The Role of Adverse Event Reporting in the FDA Response to a Multistate Outbreak of Liver Disease Associated with a Dietary Supplement

Abstract

Objective. Liver disease is a potential complication from using dietary supplements. This study investigated an outbreak of non-viral liver disease associated with the use of OxyELITE Pro™, a dietary supplement used for weight loss and/or muscle building. Methods. Illness details were ascertained from MedWatch reports submitted to the U.S. Food and Drug Administration (FDA) describing consumers who ingested OxyELITE Pro alone or in combination with other dietary supplements. FDA's Forensic Chemistry Center analyzed samples of OxyELITE Pro. Results. From February 2012 to February 2014, FDA received 114 reports of adverse events of all kinds involving consumers who ingested OxyELITE Pro. The onset of illness for the first report was December 2010 and for the last report was January 2014. Thirty-three states, two foreign nations, and Puerto Rico submitted reports. Fifty-five of the reports (48%) described liver disease in the absence of viral infection, gallbladder disease, autoimmune disease, or other known causes of liver damage. A total of 33 (60%) of these patients were hospitalized, and three underwent liver transplantation. In early 2013, OxyELITE Pro products entered the market with a formulation distinct from products sold previously. The new formulation replaced 1,3-dimethylamylamine with aegeline. However, the manufacturer failed to submit to FDA a required “new dietary ingredient” notice for the use of aegeline in OxyELITE Pro products. Laboratory analysis identified no drugs, poisons, pharmaceuticals, toxic metals, usnic acid, N-Nitroso-fenfluramine, pyrrolizidine alkaloids, aristocholic acid, or phenethylamines in the products. Conclusions. Vigilant surveillance is required for adverse events linked to the use of dietary supplements.

Hepatotoxicity associated with the dietary supplement OxyELITE Pro™ — Hawaii, 2013

“…The cases identified from these reports and the cases from Hawaii were included in a separate national investigation; findings of that investigation will be published in a forthcoming article in Drug Testing and Analysis . Furthermore, the impact of national adverse event reporting through FDA MedWatch, the only official mechanism for reporting and tracking drug and dietary supplement adverse events, and the FDA investigation of and response to this outbreak from the federal regulatory perspective were examined; those data are in publication . Possible cases in other countries have also been reported…”

Herbal and Dietary Supplement–Induced Liver Injury

“…Hospitalization was required in 33 (60%) cases and liver transplantation in 3 (5%). (76) In early 2013 the formula of OxyELITE Pro had been changed, substituting 1,3-Dimethylamylamine, which had been associated with cardiovascular toxicity, with aegeline. (76) Early reports of liver injury were from Hawaii, where an initial cluster of 7 patients was reported to develop liver injury in the period between May and September 2013.…”

“…(76) In early 2013 the formula of OxyELITE Pro had been changed, substituting 1,3-Dimethylamylamine, which had been associated with cardiovascular toxicity, with aegeline. (76) Early reports of liver injury were from Hawaii, where an initial cluster of 7 patients was reported to develop liver injury in the period between May and September 2013. (24, 77) Following this report, other cases were identified in an outbreak investigation performed by the Hawaii Department of Health, Centers for Disease Control and Prevention (CDC) and FDA.…”

Hepatotoxicity associated with weight loss or sports dietary supplements, including OxyELITE Pro™ — United States, 2013

“…A study published in 2014 documented acute liver injury in seven active duty service members who had consumed a formulation of OxyELITE Pro™ labeled as containing DMAA . The manufacturer released a DMAA‐free formulation of OxyELITE Pro™ that included aegeline in early 2013 . After FDA notified the manufacturer that it had failed to inform FDA of the use of aegeline, which was determined to be a new dietary ingredient, the manufacturer recalled aegeline‐containing formulations of OxyELITE Pro™ in November 2013.…”

“…A single, definitive etiologic agent is not typically identified in investigations of liver injury associated with a supplement . As part of the Hawaii investigation, FDA performed both a general analytic laboratory screen and targeted testing of OxyELITE Pro™ for potentially hepatotoxic agents . The testing confirmed the ingredients listed on the label and did not identify any known hepatotoxic agents, so the specific causative ingredient remains unknown.…”