pancreatitis, experienced a second episode (Grade 3). All patients demonstrated clinical evidence of pancreatitis as manifested by severe abdominal pain and nausea. In addition, all patients had biochemical and radiologic evidence of pancreatitis. Notably, no patient had an antecedent history of excess alcohol use or radiologic evidence of biliary pathology. Two patients developed progressive and fatal multiorgan dysfunction as a consequence of acute pancreatitis. An autopsy performed on one of the two fatalities showed evidence of acute necrotizing pancreatitis as the cause of death; diffuse pancreatic parenchymal necrosis and fat necrosis were seen but no cholelithiasis. Although the anti-CD30 antibody BER-H2 was previously reported to stain normal pancreas (BLOOD 1989 74:1678), routine immunohistochemical staining for CD30 on both the patient pancreas and normal pancreas controls were negative. View this table: Table 1 BV-associated pancreatitis (n = 8) Conclusion This is the first series describing pancreatitis as a rare, but serious and potentially fatal toxicity related to BV. Pancreatitis has been previously reported with other microtubule inhibitors such as taxanes and vinca alkaloids, but the mechanism, as with BV, remains unclear. Genetic factors that predispose to both acute and chronic pancreatitis have been reported and may underlie a susceptibility to this uncommon complication of treatment with BV. Clinicians prescribing BV should evaluate patients who present with abdominal pain for pancreatitis, and should consider pre-treatment biochemical assessments with serum lipase and/or amylase. Disclosures: Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Evens: Seattle Genetics : Consultancy, Honoraria. Fenske: Seattle Genetics: Consultancy. Hamlin: Seattle Genetics : Consultancy, Honoraria. Coiffier: Millennium Pharmaceuticals : Consultancy. Engert: Millennium Pharmaceuticals : Consultancy. Moskowitz: Seattle Genetics : Research Funding. Ghosh: Millennium Pharmaceuticals : Membership on an entity’s Board of Directors or advisory committees. Petrich: Seattle Genetics : Consultancy, Honoraria, Research Funding. Gordon: Seattle Genetics : Research Funding. Winter: Seattle Genetics : Research Funding. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01476410&atom=%2Fbloodjournal%2F122%2F21%2F4380.atom [2]: #T1

Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe 2 patients with systemic lupus erythematosus and 1 with rheumatoid arthritis who developed progressive multifocal leukoencephalopathy (PML) after rituximab treatment. We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and 1 patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab. Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated persons.

Background In March 2012, the Food and Drug Administration (FDA) approved peginesatide as anemia therapy for chronic kidney disease patients. In December, the manufacturer warned that a large dialysis organization identified eight patients with peginesatide-associated anaphylaxis. In February 2013, the organization again reported five anaphylaxis events, including three deaths, and discontinued administering peginesatide. After a manufacturer’s review identified five peginesatide-associated anaphylaxis deaths, the manufacturer discontinued marketing the drug. Methods We reviewed peginesatide-associated anaphylaxis in FDA’s Adverse Event Reporting System (FAERS). Clinical findings and product lot numbers were analyzed. Inclusion criteria included peginesatide administration and toxicity within thirty minutes of administration. Results Between July 2012 and February 2013, 38 CKD patients developed anaphylaxis within a median of five minutes following peginesatide administration (range, zero to 20 minutes). Findings included dyspnea (25 patients), chest pain (10), hypotension (18), diaphoresis (9), pruritis (11), rash (3), angioedema (5), and vomiting (9). Five deaths from cardio-respiratory arrests occurred. Exposure-adjusted incidence was 1.5 cases of anaphylaxis per 1,000 peginesatide-treated patients. Of five FAERS reports for anaphylaxis occurring in February 2013, three included the product lot number C18881 while two did not have lot numbers. Of 33 FAERS anaphylaxis events reported prior to December 4, 2012; 18 included the lot number C18685, two reports included the lot number C18696, one included the lot number C18881, and lot numbers were not identified for the remaining 12 reports. Conclusion Anaphylaxis can occur within minutes of initiating peginesatide therapy. Production or supply chain management problems may be the underlying etiology. Disclosures: Macdougall: Affymax and Takeda: Consultancy, Research Funding. Mikhail: Affymax and Takeda: Consultancy, Research Funding. Goldsmith: Affymax and Takeda: Consultancy, Research Funding.

