Southern Network On Adverse Reactions Research Articles

Systemic Barriers and Potential Concerns from Reporting Serious Adverse Drug Reactions.

About 1-10% of all serious adverse drug reactions (sADRs) are reported to the Food and Drug Administration (FDA) ( Moore T, Bennett C. Underreporting of Hemorrhagic and Thrombotic Complications of Pharmaceuticals to the U.S. Food and Drug Administration: Empirical Findings for Warfarin, Clopidogrel, Ticlopidine, and Thalidomide from the Southern Network on Adverse Reactions (SONAR). Semin Thromb Hemost. 2012;38(08):905-907. https://doi.org/10.1055/s-0032-1328890 ). Prevailing opinion suggests that low reporting rates reflect time constraints.

Consequences to Patients, Clinicians, and Manufacturers When Very Serious Adverse Drug Reactions Are Identified (1997-2019): A Qualitative Analysis from the Southern Network on Adverse Reactions (SONAR).

Adverse drug/device reactions (ADRs) serious enough to lead to box warnings on drug labels or drug withdrawals occur in about one fifth of all new molecular entities.

Consequences to patients, clinicians, and manufacturers when very serious adverse drug reactions are identified (1997-2019): A qualitative analysis from the Southern Network on Adverse Reactions (SONAR).

BackgroundAdverse drug/device reactions (ADRs) can result in severe patient harm. We define very serious ADRs as being associated with severe toxicity, as measured on the Common Toxicity Criteria Adverse Events (CTCAE)) scale, following use of drugs or devices with large sales, large financial settlements, and large numbers of injured persons. We report on impacts on patients, clinicians, and manufacturers following very serious ADR reporting.MethodsWe reviewed clinician identified very serious ADRs published between 1997 and 2019. Drugs and devices associated with reports of very serious ADRs were identified. Included drugs or devices had market removal discussed at Food and Drug Advisory (FDA) Advisory Committee meetings, were published by clinicians, had sales > $1 billion, were associated with CTCAE Grade 4 or 5 toxicity effects, and had either >$1 billion in settlements or >1,000 injured patients. Data sources included journals, Congressional transcripts, and news reports. We reviewed data on: 1) timing of ADR reports, Boxed warnings, and product withdrawals, and 2) patient, clinician, and manufacturer impacts. Binomial analysis was used to compare sales pre- and post-FDA Advisory Committee meetings.FindingsTwenty very serious ADRs involved fifteen drugs and one device. Legal settlements totaled $38.4 billion for 753,900 injured persons. Eleven of 18 clinicians (61%) reported harms, including verbal threats from manufacturer (five) and loss of a faculty position (one). Annual sales decreased 94% from $29.1 billion pre-FDA meeting to $4.9 billion afterwards (p<0.0018). Manufacturers of four drugs paid $1.7 billion total in criminal fines for failing to inform the FDA and physicians about very serious ADRs. Following FDA approval, the median time to ADR reporting was 7.5 years (Interquartile range 3,13 years). Twelve drugs received Box warnings and one drug received a warning (median, 7.5 years following ADR reporting (IQR 5,11 years). Six drugs and 1 device were withdrawn from marketing (median, 5 years after ADR reporting (IQR 4,6 years)).InterpretationBecause very serious ADRs impacts are so large, policy makers should consider developing independently funded pharmacovigilance centers of excellence to assist with clinician investigations.FundingThis work received support from the National Cancer Institute (1R01 CA102713 (CLB), https://www.nih.gov/about-nih/what-we-do/nih-almanac/national-cancer-institute-nci; and two Pilot Project grants from the American Cancer Society's Institutional Grant Award to the University of South Carolina (IRG-13–043–01) https://www.cancer.org/ (SH; BS).

Consequences to Patients, Clinicians, and Manufacturers When Titanic Adverse Drug Reactions are Identified (1997- 2019): A Report from the Southern Network on Adverse Reactions (SONAR)

