Safety Measures for Oseltamivir Phosphate and Chugai's Future Approach

TOKYO, June 18, 2007 - Chugai Pharmaceutical Co., Ltd. [Head Office: Chuo-ku, Tokyo; President Osamu Nagayama (hereafter, "Chugai")] announced today that on June 16, it has presented in "Sub-committee on Safety of Drug" of the Ministry of Health, Labour and Welfare, regarding Chugai's approach on the safety measures of anti-influenza drug "oseltamivir" (product name: Tamiflu), imported from F. Hoffmann-La Roche Ltd. ("Roche") [Head Office: Basel, Switzerland. CEO: Franz B. Humer] for production and marketing in Japan.
In the sub-committee, seven groups and members including Chugai, namely, Yakugai Tamiflu Higaisha no kai,iYAKUGAI Ombudsperson "Medwatcher Japan," Non Profit Organization Japan Institute of Pharmacovigilance, and preclinical and clinical researchers have presented their opinions

Oseltamivir phosphate (hereinafter, Tamiflu) was first launched around the world as an anti-influenza agent in 1999, and from February 2001 in Japan. Thereafter, it has been used quite widely, particularly in Japan, but while its clinical efficacy is well recognized, there have been tragic cases reported, which have arisen out of abnormal behaviour, and the like. With taking such status seriously, we are putting increasingly more effort into investigating whether there is any causality and are investigating possible safety measures. Furthermore, we will make our best efforts to take actions summarized below.

1. Background
Among the safety data that has been collected since Tamiflu's launch in Japan in February 2001, we have accumulated reports of serious psychiatric or neurological events, such as disturbed consciousness and abnormal behaviour. Even though no causal link between these adverse events and Tamiflu was established, in May 2004, we added a description pertaining to psychiatric or neurological events (disturbed consciousness, abnormal behaviour, delirium, hallucination, delusion, convulsions, etc.) to the section of the package insert on "Serious Adverse Drug Reactions" aimed at alerting healthcare professionals. In addition, we prepared a guide for patients in December 2005, which issued an alert to be passed on by the medical institutions.
Since then, there have been two cases reported in February this year, in which teenage patients with influenza who took Tamiflu were said to have fallen to their deaths, and on February 28 the MHLW issued regarding potential for such accidents in children with influenza regardless of whether Tamiflu was being taken as a preventive measure. Next, on March 22, the MHLW emergency safety information warned that the use of Tamiflu in teenage patients should be avoided, as a general rule. Along with this instruction, Chugai provided information to about 120,000 medical institutions that were being supplied with Tamiflu with the cooperation of the MHLW, in order to ensure that the information was properly disseminated to call for attention and to conduct a follow-up survey of cases of adverse drug reactions.

2. Chugai's Policy and Approach
Chugai have comprehensively investigated the post-marketing surveillance results for local and overseas reports regarding incidences of psychiatric and neurological events, and previous preclinical safety and pharmacokinetic data including transfer to the brain, we have not obtained results which allow us to establish a causal relationship between Tamiflu and these events.  However, Chugai as the pharmaceutical company responsible for supply of Tamiflu, places the highest priority on assuring patient safety, and as such is continuing to promote its appropriate use along with revision of the package insert. We are also trying to alert healthcare professionals so that, after thoroughly considering patient background and clinical symptoms, they only administer Tamiflu to patients who are judged to be in need.
In addition, it is Chugai's intention is to analyze information received until now in further detail, and investigate under what circumstances serious events might occur and how to best avoid their occurrence if any.

3. Approach to the Next Influenza Season
Chugai will proactively investigate whether there is anything characteristic in the background, the timing, and the pattern of onset of abnormal behaviours, by further analyzing the information gathered on adverse events.
Moreover, in addition to preclinical and clinical research that have been planned previously, Chugai and Roche will immediately conduct research on the following pertaining to safety of Tamiflu, based on the proposals of the Preclinical and Clinical Working Groups on oseltamivir phosphate of the MHLW's Sub-committee on Safety of Drug set up in April of this year.

  a) Preclinical Research
     Pharmacokinetic and metabolic studies in the brain (test article: oseltamivir phosphate (hereinafter "prodrug") and its metabolite)
     (1) In-vitro assessment of active transport processes (transporters) relevant for exposure in brain
     (2) In-vitro assessment of the conversion (ester hydrolysis) of prodrug to metabolite by carboxylesterase 1 (hCE1) in brain and in-vivo intravenous PK study to investigate the penetration of metabolite into brain
     (3) Determination of brain, CSF and plasma concentrations in rats

     Confirm whether there is any activity on endogenous targets other than virus in the brain (test article: prodrug or its metabolite)
     (4) Receptor-binding assays related to central effects

     Additional toxicity studies using immature rats (test article: prodrug)
     (5) Toxicity studies using immature and mature rats (search for behaviour, and brain transfer, etc.)

  b) Clinical research
     (1) Human volunteer study of the effect of oseltamivir phosphate administration on sleep
     (2) Human volunteer study of oseltamivir phosphate administration and transport to cerebrospinal fluid.
 
Chugai will promptly evaluate the results obtained from the above-mentioned preclinical and clinical studies from a scientific viewpoint and we will make an effort to use these results for the best possible safety measures for the next influenza season. Based on these research outcomes, Chugai will continue to investigate the points that need further clarification.

4. Epidemiological Survey
Needless to say how crucial the above preclinical and clinical research works are for the further advancement of safety measures in influenza treatment, we think it is necessary to proceed with epidemiological studies simultaneously. Our understanding, until now, is that surveys have been conducted in 2005 and 2006 on about 2,800 cases and about 10,000 cases, respectively, with respect to the incidence of influenza-associated symptoms, and we would like to use these results to issue alerts for the next influenza season and promote the most appropriate use.
Chugai and Roche think that continuously conducting large-scale epidemiological studies that enable more detailed factor analysis (all treatment drugs, clinical course and symptoms of influenza infection, courses of treatment, and patient background characteristic, etc.) is necessary to achieve a more adequate and safer influenza treatment. Chugai intends to consult related academic societies and the MHLW on how to conduct such epidemiological studies.

Posted: June 2007


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