Background Brentuximab vedotin (BV) is a novel antibody drug conjugate consisting of an anti- CD30 IgG1 antibody, cAC10, linked to monomethylauristatin E, a potent inhibitor of microtubule polymerization. It is approved for treatment of relapsed classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) in the US (FDA; 8/2011) and Europe (EMA; 10/2012). Peripheral neuropathy was the most frequent treatment-related adverse event (AE) in phase II trials, and the most common Grade 3 or higher toxicity apart from cytopenias. Although abdominal pain has been observed in up to 25% of all patients, pancreatitis is a previously unrecognized AE. We now report 8 cases of BV-associated pancreatitis, 2 of them fatal. Methods Following a grade 5 AE from pancreatitis in a patient receiving single-agent BV on an ongoing clinical trial (NCT01476410), collaborating investigators examined their collective cases of pancreatitis associated with BV. Lymphoma specialists at other centers were solicited for additional events. IRB or Ethics Committee approval as required was obtained in all cases. AE's reported to the FDA Adverse Event Report Systems (FAERS) from 6/2011-7/2013 were also examined. Data was collected and analyzed through the Research on Adverse Drug Events and Reports Project. Immunohistochemical staining with the anti-CD30 antibody BER-H2 (DAKO) was performed on residual normal pancreas from one of the fatal cases and normal control pancreas. Results Eight cases of BV-associated pancreatitis were identified by collaborators, and one additional report with limited information was listed in FAERS. Demographic, treatment and AE information for the eight complete cases is detailed in Table 1. In all cases, BV was administered as a single agent. In seven cases, the dosing was 1.8 mg/kg every 21 days with a maximum of 180 mg; in one case, BV was administered weekly at 1.2 mg/kg (days 1,8,15, q 28). Two patients were retreated with BV after resolution of pancreatitis; one had no further evidence of pancreatitis and proceeded to a stem cell transplant, whereas the other patient, having recovered from Grade 4 pancreatitis, experienced a second episode (Grade 3). All patients demonstrated clinical evidence of pancreatitis as manifested by severe abdominal pain and nausea. In addition, all patients had biochemical and radiologic evidence of pancreatitis. Notably, no patient had an antecedent history of excess alcohol use or radiologic evidence of biliary pathology. Two patients developed progressive and fatal multiorgan dysfunction as a consequence of acute pancreatitis. An autopsy performed on one of the two fatalities showed evidence of acute necrotizing pancreatitis as the cause of death; diffuse pancreatic parenchymal necrosis and fat necrosis were seen but no cholelithiasis. Although the anti-CD30 antibody BER-H2 was previously reported to stain normal pancreas (BLOOD 1989 74:1678), routine immunohistochemical staining for CD30 on both the patient pancreas and normal pancreas controls were negative. Conclusion This is the first series describing pancreatitis as a rare, but serious and potentially fatal toxicity related to BV. Pancreatitis has been previously reported with other microtubule inhibitors such as taxanes and vinca alkaloids, but the mechanism, as with BV, remains unclear. Genetic factors that predispose to both acute and chronic pancreatitis have been reported and may underlie a susceptibility to this uncommon complication of treatment with BV. Clinicians prescribing BV should evaluate patients who present with abdominal pain for pancreatitis, and should consider pre-treatment biochemical assessments with serum lipase and/or amylase. Disclosures: Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Evens:Seattle Genetics : Consultancy, Honoraria. Fenske:Seattle Genetics: Consultancy. Hamlin:Seattle Genetics : Consultancy, Honoraria. Coiffier:Millennium Pharmaceuticals : Consultancy. Engert:Millennium Pharmaceuticals : Consultancy. Moskowitz:Seattle Genetics : Research Funding. Ghosh:Millennium Pharmaceuticals : Membership on an entity’s Board of Directors or advisory committees. Petrich:Seattle Genetics : Consultancy, Honoraria, Research Funding. Gordon:Seattle Genetics : Research Funding. Winter:Seattle Genetics : Research Funding.

