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Biosimilar filgrastims are primarily indicated for chemotherapy-induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%–40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital-only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the “rebate trap” with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus reference filgrastim, should be considered. Implications for Practice We reviewed experiences and policies for biosimilar filgrastims in Europe, Japan, Canada, and the U.S. Postmarketing harmonization of regulatory policies for biosimilar filgrastims has not occurred. Acceptance of biosimilar filgrastims for branded filgrastim, increasing in the U.S. and in Canada, is commonplace in Japan and Europe. In the U.S., some factors, accepted in Europe or Japan, could improve uptake, including acceptance of biosimilars as safe and effective; larger cost savings, decreasing “rebate traps” where pharmaceutical benefit managers support branded filgrastim, decreased use of patent litigation/challenges, and allowing pharmacists to routinely substitute biosimilar for branded filgrastim.

A 43‐year‐old female with multiple sclerosis developed urethral melanoma. The only potential risk factor was treatment with natalizumab, a humanized monoclonal antibody against α4 integrins. To investigate the risk‐exposure relationship, we reviewed this case, all other published cases, and cases of natalizumab‐associated melanoma reported to regulatory agencies. Data sources included the Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) (2004–2014), a FDA Advisory Committee Meeting Report, and peer‐reviewed publications. In the United States, the manufacturer maintains an FDA‐mandated Tysabri Safety Surveillance Program (part of the Tysabri Outcomes Unified Commitment to Health (TOUCH)) of natalizumab‐treated patients. We statistically compared reporting completeness for natalizumab‐associated melanoma cases in FAERs for which information was obtained entirely from the TOUCH program versus cases where FAERS information was supplemented by TOUCH program information. FAERS included 137 natalizumab‐associated melanoma reports in patients with multiple sclerosis. Median age at melanoma diagnosis was 45 years (range: 21–74 years). Changes in preexisting nevi occurred in 16%, history of cutaneous nevi occurred in 22%, diagnosis within 2 years of beginning natalizumab occurred in 34%, and 74% had primary surgical treatment. Among seven natalizumab‐treated MS patients who developed biopsy‐confirmed melanoma on treatment and reported in the literature, median age at diagnosis was 41 years (range: 38–48 years); and the melanoma diagnosis occurred following a median of 12 natalizumab doses (range: 1–77 doses). A history of mole or nevi was noted in four patients and a history of prior melanoma was noted in one patient. Completeness scores for reports were significantly lower for FAERS cases reported from the TOUCH program versus FAERS cases supplemented by TOUCH information (median score of 2 vs. 4 items out of 8‐possible items, P

Purpose In March 2007, a US Food and Drug Administration boxed warning was issued for erythropoietin-stimulating agents (ESAs) regarding serious adverse events, such as venous thromboembolism (VTE). We evaluated the US Food and Drug Administration’s boxed warning of ESAs used to treat chemotherapy-induced anemia because evidence on the effectiveness of boxed warnings remains inconclusive. Patients and Methods Using 2004 to 2009 SEER-Medicare data, we exploited a natural experiment to examine the effects of ESA boxed warnings on utilization and risk of VTE. The intervention group included Medicare fee-for-services patients diagnosed with colorectal, breast, or lung cancers targeted by this warning and undergoing chemotherapy; the control group included patients with myelodysplastic syndromes not targeted by this warning. The period from January 2004 to September 2006 was used as the prewarning period; the period from April 2007 to September 2009 was used as the postwarning period. The two binary dependent variables included ESA use and hospitalized VTE. Linear probability models with a difference-in-differences specification were used for estimation. Results Our sample consisted of 45,319 unique patients between 2004 and 2009. The trends in ESA use remained similar between the intervention and control groups before the warning, but started declining sharply in the intervention group only after the warning. The trends in hospitalized VTE were relatively stable. Regressions showed that the ESA boxed warning was associated with a 20.2-percentage-point reduction ( P < .001) in the likelihood of ESAs being used to treat cancers targeted by the warning, but not significantly associated with the likelihood of hospitalized VTE. Conclusion Our study showed that the warning was effective in reducing ESA utilization. Future studies should examine other regulatory drug safety actions, such as the Risk Evaluation and Mitigation Strategy initiative, whose effectiveness remains unknown.

Purpose: The US Food and Drug Administration (FDA) has approved epoetin and darbepoetin for chemotherapy-induced anemia (CIA). Approved epoetin and darbepoetin dosing schedules were three times per week and weekly, respectively, although off-label, less frequent scheduling was common. In 2004, 2007, and 2008, a US Food and Drug Administration Advisory Committees warned of risks associated with erythropoiesis-stimulating agents. During this period, lawsuits alleging illegal darbepoetin marketing practices have concluded, resulting in $1.1 billion in fines and settlements and one criminal conviction. No prior study, to our knowledge, has reported on the use of darbepoetin versus epoetin for CIA. Methods: We evaluated the dosing, utilization, and costs of erythropoiesis-stimulating agents among 3,761 South Carolina Medicaid patients with CIA. Results: Epoetin and darbepoetin utilization rates were 22% and 28% in 2003, 10% and 33% in 2007, and 3% and 7% in 2010, respectively. Mean per-patient per-administration epoetin and darbepoetin doses were 40,983 IU and 191 µg, respectively, in 2003 and 47,753 IU and 369 µg, respectively, in 2010. Mean monthly patient costs for epoetin and darbepoetin were $1,030 and $981, respectively, in 2003 and $932 and $1,352, respectively, in 2010. Epoetin use decreased steadily between 2002 and 2010; darbepoetin use increased steadily between 2003 and 2007 and then decreased steadily thereafter. Per-patient dosing of darbepoetin, but not epoetin, increased steadily between 2003 and 2010, and monthly per-patient epoetin costs decreased 3% while the per-patients costs of darbepoetin increased 30% between 2003 and 2010. Conclusion: To our knowledge, our findings are the first data reporting on epoetin versus darbepoetin use for CIA and support recently concluded lawsuits involving allegations of illegal marketing practices of the manufacturer of darbepoetin.

Hepatitis B virus (HBV) is a global disease with significant morbidity and mortality. Worldwide, an estimated 257 million people are chronically infected with HBV, defined as having a positive hepatitis B surface antigen, but millions more have prior HBV exposure indicated by positive hepatitis B core antibody. Reactivation of hepatitis B implies a sudden increase in viral replication in a patient with chronic HBV infection or prior HBV exposure. Hepatitis B reactivation (HBVr) can occur spontaneously, but it is more commonly triggered by immunosuppressive therapies for cancer, immunologic diseases, or transplantation. Elimination of hepatitis C virus (HCV) in HBV-HCV co-infected individuals treated with direct-acting antivirals (DAAs) has also been identified as an important cause of HBVr. Hepatitis B virus reactivation is an underappreciated but important complication of common medical therapies that can delay treatment or result in clinical episodes of hepatitis, hepatic failure, or death. In this review factors associated with HBVr, particularly medication-related risks, will be explored. We review data involving rituximab and ofatumumab, doxorubicin, corticosteroids, tumor necrosis factor antagonists, tyrosine kinases, bortezomib, hematologic stem cell transplantation, and DAAs for HCV treatment. In addition, we will discuss screening strategies, choice of antiviral prophylaxis, and the optimal duration of therapy for HBVr. With additional awareness, screening, and appropriate antiviral therapy, it is expected that most cases of HBVr can be prevented.

