neuropsychiatric adverse effects of oseltamivir in the fda adverse event reporting system, 1999-2012

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ADVERSE EFFECTS OF OSELTAMIVIR Neuropsychiatric adverse effects of oseltamivir in the FDA Adverse Event Reporting System, 1999-2012 Keith B Hoffman vice president, scientific affairs 1 , Andrea Demakas analyst 1 , Colin B Erdman technical lead 1 , Mo Dimbil senior analyst 1 , P Murali Doraiswamy professor 2 1 AdverseEvents, 230 Center Street, Healdsburg, CA 95448, USA; 2 Departments of Psychiatry and Medicine, DUMC-3018, Duke University Medical Center, Durham, NC 27710, USA Publications from Roche and a case-control study suggest that there is no evidence, or plausible mechanism of action, to link neuropsychiatric adverse events to Tamiflu (oseltamivir). 12 Cochrane Collaborators, the BMJ, and others, however, contend that many of Roche’s data remain unavailable. 3 We examined neuropsychiatric adverse events associated with oseltamivir in the US FDA’s Adverse Event Reporting System (FAERS) from October 1999 to August 2012 by using a data mining platform (RxFilterTM; www.AdverseEvents.com 4 ) to generate case report counts and reporting ratios for multiple MedDRA (Medical Dictionary for Regulatory Activities) categories, including those queried in the Roche papers. Reporting odds ratios were calculated using standard methods, but 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. The tableshows the number of primary suspect cases found for a selection of MedDRA terms with corresponding reporting odds ratio scores. Scores of note included “abnormal behaviour” (29.35), “psychiatric and behavioural symptoms not otherwise classified” (15.36), “delirium” (13.50), “hallucination” (12.00), and “perception disturbances” (8.41). Finally, “life threatening” and “death” were listed 188 and 81 times, respectively, in case reports in the largest category searched, “psychiatric disorders (system organ class)”. Approximately half the reports originated in Japan and the rest were from the US and elsewhere. FAERS post-marketing data over the past decade suggest disproportionally increased reporting of certain neuropsychiatric adverse events linked to oseltamivir. While these data support the cautionary warnings added to the drug’s label in several countries, they cannot ascertain causality or incidence. Post-marketing data are subject to many biases, such as marked under-reporting, masking, amplification, and confounding by comorbidities. 56 Despite such limitations, we hope that these data offer an update for clinicians, while awaiting the release of all trial data. Competing interests: KBH, AD, CBE, and MD are employees of AEI. PMD has received research grants and advisory or speaking fees from several pharmaceutical companies and is a shareholder in AdverseEvents Inc (AEI). MedDRA, the Medical Dictionary for Regulatory Activities terminology, is the international medical terminology developed under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The MedDRA trademark is owned by IFPMA on behalf of ICH. Full response at www.bmj.com/tamiflu/roche/rr/651279. 1 Toovey S, Prinssen EP, Rayner CR, Thakrar BT, Dutkowski R, Koerner A, et al. Post-marketing assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: an updated review. Adv Ther 2012;29:826-48. 2 Greene SK, Li L, Shay DK, Fry AM, Lee GM, Jacobsen SJ, et al. Risk of adverse events following oseltamivir treatment in influenza outpatients, Vaccine Safety Datalink Project, 2007-2010. Pharmacoepidemiol Drug Saf 2013;22:335-44. 3 Open Data Campaign. Tamiflu correspondence with Roche. www.bmj.com/tamiflu/roche. 4 Hoffman KB, Overstreet BM, Doraiswamy PM. Development of a drug safety ePlatform for physicians, pharmacists, and consumers based on post-marketing adverse events. Drugs and Therapy Studies (in press) 5 US Food and Drug Administration. FDA Adverse Event Reporting System (FAERS) (formerly AERS). www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ Surveillance/AdverseDrugEffects/default.htm. 6 Szarfman A, Tonning J, Doraiswamy PM. Pharmacovigilance in the 21st century: new systematic tools for an old problem. Pharmacotherapy 2004;24:1099-144. Cite this as: BMJ 2013;347:f4656 © BMJ Publishing Group Ltd 2013 [email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe BMJ 2013;347:f4656 doi: 10.1136/bmj.f4656 (Published 23 July 2013) Page 1 of 2 Letters LETTERS

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Page 1: Neuropsychiatric adverse effects of oseltamivir in the FDA Adverse Event Reporting System, 1999-2012

ADVERSE EFFECTS OF OSELTAMIVIR

Neuropsychiatric adverse effects of oseltamivir in theFDA Adverse Event Reporting System, 1999-2012Keith B Hoffman vice president, scientific affairs 1, Andrea Demakas analyst 1, Colin B Erdmantechnical lead 1, Mo Dimbil senior analyst 1, P Murali Doraiswamy professor 2

1AdverseEvents, 230 Center Street, Healdsburg, CA 95448, USA; 2Departments of Psychiatry and Medicine, DUMC-3018, Duke University MedicalCenter, Durham, NC 27710, USA

Publications from Roche and a case-control study suggest thatthere is no evidence, or plausible mechanism of action, to linkneuropsychiatric adverse events to Tamiflu (oseltamivir).1 2

Cochrane Collaborators, the BMJ, and others, however, contendthat many of Roche’s data remain unavailable.3

