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Response to letter by Symmonds et al
- Dr Zoya Panahloo (27 January 2004)
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New type of influenza-related encephalopathy or new adverse drug reaction?
- Rokuro Hama (28 February 2005)
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Virus related encephalitis and adverse drug reactions
- Rajendra P Deolankar (2 April 2005)
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Confirmed Influenza A and Sudden Death during Sleep after Taking Oseltamivir
- Rokuro Hama (5 April 2005)
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Dr Zoya Panahloo, Senior Medical Adviser-UK F.Hoffmann La Roche Ltd
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In response to the letter by Symmonds et al entitled -Guidelines on neuraminidase inhibitors in children are not supported by evidence-, F.Hoffmann-La Roche Ltd. would like to clarify that data from studies WV15759/WV15871 were made available to NICE. These were double-blind, placebo-controlled trials, conducted in children aged greater than or equal to 6 and less than or equal to 12 years to investigate the efficacy and tolerability of oseltamivir in the treatment of influenza amongst asthmatic children. Of the 355 individuals randomised to treatment, 170 received oseltamivir 2mg/kg and 164 received placebo). 179 of these children had laboratory-confirmed influenza infection, which represented only 70% of the planned recruitment target. This precluded any statistical demonstration of the primary efficacy end point time to freedom from illness (incorporating resolution of symptoms and a return to normal activity). Amongst the outcomes of this study, a positive effect on FEV1 in the oseltamivir group was seen, an observation which is being further investigated in an ongoing clinical trial in asthmatic children. We would also like to also clarify that we plan to publish the results from studies WV15759/WV15871.
Competing interests: None declared |
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Rokuro Hama, Chairman of Room 502 Osaka 2-3-1, Tennoji-ku Osaka, Japan 543-0062@
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EDITOR- In addition to the efficacy issue of neuramidase inhibitors that Symmonds pointed out, I would like to mention a new possibility of adverse reaction to the drug. In Japan, influenza-associated acute encephalopathy among children is a substantial public health problem; in the winter of 1998-99, for example, a total of 148 cases of encephalitis/encephalopathy associated with influenza were reported [1]. But after warnings and restriction of non-steroidal anti-inflammatory drugs (NSAIDs) not to use as antipyretics in influenza infection for children, reports of influenza related encephalopathy apparently decreased. Few such cases had been reported in the United States [2] after restriction of salicylates not to use as antipyretics for children. However, cases of sudden death associated influenza in previously healthy children were reported in the United States during 2002-03 seasons [2]. Center of Disease Control (CDC) began to investigate severe morbidity and mortality associated with influenza in children and young adults. 93 cases were reported since October 2003 to January 2004 [3]. The median age of the 93 children was 4 years (range: 4 weeks-17 years), with 55 (59%) children aged <5 years and 24 (26%) aged 6-23 months. 41 (54%) of the 76 children whose medical history was known, were reported to have had no underlying conditions. Of the 55 children for whom the location of death was reported, 15 (27%) died at home [3]. On the other hand Shiomi [4] reported Japansese six cases of sudden death during the 2002-03 seasons. All of these cases found dead during sleep; three were during nap and three were at night. Four of 6 cases were autopsied and found that all of their brains were swollen. Taking account of these findings Shiomi proposed a new type of influenza-associated encephalopathy: acute brain swelling type (ABS type) [4]. Among six cases five aged 3 years or less. Of the five infants four suddenly died during sleep after taking the first single dose of oseltamivir, while one took amantadine (8 year old child) and one infant took none of drug[4]. One of them, for example, was found dead during two hours nap after the first dose of oseltamivir [4]. Oseltamivir for pediatric use was first marketed in July 2002. Japanese market share of oseltamivir is outstandingly the largest in the world. Shiomi reffered that several similar sudden death cases during sleep (not known whether oseltamivir were taken) were reported in US [4]. According to the BPCA Executive Summary of oseltamivir