Although the availability of generic oncology drugs allows access to contemporary care and reduces costs, there is international variability in the safety of this class of drugs. In this Series paper, we review clinical, policy, safety, and regulatory considerations for generic oncology drugs focusing on the USA, Canada, the European Union (EU), Japan, China, and India. Safety information about generic formulations is reviewed from one agent in each class, for heavy metal drugs (cisplatin), targeted agents (imatinib), and cytotoxic agents (docetaxel). We also review regulatory reports from Japan and the USA, countries with the largest pharmaceutical expenditures. Empirical studies did not identify safety concerns in the USA, Canada, the EU, and Japan, where regulations and enforcement are strong. Although manufacturing problems for generic pharmaceuticals exist in India, where 40% of all generic pharmaceuticals used in the USA are manufactured, increased inspections and communication by the US Food and Drug Administration are occurring, facilitating oversight and enforcement. No safety outbreaks among generic oncology drugs were reported in developed countries. For developing countries, oversight is less intensive, and concerns around drug safety still exist. Regulatory agencies should collaboratively develop procedures to monitor the production, shipment, storage, and post-marketing safety of generic oncology drugs. Regulatory agencies for each country should also aim towards identical definitions of bioequivalence, the cornerstone of regulatory approval.

Background Unexpected serious adverse drug reactions (sADRs) affecting patients with chronic kidney disease (CKD) who received erythropoiesis-stimulating agents were identified by study co-authors. These included pure red cell aplasia (PRCA) after administration of the Eprex formulation of epoetin or the epoetin biosimilar HX575 and fatal anaphylaxis associated with peginesatide, an erythropoietin receptor agonist. We developed and applied a structured framework to describe these sADRs, including root cause analyses and eradication efforts. Methods A 10-step framework termed "ANTICIPATE," focusing on signal identification, incidence, causality, and eradication guided our evaluations. Results Initial cases were identified by a hematologist (Eprex), clinical study monitors (HX575), and 4 nurses (peginesatide). The number of persons with individual ADRs was 13 PRCA cases for epoetin, 2 antibody-mediated PRCA cases for HX575, and 5 fatal anaphylaxis cases for peginesatide. Initial incidence estimates per 1000 treated persons were 0.27 for Eprex-associated PRCA, 11 for HX575-associated PRCA, and 0.38 for peginesatide fatalities. Likely causes were subcutaneous administration of epoetin formulated with polysorbate 80 (Eprex), tungsten leaching from pins included in product syringes (HX575), and inclusion of a phenol stabilizer (peginesatide). Eradication strategies included restricting Eprex administration to the intravenous route, excluding tungsten from HX575 syringes, and for peginesatide, proposed eradication was to return to single-dose vials without preservatives. Conclusion Although the number of cases of each sADR was small, eradication was successful for 2 sADRs, and a proposed eradication was developed for a third sADR. The structured framework used to describe the above 3 sADRs in patients with CKD can also be used in other clinical settings.

Purpose Brentuxiumab vedotin (BV) is an anti-CD30 monoclonal antibody-drug conjugate approved in 2011 for treating anaplastic large cell and Hodgkin lymphomas. The product label indicates that three BV-treated patients developed progressive multifocal leukoencephalopathy (PML), a frequently fatal JC-virus induced central nervous system infection. Prior immunosuppressive therapy and compromised immune systems were postulated risk factors. We report 5 patients who developed BV-associated PML, including two immunocompetent patients.

A 55-year-old, previously healthy woman received a diagnosis of diffuse large-B-cell lymphoma after the evaluation of an enlarged left axillary lymph node obtained on biopsy. She had been asymptomatic except for the presence of enlarged axillary lymph nodes, which she had found while bathing. She was referred to an oncologist, who performed a staging evaluation. A complete blood count and test results for liver and renal function and serum lactate dehydrogenase were normal. Positron-emission tomography and computed tomography (PET–CT) identified enlarged lymph nodes with abnormal uptake in the left axilla, mediastinum, and retroperitoneum. Results on bone marrow biopsy were normal. The patient’s oncologist recommends treatment with six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab (CHOP-R) at 21-day intervals. Is the administration of prophylactic granulocyte colony-stimulating factor (G-CSF) with the first cycle of chemotherapy indicated?

Background Central venous catheter (CVC) use is commonplace in cancer patients. Antimicrobial lock therapy (ALT), the instillation of a concentrated antimicrobial solution into the catheter lumen, is one method for preventing infection among CVCs. This systematic review discusses the effectiveness and safety of prophylactic ALT in cancer patients with CVCs. Methods A literature search was performed using the Medline database and Google Scholar from inception until April 2016. The following terms were used: ‘antimicrobial lock solution’, ‘antibiotic lock solution’, ‘oncology’, ‘hematology’, ‘pediatrics’, ‘prevention’, ‘cancer’, ‘catheter related bloodstream infections’, ‘central-line associated bloodstream infection’ (CLABSI) and ‘central venous catheter’. Studies evaluating prophylactic ALT in cancer patients alone were eligible for inclusion. Case reports, case series and in-vitro studies were excluded. Results In total, 78 articles were identified. Following all exclusions, 13 articles (three adult and 10 pediatric) were selected for evaluation. The most common agents utilized were vancomycin with heparin; ethanol; taurolidine; and minocycline with EDTA. Quality of evidence was moderate to high in adult studies and low to moderate in pediatric studies. Use of ALT decreased the incidence of CLABSI in the majority of studies; however, there were significant differences in definitions of CVC-related infection, dwell times and lock solutions. Conclusion Lock therapy may be an adjunct in high-risk cancer patients for the prevention of CLABSI; higher quality evidence is needed for specific ALT recommendations.

Background Oncology pharmacists are capable of providing medication therapy management (MTM) because of their level of training, practice experiences, and responsibilities. Very little data exist about their current practice, including changing roles in the multidisciplinary team, overall impact, and effects in the education of patients and healthcare professionals. Methods A 70-item survey about oncology pharmacists' activities in oral chemotherapy programs, MTM, and collaborative practice agreements (CPAs) was deployed using a web survey tool (Qualtrics, Provo, UT, USA), targeting pharmacist members of American College of Clinical Pharmacy (ACCP) Hematology/Oncology Practice and Research Network (PRN). The objective of this study was to determine oncology pharmacists' activities in areas of oral chemotherapy programs, MTM, and CPAs. A cross-sectional survey was distributed to the ACCP Hematology/Oncology PRN membership. Investigational Review Board approval was obtained. Results Of the 795 members who were sent the survey, 81 members (10%) responded; 33 respondents (47%) are involved with an oral chemotherapy program; with 42% measuring outcomes of programs. Only six pharmacists (19%) have published or presented their data. A total of 28 (35%) respondents provide MTM services, with almost half (43%) of these MTM services being dictated by CPAs. A small fraction of these pharmacists (21.4%) reported conducting quality assurance evaluations of their MTM services and three pharmacists (10.7%) reported publishing their results. Those pharmacists practicing under CPAs ( n = 28) were surveyed as to activities included in their CPA. The most common activities included adjusting medication, ordering, interpreting, and monitoring lab tests, developing therapeutic plans and educating patients. Reimbursement for providing these services was uncommon: MTM (4%), oral chemotherapy program (6%), and CPA services (11%). Reported obstacles to reimbursement included lack of understanding, administrative assistance, or time with setting up reimbursement models within the institution. Conclusion Many oncology pharmacists are participating in oral chemotherapy programs, MTM, and/or CPAs and perceived barriers were identified. Increased efforts should be directed toward prospectively reporting and assessing the impact these services have on patient care.