Introduction: Adverse drug/device reactions (ADRs) can result in severe patient harm. We operationally define titanic ADRs as Common Toxicity Criteria Adverse Events grade 4 or 5 that follow use of drugs or devices that have large sales, large safety financial settlements, and affect large numbers of persons. We report on the impact of titanic ADRs identified between 1997 and 2019. Methods: We reviewed clinician reported titanic ADRs. Data sources included Food and Drug Advisory (FDA) Advisory Committee transcripts, news reports, and medical journals. We reviewed data on timing of titanic ADR reports, Boxed warnings, product withdrawals, and impacts on patients, clinicians, and manufacturers. Results: Overall, twenty titanic ADRs involved 15 drugs and 1 device. Legal settlements totaled $38.4 billion for 874,000 persons reportedly developing titanic ADRs. Five clinicians reported receiving threats from manufacturers’ employees, one clinician lost a university faculty position, and five clinicians were not invited to FDA meetings where their safety findings were discussed. Annual sales for 9 still patented drugs and 1 device decreased 78% from $21.3 billion pre-ADR report to $3.9 billion afterwards. Following FDA approval, the median time to titanic ADRs reporting was 7.5 years. Fourteen drugs received Box warnings a median of 7.5 years following titanic ADR reporting. Six drugs and 1 device were withdrawn from marketing (median of 5 years after titanic ADR reporting). Conclusion: Overall, 874,000 persons were purportedly injured by fifteen drugs and one device that caused titanic ADRs, reputational harms were reported by eleven clinicians , and $38.4 billion in legal settlements were paid . Because titanic ADRs impacts are so large, and investigative processes not always transparent, policy makers should develop an independently funded drug safety board. Funding Statement: This work received support from the National Cancer Institute (1R01 A102713 (CLB), https://www.nih.gov/about-nih/what-we-do/nih-almanac/national-cancer-institute-nci; the American Cancer Society (IRG-13-043-01), https://www.cancer.org/; and an unrestricted grant from Doris Levkoff Meddin. Declaration of Interests: The authors have declared that no competing interests exist.

The benefit of integrating safety data from the FDA mandated registry with medwatch reports: A Southern Network on Adverse Reactions (SONAR) analysis based on the Tysabri Outreach Commitment to Health Registry (TOUCH).

e18237Background: Natalizumab is an effective therapy for multiple sclerosis. Its most notable toxicity is PML. The FDA mandated registry, TOUCH, focuses on PML cases. We identified an unusual case...

Fluoroquinolone-related neuropsychiatric and mitochondrial toxicity: a collaborative investigation by scientists and members of a social network.

The 3 fluoroquinolone (FQ) antibiotics - ciprofoxacin, levofoxacin, and moxifoxacin - are commonly administered to oncology patients. Although these oral antibiotics are approved by the US Food and Drug Administration (FDA) for treatment of urinary tract infections, acute bacterial sinusitis, or bacterial infection in patients with chronic obstructive pulmonary disease, they are commonly prescribed off-label to neutropenic cancer patients for the prevention and treatment of infections associated with febrile neutropenia. New serious FQ-associated safety concerns have been identified through novel collaborations between FQ-treated persons who have developed long-term neuropsychiatric (NP) toxicity, pharmacovigilance experts, and basic scientists. To conduct basic science and clinical investigations of a newly identified adverse drug reaction, termed FQ-associated disability. 5 groups of C57BL/6 mice receiving the antibiotic ciprofoxacin in 10-mg increments (10 mg/kg-50 mg/kg) and 1 group of control mice were evaluated. The Southern Network on Adverse Reactions (SONAR) and a social network of FQ-treated persons with long-term NP toxicity (the Floxed Network) conducted a web-based survey. The clinical toxicity manifestations reported by 94 respondents to the web-based survey of persons who had received 1 or more doses of an FQ prescribed for any indication (generally at FDA-approved dosages) and who subsequently experienced possible adverse drug reactions were compared with adverse event information included on the product label for levofoxacin and with FQ-associated adverse events reported to the FDA's MedWatch program. Mice treated with ciprofoxacin had lower grip strengths, reduced balance, and depressive behavior compared with the controls. For the survey, 93 of 94 respondents reported FQ-associated events including anxiety, depression, insomnia, panic attacks, clouded thinking, depersonalization, suicidal thoughts, psychosis, nightmares, and impaired memory beginning within days of FQ initiation or days to months of FQ discontinuation. The FDA Adverse Event Reporting System (FAERS) included 210,705 adverse events and 2,991 fatalities for FQs. Levofoxacin and ciprofoxacin toxicities were neurologic (30% and 26%, respectively), tendon damage (8% and 6%), and psychiatric (10% and 2%). In 2013, an FDA safety review reported that FQs affect mammalian topoisomerase II, especially in mitochondria. In 2013 and 2014, SONAR fled citizen petitions requesting black box revisions identifying neuropsychiatric toxicities and mitochrondrial toxicity as serious levofoxacin-associated adverse drug reactions. In 2015, FDA advisors recommended that FQ product labels be revised to include information about this newly identified disability syndrome termed "FQ-associated disability" (FQAD). Basic science studies evaluated NP toxicity for only 1 FQ, ciprofoxacin. Pharmacovigilance investigators, a social network, and basic scientists can collaborate on pharmacovigilance investigations. Revised product labels describing a new serious adverse drug reaction, levofoxacin-associated long-term disability, as recommended by an FDA advisory committee, are advised.