in US [5], the data that were submitted on June 15, 2000 for new drug application shows Cmax and AUC of oseltamivir in brain tissue were 1500 or more (3000 for Cmax) fold higher in 7-day old pups compared to the 42-day old (adult) rats. I wonder these experiments might be the same as the new experiments on which Roche Laboratories cited when they cautioned health care professionals about using oseltamivir in infants under one year of age in December 2003 [6]. Roche Laboratories say it is likely that these high exposures are related to an immature blood-brain barrier (BBB) and that these data do not affect the use of oseltamivir in children of one year or older and in adults [6]. But I am very much afraid that even the well developed BBB of previously healthy children might be affected and disordered by cytokines during influenza. According to the Japanese NAP of oseltmivir [7,8], more precise data are available: in an experiment, 18 (8 males and 10 females) among 24 rats administered with 1000mg/kg of oral oseltamivir died within 7 hours after the first dose of oseltamivir except two male rats. Cyanosis was observed in 6 rats but no abnormality was observed at autopsy [7]. In the other experiment [8] two of 14 rats in 700mg/kg group and three of 14 rats in 1000mg/kg group died. The body temperature decreased, spontaneous movement decreased and respiration rate decreased and get irregular in 6 among 14 of 700mg/kg group and in 12 among 14 of 1000mg/kg group, while none of these signs and symptoms was observed either in 14 rats in control group or in 500 mg/kg of oseltamivir group. In the 1000mg/kg group tremor and collapse were also observed. These signs and symptoms indicate that major cause of those animals may be respiratory suppression due to general central nervous system suppression which resembles the toxicity profile of barbiturate and/or other sedatives. 500mg/kg is about 125 times the recommended dose in children (about 4mg/kg/day) in US and in Japan too, by mg/kg base, but it is only 20 times the recommended dose by peak plasma concentration base that is preferable for this type of toxicity. Considering the similarity between the signs and symptoms of the four sudden death children during sleep reported by Shiomi [4] and the juvenile animals reported by Roche laboratories [7,8], isn't it rational to doubt about the possibilities of causal relation to oseltamivir administered. At least we have to bear in mind that sudden death during sleep after taking oseltamivir (especially after the first dose) for the treatment of influenza might be related to the drug. Such cases should be reported as adverse reactions (adverse events of which relationship cannot be ruled out) and should not be excluded as non-drug-related adverse events. HAMA, Rokuro MD Email:gec00724@nifty.com References 1. Morishima T, Togashi T, Yokota S, et al. Encephalitis and encephalopathy associated with an influenza epidemic in Japan. Clin Infect Dis 2002;35:512-7. 2. CDC. Severe Morbidity and Mortality Associated with Influenza in Children and Young Adults--Michigan, 2003 MMWR 2003; 52(35); 837-840 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5235a2.htm 3. CDC. Update: Influenza-Associated Deaths Reported Among Children Aged <18 Years--United States, 2003-04 Influenza Season. MMWR 2004; 52(53); 1286-1288 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5253a4.htm 4. Shiomi S. Clinical spectrum of influenza-related encephalopathy. Pediatric internal medicine (in Japanese). 2003: 34(10) ; 1676-1681. 5. BPCA Executive Summary NDA 21-087/NDA 21-246 gTamiflu capsules and for oral suspensionh submitted June 15, 2000, review completed December 14, 2000 http://www.fda.gov/cder/foi/esum/2004/21087,21246_Tamiflu_clinical_BPCA.pdf 6. Roche Pharmaceuticals. Dear Health Care Professional (December 2003) @http://www.fda.gov/medwatch/SAFETY/2003/tamiflu_deardoc.pdf 7.New drug approval package (NAP) of oseltmivir (in Japanese); Tamiflu dry syrup (2002): http://211.132.8.246/shinyaku/g0201/11/5303990_21400AMY00010.html? 8.New drug approval package (NAP) of oseltmivir (in Japanese); Oseltamivir capsule for prevention (2004) :http://211.132.8.246/shinyaku/g0407/g040703/index.html Competing interests: None declared |
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Rajendra P Deolankar, Assistant Director National Institute of Virology, Pune 411 001, India