Pharmaceutical safety is a public health issue. In 2005, the Connecticut Attorney General (AG) raised concerns over adverse drug reactions in off-label settings, noting that thalidomide was approved to treat a rare illness, but more than 90% of its use was off label. A hematologist had reported thalidomide with doxorubicin or dexamethasone was associated with venous thromboembolism (VTE) rates of 25%. We review US Food and Drug Administration (FDA) and manufacturer responses to a citizen petition filed to address these thalidomide safety issues.Case study.The AG petitioned the FDA requesting thalidomide-related safety actions. Coincidentally, the manufacturer submitted a supplemental New Drug Approval (sNDA), requesting approval to treat multiple myeloma with thalidomide-dexamethasone. FDA safety officers reviewed the petition and the literature and noted that VTE risks with thalidomide were not appropriately addressed in the existing package insert. In the sNDA application, the manufacturer reported thalidomide-associated toxicities for multiple myeloma were primarily somnolence and neurotoxicity, and a proposed package insert did not focus on VTE risks. In October, the FDA informed the Oncology Drug Division that VTE risks with thalidomide were poorly addressed in the existing label. After reviewing this memorandum, an Oncology Drug Division reviewer informed the manufacturer that approval of the sNDA would be delayed until several thalidomide-associated VTE safety actions, including revisions of the package insert, were implemented. The manufacturer and FDA agreed on these actions, and the sNDA was approved.New approaches addressing off-label safety are needed. The conditions that facilitated the successful response to this citizen petition are uncommon.

Objectives Three separate elective courses on medication safety, clinical research, and evidence-based medicine used a hybrid course design combining online wikis and face-to-face interaction. Enrolled students were surveyed to assess their perceptions of wiki effectiveness in reviewing course content and the engagement of students in wiki assignments was assessed through examination of wiki entries. Methods Online surveys were disseminated to enrolled students after course completion. Respondents evaluated agreement with survey statements using a five-point Likert scale, and additional space was provided for open-ended answers. Survey results were reported using descriptive statistics. Wiki entries were compared throughout the course. Results Survey responses on the use of wikis within hybrid elective courses indicate that wikis helped students review and understand course concepts and reflect on course content. A smaller percentage of students felt that wikis within a hybrid course design enhanced collegiality among their peers. Wiki entries became more complex and improved throughout each course. Conclusions Wikis within hybrid elective courses enhanced the student experience by reinforcing course concepts and objectives.

Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye’s syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States’ NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common.

Purpose: Counterfeit pharmaceuticals pose risks domestically. Because of their cost, cancer pharmaceuticals are vulnerable. We review findings from a domestic counterfeiting episode involving erythropoietin and outline anticounterfeiting recommendations for policy makers, patients, and health care professionals. Materials and Methods: Information was obtained on patients who received counterfeit erythropoietin, its distribution, and criminal investigations into counterfeiting networks. Interview sources included a physician, an attorney, employees of the Florida Department of Health and Human Services and the US Food and Drug Administration’s (FDA) Office of Criminal Investigation, manufacturers, and wholesalers. Other sources included the book “Dangerous Doses,” LexisNexis (search terms “counterfeit” and “erythropoietin”) and the FDA database. Results: Counterfeit product consisted of 2,000 U vials with counterfeit labels denoting 40,000 U. The counterfeiters, in collaboration with a Miami pharmacy, purchased 110,000 erythropoietin 2,000 U vials and affixed counterfeit labels to each vial. Products werethensoldviathepharmaceutical“graymarket”towholesalers, then pharmacy chains. Investigations by Florida government officials implicated 17 persons, all of whom were found guilty of trafficking in counterfeit pharmaceuticals. Despite the large size of the operation, the FDA received reports of only 12 patients who had received counterfeit erythropoietin and detailed information for only two individuals. A 17-year-old liver transplant recipient and a 61year-oldpatientwithbreastcancerexperiencedlossofefficacyafter receiving counterfeit erythropoietin. Conclusion: Wider use of FDA anticounterfeit initiatives, limiting pharmaceutical suppliers to reputable distributors, and educating providers and patients about signs of counterfeit drugs can improve the safety of cancer pharmaceuticals.

BACKGROUND.: In 2006, nephrologists in Denmark unexpectedly identified chronic kidney disease (CKD) patients with a new syndrome, nephrogenic systemic fibrosis (NSF). Subsequently, 1603 NSF patients were reported to the Food and Drug Administration. Sixty hospitals in the USA account for 93% of these cases, and two hospitals in Denmark account for 4% of these reports. We review Denmark's identification and subsequent rapid eradication of NSF. METHODS.: NSF reports from clinicians, the Danish Medicines Agency (DMA) and gadolinium-based contrast agents (GBCAs) manufacturers were reviewed (2002-11). RESULTS.: In 1994, the DMA approved a non-ionic linear GBCA, gadodiamide (0.1 mmol/kg), for magnetic resonance imagings (MRIs), with a renal insufficiency contraindication. In 1996, 0.3 mmol/kg dosing received DMA approval. In 1998, the DMA removed renal contraindications. In 1997 and 2002, radiologists at Skejby Hospital and Herlev Hospital, respectively, began performing gadodiamide-enhanced magnetic resonance angiography scans (0.3 mmol/kg) of CKD patients. In 2005, Herlev clinicians requested assistance in evaluating etiological causes of NSF occurring among 10 CKD patients who had developed NSF. This investigation, focusing on infectious agents, was inconclusive. In 2006, Herlev clinicians reported that of 108 CKD patients who had received gadodiamide-enhanced MRI, 20 had developed probable NSF. Herlev radiologists voluntarily discontinued administering gadodiamide to all patients and no new NSF cases at Herlev Hospital developed subsequently. After meeting with Herlev radiologists, Skejby radiologists also discontinued administering gadodiamide to all patients. In 2007, the European Medicines Agency and the DMA contraindicated gadodiamide administration to CKD patients. In 2008, in response to these advisories, radiologists at the other 36 Danish hospitals discontinued administering gadodiamide to all patients, following on practices adopted at Skejby and Herlev Hospitals. In 2009, clinicians at Skejby Hospital reported that a look-back survey identified 33 CKD patients with NSF developing after undergoing GBCA-enhanced MRIs between 1999 and 2007. In 2010, an independent review, commissioned by the Minister of Health, concluded that the DMA had erred in rescinding gadodiamide's renal insufficiency contraindication in 1998 and that this error was a key factor in the development of NSF in Denmark. In 2011, three NSF cases associated with macrocyclic GBCA-associated NSF and three NSF patients with Stages 3 and 4 CKD disease from Skejby Hospital were reported. CONCLUSION.: A confluence of factors led to the development and eradication of NSF in Denmark.

The use of granulocyte colony-stimulating (G-CSF) factors to avoid chemotherapy induced neutropenia is a major cost driver in clinical oncology. Short acting formulations, while less convenient, are 39% the cost of the longer formulation (Pegfilgrastim). We analyzed the use of G-CSF vs. Neulasta in the Veterans Administration (VA) health care system as currently practiced by clinical judgement and analyzed this economically. A survey of 23 sites within the VA on the relative frequency of use of filgrastim, Tbo-filgrastim, Filgrastim-sndz and Pegfilgrastim was conducted. Cost was estimated using 340B pricing. A maximally cost-effecient strategy of 100% Tbo-filgrastim would result in a cost of $62,336 per 100 patient episodes. Tbo-filgrastim was the preferred treatment in 18 of 23 sites surveyed. Cost results ranged from a minimum of $62,336 (4 of 23 sites) to a maximum of $201,356 (2 of 23 sites) with a mean cost of $99,080. The VA was overall 73% efficient, and therefore highly cost-effective, in minimizing use of Pegfilgrasim. As in Europe cost-efficiency favors the use of Tbo-filgrastim over Pegfilgrastim; further cost-saving opportunities exist with the following strategies : (1) avoid G-CSF use where there is no convincing evidence of efficacy (i.e. low risk patients, treatment of neutropenia rather than prophylaxis) (2) use daily filgrastim in lieu of pegfilgrastim whenever possible (3) use Tbo-filgrastrim rather than filgrastrimn (4) continue to examine strategies using 2 or 4 day courses of G-CSf as opposed to 8 days which would cut cost an additional 50 to 75%. Survey data showed that uptake of biosimilar G-CSF in the VA system has been extremely rapid. All sites are using biosimilar GCSF for all new patients; 6 of 23 sites were comfortable shifting current patients on branded G-CSF to the biosimilar. Survey data shows an overwhelming use of filgrastrim compared to pegfilgrastim in the VA system, in contradistinction to the rest of the United States - resulting in an efficiency of 73% (i.e. only 27% of patients are being given pegfilgrastrim). This represents a great savings to the VA system which can be emulated in other sites in the United States. Switching to a Tbo-filgrastim, although heralded by some as cost savings, only engendered a cost savings of 2.2% - small compared to other clinical changes. Disclosures No relevant conflicts of interest to declare.

