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)

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

Paediatric essential thrombocythaemia: clinical and molecular features, diagnosis and treatment

“…Antiplatelet agents, such as aspirin, have long been used to prevent primary or recurrent thrombosis in adult ET patients, although they may not work well in all of the low risk patients (Alvarez‐Larran et al , ). Considering the risk of Reye syndrome, caused by amino salicylic acid, in children younger than 12 years, low‐dose aspirin should be used with caution in childhood ET (Bennett et al , ). Generally, anti‐platelet agents are used only in children with severe microcirculatory symptoms or with thrombosis, except those with contraindications, such as babies, platelet count ≥1500 × 10 9 /l, ristocetin cofactor activity <30%, or previous major bleeding episode associated with aspirin therapy (Cervantes, ; Giona et al , ; Tefferi, ).…”

Introduction of biosimilar insulins in Europe

“…Increased incidence of life‐threatening pure red cell aplasia was reported as early as 2002 11, 12. These adverse events were then subsequently linked to an increased immune response to the drug 12, 13.…”

“…The clinical relevance of how the manufacturing process can affect the properties of a biological medication is illustrated by one of the human erythropoietins used to treat anaemia. Increased incidence of life-threatening pure red cell aplasia was reported as early as 2002 [11,12]. These adverse events were then subsequently linked to an increased immune response to the drug [12,13].…”

“…Increased incidence of life-threatening pure red cell aplasia was reported as early as 2002 [11,12]. These adverse events were then subsequently linked to an increased immune response to the drug [12,13]. Corrective measures included replacement of the uncoated rubber syringe stoppers with Teflon-coated stoppers, enhancement of product controls, emphasis on appropriate storage temperatures and the recommendation to administer the drug intravenously rather than subcutaneously.…”

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

“…This avenue has the potential to help bridge the gap between clinical findings and FDA action. Medicine, 2012) [38] This policy analysis looks at three instances of postmarketing safety initiatives surrounding epoetin, gadodiamide, and aspirin. In these three cases 13-81 years elapsed between the drug introduction and the recognition of the associated drug toxicities.…”