The Research on Adverse Drug Events and Reports project (RADAR) is one of only a few independent pharmacovigilance programs funded entirely by peer-reviewed grants. It is the only such program that focuses on serious adverse drug reactions (sADRs) related to hematology and oncology. RADAR leverages the resources of a comprehensive cancer center, an academic hematology/oncology program, and a global network of physicians. Since its inception in 1998, RADAR has identified 33 unique sADRs. Information about these sADRs are traditionally disseminated in peer-reviewed manuscripts (21 sADRs), warnings or black box warnings in FDA-approved package inserts or manufacturer warnings (12 sADRs), or Dear Doctor letters (8 sADRs). In the absence of formal collaborations between the FDA, drug manufacturers, and independent pharmacovigilance programs, RADAR has expanded its dissemination efforts to non-traditional strategies, such as face-to-face meetings with drug manufacturers (22 sADRs), which lead to further actions by regulatory agencies and stakeholders (Table). These actions have included revised clinical guidelines from NCCN, ASCO, ASH, and the American College of Radiology, FDA advisory hearings focusing on safety, the first ever drug safety focused citizen’s petition filed by a state attorney general, and safety statements from the Centers for Disease Control and Prevention. Moving forward, RADAR is developing novel strategies for dissemination by partnering with Consumer Reports, the internet-based Medpedia Project, and monthly safety columns published in Community Oncology and Oncology News International. Table. Hematology-related sADRs identified by RADAR and novel dissemination efforts. Drug sADR Peer-reviewed Publications (Year) FDA or Manufacturer Warnings (Year) Face-to-face meeting with drug manufacturer Actions by Regulatory Agencies or Stakeholders Ticlopidine Thrombotic Thrombocytopenic purpura Ann Intern Med (1998); Lancet (1998); Arch Intern Med (1999); JAMA (1999) Dear Doctor letter (1998); Boxed Warning (1999) Yes Drug sales diminished to minimal level due to safety concerns (even though generic drug); FDA presentation Clopidogrel Thrombotic thrombocytopenic purpura NEJM (2000); Transplantation (2002); Stroke (2004) Warnings (2000, 2006) Yes Patient message in direct-to-consumer advertisements Epoetin/darbepoetin Venous thromboembolism; mortality JAMA (2008) FDA Alerts (2006, 2007), Black box warning (2007) Yes FDA hearing; CMS policy change; EMEA guidelines change; NCCN guidelines change Epoetin Pure red-cell aplasia NEJM (2004); Blood (2005) Boxed warning (2002); Dear Doctor letter (2005) Yes Manufacturer changes; Canada Health; EMEA statements; FDA presentation Thalidomide/lenalidomide Venous thromboembolism JAMA (2006) Black box warning(2006) Yes Citizen’s petition by attorney general of Connecticut (upheld) Gemtuzumab Sinusoidal obstructive syndrome Leukemia Research (2006) Boxed warning (2001) Yes FDA-mandated postmarketing registry Rituximab Progressive multifocal leuko-encephalopathy ASH (2007); ASCO (2008) Black box warning (2006) Yes Under consideration G-CSF/GM-CSF Acute myeloid leukemia; myelodisplatic syndrome JNCI (2007) None Yes Reconsideration of G-CSF administration to pediatric donors in Japan PEG-rHuMGDF Lymphoproliferative disorder British J of Haematology (2006) None No Drug development discontinued because of safety concerns Zoledronate Osteonecrosis of the jaw Lancet Oncology (2008) Dear Doctor letter (2004) Yes Guidelines from radiology, dentistry, hematology, oncology Nevirapine Stevens-Johnson syndrome; hepatotoxicity J Acquir Immune Defic Syndr (2004) Boxed warning (1998); Warning (1999); Dear Doctor letters (2000, 2004) Yes Drug no longer. used for post-needle stick exposure to HIV by healthcare workers

Background : Many idiopathic thrombotic thrombocytopenia purpura (TTP) patients have severe deficiency of ADAMTS13, an enzyme that cleaves ultralarge von Willebrand multimers. We recently reported that thienopyridine-associated TTP is characterized by an immunologic pathway with severe ADAMTS13 deficiency and a non-immunologic pathway with higher ADAMTS13 activity levels. We now compare findings for idiopathic and thienopyridine-associated TTP patients. Methods : Clinical findings and laboratory findings were evaluated for 51 idiopathic and 39 thienopyridine-associated TTP. Results: Clinical findings were similar between idiopathic and thienopyridine-associated TTP for both severe ADAMTS13 deficient and non-deficient patients. Differences were noted in gender and age, relapse rates, and survival. Conclusion : Among TTP patients with ADAMTS13 deficiency, relapses are frequent in idiopathic TTP patients and Rituximab may be useful, while for thienopyridine-associated TTP patients spontaneous relapse are rare as long as no re-exposure occurs. Among ADAMTS13 non-deficient patients, survival is high following therapeutic plasma exchange (TPE) for idiopathic patients but not for thienopyridine-associated TTP patients. Despite similarities, idiopathic and thienopyridine associated TTP probably have different initiating factors. ADAMTS13 activity and clinical characteristics in idiopathic and thienopyridine-associated TTP Idiopathic severe ADAMTS13 deficiency (n=29) †Thienopyridine severe ADAMTS13 deficiency (n=26) Idiopathic non-severe ADAMTS13 deficiency (n=22) †Thienopyridine non-severe ADAMTS13 deficiency (n=13) *p2.5 mg/dl* 11% 27% 48% 46% 30-day survival 96% 85% 90% 62% Long-term relapse* 42% 8% 0% 0% Neutralizing autoantibodies to ADAMTS13 (prior to TPE) § 79% 100% 27% 0% Neutralizing autoantibodies to ADAMTS 13 (measured at remission) § 55% 33%‡ 33% 0%