1 South Carolina Center of Economic Excellence for Medication Safety and Efficacy and the Southern Network on Adverse Reactions (SONAR), South Carolina College of Pharmacy, University of South Carolina, Columbia, SC; 2 Pharmacoeconomics, Epidemiology, Public Policy and Outcomes Research (PEPPOR), College of Pharmacy, University of New Mexico, and Veterans Affairs Cooperative Studies Program Clinical Research Pharmacy, Albuquerque, NM; 3 Tulane Cancer Center, Tulane University, New Orleans, LA; 4 eHealthMe, Madison, WI; and 5 Hollings Cancer Center, Medical University of South Carolina, Charleston, SC

Objective: To examine the current controversies and discuss consensus recommendations regarding treatment sequencing and the role of BRAF inhibitor at disease progression. Data Source: An English-language literature search of MEDLINE/PubMed (1966-May 2014), using the keywords advanced melanoma, ipilimumab, cytotoxic T-lymphocyte antigen 4, dabrafenib, vemurafenib, BRAF inhibitor, trametinib, MEK inhibitor, and treatment sequencing was conducted. Data were also obtained from package inserts, meeting abstracts, and clinical registries. Study Selection and Data Extraction: All relevant published articles and abstracts on ipilimumab, vemurafenib, dabrafenib, and trametinib were reviewed. Clinical trial registries and meeting abstracts were used for ongoing studies. Data Synthesis: The availability of new agents has made therapy selection more complex. Immunotherapy supporters reason that immunotherapy offers the best chance for long-term benefit and does not compromise the antitumor activity of subsequent BRAF inhibitors. Targeted therapy advocates rely on the high probability and rapid onset of response to BRAF inhibitors. Currently, there is insufficient evidence regarding the role of BRAF inhibitor at disease progression. Conclusions: Therapy should be individualized based on patient- and disease-specific factors. Immunotherapy represents the best option for durable remission; however, targeted therapy is more appropriate for patients who are symptomatic or have rapidly growing tumors. The novel therapies have also demonstrated meaningful intracranial activity; thus, the presence of brain metastases should be taken into consideration in selecting therapy. Limited data exist about the continuation of BRAF inhibitors after therapeutic failure. Active research is ongoing to define the best option for patients with BRAF inhibitor refractory disease.

As of 2013, the Southern Network on Adverse Reactions (SONAR) team described 50 significant adverse drug reactions (sADRs) associated with FDA approved drugs. The team also investigates policy issues surrounding pharmacovigilance. Herein we describe the systematic approach to pharmacovigilance taken by the Southern Network on Adverse Reactions and discuss major findings from the group. By 2015, the team hopes to have identified 20 additional sADRs focusing on biologics, biosimilars, and biobetters. The ultimate goal of SONAR is to decrease the timescale between ADR detection and the dissemination of information regarding the sADR

Purpose Published stability and compatibility data on a growing array of solutions used for antimicrobial lock therapy (ALT) are reviewed. Summary ALT involves the instillation of a highly concentrated antimicrobial, often in combination with an anticoagulant, into a central venous catheter (CVC) lumen; this technique is often used for prophylaxis after CVC insertion or as an adjunctive treatment in cases of central line–associated bloodstream infection (CLABSI) if catheter removal is not feasible. Optimal selection of stable and compatible antimicrobials and additives can maximize catheter dwell times, streamline pharmacy compounding practices, and help ensure patient safety. Of 98 articles on ALT solutions identified in a literature search, 17 met the prespecified criteria for the use of validated stability and compatibility methodology. Antimicrobials active against common CLABSI pathogens that may be appropriate for ALT include cefazolin, cefotaxime, ceftazidime, ciprofloxacin, daptomycin, gentamicin, linezolid, telavancin, ticarcillin–clavulanic acid, and vancomycin; validated data demonstrate the stability of these agents in solution with heparin or nonheparin anticoagulants over 72–96 hours or longer. Other antifungal agents and antiinfectives (e.g., ethyl alcohol) have been used in specific patients and ALT situations. The prolonged stability of several antimicrobial–additive combinations may allow for extended dwell times and less frequent lock solution exchanges. Conclusion Pharmacists’ knowledge of diverse combinations of antimicrobial agents and additives in lock solutions, including several shown to be stable and compatible for extended periods, can help expand and optimize the use of ALT in both treatment and prophylactic modalities.

Erythropoiesis-stimulating agents (ESAs) prevent transfusions among anemic patients with chronic kidney disease (CKD). Clinical trials, meta-analyses, and guidelines identify arterial and venous thromboembolism as well as myocardial event risks with the traditional ESAs, erythropoietin (EPO), and darbepoietin. Side effects of anemia treatment, considering frequency and dosage of treatment as well as targeted hemoglobin levels when utilizing ESAs, greatly impact overall well-being and the quality of life. There is a need for less frequent but equally effective ESAs in this setting.The three generations of ESAs used in CKD-associated anemia are described. Cost effectiveness of the utilization of these therapies, in addition to emerging therapies, is also presented. The few clinical and controlled trials only highlight the need for clarity in molecular biology surrounding the components that control EPO levels and utilization.Anemia associated with CKD is an important area for development of newer therapies which are potentially safer and more convenient to administer.

