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http://www.fda.gov/cder/drug/infopage/tamiflu/QA20051117.htm
Tamiflu Pediatric Adverse Events: Questions and Answers
General Meeting Questions:
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 ?
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.
Date created: November 17, 2005
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