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Last Updated: Dec 27th, 2006 - 19:07:47 |
After reviewing the adverse event reports for Tamiflu, a U.S. Food and Drug Administration (FDA) advisory panel concluded Friday that there was no evidence linking the deaths of 12 Japanese children aged 1 to 16, to the antiviral drug.
The FDA conducted the review on the safety of Tamiflu required by Section 17 of the Best Pharmaceuticals for Children Act (BPCA). “BPCA mandates the review of the adverse event reports received during the one-year after a drug has been granted pediatric exclusivity,” the FDA said.
The review discussed pediatric deaths, serious skin reactions, and neuropsychiatric events. These events were reported almost entirely in children from Japan. Of 32 million people treated with Tamiflu since its approval in 1999, 24 million including 11.6 million of children were in Japan, according to Tamiflu.com.
The 12 deaths, which all occurred after the year 2000, include one suicide, four sudden deaths, four cases of cardiac arrest and three cases of pneumonia, asphyxiation and acute pancreatitis, according to BBC News.
The Japanese Health Ministry was worried and warned last week that Tamiflu might induce strange behavior after these deaths, particularly the deaths of two teenage boys shortly after taking the drug.
Tamiflu is regarded as the best available antiviral drug for preventing and or treating human bird flu. Many countries have rushed to make and stockpile the medication, fearing that the deadly bird flu strain H5N1 may soon evolve into a variant that can spread the bird flu from one person to another, causing a human flu pandemic.
Dr. Robert Nelson, chair of the FDA's Pediatrics Advisory Committee, was quoted by The Associated Press (AP) as saying "If we ever have a pandemic of avian flu, which is a debatable point, people want to know that they have a drug that will not cause more harm than the flu itself. There is no evidence that this will."
The FDA said on its web site that the children apparently died of flu-related encephalitis and encephalopathy, which affected Japanese children since the mid-1990s before Tamiflu was approved. It said there was no evidence suggesting a causal relationship between Tamiflu and the children's deaths.
The advisory panel identified nearly all 12 children suffered neurologic and psychiatric problems such as delirium, hallucinations, abnormal behavior, convulsions, and encephalitis. The FDA acknowledged "in many of these cases, a relationship to Tamiflu was difficulty to assess because of the use of other medications, presence of other medical conditions, and/or lack adequate detail in the reports,"
Flu-associated encephalitis or encephalopathy has been commonly found in Japanese children since the mid-1990s, the FDA said. "These reports originated primarily from Japan where pediatricians described a pattern of rapid onset of fever, accompanied by convulsion and altered level of consciousness, progressing to coma within a few days of the onset of flu symptoms. This syndrome frequently resulted in death or significant neurologic sequelsae."
These diseases had prompted Japan to launch a nationwide surveillance. This happened before Tamiflu was approved for treatment of flu, the FDA said.
"The increased reported of neuropsychiatric events in Japanese children are most likely related to an increased awareness of influenza-associated encephalopathy, increased assess to Tamiflu in that population, and a coincident period of intensive monitoring adverse events," the statement said.
The FDA said the review "also identified severe skin reactions (like allergic reactions in some pediatric patients. There events were not all reported in Japanese children and have also been reported in adults. Severe skin reactions in all age groups are currently being reviewed in more detail," the AP reported.
The committee asked the FDA to give an update about a year from now on adverse events related to taking Tamiflu and to provide a full report in 2 years, the AP said. But it did not recommend any warning for Tamiflu other than adding information about serious skin reactions to the label, according to the AP.
The FDA anticipated continuing the monitoring of the adverse events, including neuropsychiatric adverse events, and would report back to the Pediatric Advisory Committee within 2 years.
Roche, the maker of Tamiflu, hailed the FDA’s decision. "We welcome the outcome of the FDA advisory committee and look forward to working with the FDA and other health authorities to extend our knowledge of the use of Tamiflu and its safety profile. The positive role of Tamiflu remains unchanged," said William M. Burns, CEO Roche Pharma Division.
"Tamiflu has been used in 33 million patients worldwide, including over 13 million children,” said Roche in a fact sheet posted on its web site. "Mortality in patients taking Tamiflu, both in adults and Children, is lower than in influenza patients who are not treated with Tamiflu. Based on independent studies, death rates in children treated with Tamiflu are reduced between 60 to 90 percent.”
"There is no increase in neuropsychitric events in patients on Tamiflu versus influenza patients in general. It is important to know that neuropsyciatric events can occur often with influenza patients. Beginning in the mid-1990s, there have been many reports in the pediatric scientific literature describing a syndrome of influenza-associated encephalitis (inflammation of the brain) or encephalopathy.”
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Tamiflu Pediatric Adverse Events: Questions and Answers
Cited in verbatim from the FDA website
• Why are certain drugs having their safety reports presented to the Pediatric Advisory Committee on November 18, 2005?