Forewarned Is Forearmed- Comparison of Southern Network on Adverse Reactions (SONAR) Versus an FDA-Mandated Prospective Observational Registry Assessment of Gemtuzumab Ozogamycin-Associated Sinusoidal Obstructive Syndrome

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 manufacturerSONARPharmaceutical Investigation# of pts who received GO1071482# of pts with SOS9944DATA METHODS# of centers involved50 centers (US and UK)54 centers (US only)Interim analysisNot doneYes (2002 and 2005)Concomitant chemo given67%41%# of pts with concomitant HCT26%0%% with prior alloSCT2.6%Not reported% with prior autoSCT3.9%Not reported% with prior HSCT6.5%18.3%% with subsequent alloSCT1.2%0%% with subsequent autoSCT2.0%0%Publication Date*20072013* Gemtuzumab ozogamycin voluntarily removed from market in 2010 by the pharmaceutical manufacturer DisclosuresNo relevant conflicts of interest to declare.

Rituximab-Associated Progressive Multifocal Leukoencephalopathy (PML) in HIV-Negative Patients: An Updated Report of 231 Confirmed Cases from the Southern Network on Adverse Reactions (SONAR)/Washington University Collaboration (2000-2012)

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). [Display omitted] 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. DisclosuresOff 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.

Reply to magnetic resonance imaging‐based diagnosis of progressive multifocal leukoencephalopathy in a patient with non‐Hodgkin lymphoma after therapy with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab

Disseminating timely information concerning serious adverse drug reactions is difficult. This is the mission of the Southern Network on Adverse Reactions (SONAR). Dima et al from Romania described a patient with non-Hodgkin lymphoma who was treated with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R regimen) who developed speech and motor dysfunction. Magnetic resonance imaging identified white matter defects. Cerebrospinal fluid (CSF) analysis did not identify JC virus (John Cunningham virus). An empirical diagnosis of rituximab-associated progressive multifocal leukoencephalopathy (PML) was made. Recently proposed PML diagnostic criteria from the Neuro-infectious Disease Section of the American Academy of Neurology require evidence of clinical disease progression, imaging, and JC virus (histopathologically or in the CSF).1 If full criteria are not met, then alternative diagnoses need to be investigated. Access to relevant publications may not have been available in Romania, including our case series and review of PML.2,3 The product label also does not report this information.4 Although >300 individuals with rituximab-associated PML have been reported to regulatory authorities, the label does not report this. The label also does not describe that in the setting of a suggestive magnetic resonance imaging scan and a negative CSF evaluation for JC virus, a second lumbar puncture or a brain biopsy should be considered. Finally, emerging data have identified a low baseline PML rate in patients with lymphoma, but a 5-fold increased rate in patients treated with rituximab and chemotherapy.5 We thank Dima et al for reporting this case, thereby reinforcing the observation that the most available source of safety information is the product label.

Progressive multifocal leukoencephalopathy associated with brentuximab vedotin therapy: a report of 5 cases from the Southern Network on Adverse Reactions (SONAR) project.

Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody-drug conjugate that was approved in 2011 for the treatment of patients with anaplastic large cell and Hodgkin lymphomas. The product label indicates that 3 patients who were treated with BV 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. In the current study, the authors reported 5 patients who developed BV-associated PML, including 2 immunocompetent patients. Case information was obtained from clinicians (4 patients) or a US Food and Drug Administration database (1 patient). All 5 patients had lymphoid malignancies. Two patients with cutaneous T-cell lymphomas had not previously received chemotherapy. PML developed after a median of 3 BV doses (range, 2 doses-6 doses) and within a median of 7 weeks after BV initiation (range, 3 weeks-34 weeks). Presenting findings included aphasia, dysarthria, confusion, hemiparesis, and gait dysfunction; JC virus in the cerebrospinal fluid (2 patients) or central nervous system biopsy (3 patients); and brain magnetic resonance imaging scans with white matter abnormalities (5 patients). Four patients died at a median of 8 weeks (range, 6 weeks-16 weeks) after PML diagnosis. The sole survivor developed immune reconstitution inflammatory syndrome. PML can develop after a few BV doses and within weeks of BV initiation. Clinicians should be aware of this syndrome, particularly when neurologic changes develop after the initiation of BV treatment. The decision to administer BV to patients with indolent cutaneous lymphomas should be based on consideration of risk-benefit profiles and of alternative options.

