Risk of anaphylaxis with repeated courses of rasburicase: a Research on Adverse Drug Events and Reports (RADAR) project.

BACKGROUND: Rasburicase, a recombinant urate oxidase, is used to rapidly metabolize uric acid in patients with hyperuricaemia. Rasburicase is an immunogenic therapeutic protein, which has been shown to elicit antibody response in 64 % of healthy volunteers within 1-6 weeks after the initial course, with persistent antibodies for over 1 year. Drug labelling indicates that anaphylaxis rarely occurs (in <1 % of patients) after a single course of therapy with rasburicase, but there are no data available on the incidence of anaphylaxis in patients receiving a subsequent rasburicase course. OBJECTIVE: The objective of this study was to determine the incidence of anaphylaxis after multiple treatment courses of rasburicase. METHODS: A retrospective chart review was performed on 97 consecutively treated patients who received repeated courses of rasburicase for hyperuricaemia. RESULTS: None of the 97 patients who were reviewed experienced anaphylaxis during the first rasburicase course; however, six patients (6.2 %) experienced anaphylaxis during a subsequent rasburicase treatment course (p = 0.03). CONCLUSION: Anaphylaxis after a second course of rasburicase appears to occur more frequently than described in the US Food and Drug Administration-approved package insert for initial treatment courses. Given the serious nature of anaphylactic events, caution is advised when administering repeated courses of rasburicase.

Economics of Malignant Gliomas: A Critical Review.

PURPOSE: Approximately 18,500 persons are diagnosed with malignant glioma in the United States annually. Few studies have investigated the comprehensive economic costs. We reviewed the literature to examine costs to patients with malignant glioma and their families, payers, and society. METHODS: A total of 18 fully extracted studies were included. Data were collected on direct and indirect costs, and cost estimates were converted to US dollars using the conversion rate calculated from the study's publication date, and updated to 2011 values after adjustment for inflation. A standardized data abstraction form was used. Data were extracted by one reviewer and checked by another. RESULTS: Before approval of effective chemotherapeutic agents for malignant gliomas, estimated total direct medical costs in the United States for surgery and radiation therapy per patient ranged from $50,600 to $92,700. The addition of temozolomide (TMZ) and bevacizumab to glioblastoma treatment regimens has resulted in increased overall costs for glioma care. Although health care costs are now less front-loaded, they have increased over the course of illness. Analysis using a willingness-to-pay threshold of $50,000 per quality-adjusted life-year suggests that the benefits of TMZ fall on the edge of acceptable therapies. Furthermore, indirect medical costs, such as productivity losses, are not trivial. CONCLUSION: With increased chemotherapy use for malignant glioma, the paradigm for treatment and associated out-of-pocket and total medical costs continue to evolve. Larger out-of-pocket costs may influence the choice of chemotherapeutic agents, the economic implications of which should be evaluated prospectively.

Acute kidney injury and bisphosphonate use in cancer: a report from the research on adverse drug events and reports (RADAR) project.

PURPOSE: To determine whether acute kidney injury (AKI) is identified within the US Food and Drug Administration's Adverse Events and Reporting System (FDA AERS) as an adverse event resulting from bisphosphonate (BP) use in cancer therapy. METHODS: A search of the FDA AERS records from January 1998 through June 2009 was performed; search terms were "renal problems" and all drug names for BPs. The search resulted in 2,091 reports. We analyzed for signals of disproportional association by calculating the proportional reporting ratio for zoledronic acid (ZOL) and pamidronate. Literature review of BP-associated renal injury within the cancer setting was conducted. RESULTS: Four hundred eighty cases of BP-associated acute kidney injury (AKI) were identified in patients with cancer. Two hundred ninety-eight patients (56%) were female; mean age was 66 ± 10 years. Multiple myeloma (n = 220, 46%), breast cancer (n = 98, 20%), and prostate cancer (n = 24, 5%) were identified. Agents included ZOL (n = 411, 87.5%), pamidronate (n = 8, 17%), and alendronate (n = 36, 2%). Outcomes included hospitalization (n = 304, 63.3%) and death (n = 68, 14%). The proportional reporting ratio for ZOL was 1.22 (95% CI, 1.13 to 1.32) and for pamidronate was 1.55 (95% CI, 1.25 to 1.65), reflecting a nonsignificant safety signal for both drugs. CONCLUSION: AKI was identified in BP cancer clinical trials, although a safety signal for BPs and AKI within the FDA AERS was not detected. Our findings may be attributed, in part, to clinicians who believe that AKI occurs infrequently; ascribe the AKI to underlying premorbid disease, therapy, or cancer progression; or consider that AKI is a known adverse drug reaction of BPs and thus under-report AKI to the AERS.

Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed contributing to early hemorrhagic death.

We hypothesized that the high early death rate (EDR) due to bleeding in acute promyelocytic leukemia (APL) is in part attributable to delays in all- trans retinoic acid (ATRA). We conducted a retrospective analysis of the timing of ATRA administration. 204 consecutive patients with newly diagnosed APL between 1992 and 2009 were identified. The EDR was 11%. 44% of early deaths occurred in the first week. Hemorrhage accounted for 61% of early deaths. ATRA was ordered the day APL was suspected in 31% of patients. Delays in ATRA administration led to increases in the percentage of early deaths from hemorrhage.

Results from the first decade of research conducted by the Research on Adverse Drug Events and Reports (RADAR) project.

INTRODUCTION: In 1998, a multidisciplinary team of investigators initiated the Research on Adverse Drug events And Reports (RADAR) project, a post-marketing surveillance effort that systematically investigates and disseminates information describing serious and previously unrecognized serious adverse drug and device reactions (sADRs). OBJECTIVE: Herein, we describe the findings, dissemination efforts, and lessons learned from the first decade of the RADAR project. METHODS: After identifying serious and unexpected clinical events suitable for further investigation, RADAR collaborators derived case information from physician queries, published and unpublished clinical trials, case reports, US FDA databases and manufacturer sales figures. STUDY SELECTION: All major RADAR publications from 1998 to the present are included in this analysis. DATA EXTRACTION: For each RADAR publication, data were abstracted on data source, correlative basic science findings, dissemination and resultant safety information. RESULTS: RADAR investigators reported 43 serious ADRs. Data sources included case reports (17 sADRs), registries (5 sADRs), referral centers (8 sADRs) and clinical trial reports (13 sADRs). Correlative basic science findings were reported for ten sADRs. Thirty-seven sADRS were described as published case reports (5 sADRs) or published case-series (32 sADRs). Related safety information was disseminated as warnings or boxed warnings in the package insert (17 sADRs) and/or 'Dear Healthcare Professional' letters (14 sADRs). CONCLUSION: An independent National Institutes of Health-funded post-marketing surveillance programme can supplement existing regulatory and pharmaceutical manufacturer-supported drug safety initiatives.

Impact of United States Food and Drug Administration's boxed warnings on adverse drug reactions reporting rates and risk mitigation for multiple myeloma drugs.

PURPOSE: To determine the relationship between boxed warnings issuance by the US Food and Drug Administration (FDA) and the proportional reporting rates of the associated adverse drug reactions (ADRs) to the FDA's Adverse Event Reporting System (FAERS) for multiple myeloma (MM) drugs. METHODS: We compiled a list of all FDA approved MM drugs and identified their associated ADR boxed warnings, through FDA's website and physician desk reference. Drugs that were issued boxed warnings after their market launch were included in the analysis, i.e., melphalan, thalidomide, vincristine, carmustine and doxorubicin. For each drug/ADR boxed warning combination, we retrieved all reported cases from the FAERS and calculated their Empiric Bayes Geometric Means (EBGMs), in pre- and post-boxed warning periods. Chi-square tests were performed to compare serious adverse drug events before and after boxed warnings for all drug/ADR combinations. RESULTS: A total of 10 drug/ADR boxed warning combinations were identified, of which EBGM signals increased for six combinations after a boxed warning was issued. Reports of serious adverse drug events also increased significantly (p < 0.05). CONCLUSION: Boxed warnings were associated with increased FAERS reporting, indicating increased awareness of ADRs for MM drugs. Proactive pharmacovigilance programs, such as the FDA's Mini-Sentinel Project, may improve timeliness of detection of rare ADRs.