In this issue of the Journal, Lathia et al. (1) modeled the cost-effectiveness of primary prophylaxis with filgrastim or pegfilgrastim against febrile neutropenia in patients with diffuse large B-cell lymphoma (DLBCL) undergoing chemotherapy from the perspective of a publicly funded health-care system. The inputs for the model were obtained from published literature and clinical practice. The model indicated that in the base case analysis, costs (in 2012 Canadian dollars) associated with no primary prophylaxis, or primary prophylaxis with 10 days of filgrastim, or a single dose of pegfilgrastim per cycle were $7314, $13497, and $16290, respectively. The incremental cost-effectiveness ratios for filgrastim vs no primary prophylaxis was $5.8 million per quality-adjusted life year (QALY) and for pegfilgrastim vs filgastrim primary prophylaxis was $2.6 million per QALY. In comparison with no prophylaxis, there was a slight increase in QALYs with filgastrim (0.2015 vs 0.2004) and pegfilgrastim (0.2024 vs 0.2004). However, this model was based on the important assumption (in accordance with current evidence) that the primary benefit of granulocyte colony-stimulating factor is in preventing chemotherapy-induced neutropenia and that there is no survival benefit associated with use of these drugs in persons with DLBCL (2–5). These results are in sharp contrast to a previously reported analysis in lymphoma patients where pegfilgrastim prophylaxis was associated with an incremental cost-effectiveness ratio of $6190 per QALY when a febrile neutropenia–related mortality benefit was assumed and $1677 per QALY when a long-term mortality benefit was assumed (6). On the other hand, a model of the cost-effectiveness of filgrastim, using a death state in the model and not including a mortality benefit found an incremental cost-effectiveness ratio of $700000 per QALY. This estimate, similar to the estimates of Lathia et al. (1), is consistent with a conclusion that filgrastim is not cost-effective (7). If primary prophylaxis with filgastrim or pegfilgastrim resulted in improvements in progression-free survival or overall survival, the strategy would become cost-effective. However, even though primary prophylaxis decreases by half the rate of febrile neutropenia in the first cycle of chemotherapy for DLBCL, the long-term beneficial effects appear to be unlikely. As demonstrated by sensitivity analysis, if costs of filgastrim were reduced to $70 per dose (60% reduction), the cost of the 10-day filgastrim strategy would be equal to the cost of the no primary prophylaxis strategy (secondary prophylaxis). Similarly, if the cost of pegfilgrastim were reduced to $908 (63% reduction), the cost of the pegfilgrastim strategy would be equal to the cost of the no primary prophylaxis (secondary prophylaxis) strategy. With the advent of a new granulocyte colony-stimulating factor, it is possible that competitive pricing will result and true cost equivalency could be achieved. In Europe, the use of biosimilar versions of filgastrim and pegfilgrastim in the past few years has made such a goal possible. Although this model used the median age of persons diagnosed with lymphoma, the recommendations from this cost-effectiveness model are in line with those reported recently in a clinical review of filgastrim and pegfilgrastim as primary prophylaxis against febrile neutropenia for a 55-year-old patient receiving rituxan, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (8). In contrast, a report by Potosky et al. found that 96% of filgastrim use in lung and colorectal cancer patients was not supported by evidence-based guidelines (9). With current annual filgastrim sales at $5.2 billion, decreasing use of filgastrim and pegfilgrastim where appropriate, as in the setting of primary prophylaxis for younger persons with DLBCL receiving a first cycle of R-CHOP, would reduce costs without adversely affecting clinical outcomes. The findings from this model are similar to those reported by Weeks et al. when evaluating the cost-effectiveness of immune globulin for infection prevention among persons with chronic lymphocytic leukemia—estimated at $6 million per QALY (10). Sensitivity analyses in that study indicated that if subgroups of patients who would achieve a survival benefit with immune globulin could be identified, then this could be proven to be a cost-effective strategy for those patients. Similarly, in the setting of DLBCL, identification of high-risk patient subgroups could yield similarly favorable cost-effectiveness estimates. The Lathia et al. (1) analysis is limited in that some data were used from studies conducted in populations other than the one considered in the analysis and the clinical data for febrile neutropenia rates for lymphoma patients receiving pegfilgrastim were based on patients who were experiencing a disease relapse and received chemotherapy other than R-CHOP (11). Despite these limitations, sensitivity analyses indicated that without a substantial price reduction or identification of survival benefits, primary prophylaxis with either filgastrim or pegfilgastrim is unlikely to be cost-effective from a health-system perspective. Until one or both of these events occur, primary prophylaxis with filgastrim or pegfilgrastim should be regarded as an expensive therapy that is not recommended for use as primary prophylaxis for persons with DLBCL who do not have comorbid illnesses or who are older. Beyond the clinic, this analysis touches on the role of supportive and symptomatic care in persons who have cancer and the use of cost-effectiveness criteria in determining coverage of supportive care agents. Given the median age of diagnosis noted by Lathia et al. (1), about 50% of persons with lymphoma will qualify for Medicare at diagnosis; thus how insurers make use of cost-effectiveness information has important implications for national health policy (12). Furthermore, incremental costs per QALY (or other measure of time) are challenging to estimate and use in clinical practice and policy making, particularly estimates of survival benefits and longer term benefits as well as inclusion of nonclinical outcomes such as hospital avoidance. Additionally, situations like the one modeled here, in which the time horizon is very short, complicate the use of outcomes like the QALY. Despite this understanding, the optimal choice of an outcome to model in persons with cancer remains incompletely understood (13). Last, the importance of patient-reported outcomes is rising. In the current case, the potential to avoid hospitalizations is likely to be important from the patient’s perspective. Although this trend does not change the conclusions Lathia et al.pe make regarding prophylactic use of filgastrim and pegfilgrastim, patient satisfaction, ability to function, and time preferences are likely to play an increasing role in future coverage and clinical use decisions.

The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin prevent transfusions among chemotherapy-associated anemia patients. Clinical trials, meta-analyses, and guidelines identify mortality, tumor progression, and venous thromboembolism (VTE) risks with ESA administration in this setting. Product labels advise against administering ESAs with potentially curative chemotherapy (United States) or to conduct risk–benefit assessments (Europe/Canada). Since 2007, fewer chemotherapy-associated anemia patients in the United States and Europe receive ESAs. ESAs and the erythropoietin receptor agonist peginesatide prevent transfusions among chronic kidney disease (CKD) patients; clinical trials, guidelines, and meta-analyses demonstrate myocardial infarction, stroke, VTE, or mortality risks with ESAs targeting high hemoglobin levels. U.S. labels recommend administering ESAs or peginesatide at doses sufficient to prevent transfusions among dialysis CKD patients. For dialysis CKD patients, Canadian and European labels recommend targeting hemoglobin levels of 10 to 12 g/dL and 11 to 12 g/dL, respectively, with ESAs. ESA utilization for dialysis CKD patients has decreased in the United States.

BACKGROUND: Historically, clinicians have demonstrated a lack of confidence and poor aptitude for biostatistics as a tool for medical literature interpretation. Evaluation of pharmacy residents' ability to interpret biostatistics commonly used in peer-reviewed literature has not been previously conducted. OBJECTIVE: To evaluate the level of understanding and perception of biostatistics concepts among pharmacy residents. METHODS: A survey of postgraduate year 1 (PGY1) residents in American Society of Health-System Pharmacists–accredited residency programs was conducted in May 2009. The survey instrument consisted of 27 items, including 10 knowledge-based questions, and was distributed to residency programs for anonymous reporting via SurveyMonkey. The primary outcome of interest was biostatistics knowledge, defined as the percent total score of correct knowledge items. Statistical attitude and confidence questions were rated on a 5-point Likert-type scale (1 = strongly disagree, 5 = strongly agree). The t-test or 1-way analysis of variance was conducted, as appropriate, to assess for differences in mean biostatistics knowledge scores by respondent characteristics. Forward stepwise regression was used to identify which characteristics were independently associated with biostatistics knowledge. RESULTS: A total of 214 PGY1 residents responded to the online survey assessment, and a subset of respondents (n = 166) answered 1 or more of the biostatistics knowledge questions. Of those who responded to at least 1 knowledge assessment, the overall mean (SD) biostatistics knowledge score was 47.3% (18.50%; range 0-90). Overall, respondents were predominantly female (74%) and younger than 30 years (81%). Residents scored highest in the recognition of the purpose of a double-blind study (92.6%; 95% CI 88.52 to 96.67), interpretation of relative risk (75.8%; 95% CI 69.02 to 82.57), and identification of the appropriate analytic method for a nominal variable (69.4%; 95% CI 62.16 to 76.59). Bivariate analyses showed that there were statistically significant mean differences in knowledge scores by attitude (p = 0.001) and confidence (p < 0.001). The multivariate model showed that above-average confidence ratings were associated with an absolute increase of 7.6% in biostatistics knowledge score (p < 0.019) compared to those whose confidence rating was at or below average. CONCLUSIONS: Overall, pharmacy residents' perception and understanding of biostatistics were poor in this assessment, which correlates with previous reports. Enhanced training in biostatistics and literature evaluation of both mentors and trainees should be incorporated in PharmD programs and residency training sites.