Thrombotic thrombocytopenic purpura (TTP) is a microvascular occlusive disorder characterized by systemic aggregation of platelets, thrombocytopenia, and mechanical injury to erythrocytes. Between 30% and 80% of TTP cases are associated with ADAMTS13 deficiency. Thienopyridine-derivative anti-platelet agents, ticlopidine and clopidogrel, are the drugs most commonly associated with TTP. The structures differ only by a carboxymethyl side-chain and have no common metabolites. Since 2002, our R01 research project has focused on evaluating thienopyridine-associated TTP. Herein, we present the final results. Clinical and laboratory data were obtained from case reports, the FDA’s MedWatch program, a Japanese national reference laboratory for ADAMTS13 assays, and apheresis centers at Duke University, University of North Carolina, Northwestern University, and the Mayo Clinic. Epidemiologic data for rate estimation for thienopyridine-associated TTP among persons who receive cardiac stents were obtained from international cardiology laboratories. Pharmacovigilance information was obtained from package inserts for the drugs. Most thienopyridine-associated TTP cases are associated with two weeks or more of ticlopidine rather than clopidogrel, are immune-mediated involving neutralizing antibodies to ADAMTS13, resolve with therapeutic plasma exchange (TPE), and have spontaneous relapses. Less frequently, cases are associated with clopidogrel, occur within days of drug initiation, may be a direct result of endothelial cell damage, are less responsive to TPE, and are less likely to recur. Thienopyridine-associated TTP patients with severe deficiency of ADAMTS13 activity have a different profile than those with normal ADAMTS13 levels. Among thienopyridine-associated TTP patients who have ADAMTS13 deficiency, TPE is usually performed for a few days and patients recover without detectable organ damage. In contrast, among thienopyridine-associated TTP patients who do not have ADAMTS13 deficiency, several weeks of TPE is required for recovery, and 30% mortality rates have been reported. Despite similar chemical structures, ticlopidine- and clopidogrel-associated TTP probably occur by different mechanisms and have different clinical presentations and expected outcomes. Clinical Characteristics Onset Platelet Count 2 weeks 60* 55* 32 28/33 Rare Epidemiology, Pharmacovigilance & Basic Science Incidence (cases per treated patients) Safety ADAMTS13 Activity (%) ADAMTS13 Antibodies (%) ticlopidine 1:1,600 “Black Box” warning

Current FDA and pharmaceutical industry drug safety efforts rely on statistical review of large databases populated with voluntary reports of sADRs. These data are limited by low rates of complete reporting and high rates of underreporting. Improved post-marketing drug surveillance efforts are needed to improve patient safety. The RADAR project is an academic pharmacovigilance program that focuses on small numbers of thoroughly researched cases of sADRs. In the last decade, RADAR has utilized the resources of a comprehensive cancer center and a global network of collaborators to evaluate and disseminate information on sADRs, many of which are related to hematology. Between 1998 and 2007, RADAR investigated and reported 16 hematology-associated sADRs. RADAR disseminated information on over half of the sADRs within 2 years of FDA approval, compared to half of all new sADRs documented in the Physician’s Desk Reference within 7 years of FDA approval. RADAR’s novel pharmacovigilance methods identified previously undetected sADRs based on small numbers of completely described reports. The RADAR project’s experience shows that private sector programs that utilize small yet comprehensive datasets can significantly contribute to pharmacovigilance networks in hematology. As the FDA develops public-private networks to evaluate safety concerns associated with new drugs, focused independent efforts can assume increasing importance to address unmet needs. Summary of 16 hematology-associated sADRs reported by RADAR since 1998. Drug (FDA approval) sADR (# of reports) Clinical Setting (yr) Data Source Time to detection (yrs) FDA/Company alert PEG-rHuMGDF(unapproved) ITP (13) Healthy volunteers (2001) Phase I trials Preclinical detection NA PEG-rHuMGDF(unapproved) Lymphomas (3) Healthy volunteers (2003) Case reports Preclinical detection NA Ticlopidine (1991) TTP (13) CVA pts (1998) Case reports

