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Assessment of Neuropsychiatric Adverse Events in Influenza Patients Treated with Oseltamivir

A Comprehensive Review

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Abstract

After reports from Japan of neuropsychiatric adverse events (NPAEs) in children taking oseltamivir phosphate (hereafter referred to as oseltamivir [Tamiflu®; F. Hoffmann-La Roche Ltd, Basel, Switzerland]) during and after the 2004–5 influenza season, Roche explored possible reasons for the increase in reporting rate and presented regular updates to the US FDA and other regulatory authorities. This review summarizes the results of a comprehensive assessment of the company’s own preclinical and clinical studies, post-marketing spontaneous adverse event reporting, epidemiological investigations utilizing health claims and medical records databases and an extensive review of the literature, with the aim of answering the following questions: (i) what the types and rates of neuropsychiatric abnormalities reported in patients with influenza are, and whether these differ in patients who have received oseltamivir compared with those who have not; (ii) what levels of oseltamivir and its active metabolite, oseltamivir carboxylate are achieved in the CNS; (iii) whether oseltamivir and oseltamivircarboxylate have pharmacological activity in the CNS; and (iv) whether there are genetic differences between Japanese and Caucasian patients that result in different levels of oseltamivir and/or oseltamivir carboxylate in the CNS, differences in their metabolism or differences in their pharmacological activity in the CNS.

In total, 3051 spontaneous reports of NPAEs were received by Roche, involving 2466 patients who received oseltamivir between 1999 and 15 September 2007; 2772 (90.9%) events originated from Japan, 190 (6.2%) from the US and 89 (2.9%) from other countries. During this period, oseltamivir was prescribed to around 48 million people worldwide. Crude NPAE reporting rates (per 1 000 000 prescriptions) in children (aged ≤16 years) and adults, respectively, were 99 and 28 events in Japan and 19 and 8 in the US. NPAEs were more commonly reported in children (2218 events in 1808 children aged >16 years vs 833 in 658 adults) and generally occurred within 48 hours of the onset of influenza illness and initiation of treatment. After categorizing the reported events according to International Classification of Diseases (9th edition) codes, abnormal behaviour (1160 events, 38.0%) and delusions/perceptual disturbances (661 events, 21.7%) were the largest categories of events, and delirium or delirium-like events (as defined by the American Psychiatric Association) were very common in most categories.

No difference in NPAE reporting rates between oseltamivir and placebo was found in phase III treatment studies (0.5% vs 0.6%). Analyses of US healthcare claims databases showed the risk of NPAEs in oseltamivir-treated patients (n =159 386) was no higher than those not receiving antivirals (n = 159 386). Analysis of medical records in the UK General Practice Research Database showed that the adjusted relative risk of NPAEs in influenza patients was significantly higher (1.75-fold) than in the general population. Based on literature reports, NPAEs in Japanese and Taiwanese children with influenza have occurred before the initiation of oseltamivir treatment; events were also similar to those occurring after the initiation of oseltamivir therapy.

No clinically relevant differences in plasma pharmacokinetics of oseltamivir and its active metabolite oseltamivir carboxylate were noted between Japanese and Caucasian adults or children. Penetration into the CNS of both oseltamivir and oseltamivir carboxylate was low in Japanese and Caucasian adults (cerebrospinal fluid/plasma maximum concentration and area under the plasma concentration-time curve ratios of approximately 0.03), and the capacity for converting oseltamivir to oseltamivir carboxylate in rat and human brains was low. In animal autoradiography and pharmacokinetic studies, brain: plasma radioactivity ratios were generally 20% or lower. Animal studies showed no specific CNS/behavioural effects after administration of doses corresponding to ≥100 times the clinical dose. Oseltamivir or oseltamivir carboxylate did not interact with human neuraminidases or with 155 known molecular targets in radioligand binding and functional assays. A review of the information published to date on functional variations of genes relevant to oseltamivir pharmacokinetics and pharmacodynamics and simulated gene knock-out scenarios did not identify any plausible genetic explanations for the observed NPAEs.