Anaphylactic reactions (ARs) have been frequently reported with taxanes. The authors' purpose was to summarize published case reports and describe ARs from taxanes reported to the Food and Drug Administration (FDA) with a focus on use of package insert-specified prophylactic premedications (PPMs).The authors searched PubMed for the relevant literature. The authors obtained cases of ARs reported to the FDA through 31 December 2009 using the drug names and preferred terms for ARs. The authors used χ² and Student's t-tests to compare ARs from paclitaxel and docetaxel. The authors compared mortality based on presence/absence of PPMs. For signal detection, the authors calculated empirical Bayes geometric mean (EBGM) values.There was one docetaxel and eight paclitaxel case report articles describing ARs. The authors found 290 and 683 FDA reports of ARs from docetaxel and paclitaxel, respectively. More docetaxel cases were associated with mortality (54 vs 29%, p0.001). When PPMs were administered, mortality occurred in more docetaxel cases (52 vs 18%, p0.001). EBGM signals were 1.74 for docetaxel and 2.50 for paclitaxel.Mortality was reported in more docetaxel ARs than paclitaxel. Documented use of PPMs did not significantly impact mortality from ARs with docetaxel, but was associated with significantly lower mortality from ARs with paclitaxel.

addresses equally important but different questions. What are theadverse effects of new anticancer drugs? Are more targeted drugsdistinctlydifferentfromothercancertherapieswithrespecttotoxici-ties? What is the financial burden associated with these toxicities?These therapies bring new therapeutic possibilities. However, highexpectations can be easily dampened by the occurrence of serious,frequent, or costly toxicities. As the authors opine, it is important toknowinadvancewhetherallocatingresourcestonewanticancerdrugsis reasonable in relation to other priorities and whether allocation ofresourcesisefficientandappropriate.The authors

P Brandon Bookstaver, April D Miller, Celeste N Rudisill, LeAnn B NorrisDepartment of Clinical Pharmacy and Outcomes Sciences, South Carolina College of Pharmacy, University of South Carolina Campus, Columbia, South Carolina, USAAbstract: This paper reviews the current data on the use of the first approved intravenous ibuprofen product for the management of post-operative pain and fever in the United States. The management of acute and post-operative pain and fever with nonsteroidal anti-inflammatory agents (NSAIDs) is well documented. A search in Medline and International Pharmaceutical Abstracts of articles until the end of November 2009 and references of all citations were conducted. Available manufacturer data on file were also analyzed for this report. Several randomized controlled studies have demonstrated the opioid-sparing and analgesic effects of 400 and 800 mg doses of intravenous ibuprofen in a series of post-operative patient populations. Two recent studies have also noted the improvement in fever curves in critically ill and burn patients. These data, along with pharmacokinetic and pharmacologic properties, are explored in this review, which addresses the clinical utility of a parenteral NSAID in a hospitalized patient for post-operative pain management and fever reduction. Further data on intravenous ibuprofen are needed to define long-term utilization, management of acute pain, and use in special populations.Keywords: ibuprofen, intravenous, injectable, nonsteroidal anti-inflammatory drug

Purpose. A case of toxicity encountered with low-dose methotrexate therapy is discussed. Summary. A 59-year-old African American woman receiving long-term therapy for psoriasis came to the hospital with painful ulcers, difficulty swallowing, cutaneous lesions, and acute renal failure. Her medical history included type 2 diabetes mellitus, hypertension, coronary artery disease, morbid obesity, and psoriasis. On admission, the patient looked ill and had a low-grade fever; maculopapular skin lesions; and bullae and vesicles in her mouth and on her hands, legs, groin, and buttocks. With the exception of carvedilol, all home medications, including methotrexate, were discontinued. A complete medication history revealed that the patient had been taking methotrexate 2.5 mg daily, instead of 2.5 mg three times weekly as prescribed. This error translated into an estimated cumulative dose of 360 mg, nearly twice the prescribed amount. There were no clinically significant drug–drug interactions noted among her prescribed medications; however, the patient did report increased ibuprofen use secondary to the painful ulcerations in the previous few months. Leucovorin 15 mg i.v. every six hours was initiated along with additional supportive care. Skin and mucosal lesions, as well as her pain, had dramatically improved on day 5 of hospitalization. The patient was discharged after a six-day hospitalization and was provided with leucovorin 15 mg orally ever day for seven additional days until rheumatology follow-up. The patient was instructed to avoid any future methotrexate therapy. Conclusion. A patient who erroneously took oral methotrexate daily rather than thrice weekly for psoriasis developed multiple manifestations of methotrexate toxicity.

e18033 Background: PML is a rare, fatal disease that results from reactivation of the JC virus during immunosuppressed states. Previously we reported that rituximab is associated with a 5-fold incr...

Background: PML is an often fatal demyelinating disease of the brain due to reactivation of latent JC polyoma virus. Rituximab is an anti-CD20 monoclonal antibody associated with PML, as outlined briefly in a revised Black Box warning in 2007 and a series of Dear Healthcare Professional Letters sent by the manufacturer between 2006 and 2008. In 2009, we described 57 HIV-negative patients who developed PML after rituximab treatment [Blood. 2009; 113(20):4834–40]. Since then, the use of rituximab has continued to increase as has awareness of this association. Methods: A Freedom of Information (FOI) Act request was submitted to the U.S. Food and Drug Administration (FDA) for reports of PML cases occurring in rituximab-treated patients. These reports were obtained from the FDA in September 2013, and by definition of the FOI request, were at least 6 months old at the time obtained. Of the 483 total reports received, 173 duplicate cases were identified based on similar dates, ages, and other clinical information, resulting in 310 unique cases. An additional 14 cases were added from our 2009 publication that were not included in the original 310 cases, totaling 324 unique cases. Our case definition included HIV-negative patients in whom rituximab was administered prior to the onset of PML symptoms, with PML confirmed via brain biopsy, autopsy, or having JC virus in cerebrospinal fluid (CSF) plus brain MRI findings of PML. Results: Of the 324 unique cases, there were 231 confirmed cases of rituximab-associated PML in HIV-negative patients, from 23 countries. The majority of excluded cases lacked the necessary details in the reports to confirm the diagnosis of PML. Among the confirmed cases, case mortality rate was 89.1%. PML diagnosis was made by brain MRI AND positive JC virus CSF PCR (67.5%), brain biopsy (34.6%), or autopsy (7.8%). Indications for rituximab use included non-Hodgkin lymphoma (58.8%), chronic lymphocytic leukemia (28.4%), rheumatoid arthritis (3.1%), systemic lupus erythematosus (2.6%), autoimmune hemolytic anemia/idiopathic thrombocytopenic purpura (2.6%), and other rheumatologic conditions (3.5%). The non-Hodgkin lymphomas were subdivided into follicular (13.5%), diffuse large B-cell (9.2%), unspecified non-Hodgkin (22.7%), mantle cell (7%), Waldenstrom (4.4%), and marginal zone (1.7%). Median age was 64.5 years (range 19-90), 53% female and 47% male, with 25 patients (10.8%) having undergone prior transplantation (12 autologous stem cell, 8 allogeneic stem cell, and 5 solid organ). The median number of rituximab doses received was 6 (range 1-24), with a median of 15 months (range 0.5-128) from first dose of rituximab to PML diagnosis, and median of 4 months (range 0-65) from last rituximab dose to PML. The median time from PML diagnosis to death was 2 months (range 0-14). It is noteworthy that of the cases diagnosed by brain biopsy or autopsy, 17 had a negative JC virus CSF PCR, and of the cases diagnosed with a positive JC virus CSF PCR, 8 had at least one negative test before the diagnosis was made. Less than 10 cases per year were diagnosed until 2006 when there were 22, peaking at 40 in 2010 (figure). Figure 1 Figure 1. Conclusions: PML continues to be increasingly reported by clinicians who administer rituximab with or without concomitant chemotherapy. The temporal increase in the number of reports suggests that either the incidence may be higher than initially thought or increased awareness has led to more reporting. Furthermore, the lower number of reports in 2012 likely illustrates the delay between incident cases, reporting, and availability through FOI requests. Our findings highlight the importance of detailed adverse event reporting (as is characteristic of SONAR) to enhance clinician awareness of rare but serious toxicities, as well as the need for faster public availability of adverse event reports. Disclosures Off Label Use: Rituximab is used for a variety of indications. Our abstract describes the indications with percentages that rituximab was used from our analysis. These FDA-approved indications include chronic lymphocytic leukemia, lymphomas as listed, and rheumatoid arthritis. Indications listed that are not FDA-approved (the minority) include systemic lupus erythematosus, autoimmune hemolytic anemia/idiopathic thrombocytopenic purpura, and other rheumatologic conditions.. Carson:Genentech: Consultancy, Honoraria, Speakers Bureau.