Variability of cyclosporine concentrations by HPLC and TDX monoclonal assay methods, application of a correction factor, and description of a novel clinical approach to determine the practical consequences of changing assay technique.

Cyclosporine (CSA) is an immunosuppressant used for the prevention of graft rejection and graft-versus-host disease (GVHD) during hematopoietic stem cell transplantation. Therapeutic drug monitoring (TDM) is recommended to ensure efficacy and prevent toxicity. Several immunoassay assay are commercially available for measuring CSA drug concentrations. Differences in the cross-reactive metabolites measured by specific immunoassay tests contribute to the significant lack of specificity which has been reported between immunoassays and high performance liquid chromatography (HPLC) test results. Inter-assay test results can affect interpretation of CSA drug concentrations and potentially compromise patient outcomes. The current study analyzed 72 paired HPLC-monoclonal TDX (TDXm) CSA drug concentrations and calculated a clinically reliable correction factor which could be applied to HPLC-TDXm results for TDM. A unique concordance-discordance simulation model was utilized to validate the correction factor for clinical use.

Changing epidemiology of Clostridium difficile-associated disease during stem cell transplantation.

The incidence and severity of Clostridium difficile-associated disease (CDAD) within the general population has risen dramatically over the past decade, yet little data are available from hematopoietic stem cell transplantation (HSCT) centers. In the present study, we performed a chart review of 822 consecutive autologous and allogeneic HCST recipients treated at Northwestern Memorial Hospital between 2004 and 2008 to determine the incidence of CDAD at our institution. Variables including age, sex, diagnosis, chemotherapy regimen, transplantation type, microbial colonization, coinfections, diet, antibiotic use, neutropenic fever, comorbid conditions, time to engraftment, growth factor administration, and occurrence of graft-versus-host disease were assessed as potential risk factors for the development of CDAD. Eighty-five CDAD cases (10.3%) were identified. Bivariate analysis revealed a significant association between CDAD and neutropenic fever, administration of a neutropenic diet, ciprofloxacin and aztreonam use and duration of therapy, vancomycin and aztreonam use and duration of therapy, receipt of an allogeneic transplantation, bacterial coinfection, and vancomycin-resistant Entereococcus faecium (VRE) colonization. Cox regression analysis identified the following as factors associated with the development of CDAD: age >60 years, allogeneic transplantation, and prior VRE colonization. Allogeneic recipients with CDAD experienced increased higher rates of grades II to IV gastrointestinal graft-versus-host disease and nonrelapse mortality. A risk stratification model was developed to identify HSCT recipients at different levels of risk. With an incidence >10%, CDAD is a significant infectious complication of stem cell transplantation.

Mitoxantrone and etoposide with or without intermediate dose cytarabine for the treatment of primary induction failure or relapsed acute myeloid leukemia.

Mitoxantrone and etoposide (ME) salvage regimens have been successfully used for the treatment of primary induction failure or relapsed acute myeloid leukemia (AML). Whether the addition of intermediate dose cytarabine to ME increases complete remissions is unknown. To date, these regimens have not been directly compared. Herein, we report the response to treatment with a fixed dosing schedule of ME or MEC in 65 patients treated for primary refractory or relapsed AML with intermediate or unfavorable risk cytogenetics. Differences in CR between ME and MEC subsets were analyzed to determine the effect of cytarabine to ME.