Systematic Approach to Pharmacovigilance beyond the Limits: The Southern Network on Adverse Reactions (SONAR) Projects

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

Levamisole contamination of cocaine resulting in neutropenia and thrombovasculopathy: a report from the Southern Network on Adverse Reactions (SONAR)

Levamisole contamination of cocaine resulting in neutropenia and thrombovasculopathy: a report from the Southern Network on Adverse Reactions (SONAR)

Progressive multifocal leucoencephalopathy (PML): A novel complication of brentuximab vedotin from the Southern Network on Adverse Reactions (SONAR) project.

e22181 Background: BV is FDA approved for angio-immunoblastic large cell lymphoma and refractory Hodgkin’s lymphoma (HL). BV-linked PML cases reviewed. Methods: Case 1—Age:47/HIV negative male relapsed stage IIIB mixed cellularity undergoing treatment with BV. Prior therapies: 8 cycles of ABVD, ESHAP, BEAM, autologous stem cell transplant, involved field radiotherapy to the neck and mediastinum in 2008 and GVD ending in 2009. A 2011 relapse treated with BV q 3 weeks. Patient complained of impaired coordination and left greater than right dysdiadokinesis after 2 BV doses. Third BV cycle administered. Patient formed dysarthria, left-sided hemianopsia, hemiparesis. CSF analysis for JC virus DNA by PCR positive. Patient died shortly after. Case 2—Age:38/female revealed cutaneous anaplastic T-cell lymphoma refractory started on BV in mid-2011 led to loss of cutaneous tumors. A day after 2ndBV dose, difficulty finding words and unsteady gait. MRI revealed multifocal white matter lesions in bilateral cerebral hemispheres. Brain biopsy revealed PML. Prednisone initiated. Patient continued mixed non-fluent aphasia, quadriparesis, gait ataxia. MRI showed white matter lesions and contrast enhancement consistent with IRIS. High dose oral corticosteroids continued. Repeat MRI shows decreased lesion load, resolution of enhancement. Patient improving. Case 3—Age:72/female stage IB mycosis fungoides (MF) controlled with topical steroids and nitrogen mustard, phototherapy and interferon alpha, developed painful ulcerated plaques and tumors 4 years after diagnosis. BV administered, clinical response of skin tumors, decreased pain. Two weeks after 3rdBV dose: disoriented, poor short term memory. MRI revealed right frontal white matter. CSF sent for JC virus DNA was negative. Patient died 2 months after last BV dose. Autopsy: demyelination associated JC virus positive cells. Results: Shown. Conclusions: Unexpected PML occurrences after 2 or more BV doses, with IRIS and survival in 1 patient.

Thromboprophylaxis Guidelines in Cancer with a Primary Focus on Ambulatory Patients Receiving Chemotherapy: A Review from the Southern Network on Adverse Reactions (SONAR)

Patients with cancer are at increased risk for venous thromboembolism (VTE). Factors related to cancer type, site, stage, duration, and extent of disease contribute to the oncology patient's risk of VTE. Patient-specific factors such as history of prior VTE and comorbidity are also contributory. The role of treatment-related factors, including chemotherapy regimen, has been a focus of recent investigation because most cases of VTE in the oncology setting occur in ambulatory patients. Thus, an emerging area of clinical research is primary VTE prophylaxis in the ambulatory cancer setting. Clinical guidelines currently recommend primary thromboprophylaxis in cancer patients who are undergoing surgery, who are hospitalized, and who are in a specific subset of high-risk ambulatory cancer patients. Validated risk stratification tools are essential for identification of patients who are at high risk of thrombosis. Emerging data from recently published clinical trials, as well as ongoing studies, are likely to advance our understanding of the potential utility of antithrombotic agents for primary prophylaxis in ambulatory patients with cancer and may influence future clinical guideline recommendations.

A Review of Safety, Efficacy, and Utilization of Erythropoietin, Darbepoetin, and Peginesatide for Patients with Cancer or Chronic Kidney Disease: A Report from the Southern Network on Adverse Reactions (SONAR)

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.