The available data do not suggest that the incidence of NPAEs in influenza patients receiving oseltamivir is higher than in those who do not, and no mechanism by which oseltamivir or oseltamivir carboxylate could cause or worsen such events could be identified.

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Notes

  1. 1The use of trade names is for product identification purposes only.

References

  1. US FDA. Meeting of the FDA Pediatric Advisory Committee, 16 November 2006 [online]. Available from URL: http://www.fda.gov/OHRMS/DOCKETS/ac/oc06.htm [Accessed 2008 Jul 3]

  2. US FDA. Memorandum: Department of Health and Human Services Public Health Service FDA Centre for Drug Evaluation and Research: post-marketing adverse events reports review of central nervous system/psychiatric disorders associated with the use of Tamiflu, September 2006 [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4254b_09_01_Tamiflu%20AE%20Review%202006%20Redacted_D060309_092.pdf [Accessed 2008 Jun 30]

  3. US FDA. Meeting of the FDA Pediatric Advisory Committee, 27 November 2007 [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/07/transcripts/2007-4325tl_transcript.pdf [Accessed 2008 Jul 3]

  4. Fujita T, Mori M, Okumura A, et al. Epidemiologie survey of influenza-associated complications: II. A statistical analysis of symptoms and signs, and medication. J Japan Ped Soc 2007; 111(12): 2 [online]. Available from URL: http://www.jpeds.or.jp/english/journal/111-12e.html [Accessed 2008 Oct 31]

    Google Scholar 

  5. Data on file, Roche, 2008

  6. Chung BH, Tsang AM, Wong VC. Neurologic complications in children hospitalized with influenza: comparison between USA and Hong Kong. J Pediatr 2007; 151(5): el7–8

    Google Scholar 

  7. WHO. Suicide Prevention (SUPRE): suicide statistics, last updated 2007 [online]. Available from URL: http://www.who.int/mental_health/prevention/suicide/country_reports/en/index.html [Accessed 2007 Nov 18]

  8. Wilcox M, Zhu S. Oseltamivir therapy appears not to affect the incidence of neuropsychiatric adverse events in influenza patients [abstract]. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2007 Sep 17–20; Chicago (IL)

  9. Blumentals WA, Song X. The safety of oseltamivir in patients with influenza: analysis of healthcare claims data from six influenza seasons. MedGenMed 2007; 9(4): 23

    PubMed  Google Scholar 

  10. Robinson D, Schultz E, Brown P, et al. Updating the Read codes: user-interactive maintenance of a dynamical clinical vocabulary. J Am Med Inform Assoc 1997; 4: 465–72

    Article  PubMed  CAS  Google Scholar 

  11. Okumura A, Kubota T, Kato T, et al. Oseltamivir and delirious behavior in children with influenza [letter]. Pediatr Infect Dis J 2006; 25(6): 572

    PubMed  Google Scholar 

  12. Goshima N, Nakano T, Nagao M, et al. Clinical study of abnormal behaviour during influenza [in Japanese]. Infect Immun Child 2006; 18(371): 376

    Google Scholar 

  13. Wang YH, Huang YC, Chang LY, et al. Clinical characteristics of children with influenza A virus infection requiring hospitalization. J Microbiol Immunol Infect 2003; 36(2): 111–6

    PubMed  Google Scholar 

  14. Lin CH, Huang YC, Chiu CH, et al. Neurologic manifestations in children with influenza B virus infection. Pediatr Infect Dis J 2006; 25(11): 1081–3

    Article  PubMed  Google Scholar 

  15. Huang YC, Lin TY, Wu SL, et al. Influenza A-associated central nervous system dysfunction in children presenting as transient visual hallucination. Pediatr Infect Dis J 2003; 22(4): 366–8

    PubMed  Google Scholar 

  16. He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet 1999; 37(6): 471–84

    Article  PubMed  CAS  Google Scholar 

  17. Doucette KE, Aoki FY. Oseltamivir: a clinical and pharmacological perspective. Expert Opin Pharmacother 2001; 2(10): 1671–83

