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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)

Journal of General Internal Medicine volume 27, pages 1697–1703 (2012)Cite this article

Abstract

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.

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Funding

Funding was provided by grants from the National Cancer Institute (1R01CA 102713–01) (CLB) the South Carolina Center of Economic Excellence Center for Medication Safety initiative (CLB), and the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health (DRM). This paper was prepared in part by DRM as an employee of the US Government making this a “work of the US Government” and therefore the copyright is non-transferable. The opinions stated in this paper are those of the authors and do not necessarily represent views of the Department of Health and Human Services, the National Institutes of Health or the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of Interest

The authors declare that they do not have a conflict of interest.

Author information

Author notes

  1. Donald R. Mattison MD

    Present address: Risk Sciences International, Ottawa, ON, Canada

Affiliations

  1. South Carolina College of Pharmacy, 715 Sumter Street, Suite 311, Columbia, SC, 29208, USA

    Charles L. Bennett MD, PhD, MPP, Zaina P. Qureshi PhD, MPH, P. Brandon Bookstaver PharmD, April D. Miller PharmD, LeAnn B. Norris PharmD, Alyssa Trenery, Isaac Lopez, Adam Kahn MA, Alanna Murday BS & Paul Ray DO

  2. Arnold School of Public Health of the University of South Carolina, Columbia, SC, USA

    Charles L. Bennett MD, PhD, MPP, Zaina P. Qureshi PhD, MPH & Sudha Xirasagar MBBS, PhD

  3. Hollings Cancer Center, Charleston, SC, USA

    Charles L. Bennett MD, PhD, MPP

  4. Burlingame, CA, USA

    Karen M. Starko MD

  5. Department of Diagnostic Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    Henrik S. Thomsen MD

  6. Department of Dermatology, Yale School of Medicine, New Haven, CT, USA

    Shawn Cowper MD

  7. Departments of Medicine and Urology, Tulane College of Medicine and the Tulane Cancer Center, New Orleans, LA, USA

    Oliver Sartor MD

  8. Renal Unit, King’s College Hospital, London, England, UK

    Iain C. Macdougall MD, FRCP

  9. Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy

    Stefano Luminari MD

  10. Department of Oncology, McGill University, Montreal, Canada

    Denis Cournoyer MD

  11. Department of Nephrology, Alessandro Manzoni Hospital, Lecco, Italy

    Francesco Locatelli MD

  12. Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA

    Donald R. Mattison MD

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  1. Charles L. Bennett MD, PhD, MPP
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Correspondence to Charles L. Bennett MD, PhD, MPP.

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Bennett, C.L., Starko, K.M., Thomsen, H.S. et al. 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). J GEN INTERN MED 27, 1697–1703 (2012). https://doi.org/10.1007/s11606-012-2098-1

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KEY WORDS

  • pure red cell aplasia
  • nephrogenic systemic fibrosis
  • Reye’s syndrome