BACKGROUND: At ASH 2004, we reported > 20% VTE rates with thal/dexamethasone (thal/dex) use as an off-label treatment for MM. The abstract prompted Richard Blumenthal, the Connecticut Attorney General, to file a Citizen’s Petition with the FDA in 2005 outlining six recommendations to address this safety concern. In 2006, the FDA indicated that four recommendations were approved. The AG’s request for a randomized clinical trial of aspirin, low molecular weight heparin (LMWH), and warfarin as VTE prophylaxis was denied- with the FDA indicating that preliminary data suggested that these agents are effective for prophylaxis. At ASH 2005, we reported > 20% VTE rates with len/dex treatment for MM. In response, the manufacturer pre-emptively included a “Black Box” warning describing high VTE rates when len was used off-label for MM. In 2006, len and thal received FDA approval for MM. The Research on Adverse Drug Events and Reports (RADAR) project conducted a systematic review of VTE rates when len or thal is prescribed for MM. METHODS: Reports of VTE with thal or len treatment of MM were reviewed. Data sources included: the FDA’s MedWatch program and phase II/III clinical trial reports from 1998 to 7/2006. RESULTS: FDA’s MedWatch program included reports of VTE occurring among 8 len- (3 on aspirin, 2 on warfarin, and 1 on MLWH) and 1076 thal-treated cancer patients. Clinical trials identified VTE rates of 15% among thal/dex treated patients and 14% among len/dex- treated MM patients (Table). Uncontrolled trials found that thal/dex-associated VTE rates were sometimes, but not always, lower with aspirin, LMWH, or warfarin (INR of 2 to 3), while little information on VTE prophylaxis is available for len-dex treated MM patients. CONCLUSIONS: The extant data continue to support our assertion that randomized controlled trials are needed to identify appropriate VTE prophylaxis agents when MM patients receive len or thal with dex. Data on aspirin prophylaxis remain premature. Clinical Trial VTE Results VTE rate among Thal treated MM patients (n = 2690) VTE rates among Len treated MM patients (n = 702) MM-extent of disease Untreated Relapsed/Refractory Untreated Relapsed/Refractory n/a = data not available Thal/Dex None 96/667 (14.4%) 11/256 (4.3%) 38/278 (13.7%) 48/346 (13.9%) Warfarin (1–1.25 mg/d) 16/105 (15.2%) 8/85 (9.4%) n/a n/a Aspirin (81 mg/d) n/a n/a 9/54 (16.7%) n/a LMWH/Warfarin (INR 2–3) 0/63 (0.0%) 2/26 (7.7%) n/a n/a Thal/Dex/Doxorubicin None 148/610 (24.3%) 47/271 (17.3%) n/a n/a Aspirin (81 mg/d) 3/45 (6.7%) n/a n/a n/a LMWH 19/211 (9.0%) n/a n/a n/a Thal/Melphalan/Prednisone None 43/287 (15.0%) n/a n/a n/a Aspirin (81 mg/d) n/a n/a 1/24 (4.2%) n/a LMWH 2/64 (3.1%) n/a n/a n/a

Introduction: Loss of response to recombinant erythropoietin is a rare event typically seen only in the setting of iron deficiency or serious blood dyscrasia. In 2004, the Research on Adverse Drug Events and Reports group reported on 191 cases of antibody-mediated pure red cell aplasia (PRCA) primarily associated with the human albumin free formulation of Eprex. There were no reports of loss of response to darbepoetin alfa at that time. Since 2004, additional causes of loss of efficacy of epoetin therapy have been identified or described in detail. Methods: Data were obtained from the FDA’s adverse event reporting system (AERS), and published literature, both medical and non-medical. Results: In the AERS system, we found nine reports of patients who developed anti-erythropoietin antibodies after exposure to darbepoetin alfa, seven of which occurred after recent exposure to Eprex. All of these patients received darbepoetin alfa for the anemia of chronic kidney disease (CKD). We also identified eight cases of loss of efficacy due to counterfeit epoetin in the literature and AERS reports. All of these patients received epoetin alfa for an indication other than anemia of CKD. Of the seven counterfeit cases found in AERS, five were reported by pharmacists, one by a consumer, and one by a nurse. In contrast, more than 90% of the 191 initial cases of antibody-mediated PRCA and all 9 cases associated with darbepoietin alfa were reported by physicians. Three cases of exposure to counterfeit epoetin in our series were linked to a single counterfeit supplier. Only two of these three cases were found in AERS out of an estimated 25,000–75,000 patients exposed to epoetin vials from that counterfeit supplier, for a reporting rate of less than 1/12,000 (.01%). This is lower than the estimated reporting rate for all adverse events of 1% to 10%, and markedly lower than the 90% or greater estimated reporting rate for antibody associated PRCA. Conclusion: Physicians should be aware of multiple the multiple possible etiologies for decreased recombinant erythropoietin efficacy, including the possible link between darbepoetin alfa and antibody mediated PRCA in patients with CKD. In addition, loss of efficacy related to counterfeit recombinant erythropoietin should be considered, especially in patients with anemia from conditions other than CKD. Underreporting of counterfeit epoetin exposure occurred despite the fact that “dear doctor” warning letters were sent to physicians at the time of two major counterfeit events. Unlike the warning letters for antibody-mediated PRCA, these letters did not contain information about clinical signs and symptoms that could be observed or elicited from patient history. In the future, warning letters for counterfeit pharmaceutical products should describe the potential clinical effects of the counterfeit medications in an effort to improve reporting and tracking of counterfeit medications through AERS. Table of Findings darbepoetin alfa epoetin alfa/beta counterfeit epoetin alfa Number of cases 9 191 8 Causality established No Yes Yes Reported by MD 100% >90% 0% Reported in AERS 100% 95% 88% Clinical findings Loss of Efficacy, rapid onset anemia, transfusion requirement Loss of efficacy, rapid onset anemia, transfusion requirement Loss of efficacy, slow onset anemia, may need transfusion Clinical findings described in warning letter Yes Yes No