Serial plasma voriconazole concentrations after allogeneic hematopoietic stem cell transplantation.

Plasma voriconazole concentrations vary considerably between patients receiving standard dosing, and trough voriconazole concentrations are known to affect efficacy and toxicity. Temporal variations in serial plasma voriconazole concentrations through the course of therapy in hematopoietic stem cell transplantation patients has not been carefully described. Paired voriconazole concentrations in 64 patients were studied to determine the predictability of the second concentration based on the first. The difference between the two values was < or = 5% in six patients. In 25 patients, the second concentration was higher by a median of 40%. In 33 patients, the subsequent concentration was lower by a median of 59%. For patients with an initial concentration of < 2 microg/ml, the correlation between the two values was poor (r = 0.24; P < 0.17). For those with an initial concentration of > or = 2 microg/ml, the correlation was good (r = 0.72; P < 0.0001). There was no relationship between the magnitude of the change and the time elapsing between the two measurements. Among the 43 patients who had an initial concentration of > or = 1 microg/ml, the two voriconazole measurements were strongly correlated (r = 0.66, P < 0.0001), but only 67% had a voriconazole serum concentration of > or = 1 microg/ml on the second measurement. No studied variables were reliable predictors in identifying concentrations above or below 1 or 2 microg/ml. Our data suggest that variations in voriconazole concentrations are unpredictable despite standard dosing, and the acceptability of a concentration on one occasion cannot be extrapolated to future concentrations in the same patient. This suggests that ongoing therapeutic drug monitoring and dose adjustment may be beneficial in patients requiring prolonged voriconazole therapy.

Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia.

CONTEXT: The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin are licensed to treat chemotherapy-associated anemia in patients with nonmyeloid malignancies. Although systematic overviews of trials have identified venous thromboembolism (VTE) risks, none have identified mortality risks with ESAs. OBJECTIVE: To evaluate VTE and mortality rates associated with ESA administration for the treatment of anemia among patients with cancer. DATA SOURCES: A published overview from the Cochrane Collaboration (search dates: January 1, 1985-April 1, 2005) and MEDLINE and EMBASE databases (key words: clinical trial, erythropoietin, darbepoetin, and oncology), the public Web site of the US Food and Drug Administration and ESA manufacturers, and safety advisories (search dates: April 1, 2005-January 17, 2008). STUDY SELECTION: Phase 3 trials comparing ESAs with placebo or standard of care for the treatment of anemia among patients with cancer. DATA EXTRACTION: Mortality rates, VTE rates, and 95% confidence intervals (CIs) were extracted by 3 reviewers from 51 clinical trials with 13 611 patients that included survival information and 38 clinical trials with 8172 patients that included information on VTE. DATA SYNTHESIS: Patients with cancer who received ESAs had increased VTE risks (334 VTE events among 4610 patients treated with ESA vs 173 VTE events among 3562 control patients; 7.5% vs 4.9%; relative risk, 1.57; 95% CI, 1.31-1.87) and increased mortality risks (hazard ratio, 1.10; 95% CI, 1.01-1.20). CONCLUSIONS: Erythropoiesis-stimulating agent administration to patients with cancer is associated with increased risks of VTE and mortality. Our findings, in conjunction with basic science studies on erythropoietin and erythropoietin receptors in solid cancers, raise concern about the safety of ESA administration to patients with cancer.

Cancer-associated neutropenic fever: clinical outcome and economic costs of emergency department care.