Gemtuzumab ozogamycin (GO) received initial approval in 2000 from the Food and Drug Administration (FDA) for patients age 60 and older suffering with relapsed acute myeloid leukemia. After 10 years of administering GO-containing combination chemotherapy regimens, the drug was voluntarily removed from the commercial market in 2010 amid reports of unexpected development of sinusoidal obstructive syndrome (SOS); which has the potential to be fatal. Four months after the initial approval for marketing in 2000, SONAR initiated an investigation of GO-associated SOS. SONAR reported an incidence rate of 38% among allogeneic stem-cell transplants and 16% among autologous stem-cell transplant (SCT) patients. Ultimately, there was an overall incidence rate of 3% when single-agent GO was administered as directed by the FDA. In 2007, as a result of the examination of the reports from clinical trials and observational studies; data mining of interim reports from the manufacturer’s Prospective Observational Registry and the FDA’s Adverse Event Reporting System was undertaken. In 2013, the pharmaceutical manufacturer reported results from its FDA-mandated prospective observational study. Major differences between the SONAR report and the mnaufacturer’s report include: timing of publication (2007 versus 2013); inclusion of information on allogeneic stem cell versus autologous stem cell transplantation prior to GO administration (in our reports only) and identification of risk factors associated with higher rates of SOS (SCT within 3 months of GO administration, off-label administration of high doses of GO, and concomitant administration of 6-TG in our analysis versus no identified risk factors in the manufacturer’s analysis). The incidence of SOS was 9.1% among 482 patients at 54 centers in the manufacturer’s registry. Table 1: Comparison of gemtuzumab ozogamycin (GO) safety reports analyses between SONAR and manufacturer SONAR Pharmaceutical Investigation # of pts who received GO 1071 482 # of pts with SOS 99 44 DATA METHODS # of centers involved 50 centers (US and UK) 54 centers (US only) Interim analysis Not done Yes (2002 and 2005) Concomitant chemo given 67% 41% # of pts with concomitant HCT 26% 0% % with prior alloSCT 2.6% Not reported % with prior autoSCT 3.9% Not reported % with prior HSCT 6.5% 18.3% % with subsequent alloSCT 1.2% 0% % with subsequent autoSCT 2.0% 0% Publication Date* 2007 2013 * Gemtuzumab ozogamycin voluntarily removed from market in 2010 by the pharmaceutical manufacturer Disclosures No relevant conflicts of interest to declare.

e19540 Background: Progressive multifocal leukoencephalopathy (PML) is a rare, fatal disease that results from activation of a highly prevalent, dormant JC virus during immunosuppressed states. Rit...

The Centers for Disease Control and Prevention recommends the use of hand sanitizers for all health care professionals before and following direct patient contact.[1][1] Alcohol-based sanitizers containing 60–95% ethyl or isopropyl alcohol are used in many health care institutions as a primary

5091 Background: Prostate cancer patients with locally advanced /metastatic disease have a poor prognosis and although hormonal therapy can induce long-term remission, development of hormone-resistant prostate cancer (HRPC) is inevitable. The goal of this study is to evaluate overall survival in HRPC patients with different transition of care in the Veterans Affairs (VA) system. We hypothesized that prostate cancer patients with late referral to medical oncologists were more likely to have decreased overall survival. Methods: This is a retrospective, observational analysis of patients enrolled in the Veterans Health Administration system from October 2003 to March 2011. Patients were followed from initial evaluation and treatment by urology until an endpoint of death or the end of the study period. VA patients with a diagnosis of HRPC were identified; prostate specific antigen (PSA), medical and pharmacy records were collected. HRPC was defined as PSA doubling after treatment with hormonal therapy. Transition of care was defined as two encounters with the medical oncology service and at least one encounter was a medical oncologist. Three cohorts were created: patients transitioned to oncology before HRPC, those transitioned to oncology after HRPC, and patients who were never transitioned to oncology. Primary outcome was overall survival (OS). The Charlson score was utilized for comorbidity assessment. Statistical analysis was conducted using chi square test for categorical variables. Results: Total number of patients evaluated was 8,281; 2,168 in transition before HRPC (tbHRPC) cohort, 2,052 in transition after HRPC (taHRPC), and 4,061 patients that never transitioned (tnHPRC). The mean ages for the respective cohorts were: 69.35, 69.69, and 71.64. The Charlson comorbidity scores were 3.79 (tbHRPC), 3.06 (taHRPC), and 3.14 (tnHRPC); p-values < 0.05. Mortality rates among the cohorts were 57% tbHRPC, 69% taHRPC, and 62% tnHRPC; p-values

Abstract 2752 Introduction: Progressive multifocal leukoencephalopathy (PML) is a rare but fatal disease that is the result of activation of a highly prevalent dormant JC virus during immunosuppressed states such as advanced HIV, malignancy or immune-modulating medications. Rituximab, an immunomodulator, has been approved for both Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). We previously reported 57-non-HIV patients developed PML after rituximab (1). This report identified the need for epidemiological cohort studies to further evaluate incidence rates and risk factors for PML by comparing Rituximab treated patients with suitable non-treated patients. Of note, natilzumab-associated PML is now well-characterized, with a reported incidence of 21 PML cases per 10,000 natilizumab-treated persons (2). Methods: In this first such epidemiological study we identified from the national data of the Department of Veteran's Affairs (VA), 61,132 patients with a primary International Classification of Diseases version 9 (ICD-9) code for either HL or NHL between 1999 to 2011 and reported the use of Rituximab among patients with and without PML. This project was conducted inside the Veterans Affairs Informatics and Computing Infrastructure (VINCI) after obtaining approvals from the VA Institutional Review Board and other oversight groups. Results: We identified 62,642 with a primary diagnosis of HL or NHL and excluded 1,510 (2.4%) patients with VA lab confirmed HIV. Our final cohort had 61,132 patients, 10,459 (17.1%) received Rituximab. A total of 12 (0.020%) patients had developed PML, 5 (0.008%) belonged to the Rituximab group and 7 (0.011%) to non-rituximab group; which results in a statistically significant unadjusted relative risk of 3.46 (95% confidence interval 1.1, 10.9). Univariate analyses of outcomes other than rate-estimates are not statistically significant between PML patients who received rituximab and those that did not receive rituximab, primarily due to extremely small sample sizes (5 and 7 patients, respectively) (Table 1). Overall, compared to non-rituximab PML patients, rituximab PML patients were younger at PML diagnosis and age of death by more than 6-years; although they did appear to live slightly longer post PML diagnosis by about 4-months. Conclusions: These results show that among lymphoma patients, the use of Rituximab is associated with a statistically significant relative risk for documented PML of 3.46. We now report a baseline rate among Veterans of 4.78 PML cases per 10,000 rituximab treated Veterans with lymphoma (25% of the rate reported among natilizumab-treated multiple sclerosis patients). As with hepatitis B, measurement of JC virus might be considered prior to initiation of rituximab therapy. Acknowledgment: This project was supported through the resources of the Wiliam JB Dorn Veterans Affairs Medical Center. Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. Disclosures: No relevant conflicts of interest to declare.

