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Fifty sudden deaths are more serious reactions probably related to CNS suppressive action of Tamiflu (oseltamivir phosphate)

Rokuro Hama   (21 June 2007)

Fifty sudden deaths are more serious reactions probably related to CNS suppressive action of Tamiflu (oseltamivir phosphate) 21 June 2007
Rokuro Hama, Chairman of Japan Institute of Pharmacovigilance, Editor of Kusuri-no-Check (a drug bulletin) #402 Osaka 2-3-2, Tennoji-ku Osaka, Japan 543-0062�@ Send response to journal: Re: Fifty sudden deaths are more serious reactions probably related to CNS suppressive action of Tamiflu (oseltamivir phosphate)	EDITOR- On 16th June 2007, Japanese Ministry of Health Labour and Welfare (MHLW) announced that they had received 1377 adverse reaction reports by 31st May 2007 since marketing commencement of oseltamivir- phosphate (Tamiflu or oseltamivir-P) in Japan [1]. Of these, 567 are serious neuropsychiatric cases in which 211 are those with abnormal behavior. The number of death cases due to adverse reactions to Tamiflu that MHLW reported is 71. These are not only "adverse events" after taking Tamiflu but also "adverse reactions" to Tamiflu, because many physicians reported as adverse reactions probably or possibly related to the drug or because they thought that causality could not be ruled out, while MHLW classified all but four as "rather negative". Only four classified as "cannot be ruled out" are toxic epidermal necrolysis, multi-organ failure, anaphylaxis (unproven) and fulminant hepatitis. In addition, there are 4 sudden deaths due to adverse event which MHLW did not classify as adverse reactions and there are 5 sudden deaths that I gathered independently which are not included in 71. Of the total 80 deaths, 50 are sudden deaths or deaths from sudden cardiopulmonary arrest (18 are under 10 years old and 32 are above 20 years old), while eight are accidental deaths from abnormal behavior (5 are in teens and 3 are above 20 years old). All these 58 sudden deaths and accidental death from abnormal behavior were classified as "rather negative" by MHLW, even though many physicians reported as adverse reactions probably or at least "cannot be ruled out". Four are deaths from sepsis following exacerbation of pneumonia after possible respiratory suppression. Nine cases are those possibly related to exacerbation of mainly pneumonia. Other eight deaths were from hepatic failure, pancytopenia, GI bleeding and so on. Thus adverse reactions to oseltamivir may be roughly classified in three groups: 1) acute onset adverse reactions probably related to the central nervous system suppressive action of oseltamivir-phosphate (oseltamivir-P) including sudden death, abnormal behaviors and other acute onset neuropsychiatric disorders [2-14], 2) delayed onset serious adverse reactions such as pneumonia, sepsis and hyperglycemia possibly related to the active form of oseltamivir- carboxylate (oseltamivir-C) and 3) allergic reactions and others. As I initially [2-4] and recently commented [5] by overviewing animal data disclosed by MHLW [6,7] , adverse reaction cases of which bereaved families consulted me and also whose medical records were available [8,9], and those disclosed by MHLW [1,10,11] and FDA(US)[12,13], spectrum of action and toxicity of oseltamivir is very similar to that of central nervous system suppressants such as benzodiazepines, barbiturates and general anesthetics. From this viewpoint, potential mechanisms of acute onset adverse reactions to oseltamivir are summarized as follows [5] : (1) oseltamivir-P, a prodrug of oseltamivir-C, has central nervous system (CNS) suppressive action. This is based on the following facts: It exhibited similar signs, symptoms and pathological findings with those of hypnotics, sedatives and general anesthetics in animal studies and human cases. They include sleep, decreased body temperature, decreased spontaneous movements, slow/irregular breathing, cyanosis before death, and lung edema at autopsy. Ten minutes to seven hours after the first dose of oseltamivir-P, 18 of 24 seven-day old rats before weaning spontaneously decreased movements, had weakened respiration which subsequently became irregular, and died probably from respiratory suppression. Cyanosis was observed in 6 of 18, but no abnormality was found at autopsy except lung edema. Nine of 18 dead rats had lung edema at autopsy. However, no animal died after the second or further doses [6,7]. (2) Oseltamivir-P increased in the brain of 7-day old rats but not in 42-day old mature rats, undoubtedly because of the difference in their maturity of esterase activity and maturity of blood-brain barrier (BBB). Average brain tissue Cmax of oseltamivir-P in 7-day old rats was 3000 times higher than that of mature rats [7]. Brain Cmax of oseltamivir-P was significantly correlated to proportion of dead rats (p<0.05), but Cmax of oseltamivir-C was not [7,14]. (3) When one has infection, pro-inflammatory cytokines may impair the function of BBB (especially efflux mechanism), resulting in oseltamivir-P to increase in the brain. However, the function of BBB may recover rapidly as the flu recovers. (4) Delirium, abnormal behaviors, hallucinations and even suicide could be the symptoms resulting from disinhibition or dyscontrol induced by the action of central nervous system suppressants. The second group of serious adverse reactions to oseltamivir may include late onset pneumonia, exacerbation of infection, sepsis, hyperglycemia and bleeding. Late onset pneumonia and hyperglycemia were