Oseltamivir and Neuropsychiatric Adverse Effects in the FDA Adverse Event Reporting System through 2012
Keith B. Hoffman1*, Andrea Demakas1, Colin B. Erdman1, Mo Dimbil1, P. Murali Doraiswamy2
1AdverseEvents, Inc., 2Departments of Psychiatry and Medicine, Duke University Medical Center
*Corresponding Author: Keith B. Hoffman, 230 Center Street, Healdsburg, CA 95448, Email: email@example.com
We provide an update to the on-going controversy regarding neuropsychiatric adverse events (NPAE) linked to Tamiflu (oseltamivir). These were initially noted in Japanese reports (Yokota et al., 2007; Fujiwara et al., 2008) as well as in cases from around the world. Publications from Roche (Blumentals and Song, 2007; Smith and Sacks, 2009; and Toovey et al., 2008 and 2012), as well as analyses of data from a 2007-2010 cohort of matched pairs in the Vaccine Safety Datalink Project (Green, 2013), suggest that there is no evidence, nor plausible mechanism of action, to link oseltamivir with NPAEs. They surmise that the side effects associated with oseltamivir are symptoms of influenza itself.
Members of the Cochrane Collaboration, the Editor of BMJ, and others, however, contend that Roche’s assertions can neither be confirmed nor denied because much of the data from oseltamivir clinical trials remains unpublished and unavailable (http://www.bmj.com/tamiflu/roche and Doshi, 2009). Roche recently agreed to make their data available in a “staggered” fashion but updated side effect data through 2013 are not yet available.
To shed further light, we examined NPAE signals associated with oseltamivir in the US Food and Drug Administration’s Adverse Event Reporting System (FAERS) from October 27, 1999 through August 27, 2012, the most current data available. We used a data mining platform (RxFilterTM) to generate case report counts and reporting ratios for multiple NPAE MedDRA®* categories, including those queried in the Roche papers. The platform is a combination of computer algorithms and in-house data analysis designed to make FAERS data more accessible to healthcare providers, consumers and health management companies (www.AdverseEvents.com Hoffman et al., 2013). The proportionality measure known as the Reporting Odds Ratio (ROR) was calculated using methods as outlined in Bate and Evans, 2009, however, data for numerator and denominator variables were constrained to the period of time beginning with oseltamivir’s FDA approval date and ending with the most recent FAERS data (August 2012). An ROR provides a reporting estimate for a given agent-side effect combination relative to other side effects with that agent and how this compares to other side effect-drug combinations in the database for the chosen time period. High RORs suggest disproportional reporting of a given drug-side effect combination.
Table 1 shows the number of primary suspect cases found for a selection of NPAE-related MedDRA terms for the time period of 1999-2012, with corresponding ROR scores and 95% Confidence Intervals (CI) (for CI method see Liu et al., 2013). MedDRA categories included in the Roche papers are marked with an asterisk. ROR results of note included: “abnormal behaviour” with an ROR of 29.35; “psychiatric and behavioural symptoms not otherwise classified (NEC)” with an ROR of 15.36; “delirium” with an ROR of 13.50; “hallucination” with an ROR of 12.00; “perception disturbances,” with an ROR of 8.41; and “depressed level of consciousness” with an ROR of 4.69. Roughly half of the reports were from Japan (consistent with large usage in Japan) but reports were also observed in US and other countries. Temporal patterns suggest that NPAEs linked to oseltamivir peaked in the 1999-2007 period, but new reports continued through the present. Finally, “life-threatening” and “death” were listed 188 and 81 times, respectively, within case reports in the largest NPAE category searched, “psychiatric disorders (SOC)” (2,527 total primary suspect cases).
FAERS post-marketing data over the past decade show disproportionally elevated reporting of certain NPAEs linked to oseltamivir. While these data support the cautionary warnings added to the drug’s label in several countries, the absolute number of FAERS reports remains small in relation to the millions of people treated with oseltamivir. Thus, potential safety signals are likely to be small and difficult to detect. Post-marketing data are subject to many biases, such as inability to ascertain causality, marked underreporting, masking, amplification, and confounding by comorbidities (Szarfman et al., 2004; FDA, 2013). On the other hand, the marked under-reporting that is common in FAERS may have resulted in ROR being underestimated. Further, it can be difficult to causally link NAPEs to oseltamivir, since a dose response or withdrawal and rechallenge are not usually tested in patients. Despite such limitations, we hope these findings offer an update for clinicians, while awaiting the release of all prospective trial data.
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PMD has received research grants and advisory or speaking fees from several pharmaceutical companies and is a shareholder in AdverseEvents Inc. (AEI). KBH, AD, CBE, and MD are employees of AEI.