Purpose. Febrile neutropenia (FN) is a common, costly, and potentially fatal complication in oncology. While FN in the inpatient setting has been extensively studied, only one study has evaluated emergency department (ED) care for FN cancer patients. That study found that 96% of patients survived the complication. We evaluated clinical and economic outcomes for cancer patients with chemotherapy-associated FN treated in an ED. Methods. ED records for consecutive oncology patients with FN were reviewed for information on death, intensive care unit (ICU) use, blood cultures, and costs. Results. Forty-eight patients (n = 57 visits) were evaluated. Six patients died from FN (12%) and four received ICU care within 2 weeks and survived (8%). Blood cultures were positive for 37% of the ED visits. The median ED time was 3.3 hours. In 91% of visits, i.v. antibiotics were administered in the ED, ordered at a median of 1.7 hours from triage (interquartile range [IQR], 1.2-2.8 hours). All patients with death or ICU in 2 weeks and all but one patient with positive blood cultures received antibiotics. The median per patient ED costs were $1,455 (IQR, $1,300-$1,579)-42.4% for hospital/nursing, 23.5% for radiology, 20.8% for physician services, 10.9% for diagnostic tests, and 2.4% for antibiotics. Conclusions. Cancer patients with FN in this sample presenting to the ED frequently had no identified source of infection. One third of the patients had positive ED blood cultures and one fifth died or required ICU care within 2 weeks. Costs of ED care were similar to the cost of a single day of inpatient care. Disclosure of potential conflicts of interest is found at the end of this article.

Evaluation of serious adverse drug reactions: a proactive pharmacovigilance program (RADAR) vs safety activities conducted by the Food and Drug Administration and pharmaceutical manufacturers.

BACKGROUND: The Food and Drug Administration (FDA) and pharmaceutical manufacturers conduct most postmarketing pharmaceutical safety investigations. These efforts are frequently based on data mining of databases. In 1998, investigators initiated the Research on Adverse Drug events And Reports (RADAR) project to investigate reports of serious adverse drug reactions (ADRs) and prospectively obtain information on these cases. We compare safety efforts for evaluating serious ADRs conducted by the FDA and pharmaceutical manufacturers vs the RADAR project. METHODS: We evaluated the completeness of serious ADR descriptions in the FDA and RADAR databases and the comprehensiveness of notifications disseminated by pharmaceutical manufacturers and the RADAR investigators. A serious ADR was defined as an event that led to death or required intensive therapies to reverse. RESULTS: The RADAR investigators evaluated 16 serious ADRs. Compared with descriptions of these ADRs in FDA databases (2296 reports), reports in RADAR databases (472 reports) had a 2-fold higher rate of including information on history and physical examination (92% vs 45%; P<.001) and a 9-fold higher rate of including basic science findings (34% vs 4%; P = .08). Safety notifications were disseminated earlier by pharmaceutical suppliers (2 vs 4 years after approval, respectively), although notifications were less likely to include information on incidence (46% vs 93%; P = .02), outcomes (8% vs 100%; P<.001), treatment or prophylaxis (25% vs 93%; P<.001), or references (8% vs 80%; P<.001). CONCLUSION: Proactive safety efforts conducted by the RADAR investigators are more comprehensive than those conducted by the FDA and pharmaceutical manufacturers, but dissemination of related safety notifications is less timely.

Haematological malignancies developing in previously healthy individuals who received haematopoietic growth factors: report from the Research on Adverse Drug Events and Reports (RADAR) project.

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) and granulocyte colony-stimulating factor (G-CSF) promote haematopoietic progenitor cell maturation. We reviewed the findings for healthy volunteers/donors who developed haematological malignancies following PEG-rHuMGDF or G-CSF administration. Information was reviewed for three of 538 volunteers who received PEG-rHuMGDF in clinical trials and two of 200 donors who underwent G-CSF mobilised stem cell harvesting procedures for sibling stem cell transplants. Mantle cell, diffuse large B-cell lymphoma and chronic lymphocytic leukaemia were diagnosed 1-5 years after PEG-rHuMGDF exposure among three volunteers. For one patient, thrombocytopenia due to autoantibodies to PEG-rHuMGDF developed shortly after PEG-rHuMGDF administration and persisted until chemotherapy was administered. All three achieved complete remission, although one patient relapsed. Acute myeloid leukaemia was diagnosed 4 and 5 years after G-CSF mobilisation in two donors who underwent peripheral blood stem cell donation for sibling allogeneic haematopoietic stem cell transplantation. Following intensive chemotherapy, one died from acute leukaemia and the second is in complete remission. Controversy exists over the appropriateness of administering haematopoietic growth factors to healthy individuals. While a causal relationship with haematological malignancies cannot be demonstrated, long-term follow-up among healthy individuals who receive haematopoietic growth factors is needed.