the adverse reactions that were observed significantly more in the randomized controlled trials (RCTs) for the approval of oseltamivir in many countries [6,7]. Recently Li and Wei [15] reported that oseltamivir-C reduced human cytosolic sialidase activity, and they postulated it as the potential mechanism of neuropsychiatric adverse reactions to the drug. Their results are very interesting for discussing the possible mechanism of delayed onset adverse reactions above, because these might occur if cell function of various tissues were impaired through neuraminidase (sialidase) inhibition by oseltamivir-C [5]. However, the mechanisms of acute-onset neuropsychiatric disorders, such as abnormal behavior and sudden death during sleep are different from their hypothesis, I believe [5]. Although causal relationship of acute onset adverse reactions (sudden death and abnormal behavior) with Oseltamivir-P is almost definite considering the evidences above [5,9], I have proposed a series of animal experiments to examine toxicokinetics of oseltamivir-P using infected mature animals to confirm the excess increase of oseltamivir-P in their brain to establish further causality [5]. Working group of The Sub-Committee on Safety of Medicine of MHLW once decided that infected mature animal studies should be conducted, but recently they cancelled the decision [1]. Other important things for establishing causality are confirmation of the affinity of oseltamivir-P to the benzodiazepine receptors (both central and peripheral type) and, confirmation of high concentration of oseltamivir-P in the brain, low concentration of oseltamivir-C in the brain and low concentration both in the brain and plasma in death cases (both deaths from abnormal behavior and sudden deaths) [5]. References 1)Documents at The Advisory Committee on Drug and Food �gThe Second annual meeting of the Sub-Committee on Safety of Medicine for 2007�h held at 16th June 2007 http://www.mhlw.go.jp/shingi/2007/06/s0616-1.html (in Japanese)�@ 2)Hama R., New type of influenza-related encephalopathy or new adverse drug reaction? BMJ rapid response; available at http://www.bmj.com/cgi/eletters/328/7433/227#98374 3)Hama R. Sudden deaths during sleep after taking the first dose of oseltamivir----It should be contraindicated to infants. The informed Prescriber (2005): 20 (2): 21-25 (in Japanese available at http://www.tip.gr.jp/pdf/2005/2005_02.pdf) 4)Kusuri-no-Check editorial team: Don�ft use Tamiflu to infants: sudden deaths during sleep after the first dose. Kusuri-no-Check No12 (revised) http://www.npojip.org/contents/book/mag012.html 5)Hama R. Seven fatal or life threatening neuropsychiatric adverse reactions to oseltamivir: case series and overview of causal relationship. Under preparation to submit to a medical Journal. 6)Chugai Pharm Co. New drug approval package (NAP) of oseltamivir (in Japanese); Tamiflu dry syrup (2002): available at [http://211.132.8.246/shinyaku/g0201/11/5303990_21400AMY00010.html?] 7)Chugai Pharm Co. New drug approval package (NAP) of oseltamivir (in Japanese); Oseltamivir capsule for prevention (2004) : available at [http://211.132.8.246/shinyaku/g0407/g040703/index.html] 8)Hama R. Three boys died from adverse reactions probably related to Tamiflu: Presentation at a scientific meeting Web-Kusuri-no-Check International No5 (English version of Web-Kusuri-no Check No59, Nov 25 2005) available at http://npojip.org/english/no59.html 9)Hama R. Tamiflu-related Strange Behavior and Sudden Death: Three cases and 10 reasons why I think it relates to Tamiflu: Web-Kusuri-no- Check International No6 (English version of Web-Kusuri-no Check No61, Nov 26 2005) available at http://npojip.org/english/no61.html 10) Documents for The Advisory Committee on Drug and Food �gThe first annual meeting of the Sub-Committee on Safety of Medicine for 2005�h held at 27th January 2006 (in Japanese): a) Death cases in children (1) [http://www.mhlw.go.jp/shingi/2006/01/dl/s0127-9d02.pdf] b) Death cases in children (2) [http://www.mhlw.go.jp/shingi/2006/01/dl/s0127-9d02-1.pdf] c) Death cases in adults (1) [http://www.mhlw.go.jp/shingi/2006/01/dl/s0127-9d03.pdf] d) Death cases in adults (2) [http://www.mhlw.go.jp/shingi/2006/01/dl/s0127-9d03-1.pdf] 11) Documents for The Advisory Committee on Drug and Food �gThe first annual meeting of the Sub-Committee on Safety of Medicine for 2007�h held at 4th April 2007 (in Japanese): available at: http://www.mhlw.go.jp/shingi/2007/04/s0404-2.html 12) FDA-CDER executive summary: One-Year Post Marketing Exclusivity Postmarketing Adverse Events Review (Oseltamivir phosphate): [http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005- 4180b_06_01_Tamiflu%20AE_reviewed.pdf] 13) Edwards ET. et al (Post-Marketing Safety Evaluator: Division of Drug Risk Evaluation :DDRE) Tamiflu AE Review 2006 Memorandum�iDepartment of Health and Human Services, Public Health Services, Food and Drug administration: Center for Drug Evaluation and Research=FDA CDER�j Sept. 20 2006 http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006- 4254b_09_01_Tamiflu%20AE%20Review%202006%20Redacted_D060309_092.pdf 14) Hama R. Tamiflu induces abnormal behavior after the first dose. The Informed Prescriber (2006): 21 (11): 21-25 (in Japanese available at http://npojip.org/sokuho/tip0611-12.pdf) 15) Li CY, Yu Q, Wei L et al. A nonsynonymous SNP in human cytosolic sialidase in a small Asian population results in reduced enzyme activity: potential link with severe adverse reactions to oseltamivir. Cell Res. 2007 Apr;17(4):357-62. Competing interests: None declared