Underreporting of Hemorrhagic and Thrombotic Complications of Pharmaceuticals to the U.S. Food and Drug Administration: Empirical Findings for Warfarin, Clopidogrel, Ticlopidine, and Thalidomide from the Southern Network on Adverse Reactions (SONAR)

The U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (AERS), familiarly known as "MedWatch," is the nation's primary tool for postmarket pharmaceutical safety surveillance. This system relies on adverse events voluntarily reported by health care providers and consumers either directly to the FDA or to drug manufacturers, which are required to prepare and forward the information to the agency. Little is known about how frequently adverse events are reported. Previous estimates range from 1 to 31% depending on the event, drug, and time period. We used published incidence studies to calculate reporting rates for hemorrhage, emergency hospitalization, and venous thromboembolism (VTE) associated with four drugs. We estimated annual reporting rates of 1.07% for 33,171 emergency hospitalizations of patients older than 65 years associated with warfarin, 0.9% for 13,363 hospitalizations of clopidogrel and ticlopidine, and 1.02% for an estimated 67,200 hemorrhage cases associated with warfarin. We also estimated a 9-year reporting rate of 2.3% for VTE associated with thalidomide. The incidence of these hematologic adverse drug events is high and reporting rates are low, and near the lower boundary of the 1 to 15% range seen for other events.

Linking Drugs to Obscure Illnesses: Lessons from Pure Red Cell Aplasia, Nephrogenic Systemic Fibrosis, and Reye’s Syndrome. A Report From the Southern Network on Adverse Reactions (SONAR)

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.

Serious Adverse Drug Reactions (sADRS) Associated with Hematopoietic Growth Factors: A Systematic Review From the Southern Network on Adverse Reactions (SONAR) Program

AbstractAbstract 2555Erythrpoiesis stimulating agents (ESAs) and the granulocyte hematopoietic growth factors granulocyte colony stimulating factor (G-CSF) and pegylated G-CSF revolutionized supportive care approaches to anemia and neutropenia, respectively. Thrombopoietin-receptor agonists improve antibody-mediated thrombocytopenia management. For these drugs, as with all agents, a comprehensive understanding of sADRs is important, however, often difficult to do. We reviewed sADRS described in meta-analyses and web-site materials maintained by regulatory agencies and manufacturers reports (1989 to July 2010; n=2,094). Overall, 28 systematic reviews, six package inserts, three medication guides, four FDA Risk Evaluation and Mitigation Systems (REMS) materials, 16 Summaries of Product Characteristics/Product Assessment Reports were included. For ESAs, common sADRs associated with increased relative risks (RRs) included: mortality among cancer patients with chemotherapy-associated anemia or cancer patients not receiving active treatment (RRs: 1.1–1.2); cerebrovascular and cardiovascular events among chronic kidney disease patients ((RRs: 1.3, 1.9), and venous thromboembolism in the cancer setting (RRs;16-1.7). For G-CSF/pegylated-GCSF, rare instances of myelodysplasia/acute myeloid leukemia (MDS/AML) associated with statistically increased RRs were reported among breast cancer patients receiving chemotherapy in trials reported from one NCI-sponsored clinical trials group, one meta-analysis, and one review of Medicare/SEER databases (RR: 1.9–2.1), although the absolute risks were very small (< 2 per 100,000 treated patients). Other rarely reported sADRs (total N < 20) included splenic rupture following G-CSF stimulation of healthy peripheral blood stem donors. Bone marrow fibrosis and collagen deposition were reported with thrombopoietin receptor agonists, although the implications of this finding is uncertain. Also, instances of VTEs were reported among persons who developed high platelet counts following administration of these thrombopoeitin receptor agonists. SADRs are commonly associated with ESA administration in a range of settings, are uncommon occurrences with G-CSF/pegylated G-CSF, and are not well characterized for thrombopoieitin receptor agonists. Formal pharmacovigilance initiatives are ongoing, including FDA mandated REMS with restricted distribution requirement for ESAs in the cancer setting (APPRISE) and the NEXUS and the PROMACTA CARES programs for thrombopoeitin receptor agonists.ESAs (Cancer)ESAs (CKD)G-CSF/Pegylated G-CSFVTEMortalityCerebrovascular and CVDAML/MDSRR1.57 and 1.671.10 to 1.171.34 and 1.922.14 and 1.9295% CI1.31–1.87 and 1.35–2.061.02–1.20 and 1.06–1.301.03–1.74 and 1.38–2.261.12–4.08 and 1.19–3.07Baseline RiskAbsolute RiskCommonCommonCommonRare (2/100,000) Disclosures:Bennett:Pfizer: Consultancy.

Polysorbate 80 hypersensitivity reactions: a renewed call to action

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