Introduction: In 2002 and 2003, Ortho Biotech Products, L.P. issued “Dear Health Professional” letters describing two distinct episodes with distribution of counterfeit epoetin (ProcritÒ). The first episode in 2002 occurred when counterfeit labels marked as “40,000 Unit” vials were switched onto 2,000 Unit Procrit vials (5% potency). An estimated 97,000 vials of this product were not recovered, as many as 25,000 patients may have been exposed. A second episode occurred in 2003 when bacteria-contaminated tap water was added to vials that were labeled as containing “40,000 Units” of Procrit®. The “Dear Doctor” letters describe the subtle labeling and other product packaging features that distinguish the products from authentic. In addition, specific lot numbers are identified. We reviewed all MedWatch reports from the United States’ Food and Drug Administration (FDA) for confirmed or possible cases of counterfeit epoetin. Methods: For the years 1998 to 2004, the FDA’s adverse event reporting system (AERS) was searched, using key words: “suspected product tampering,” “decreased drug effect” and related terms, and all epoetin product names. We summarized the demographic variables for the cases and identified the lot numbers reported within the cases. Results: Seven cases of “medication tampering” were identified in the FDA’s Adverse Event Reporting System (AERS) database - all 7 included Procrit® lot numbers identified in the “Dear Health Professional” Warning Letters from OrthoBiotech. The cases had been reported to the FDA by pharmacists (n=5), a consumer (n=1), and a nurse (n=1). In six of these case reports, among cancer patients, death also listed on the report, although counterfeit product was not listed as the proximate cause of death. There were no case reports identified by the diagnostic term of “pharmaceutical product counterfeit”, which was added to the FDA’s AERS in 2004. We identified an additional 643 cases of MedWatch cases that were coded with the diagnostic labels of “drug ineffective”, “therapeutic response decreased”, “drug effect decreased”, “condition aggravated”, and similar terms. The mean age equal to 59.7± 17.7 years, range 5–95 years. There were 269 females (42%) and 358 males (55%), gender not reported for 3%. All epoietin products were included. Finally, one case was found with a reported lot number corresponding to one listed in the warning letters. Death occurred in this 89 year-old patient. Conclusion: Health professionals should be alert for potential counterfeit drugs whenever drug effects are less than expected and the pharmaceutical is costly. Whenever suspected, the occurrences should be reported to the FDA and the manufacturer as possible “pharmaceutical product counterfeit.” The use of radio frequency identification (RFID), planned to be implemented in 2007 may help prevent the domestic distribution of counterfeit drugs, but increases in direct importation of drugs from international sources will potentially increase the likelihood of distribution of counterfeit drugs domestically.

Background: Follow-up reports describing the long-term prognosis of 47 patients with epoetin induced PRCA have been confined to a single study from France, England, and Germany, investigated through active surveillance efforts. There is concern that reporting quality may differ between active versus voluntary reporting efforts. Methods: Investigators from the Research on Adverse Drug reactions And Reports (RADAR) program compared clinical findings for epoetin-associated PRCA cases reported by voluntary surveillance efforts (n= 47) versus active surveillance (n= 47). (Verhelst et at, Lancet 2004). Recovery from PRCA was defined as transfusion independence, normalized reticulocyte count, and/or disappearance of anti-erythropoietin antibody. Results: Baseline characteristics of age and gender were similar in both the MEDWatch and active surveillance groups. The two groups were similar with respect to median age similar (67 years) and gender (70%) and follow-up duration for patients who recovered (mean of 3 months). Median follow-up was shorter for passive surveillance patients who did not recover (6 versus 11 months). Recovery rates with immunosuppression differed (39.5% for MedWatch versus 21.6% for active surveillance). Conclusions: Follow-up of active versus passive pharmacovigilance differed markedly for epoetin-associated PRCA cases in France, Germany, and the UK, in part due to differences in follow-up time. Active pharmacovigilance efforts should be supported by national health authorities. | Surveillance of Rx’ed patients | Active N=37 (%) | Passive N=38 (%) | |:---------------------------------:| --------------- | ---------------- | | Patients with known follow-up (%) | 100 | 100 | | Recovered w/transplant | 16.2 | 18.4 | | Recovered w/Immunosuppression | 62.2 | 42.1 | | No recovery | 21.6 | 39.5

Background– Although thalidomide (Th) was granted FDA approval in 1998 for erythema nodosum leprosum, >99% of its use is off-label for cancer. As with all off-label therapies, FDA regulations prohibit dissemination of clinical information by the manufacturer. Nonetheless, concern over off-label toxicities arose in a 2001 phase III study in which 28% of myeloma patients developed deep vein thrombosis (DVT) and pulmonary embolism (PE) with concurrent Th-chemotherapy. We investigated the clinical characteristics and reporting quality of all adverse event (AE) reports describing Th-associated thromboembolism (TE). Methods– Data sources included 190 AE reports obtained from the FDA and 38 published phase II and III trials with 1,857 Th-treated individuals (for rate estimation), with exclusion of cases/trials reported in duplicate. AE reporting quality comparisons were made for events, which occurred in clinical trials (n=49) or in clinical practice settings (n=141). Results– Overall, 190 cancer patients were reported as having Th-associated TE, based on AE reports submitted to the drug manufacturer (n=49 from prospective clinical trials and n=131 from non-clinical trial setting) or directly to MedWatch (n=10). Only 6 cases were reported through the System for Th Education and Prescriber Safety (STEPS), an FDA mandated teratogenicity-focused safety program. DVT/PE occurred at a median of 52 days Th use (range, 6 to 469 days). Completeness and certainty of DVT/PE diagnoses were best for AE reports submitted directly to the manufacturer from clinical trials versus those from non-clinical trial settings (p