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Re: New type of influenza-related encephalopathy or new adverse drug reaction? Rokuro Hama has described the encephalitis/ encephalopathy as influenza-related encephalopathy and suspected the disease as adverse drug reaction [1]. It is interesting. It could be proper for several other encephalitis diseases attributed to different viruses and other pathogens. Japanese encephalitis (JE) virus is characterized as a virus that produces a large number of subclinical infections [2]. If this is true then the virus should be called as Japanese Virus and the disease should be called as Japanese Virus Encephalitis. Infections associated with encephalitis West Nile virus [3] would produce a similar picture of encephalitis as that of JEV [4]. Herpes simplex virus (HSV) causes cold sores around the mouth; however, when it attacks the brain and causes encephalitis it may be fatal in as many as half of those who are brain-diseased. HSV encephalitis could be misdiagnosed as JE [5]. Outbreak of acute encephalitis with high fatality rate had recently occurred in children of Andhra Pradesh, India, which was associated with Chandipura virus [6]. Milder forms of encephalitis can follow or accompany common childhood illnesses, including measles [7], mumps [8], chicken pox [9], rubella (German measles) [10], and mononucleosis [11]. About one out of every 1,000 people with measles will develop measles encephalitis, which begins 4 to 7 days after the measles rash appears. Encephalitis can result from rabies [12] and cytomegalovirus [13] (viral causes) and also from listeriosis [14], syphilis [15], or Lyme disease [16]. The people with weakened immune systems like those with HIV/AIDS or cancer may develop encephalitis due to toxoplasmosis [17]. Japanese encephalitis virus is detected in aseptic meningitis patients [18]. Acute undifferentiated fever caused by infection with Japanese encephalitis virus is also known [19]. There is thus a strong possibility that virus alone is not enough to cause encephalitis. In practice, the precise viral cause of the encephalitis may never be established. It is essential to commence early treatment to save the patient. The intravenous acyclovir is generally implemented [20]. Acyclovir is a tubuloobstructive drug [21] and may interfere in the synthesis of calcitriol and hence should be used with caution. It could harm rather than benefit. It is hypothesized that Calcitriol injection can be used as an emergency therapy in the encephalitis cases in the normal VDR patients [22]. Kidney and liver vitamin D event due to adverse drug reaction might precede encephalitis [23]. Virus surface glycoproteins and viral proteins produced in the infected cells cause stress signaling, activate transcription factors and induce proinflammatory cytokines and chemokines [24]. Grossly, proinflammatory events are associated with Th1 cytokines. Th1 responses are very sensitive to UVB radiation and can be suppressed. Remission of symptoms is linked to the appearance of a Th2 protective immune response. In mice, repeated UVB exposure has suppressed Th1 as well as Th2 response [25] and hence UVB treatment in encephalitis directed towards calciferol / anti-inflammatory cytokine synthesis could be useful but needs meticulous planning. Encephalitis is an inflammatory disease. Elevated levels of proinflammatory cytokines (interferon alpha and interleukin-6) and chemokines (interleukin-8) could be probable agents as these are associated with Japanese Encephalitis in human patients [26]. Interleukin-4 and transforming growth factor beta (TGF-beta) are protective against encephalitis [27] and up regulated by calcitriol. Interleukin-4 gene therapy protected monkeys from hyperacute autoimmune encephalomyelitis. The protective effect was associated with in situ downregulation of inflammatory mediators such as tumor necrosis factor alpha (TNF-alpha) and monocyte chemoattractant protein 1 (MCP-1) and also preservation of Blood Brain Barrier integrity [28]. References 1. Rokuro Hama. New type of influenza-related encephalopathy or new adverse drug reaction? BMJ Rapid Response, 28 February 2005.[Full Text] 2. Konishi E, Suzuki T. Ratios of subclinical to clinical Japanese encephalitis (JE) virus infections in vaccinated populations: evaluation of an inactivated JE vaccine by comparing the ratios with those in unvaccinated populations. Vaccine. 2002 Nov 22;21(1-2):98-107.[Medline] 3. Feki I, Marrakchi C, Ben Hmida M, Belahsen F, Ben Jemaa M, Maaloul I, Kanoun F, Ben Hamed S, Mhiri C. Epidemic West Nile virus encephalitis in Tunisia. Neuroepidemiology. 2005;24(1-2):1-7. Epub 2005. [Medline] 4. Morgan R. West Nile viral encephalitis: a case study. J Neurosci Nurs. 2004 Aug;36(4):185-8..[Medline] 5. Jha S, Patel R, Yadav RK, Kumar V. Clinical spectrum, pitfalls in diagnosis and therapeutic implications in herpes simplex encephalitis. J Assoc Physicians India. 