The eight products being reviewed are presently due for a public discussion of their adverse events as required by Section 17 of the Best Pharmaceuticals for Children Act (BPCA). BPCA mandates the review of the adverse event reports received during the one-year after a drug has been granted pediatric exclusivity. The FDA's Office of Pediatric Therapeutics (OPT) is authorized to carry out this mandate and is directed by law to refer such adverse event reports to the Pediatric Advisory Committee (PAC) for their review and recommendations regarding any regulatory actions.
• What are the drugs being presented on November 18, 2005?
The following drugs, which received their marketing exclusivity at least one year prior to this meeting, will be discussed:
Anagrelide (Agrylin)
Carboplatin (Paraplatin)
Fluconazole (Diflucan)
Irinotecan (Camptosar)
Oseltamivir (Tamiflu).
Rofecoxib (Vioxx)
Sodium ferric gluconate complex (Ferrlecit)
Sumatriptan (Imitrex)
• Why is there an in-depth presentation on Tamiflu (oseltamivir)? What will the presentation include?
The PAC will hear several presentations on oseltamivir (Tamiflu) including adverse event reports, a literature review, and analysis of the clinical trials data. In addition, the sponsor will present data from the clinical trials and safety assessments. A CDC presentation will also provide background information on the United States Surveillance Data on Influenza and their new pediatric influenza surveillance efforts. The review of the adverse event reports for Tamiflu will discuss pediatric deaths, serious skin reactions, and neuropsychiatric events. These events were reported almost entirely in children from Japan.
Specific Questions on Tamiflu:
• What is Tamiflu and what is it approved for?
Tamiflu (oseltamivir phosphate) is an antiviral drug approved for treatment of uncomplicated influenza A and B in patients 1 year of age or older. It is also approved for prophylaxis (prevention) of influenza in people 13 years or older after household contact or at high risk for exposure during influenza season. Tamiflu is one of a group of anti-influenza drugs called neuraminidase inhibitors that act by blocking the viral enzyme neuraminidase which helps the influenza virus invade cells in the respiratory tract.
• Does this discussion have anything to do with the pandemic preparations?
The Pediatric Advisory Committee discussion is not directly addressing any issues related to pandemic flu preparations. Indirectly, a better understanding of Tamiflu safety in children will be useful should a pandemic occur and there is widespread use of Tamiflu.
• Is Tamiflu approved for use in pediatric patients?
Tamiflu is available in both capsule and liquid formulations. It is approved for treatment of influenza in children over 1 year of age. In the U.S., Tamiflu is dosed according to body weight in younger children. Older children (over 40 kg or 88 lbs) and adolescents receive the same dose as adults. It is also approved for prophylaxis (prevention) of influenza in children over 13 years of age.
• What is useful about Tamiflu in pediatric patients? Who should use it?
When used as directed (twice daily for 5 days) Tamiflu can reduce the duration of influenza symptoms in otherwise healthy children by 1 to 1 ½ days. It also appears to reduce the severity of common flu symptoms. Consequently, it may allow children to return to school or other normal activities sooner. Tamiflu was also shown to be similarly effective in children who had a history of asthma and did not worsen the asthma symptoms.
Tamiflu is most effective when taken within 48 hours after the beginning of flu symptoms and not likely to be effective if patients have already had flu symptoms for several days. Patients (and their parents) should be aware that some patients with influenza may be at risk for secondary bacterial infections and should seek medical care if they are not improving within a few days of beginning Tamiflu.
Tamiflu has not been studied in children with very severe or complicated influenza who require hospitalization and it is not known whether it will provide the same benefit to children with severe illness.
• What are the important safety issues and adverse events?
When Tamiflu was studied in clinical trials as treatment for children with influenza, children taking Tamiflu experienced similar side effects as children not taking Tamiflu. Serious side effects were not identified. The most common side effects observed in both the treatment and prophylaxis trials were nausea and vomiting. In these trials, a small number of children stopped taking their Tamiflu because of nausea and vomiting or other adverse reactions.
In the safety review mandated by the BPCA, a number of adverse event reports were identified associated with the use of Tamiflu in children 16 years of age or younger. These adverse event reports were primarily related to unusual neurologic or psychiatric events such as delirium, hallucinations, confusion, abnormal behavior, convulsions, and encephalitis. These events were reported almost entirely in children from Japan who received Tamiflu according to Japanese treatment guidelines (very similar but not identical to U.S. treatment guidelines). The review identified a total of 12 deaths in pediatric patients since Tamiflu's approval. All of the pediatric deaths were reported in Japanese children. In many of these cases, a relationship to Tamiflu was difficult to assess because of the use of other medications, presence of other medical conditions, and/or lack of adequate detail in the reports.
The review also identified severe skin reactions (like allergic reactions) in some pediatric patients. These events were not all reported in Japanese children and have also been reported in adults. Severe skin reactions in all age groups are currently being reviewed in more detail.