Background: In view of concern about substantially increased risk of gemcitabine-associated lung injury (ALI), vigilant post-marketing surveillance is necessary to further characterize the frequency, severity, and clinical features of gemcitabine-associated pulmonary injury. Methods: From 2001–2003, investigators with the Research on Adverse Drug reactions And Reports (RADAR) program compared the clinical characteristics and adverse event reporting quality of gemcitabine-associated lung injury contained in published case reports and adverse event reports submitted in the setting of clinical trials or the non-clinical trial setting. Results: Completeness of reporting was excellent for published case reports and intermediate to poor for FDA adverse event reports from clinical trials or observational studies, including age (100%, 92%, 91%); time to onset of toxicity (100%, 63%, 58%); dose (97%, 63%, 79%); results of imaging studies (94%, 56%, 59%); presence/absence of hypoxia (97%, 6%, 4%); and cause of death (88%, 82%, 66%). Temporal analyses identified a bimodal pattern for the onset of pulmonary symptoms: 90% occurred before 150 days and 8% after 300 days. The highest rates of severe lung injury were in high dose patients co-administered bleomycin (28%) and in lung cancer patients (16%). Conclusions: Reporting completeness for severe gemcitabine-ALI to the FDA from the clinical trial and the non-clinical trial setting is poor, limiting the ability of the RADAR group to comprehensively assess this toxicity. Nonetheless, this toxicity is severe and, as shown in published case reports, frequent in the presence of concomitant pulmonary insults such as bleomycin-containing combination chemotherapy regimens for Hodgkin’s disease and taxol-containig combination chemotherapy regimens for lung cancer. Gemcitabine-associated Acute Lung Injury in Selected Clinical Trials Author DX Other ChemoRx N ALI % Friedberg JW Hodgkin Doxorubicin, Bleomycin, Vinblastine 12 5 42 Bredenfeld H Hodgkin BA_COPP 27 6 22 Chen YM Non-SCLC Vinorelbine 20 5 25 Popa IE Non-SCLC Docetaxel 32 6 19 Herbst RS Non-SCLC Vinorelbine 36 5 14 Blackstock AW Non-SCLC 16 2 13 Bhatia S Non-SCLC Paclitaxel 34 4 12 Safran H Pancr. Ca Paclitaxel, Radiation 19 2 11 Lobo F Breast Ca Vinorelbine, Anthracyclines 21 2 10

Background: With the recent reporting of 191 cases of epoetin induced PRCA (Bennett CL, NEJM 2004), information is needed about the long-term follow-up of individuals with this diagnosis. While 47 cases from France, Germany, and England have been reported recently (Verhelst D, Lancet 2004), these data are limited by short follow-up and absence of information from other regions. Methods: RADAR investigators identified cases of epoetin-associated PRCA from the Food and Drug Administration MEDWatch database and proprietary reports from both the manufacturers epoetin alpha (Epogen from AMGEN, and Eprex from Johnson and Johnson) and epoetin beta (Neorecormon from Roche). Patients exposed to more than one epoetin form were excluded. PRCA recovery was operationally defined as transfusion independence, clearance of anti-erythropoietin antibody, and/or normalization of reticulocyte count. Results: See table. Conclusions: The overall recovery rate of 82% following transplantation versus 40% following immunosuppression suggests that transplantation might be the optimal therapy for epoetin-associated PRCA. Almost half of the patients rechallenged with epoetin developed recurrent PRCA, raising concern over the benefits of rechallenge. Eprex (N=82) Neorecormon (N=11) Epogen (N=5) Origin: US 60% 64% 100% Europe 60% 64% – Pacific Rim/Asia 21% 36% – Canada 19% – – Subcutaneous delivery 99% 100% 60% Recovery with Immunosuppression 37% 73% 0% Recovery with renal Transplant 11% – – No recovery with renal transplant 1% – 20% No Recovery 41% 18% 40% Unknown Recovery 10% 9% 40% Male gender 68% 73% 40% Rechallenged with epoetin N=12 – – Response rate 50% Median age 68 years 47 years 51 years