2004 Jan;52:24-6. [Medline] 6. Rao BL, Basu A, Wairagkar NS, Gore MM, Arankalle VA, Thakare JP, Jadi RS, Rao KA, Mishra AC. A large outbreak of acute encephalitis with high fatality rate in children in Andhra Pradesh, India, in 2003, associated with Chandipura virus. Lancet. 2004 Sep 4;364(9437):869-74. [Medline] 7. Takebayashi K, Aso Y, Wakabayashi S, Matsutomo R, Okumura K, Sugita R, Inukai T. Measles encephalitis and acute pancreatitis in a young adult. Am J Med Sci. 2004 May;327(5):299-303.[Medline] 8. Koyama S, Morita K, Yamaguchi S, Fujikane T, Sasaki N, Aizawa H, Kikuchi K. An adult case of mumps brainstem encephalitis. Intern Med. 2000 Jun;39(6):499-502. [Medline] 9. Sauerbrei A, Wutzler P. Laboratory diagnosis of central nervous system infections caused by herpesviruses. J Clin Virol. 2002 Jul;25 Suppl 1:S45-51.[Medline] 10. Desmond MM, Wilson GS, Melnick JL, Singer DB, Zion TE, Rudolph AJ, Pineda RG, Ziai MH, Blattner RJ. Congenital rubella encephalitis. Course and early sequelae. J Pediatr. 1967 Sep;71(3):311-31.[Medline] 11. Greenberg DA, Weinkle DJ, Aminoff MJ. Periodic EEG complexes in infectious mononucleosis encephalitis. J Neurol Neurosurg Psychiatry. 1982 Jul;45(7):648-51.[Medline] 12. Mrak RE, Young L. Rabies encephalitis in a patient with no history of exposure. Hum Pathol. 1993 Jan;24(1):109-10.[Medline] 13. Schwarz TF, Loeschke K, Hanus I, Jager G, Feiden W, Stefani FH. CMV encephalitis during ganciclovir therapy of CMV retinitis. Infection. 1990 Sep-Oct;18(5):289-90.[Medline] 14. Hof H, Nichterlein T, Kretschmar M. Management of listeriosis. Clin Microbiol Rev. 1997 Apr;10(2):345-57.[Full Text] 15. Marano E, Briganti F, Tortora F, Elefante A, De Rosa A, Maiuri F, Filla A. Neurosyphilis with complex partial status epilepticus and mesiotemporal MRI abnormalities mimicking herpes simplex encephalitis. J Neurol Neurosurg Psychiatry. 2004 Jun;75(6):833.[Full Text] 16. Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. N Engl J Med. 1990 Nov 22;323(21):1438-44.[Medline] 17. Meisheri YV, Mehta S, Patel U. A prospective study of seroprevalence of Toxoplasmosis in general population, and in HIV/AIDS patients in Bombay, India. J Postgrad Med. 1997 Oct-Dec;43(4):93-7.[Medline] 18. Kuwayama M, Ito M, Takao S, Shimazu Y, Fukuda S, Miyazaki K, Kurane I,Takasaki T. Japanese encephalitis virus in meningitis patients. Emerg Infect Dis. 2005 Mar;11(3):471-3..[Medline] 19. Watt G, Jongsakul K. Acute undifferentiated fever caused by infection with Japanese encephalitis virus. Am J Trop Med Hyg. 2003 Jun;68(6):704-6. [Full Text] 20. Kennedy PG. Viral encephalitis. J Neurol. 2005 Mar 11. [Epub ahead of print] [Medline] 21. Schwarz A, Perez-Canto A. Nephrotoxicity of antiinfective drugs. Int J Clin Pharmacol Ther. 1998 Mar;36(3):164-7.[Medline] 22. Deolankar RP, Calcitriol (1,25-dihydroxyvitamin D) for emergency encephalitis treatment in the normal VDR patients. BMJ Rapid Response, 31 March 2005.[Full Text] 23. Deolankar RP. Kidney and liver vitamin D event might precede encephalitis. BMJ Rapid Response, April 1, 2005.[Full Text] 24. Trine H. Mogensen and Søren R. Paludan. Molecular Pathways in Virus-Induced Cytokine Production. Microbiology and Molecular Biology Reviews, March 2001, p. 131-150, Vol. 65, No. 1. 1092-2172.[Full Text] 25. Garssen J, Vandebriel RJ, De Gruijl FR, Wolvers DA, Van Dijk M, Fluitman A, Van Loveren H. UVB exposure-induced systemic modulation of Th1- and Th2-mediated immune responses. Immunology. 1999 Jul;97(3):506-14.[Medline] 26. Winter PM, Dung NM, Loan HT, Kneen R, Wills B, Thu le T, House D, White NJ,Farrar JJ, Hart CA, Solomon T. Proinflammatory cytokines and chemokines in humans with Japanese encephalitis. J Infect Dis. 2004 Nov 1;190(9):1618-26. [Medline] 27. Cantorna MT, Woodward WD, Hayes CE, DeLuca HF. 1,25-dihydroxyvitamin D3 is a positive regulator for the two anti-encephalitogenic cytokines TGF-beta 1 and IL-4. J Immunol. 1998 Jun 1;160(11):5314-9. [Full Text] 28. Poliani PL, Brok H, Furlan R, Ruffini F, Bergami A, Desina G, Marconi PC, Rovaris M, Uccelli A, Glorioso JC, Penna G, Adorini L, Comi G, 't Hart B, Martino G. Delivery to the central nervous system of a nonreplicative herpes simplex type 1 vector engineered with the interleukin 4 gene protects rhesus monkeys from hyperacute autoimmune encephalomyelitis. Hum Gene Ther. 2001 May 20;12(8):905-20.[Medline]
Competing interests: None declared |
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Rokuro Hama, Chairman of Japan Institute of Pharmacovigilance Room 502 Osaka 2-3-1, Tennoji-ku Osaka, Japan 543-0062@