Long-term outcome of individuals with pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant epoetin: a follow-up report from the Research on Adverse Drug Events and Reports (RADAR) Project.

Since its introduction in 1988, recombinant human erythropoietin (epoetin) has been standard treatment for patients with anemia due to chronic kidney disease. From 1998 to 2004, nearly 200 epoetin-treated persons with chronic kidney disease developed antibodies to epoetin, resulting in pure red cell aplasia (PRCA). The majority of these patients received Eprex, an epoetin alfa product marketed exclusively outside the United States. Herein, we report on the long-term outcome of these individuals. For 170 chronic kidney disease patients who developed epoetin-associated PRCA and had 3 months or more follow-up information available, case reports from the Food and Drug Administration and epoetin manufacturers were reviewed for information on clinical characteristics of the patients, immunosuppressive treatments, epoetin responsiveness, and hematologic recovery. Overall, 64% of the PRCA patients received immunosuppressive therapy, including 19 who also underwent a renal transplantation. Thirty-seven percent experienced a hematologic recovery, with higher hematologic recovery rates among PRCA patients who received immunosuppressive therapy (57% vs 2%, P < .001). Among 34 patients who received epoetin after the onset of PRCA, 56% regained epoetin responsiveness. The highest rates of epoetin responsiveness were observed among persons whose antierythropoietin antibodies were undetectable when epoetin was administered (89%). Among chronic kidney disease patients with epoetin-associated PRCA, epoetin discontinuation and immunosuppressive therapy or renal transplantation is necessary for hematologic recovery. Reinitiation of epoetin therapy among individuals could be considered if antierythropoietin antibodies are undetectable.

The Research on Adverse Drug Events and Reports (RADAR) project.

CONTEXT: In 1998, a multidisciplinary team of investigators initiated RADAR (Research on Adverse Drug events And Reports), a clinically based postmarketing surveillance program that systematically investigates and disseminates information describing serious and previously unrecognized adverse drug and device reactions (ADRs). OBJECTIVE: To describe the structure, operations, and preliminary findings from the RADAR project and related dissemination efforts by pharmaceutical suppliers and the US Food and Drug Administration (FDA). DESIGN: After identifying a serious and unexpected clinical event suitable for further investigation, RADAR collaborators postulated clinical hypotheses and derived case series and incidence estimates from physician queries, published and unpublished clinical trials, published case reports, FDA databases, and manufacturer sales figures. RESULTS: RADAR investigators identified 16 types of serious ADRs among 1699 patients, of whom 169 (10%) died as a result of the reaction. Initial cases were identified by 7 RADAR investigators, 4 collaborating physicians, 2 attorneys, and by reviewing 3 published reports. Additional sources included queries of occupational health programs and medical directors of interventional cardiology laboratories (3 types of ADRs), published manuscripts and clinical trials (11 types of ADRs), review of medical records at a RADAR site (2 types of ADRs), unpublished clinical trial reports (3 types of ADRs), and reports from attorneys, family members, or patients (4 types of ADRs). Incidence estimates, ranging from 0.4% to 33%, were derived from 5 clinical trial reports, 2 physician queries, and 2 observational databases. Laboratory support for hypotheses included identification of 3 neutralizing antibodies and 3 histopathological findings. ADR reports were disseminated as 8 revised package inserts, 7 "dear doctor" letters, and 9 peer-reviewed articles. CONCLUSION: A new, clinically based, hypothesis-driven approach to postmarketing surveillance may supplement existing regulatory surveillance systems and improve patient safety.