Introduction: The antiplatelet agents ticlopidine and clopidogrel are thienopyridine derivatives that are commonly used for secondary prevention of cerebrovascular events, prevention of coronary artery stent thrombosis, and for treatment of acute coronary syndrome. While these chemically related agents are the first and third most common causes of drug-associated TTP respectively, clinical presentations, laboratory findings, and outcomes suggest that there may be two distinct mechanistic pathways. Methods: Clinical and laboratory data for 60 cases of ticlopidine-associated TTP and 35 cases of clopidogrel associated TTP were reviewed. Results: Type 1 thienopyridine-associated TTP, characterized by onset of disease > 5 days after drug initiation, occurred in 98% of the ticlopidine patients versus 63% of the clopidogrel patients. Laboratory studies identified severe deficiency of ADAMTS13 activity and the presence of IgG inhibitors in 7 ticlopidine (Tsai, et al.; Annals of Internal Medicine, 2000) and 2 clopidogrel (Bennett, et al.; NEJM, 2000) patients. Survival was 68% in the ticlopidine patients versus 91% in the clopidogrel patients. Type 2 thienopyridine-associated TTP, consisting of TTP onset within 5 days of drug initiation, occurred in 2% of the ticlopidine patients versus 37% of the clopidogrel patients. Laboratory studies failed to identify deficient ADAMTS13 activity or the presence of IgG inhibitors in 1 clopidogrel patient (Zheng, et al.; Blood, 2004). Survival was 0% in the ticlopidine patients versus 38% in the clopidogrel patients. Conclusion: The proposed type 1 and type 2 thienopyridine-associated TTP may be distinguished on the basis of clinical presentation, ADAMTS13 levels, and outcome. Type 1 thienopyridine-associated TTP—characterized as occurring after > 5 days of thienopyridine treatment, severely deficient ADAMTS13 activity and presence of IgG inhibitors, and high survival rates with plasmapheresis—is more likely to occur in patients receiving ticlopidine. Type 2 thienopyridine-associated TTP—characterized as occurring within 5 days of thienopyridine therapy initiation, normal ADAMTS13 activity and undetectable IgG inhibitors, and poor survival rates despite plasmapheresis—is more likely to occur in patients receiving clopidogrel. Additional confirmatory studies on larger numbers of patients are needed.

Background: In October 2003, six months after approval of the first drug-eluting coronary stent (CYPHER™ stent), the FDA reported 50 stent-associated hypersensitivity reactions. In November 2003, FDA officials reported that these reactions were probably due to concomitantly prescribed medications. Methods: All adverse device event reports for CYPHER stent associated hypersensitivity- reactions in the FDA’s adverse event reporting system, the published literature, or from RADAR, between April 2003 and June 2004 were reviewed. Causality was evaluated using World Health Organization criteria. Results: Review of FDA reports (n=2,607) identified 161 persons with hypersensitivity symptoms. Fewer than 20 hypersensitivity cases were reported monthly, except for 43 and 42 reports in October and November 2003. Symptoms began within 2 days of stent implantation (21%), between 2 and 7 days (43%) and between 7 and 14 days (19%) following stent implantation and persisted for less than 8 days for 17%, 8–30 days for 29% and > 30 days for 55%. Findings included rash (80%), itching (28%), hives (19%), dyspnea (12%), fever (12%), chest pain (8%), anaphylaxis (7%), joint pain or swelling (7%) and high or low blood pressure (5%). Among persons with rashes, 25% covered the entire body, 21% developed hives, 7% had localized maculopapular eruptions and 4% developed blisters or desquamation. Treatment included emergency interventions (26%) or hospitalization (19%). Outcomes included permanent disability (5%) or death (2%). Aspirin or clopidogrel was discontinued at the time of hypersensitivity onset for 42. Using WHO criteria, clopidogrel, aspirin, ticlopidine and/or the stent itself were classified as possible causes for > 85% of cases. Of 150 events possibly caused by the CYPHER stent, 35 persisted for > 30 days. For 7 probable CYPHER-stent induced hypersensitivity cases identified by RADAR (n=4), the FDA (n=2) or the literature (n=1), symptom onset was < 5 days (n=3) and at 3 weeks, 1 month, 4 months, and 7 months after stent implantation. Findings included rash (n=4), hives (n=1), blisters on both hands (n=1), dyspnea (n=2), eosinophilia (n=1), elevated IgE levels (n=2) and Gallium-67 scan findings at the stent (n=1). Findings did not abate with thienopyridine discontinuation (n=5). Outcomes included resolution of symptoms with hospitalization (n=1) or corticosteroids (n=2), persistent angina (n=1) and subsequent occurrence of fatal cardiac events, with autopsy identification of eosinophilic infiltrates at the stent site (n= 2 patients). Conclusion: Rash, hives, dyspnea and catastrophic cardiac events may represent local and systemic hypersensitivity reactions from the CYPHER-stent. Reporting of these events decreased by > 90% following a FDA advisory that suggested that skin reactions were unrelated to the stent. However, our findings highlight the importance of continued vigilance for hypersensitivity reactions that may represent an early manifestation of a catastrophic hypersensitivity event.