9143 Background: Benefits of ESAs in the treatment of cancer-induced anemia have been well documented, most importantly reducing the likelihood of patients needing red blood cell transfusions. However, in early 2007, the FDA issued a series of cautions and Black Box Warning (BBW), that ESAs may enhance tumor progression, increase likelihood of a VTE and decrease patient survival. The objective of this study is to elucidate population patterns and trends in ESA use for cancer patients pre- and post- the BBW and examine their associated outcomes. Methods: Data for this analysis was derived from South Carolina Medicaid claims. Patients with a diagnosis of Lung Cancer (162.x), Breast Cancer (174.x) or Non-Hodgkin's Lymphoma (200.x or 202.x) receiving chemotherapy between January 1, 1994 and December 31, 2010 were eligible for inclusion. The main outcome measures were ESA utilization, blood transfusion, and venous thromboembolism. The percentage of patients experiencing these outcomes were plotted over time to allow for visual examination of changes due to the BBW. In addition, we used multivariable logistic regression models to analyze each of the associated outcomes with clinical and demographic variables. Results: Among the 9,280 patients with one of the study cancers, an average of 25.4% received an ESA. The proportion of patients receiving an ESA increased from 6.2% in 1994 to a high of 47.1% in 2005 at which time utilization began to decline. In 2010, only 7.8% of these patients received an ESA. Use was associated with older age, female sex, and receipt of radiation therapy. The rate of blood transfusion varied sporadically throughout the study period from 5.2% (2008) to 11.7% (1994) (p

Abstract 4756 Introduction: SONAR, the only state-funded (South Carolina) pharmacovigilance initiative in the nation, focuses on identifying near fatal side effects of hematology and oncology therapeutics. Most safety findings are like “trees falling in the forest” – with no one hearing the noise. Our objective was to describe the outcomes from the findings of the pharmacovigilance efforts from the SONAR group. Methods: SONAR investigators reviewed practice and policy outcomes to our identification of adverse drug reactions with hematologic implications. Data sources used were PubMed, the Food and Drud Administration (FDA) files, and the Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). Results: Drug SONAR finding Confirmation Peak at risk per year #pts/deaths % of ADR reports in the FDA database FDA Response Market Action Gemtuzumab for AML patients Sinusoidal-obstructive syndrome- Leukemia Research 2007 Biopsy findings 50,000 93/67 100% Black Box Drug Withdrawn Ticlopidine, clopidogrel, prasugrel (antiplatelet agents) Thrombotic Thrombocytopenic Purpura (TTP)- NEJM 2000, Lancet 1998, JAMA 1998 Antibodies Ticlopidine 1 million, Clopidogrel 5 million Ticlopidine 60/20, clopidogrel 37/5, prasugrel 9/0 60%, 90%, and 100% respectively Black Box, Warnings Ticlopidine market sales Rituximab- for lymphoma treatment PML- Blood 2009 Warnings None Nevirapine for post-HIV-exposure following exposure to blood products Fulminant hepatitis in HCWs following needle-stick- Ann of Int Med 2002 Biopsy findings 30/0 20% Dear Doctor Drug not used in this setting. CD4 thresholds added for use among HIV-infected individuals. Thalidomide, lenalidomide for multiple myeloma patients Venous thromboembolism (VTE)- JAMA 2006 17,000 96/12 71% Warning, Dear Dr VTE prophylaxis is now routine – based on survey data Voriconazole for anti-fungal prophylaxis Breakthrough Zygomycoses following stem cell transplantation for hematologic malignancies - BMT 2007 Label change None Eprex-formulation of Epoetin Pure red cell aplasia- NEJM 2000 Neutralizing antibodies 208/0 100% Warning, Dear Dr SQ use discontinued Epoetin, darbepoetin- cancer pts Mortality, tumor progression- JAMA 2008 Black Box, warning Marked decrease in ESA use- based on survey data Megakaryocyte growth and development factor administration to healthy volunteers Lymphoid malignancies - B J of Haematology 2006 13/0 0% None Drug development discontinued Granulocyte colony-stimulating factor treated cancer patients Leukemia/MDS - JNCI 2008, B J Haematol 2006 None None Gemcitabine Pneumonitis 150/52 100% Label change CYPHER stents for coronary artery disease Hypersensitivity at the stent site Autopsy findings 1 million 12/2 43% Dear Doctor Enoxaparin – following coronary artery stent procedures Severe hemorrhage and pseudoaneurysm formation Known toxicity 5/0 0% None Conclusions: Most SONAR findings have been followed by FDA notifications and market responses. Identifying and reporting sADRs can have marked beneficial effects on medical care. Disclosures: No relevant conflicts of interest to declare.

Abstract 4753 Background: Erythropoiesis stimulating agents (ESAs) are approved for preventing transfusions (United States (US)) or treating symptomatic anemia (Canada/Europe) among chemotherapy or chronic kidney disease (CKD) patients. Extensive reassessments of safety, efficacy, dosing, and target hemoglobin levels have occurred. Methods: Regulatory agencies', ESA manufacturer notifications, clinical guidelines, phase III trials and meta-analyses cited in clinical guidelines were reviewed (2007 to 2011). Results: CKD and Cancer: Quality of life benefits are reported in Europe and Canada. In the US, product labels report exercise capacity improvements for CKD patients. CKD: Clinical trials reported cardiovascular, cerebrovascular, and mortality risks with ESAs targeting high versus low hemoglobin levels or cardiovascular and mortality risks with ESAs versus placebo. 2011 US' advisories recommend ESA doses sufficient to prevent transfusions among dialysis patients and caution with ESA administration to non-dialysis patients. Canadian and European recommendations target hemoglobin levels between 10 and 12 g/dl and 11 to 12 g/dl, respectively. Following these recommendations among non-dialysis US patients, ESA use decreased 16%. Most US dialysis CKD patients receive ESAs, with lower achieved hemoglobin levels, and 30% decreased ESA usage since 2008. In Europe and Canada, which initially had substantially lower ESA use, there has been a gradual increase. Cancer: Trials identified mortality, tumor progression, and venous thromboembolism risks with ESAs targeting higher versus lower hemoglobin levels. US labels warn against administering ESAs with potentially curative chemotherapy. European guidelines recommend ESAs for symptomatic patients at hemoglobin levels of 9 to 11 g/dL and consider for asymptomatic patients at levels of 11 to 11.9 g/dL. Canadian advisories report cost-utility ratios exceeding accepted standards. ESA use decreased by 70% in the US. Current ESA utilization rates for cancer are higher in Europe and lower in Canada. Conclusions: International differences in interpreting efficacy and safety data and ESA utilization exist. The changes have been most apparent in the US. Disclosures: No relevant conflicts of interest to declare.