We examined neuropsychiatric adverse events associated withoseltamivir in the US FDA’s Adverse Event Reporting System(FAERS) from October 1999 to August 2012 by using a datamining platform (RxFilterTM; www.AdverseEvents.com4) togenerate case report counts and reporting ratios for multipleMedDRA (Medical Dictionary for Regulatory Activities)categories, including those queried in the Roche papers.Reporting odds ratios were calculated using standard methods,but numerator and denominator variables were constrained tothe period of time beginning with oseltamivir’s FDA approvaldate and ending with the most recent FAERS data.The table⇓ shows the number of primary suspect cases foundfor a selection of MedDRA terms with corresponding reportingodds ratio scores. Scores of note included “abnormal behaviour”(29.35), “psychiatric and behavioural symptoms not otherwiseclassified” (15.36), “delirium” (13.50), “hallucination” (12.00),and “perception disturbances” (8.41). Finally, “life threatening”and “death” were listed 188 and 81 times, respectively, in casereports in the largest category searched, “psychiatric disorders(system organ class)”. Approximately half the reports originatedin Japan and the rest were from the US and elsewhere.FAERS post-marketing data over the past decade suggestdisproportionally increased reporting of certain neuropsychiatricadverse events linked to oseltamivir. While these data supportthe cautionary warnings added to the drug’s label in severalcountries, they cannot ascertain causality or incidence.

Post-marketing data are subject to many biases, such as markedunder-reporting, masking, amplification, and confounding bycomorbidities.5 6 Despite such limitations, we hope that thesedata offer an update for clinicians, while awaiting the releaseof all trial data.

Competing interests: KBH, AD, CBE, and MD are employees of AEI.PMD has received research grants and advisory or speaking fees fromseveral pharmaceutical companies and is a shareholder inAdverseEvents Inc (AEI). MedDRA, theMedical Dictionary for RegulatoryActivities terminology, is the international medical terminology developedunder the auspices of the International Conference on Harmonizationof Technical Requirements for Registration of Pharmaceuticals forHuman Use (ICH). The MedDRA trademark is owned by IFPMA onbehalf of ICH.Full response at www.bmj.com/tamiflu/roche/rr/651279.

1 Toovey S, Prinssen EP, Rayner CR, Thakrar BT, Dutkowski R, Koerner A, et al.Post-marketing assessment of neuropsychiatric adverse events in influenza patientstreated with oseltamivir: an updated review. Adv Ther 2012;29:826-48.

2 Greene SK, Li L, Shay DK, Fry AM, Lee GM, Jacobsen SJ, et al. Risk of adverse eventsfollowing oseltamivir treatment in influenza outpatients, Vaccine Safety Datalink Project,2007-2010. Pharmacoepidemiol Drug Saf 2013;22:335-44.

3 Open Data Campaign. Tamiflu correspondence with Roche. www.bmj.com/tamiflu/roche.4 Hoffman KB, Overstreet BM, Doraiswamy PM. Development of a drug safety ePlatform

for physicians, pharmacists, and consumers based on post-marketing adverse events.Drugs and Therapy Studies (in press)

5 US Food and Drug Administration. FDA Adverse Event Reporting System (FAERS)(formerly AERS). www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.htm.

6 Szarfman A, Tonning J, Doraiswamy PM. Pharmacovigilance in the 21st century: newsystematic tools for an old problem. Pharmacotherapy 2004;24:1099-144.

Cite this as: BMJ 2013;347:f4656© BMJ Publishing Group Ltd 2013

[email protected]

For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2013;347:f4656 doi: 10.1136/bmj.f4656 (Published 23 July 2013) Page 1 of 2

Letters

LETTERS

Page 2: Neuropsychiatric adverse effects of oseltamivir in the FDA Adverse Event Reporting System, 1999-2012

Table

Table 1| Neuropsychiatric adverse events associated with oseltamivir in FDAAdverse Event Reporting System (27 October 1999–27 August2012)

Reporting odds ratio (95% CI)Total primary suspect cases†MedDRA terms*

29.35 (27.43 to 31.40)980Abnormal behaviour (PT)‡

15.36 (14.39 to 16.39)1040Psychiatric and behavioural symptoms NEC (HLGT)

13.50 (12.05 to 15.12)317Delirium (PT)‡

12.00 (10.93 to 13.17)477Hallucination (PT)

8.41 (7.74 to 9.14)597Perception disturbances (HLT)

8.09 (7.46 to 8.77)643Delusional disorders, delusional symptoms, perceptiondisturbances (HLTs)

4.69 (4.09 to 5.38)211Depressed level of consciousness (PT)‡

3.85 (3.54 to 4.20)560Deliria (including confusion) (HLGT)‡

2.64 (2.36 to 2.95)322Convulsion (PT)‡

2.01 (1.75 to 2.31)205Confusional state (PT)

2.00 (1.77 to 2.26)262Confusion and disorientation (HLT)

1.82 (1.74 to 1.90)2527Psychiatric disorders (SOC)

1.82 (1.60 to 2.07)234Cortical dysfunction NEC (HLT)

1.58 (1.36 to 1.84)168Loss of consciousness (PT)‡

*MedDRA (Medical Dictionary for Regulatory Activities) classes included: PT (preferred term); HLT (high level term); HLGT (high level group term); and SOC(system organ class); NEC=not otherwise classified.†Case counts may reflect multiple neuropsychiatric adverse events in a given subject.‡Categories included in the referenced Roche papers.

For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2013;347:f4656 doi: 10.1136/bmj.f4656 (Published 23 July 2013) Page 2 of 2

LETTERS