    Article  PubMed  CAS  Google Scholar 

  18. Schentag JJ, Hill G, Chu T, et al. Similarity in pharmacokinetics of oseltamivir and oseltamivir carboxylate in Japanese and Caucasian subjects. J Clin Pharmacol 2007; 47(6): 689–96

    Article  PubMed  CAS  Google Scholar 

  19. Gieschke R, Dutkowski R, Smith J, et al. Similarity in the pharmacokinetics of oseltamivir and oseltamivir carboxylate in Japanese and Caucasian children. Options for the Control of Influenza VI; 2007 Jun 17–23; Toronto (ON)

  20. Jhee SS, Yen M, Ereshefsky L, et al. Low penetration of oseltamivir and its carboxylate into cerebrospinal fluid in healthy Japanese and Caucasian volunteers. Antimicrob Agents Chemother 2008; 52: 3687–93

    Article  PubMed  CAS  Google Scholar 

  21. Loscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx 2005; 2(1): 86–98

    Article  PubMed  Google Scholar 

  22. Ose A, Kusuhara H, Yamatsugu K, et al. P-glycoprotein restricts the penetration of oseltamivir across the blood-brain barrier. Drug Metab Dispos 2008; 36(2): 427–34

    Article  PubMed  CAS  Google Scholar 

  23. Morimoto K, Nakakariya M, Shirasaka Y, et al. Oseltamivir (Tamiflu) efflux transport at the blood-brain barrier via P-glycoprotein. Drug Metab Dispos 2008; 36(1): 6–9

    Article  PubMed  CAS  Google Scholar 

  24. Irwin S. Comprehensive observational assessment: Ia. A systematic, quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia 1968; 13(3): 222–57

    Article  PubMed  CAS  Google Scholar 

  25. Chavas LM, Tringali C, Fusi P, et al. Crystal structure of the human cytosolic sialidase Neu2: evidence for the dynamic nature of substrate recognition. J Biol Chem 2005; 280(1): 469–75

    PubMed  CAS  Google Scholar 

  26. Magesh S, Suzuki T, Miyagi T, et al. Homology modeling of human sialidase enzymes NEU1, NEU3 and NEU4 based on the crystal structure of NEU2: hints for the design of selective NEU3 inhibitors. J Mol Graph Model 2006; 25(2): 196–207

    Article  PubMed  CAS  Google Scholar 

  27. Mendel DB, Tai CY, Escarpe PA, et al. Oral administration of a prodrug of the influenza virus neuraminidase inhibitor GS 4071 protects mice and ferrets against influenza infection. Antimicrob Agents Chemother 1998; 42(3): 640–6

    PubMed  CAS  Google Scholar 

  28. Monti E, Preti A, Venerando B, et al. Recent development in mammalian sialidase molecular biology. Neurochem Res 2002; 27(7-8): 649–63

    Article  PubMed  CAS  Google Scholar 

  29. Yamaguchi K, Hata K, Koseki K, et al. Evidence for mitochon-drial localization of a novel human sialidase (NEU4). Biochem J 2005; 390 (Pt 1): 85–93

    Article  PubMed  CAS  Google Scholar 

  30. Hata K, Koseki K, Yamaguchi S, et al. Limited inhibitory effects of oseltamivir and zanamivir on human sialidases. Antimicrob Agents Chemother 2008; 52: 3484–91

    Article  PubMed  CAS  Google Scholar 

  31. Shi D, Yang J, Yang D, et al. Anti-influenza prodrug oseltamivir is activated by carboxylesterase human carboxylesterase 1, and the activation is inhibited by antiplatelet agent clopidogrel. J Pharmacol Exp Ther 2006; 319(3): 1477–84

    Article  PubMed  CAS  Google Scholar 

  32. Charasson V, Bellott R, Meynard D, et al. Pharmacogenetics of human carboxylesterase 2, an enzyme involved in the activation of irinotecan into SN-38. Clin Pharmacol Ther 2004; 76(6): 528–35