• Why are many of the adverse events being reported from Japan?
Initially, it was not clear why the neuropsychiatric adverse events and deaths were reported almost entirely in Japanese children. The FDA receives adverse event reports from all over the world and usually adverse events are roughly the same from different reporting countries. The reports of death and neuropsychiatric events associated with Tamiflu, almost entirely from Japan, was unusual enough to prompt further evaluation.
The FDA requested additional information from both Hoffman-La Roche, the pharmaceutical company which produces Tamiflu, and the Japanese Ministry of Health, Labor, and Welfare. FDA then evaluated several possible explanations for the neuropsychiatric adverse events.
Was it possible that Japanese patients metabolize Tamiflu differently than American or European patients or have higher levels of the drug in their bodies? There is no scientific evidence that this is true and Japanese dosing recommendations are very similar to U.S. and European recommendations.
Was it possible that these events were an unusual manifestation of influenza infection? There is good evidence that neuropsychiatric events can occur with influenza, in the absence of Tamiflu or other treatment. Beginning in the mid-1990s, there have been many reports in the pediatric scientific literature describing a syndrome of influenza-associated encephalitis (inflammation of the brain) or encephalopathy. These reports originated primarily from Japan where pediatricians described a pattern of rapid onset of fever, accompanied by convulsions and altered level of consciousness, progressing to coma within a few days of the onset of flu symptoms. This syndrome frequently resulted in death or significant neurologic sequelae. These reports prompted nationwide surveillance of influenza-associated encephalopathy in Japan. This syndrome was described and the surveillance in Japan was in progress before Tamiflu was approved for the treatment of influenza.
Was it possible that the large number of adverse events from Japan was because the Japanese use more Tamiflu? Is it possible that we may see more U.S. cases as use of Tamiflu increases in this country? Partly because of the awareness in Japan of influenza-associated encephalopathy, the Japanese health service will pay for rapid diagnostic testing for influenza in children and subsequent treatment. Japan currently uses the majority of the world's supply of Tamiflu distributed for seasonal influenza. It is possible that some of these events might be observed in the U.S. population if the use of Tamiflu increases substantially.
Finally, was it possible that the neuropsychiatric events reported from Japan reflect different methods and requirements for adverse event reporting? Both the Japanese Ministry of Health, Labor and Welfare and Roche confirmed that Japanese regulators require an intensive period of active adverse event reporting for 6 months after a product is approved. When Tamiflu was approved for prophylaxis of influenza in Japan, Roche and its Japanese pharmaceutical affiliate actively solicited adverse event reports from 70,000 institutions and physicians in Japan. These adverse event reports included the 2003-04 flu season and were subsequently reported to the FDA and are included in the BPCA safety review.
It is particularly difficult to assess the relationship of Tamiflu to the reported pediatric deaths. It is known that young children (less than 2 years of age) are hospitalized more often for influenza-associated illness than older children and young adults. Infants and the elderly are known to have higher influenza-associated death rates than other age groups. However, in the U.S., influenza deaths in children were not among the events requiring reporting to public health departments and the CDC until the 2004-05 flu season.
Review of the available information on the safety of Tamiflu in pediatric patients suggests that the increased reports of neuropsychiatric events in Japanese children are most likely related to an increased awareness of influenza-associated encephalopathy, increased access to Tamiflu in that population, and a coincident period of intensive monitoring adverse events. Based on the information available to us, we can not conclude that there is a causal relationship between Tamiflu and the reported pediatric deaths.
• What are FDAs next steps?
The evaluation of the pediatric adverse events will be discussed in more detail at the Pediatric Advisory Committee on November 18, 2005; FDA looks forward to comments from the Advisory Committee members. FDA anticipates it will continue to monitor the adverse event profile, including neuropsychiatric adverse events, in all ages including pediatric patients, and will report back to the Pediatric Advisory Committee within 2 years. Through these activities we expect to further refine our understanding of the adverse event profile of Tamiflu. As we did last flu season, we will continue to collaborate with the Centers for Disease Control and Prevention to share information regarding influenza surveillance in the U.S. population and the use of antivirals, including Tamiflu, for treatment.
• What should I do about this information?
If you or your child is receiving Tamflu for the treatment of influenza and you are concerned that you may be experiencing a drug-related adverse event, you should contact your physician for advice and management. Adverse events should be reported to the FDA through the on-line MedWatch system or by phone.
Keep in mind that the most effective way to prevent influenza and its complications is by getting the annual influenza vaccine. Children younger than or equal to 8 years of age receiving their first influenza vaccine should receive the vaccine split into 2 doses given one month apart. Children from 6 months to 2 years of age and those with certain underlying medical conditions are considered at high risk for developing complications of influenza and are strongly encouraged to get the vaccine.
For more information, visit tamiflu.com and FDA Tamiflu info pages
© 2004-2005 by foodconsumer.org unless otherwise specified
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