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Re: Virus related encephalitis and adverse drug reactions Responding to my last letter [1], Rajendra P Deolankar said it was interesting but the cases I introduced could be proper for several other encephalitis diseases attributed to different viruses and other pathogens [2]. I did not include in my last letter, but according to Shiomi's paper [3], all of the six cases reported were confirmed as influenza A diagnosed by rapid antigen testing for influenza. Therefore, it could be difficult to say that all of the six patients with confirmed influenza A had other encephalitis diseases attributed to different viruses and other pathogens simultaneously. Contribution of elevated levels of proinflammatory, cytotoxic cytokines (interferon alpha, interleukin-6 and tumor necrosis factor- alpha=TNF-alpha),and/or chemokines (interleukin-8) may be very important for inducing influenza-related encepahalopathy/encephalitis and/or Reye's syndrome induced by non-steroidal anti-inflammatory drugs (NSAIDs), including diclofenac, mefenamic acid and salicylates, because release of TNF-alpha by macrophages increased by treatment with NSAIDs [4]. As far as I know, it took more than half a day from the onset to death in such diseases as encepahalopathy/encephalitis. However, at least four cases show that patients treated with oseltamivir died within only two to several hours after taking the first dose of oseltamivir. Among them, two died within a few hours during nap, and the other two died within several hours during night sleep. As I described in my last letter [1], Roche Laboratories say it is likely that the high level of exposures to oseltamivir (unchanged form) in the brain of 7-day old pups is related to an immature blood-brain barrier (BBB). I am very much afraid that well developed BBB of previously healthy children might be affected and disordered by cytokines if they are excessively produced during influenza infection. Through the disordered BBB, oseltamivir will easily penetrate into the brain tissue even of previously healthy children. I sent my last letter [1] to Chugai, the pharmaceutical industry that sells oseltamivir in Japan, suggesting that they should report these cases as adverse reactions to oseltamivir to Japanese drug regulatory agencies, because causal relation cannot be ruled out as this disease entity is entirely new. Chugai did not agree with my opinion that these cases should be classified as adverse reactions to oseltamivir. However, they agreed that these cases were adverse events after taking oseltamivir, and they were going to report these cases to regulatory agency in the letter addressed to me dated on March 4 2005. They replied today that they have reported 4 cases on March 31 2005. Regulatory agencies have to investigate whether additional cases have been occurring or not, and whether other adverse reactions might be induced in different age groups. While only seizure and confusion are included as psychiatric disorders in the US labeling of oseltamivir [5], hallucination, delirium, delusion, seizure, abnormal behavior and other disturbed consciousness were reported as psychiatric and nervous system adverse reactions to oseltamivir after being marketed in Japan [6]. They are well known paradoxical adverse reactions to sedatives, hypnotics and anesthetics, including barbiturate and benzodiazepins. By adding respiratory suppression, full spectrum of psychiatric and nervous system adverse effect of oseltamivir is very similar to that of sedatives and hypnotics. This is one of the most important reasons why those cases may be related to oseltamivir administered for treating influenza A and not to different viruses and other pathogens. Chugai said that 70 % or more of the world oseltamivir were prescribed in Japan in 2002/03. The large market share may be another important reason why a cluster of sudden death cases and various adverse reactions of psychiatric and nervous system were reported in Japan. However, if oseltamivir was prescribed more in other countries, similar cases might be observed in the future. Careful monitoring is essential. HAMA, Rokuro MD References 1.Hama R. New type of influenza-related encephalopathy or new adverse drug reaction? BMJ Rapid Response, 28 February 2005.[Full Text] 2.Deolankar RP. Virus related encephalitis and adverse drug reactions 3.Shiomi S. Clinical spectrum of influenza-related encephalopathy. Pediatric internal medicine (in Japanese). 2003: 34 (10); 1676-1681 4.Larrick JW and Kunkel SL. Is Reye's syndrome caused by augmented release of tumour necrosis factor? Lancet. 1986 Jul 19; 2(8499): 132-3. 5.label of Tamiflu approved on 06/24/2004 in US http://www.fda.gov/cder/foi/label/2004/21087slr016,21246slr010_Tamiflu_lbl.pdf 6.label of Tamiflu approved on July 2004 in Japan http://www.info.pmda.go.jp/go/pack/6250021M1027_1_07/ (in Japanese) Competing interests: None declared |
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