    Article  PubMed  CAS  Google Scholar 

  33. Tanimoto K, Kaneyasu M, Shimokuni T, et al. Human carboxylesterase 1A2 expressed from carboxylesterase 1A1 and 1A2 genes is a potent predictor of CPT-11 cytotoxicity in vitro. Pharmacogenet Genomics 2007; 17(1): 1–10

    Article  PubMed  CAS  Google Scholar 

  34. Hosokawa M, Furihata T, Yaginuma Y, et al. Structural organization and characterization of the regulatory element of the human carboxylesterase (CES1A1 and CES1A2) genes. Drug Metab Pharmacokinet 2008; 23(1): 73–84

    Article  PubMed  CAS  Google Scholar 

  35. Hill G, Cihlar T, Oo C, et al. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies. Drug Metab Dispos 2002; 30(1): 13–9

    Article  PubMed  CAS  Google Scholar 

  36. Fujita T, Brown C, Carlson EJ, et al. Functional analysis of polymorphisms in the organic anion transporter, SLC22A6 (OAT1). Pharmacogenet Genomics 2005; 15(4): 201–9

    Article  PubMed  CAS  Google Scholar 

  37. Bleasby K, Hall LA, Perry JL, et al. Functional consequences of single nucleotide polymorphisms in the human organic anion transporter hOAT1 (SLC22A6). J Pharmacol Exp Ther 2005; 314(2): 923–31

    Article  PubMed  CAS  Google Scholar 

  38. Kroetz DL, Pauli-Magnus C, Hodges LM, et al. Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics 2003; 13(8): 481–94

    Article  PubMed  CAS  Google Scholar 

  39. Sakurai A, Tamura A, Onishi Y, et al. Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications. Expert Opin Pharmacother 2005; 6(14): 2455–73

    Article  PubMed  CAS  Google Scholar 

  40. Ishikawa T, Hirano H, Onishi Y, et al. Functional evaluation of ABCB1 (P-glycoprotein) polymorphisms: high-speed screening and structure-activity relationship analyses. Drug Metab Pharmacokinet 2004; 19(1): 1–14

    Article  PubMed  CAS  Google Scholar 

  41. Kusuhara H, Sugiyama Y. Active efflux across the blood-brain barrier: role of the solute carrier family. NeuroRx 2005; 2(1): 73–85

    Article  PubMed  Google Scholar 

  42. Marzolini C, Tirana RG, Kim RB. Pharmacogenomics of the OATP and OAT families. Pharmacogenomics 2004; 5(3): 273–82

    Article  PubMed  CAS  Google Scholar 

  43. Nishizato Y, Ieiri I, Suzuki H, et al. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther 2003; 73(6): 554–65

    Article  PubMed  CAS  Google Scholar 

  44. Lee W, Glaeser H, Smith LH, et al. Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2): implications for altered drug disposition and central nervous system drug entry. J Biol Chem 2005; 280(10): 9610–7

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

All of the investigations described in this article were supported by Roche. All authors are current employees of Roche, and Stephen Toovey, Eric Prinssen, Bharat Thakrar, Regina Dutkowski, Gerhard Hoffmann, Alexander Breidenbach, Susan Sacks, Jonathan Solsky and David Reddy have stock ownership options in the company

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Authors and Affiliations

  1. F. Hoffmann-La Roche Ltd, Basel, Switzerland

    Stephen Toovey, Craig Rayner, Eric Prinssen, Barbara Donner, Bharat Thakrar, Gerhard Hoffmann, Alexander Breidenbach, Lothar Lindemann, Ronald Gieschke & David Ready

  2. Roche Palo Alto LLC, Palo Alto, California, USA

    Tom Chu

  3. Hoffmann-La Roche Inc., Nutley, New Jersey, USA

    Regina Dutkowski, Ellen Carey, Susan Sacks & Jonathan Solsky

  4. Roche Products Ltd, Welwyn Garden City, UK

    Lauren Boak & Ian Small

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Toovey, S., Rayner, C., Prinssen, E. et al. Assessment of Neuropsychiatric Adverse Events in Influenza Patients Treated with Oseltamivir. Drug-Safety 31, 1097–1114 (2008). https://doi.org/10.2165/0002018-200831120-00006

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