Dangerous Abnormal Behavior In Children And Adolescents Treated With Flu Drug Oseltamivir (TAMIFLU)

The manufacturer of the flu drug oseltamivir (TAMIFLU), Roche Laboratories Inc., announced on November 14, 2006, that new precautions have been added to the drug’s professional product label (also known as a package insert) about the possibility of abnormal behavior in children and adolescents that, in extreme cases, has resulted in deaths.

The new professional label with the updated precaution about abnormal behavior is posted on the Food and Drug Administration’s (FDA) Web site at: www.fda.gov/medwatch/safety/2006/Tamiflu_PI.pdf.

The FDA’s Pediatric Advisory Committee met on November 16, 2006, two days after the label was changed, to review the adverse reaction reports of abnormal behavior associated with the use of oseltamivir. FDA advisory committees such as the Pediatric Advisory Committee are composed of outside experts that are asked to advise the agency on important issues of science and public health.

The FDA is required to make all documents that will be discussed at advisory committee meetings available to the public before the meeting. In the FDA documents released three days before the Pediatric Advisory Committee meeting, a memo from pharmacists and a physician in the FDA’s Division of Drug Risk Evaluation (DDRE) recommended a much more detailed precaution for the use of oseltamivir in children and adolescents than the one that was announced on November 14, 2006.

The DDRE recommended the following precaution statement for oseltamivir in their memo:

PRECAUTIONS
Neuropsychiatric Events: There have been postmarketing reports, predominately from Japan, of neuropsychiatric events (abnormal behavior, delirium, hallucinations, delusions, aggression, suicidal ideation, and other mental status changes) with the use of oseltamivir for the treatment of influenza, primarily among pediatric and adolescent patients, but also in adults. In extreme cases, patients have engaged in dangerous behaviors, such as running away or jumping from heights, resulting in injury or death. The relative contribution of exposure to the drug versus the influenza-illness itself to the development of these neuropsychiatric events is not known.

Patients, especially pediatric and adolescent patients, should be monitored closely for such abnormal behavior. This close monitoring is particularly important after first starting treatment with oseltamivir because the median time to onset of symptoms in postmarketing reports was 1-2 doses. If patients develop abnormal behaviors, their healthcare provider should be contracted immediately to determine appropriate treatment and whether their Tamiflu (oseltamivir) therapy should be discontinued.  

This memo was dated September 20, 2006 – almost three months before the Pediatric Advisory Committee meeting held on November 16, 2006, and about two months before the labeling change was announced.  

A complete set of the documents discussed at the November 16, 2006, Pediatrics Advisory Committee are posted on the FDA’s Web site at: http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4254b1-index.htm.  

There are two important differences between the precaution that now appears in oseltamivir’s professional product labeling and the recommendations made by the DDRE:

1. The descriptions of the types of abnormal behavior that has been reported in children and adolescents treated with oseltamivir in addition to delirium, such as hallucinations, delusions, aggression and suicidal ideation are contained in the DDRE language.
2. The fact that in extreme cases, abnormal behavior has resulted in deaths is included in the precaution recommended by DDRE.

The oseltamivir professional product label that was in effect prior to the November 14, 2006, labeling revision made no reference to the possibility of abnormal behavior in children and adolescents using oseltamivir. An older version of the drug’s professional product labeling was distributed to committee members prior to the November 16, 2006, Pediatric Advisory Committee meeting.

In effect, the advisory committee was asked to discuss and make recommendations based on the labeling changes recommended by the DDRE without clearly knowing that an abbreviated precaution had been adopted two days earlier (on November 14th). The advisory committee members were largely in favor of the language suggested by the DDRE with one important exception that will be discussed below.  

The precaution recommended by the DDRE was based on the labeling changes required by Japanese regulators in October 2005 for oseltamivir sold in Japan. The Japanese labeling recommended that oseltamivir treatment be stopped if abnormal behavior developed in children or adolescents taking the drug. The DDRE precaution statement said that if abnormal behavior develops, the physician should be contacted immediately and then the decision will be made to continue or discontinue the drug. 

Several members of the advisory committee noted that waiting to discontinue the oseltamivir may be too late if the abnormal behavior is extreme. Further, for a large portion of the U.S. population, it is impossible to reach a physician in a reasonable period of time for emergency advice.

The fact that the FDA did not make it clear to the members of the Pediatric Advisory Committee that the precaution statement announced on November 14th was not the same as the suggested statement presented to the committee on November 16th is troubling. We have no explanation for the agency’s action. We do urge that the FDA require the precaution statement in oseltamivir’s professional label as suggested by the DDRE with the change mentioned above to stop the drug immediately and then contact the prescriber.

Oseltamivir Adverse Reactions in Children and Adolescents
During the time from August 29, 2005 through July 6, 2006, there were 129 reports of neuropsychiatric adverse events associated with the use of oseltamivir. There were 26 reports excluded for various reasons, leaving 103 reports to be discussed by the Pediatric Advisory Committee. Of these 103 reports, about 67 percent involved pediatric patients whose ages ranged up to 17 years old. The use of oseltamivir in these reports was predominantly for the treatment of the flu. There were three reports of deaths.  

The patients in the three fatal reports were healthy except for having the flu at the time they received oseltamivir. One patient was a 14 year old boy who apparently fell to his death after climbing on his condominium balcony railing. The other two cases were adult males who also fell to their deaths; one of these two patients left a suicide note.

These three patients reportedly had not shown any psychological or neurological abnormalities before they were treated with oseltamivir for the flu. There were additional reports of patients who had jumped or fallen, but had survived their injuries.

Oseltamivir Prescriptions in the U.S. and Japan
Remarkably, there are only two countries in the world that are major users of oseltamivir: the U.S. and Japan. The use of oseltamivir in all other countries combined is negligible compared to the drug’s use in these two countries. The reasons for this huge difference is unknown. Possible explanations for the large number of oseltamivir prescriptions in the U.S. are direct-to-consumer (DTC) prescription drug advertising and media coverage of an impending bird flu pandemic that resulted in the hoarding of the drug in this country.  

The high use of oseltamivir in Japan may, in part, be explained by the fact that Japanese physicians sell the drugs they prescribe to their patients. This is apparently a very lucrative activity for Japanese physicians.

The only countries that allow DTC advertising are the U.S. and New Zealand. Shortly after oseltamivir was approved in this country, Roche Pharmaceuticals Inc. was reported to have spent $27.9 million for DTC ads, some of which were found to be misleading. On at least two occasions, the FDA cited Roche Pharmaceuticals Inc., for the false and misleading advertising of oseltamivir including false and misleading DTC ads.

The table that accompanies this article compares the numbers of prescriptions dispensed for oseltamivir in the U.S. and Japan for the time period covering 2001 through 2005. In total, the number of prescriptions for pediatric patients in Japan is about 11 times greater than the numbers of prescriptions for the drug in this country.

Oseltamivir was approved by the FDA in October 1999. In 2005, there were more than 2.2 million prescriptions dispensed in the U.S. for oseltamivir. This was an increase of about 370 percent over the number of prescriptions for the drug in 2004. Sales of the drug approached $160 million in 2005 – an increase of almost 390 percent over 2004 sales.

Does Oseltamivir Cause Abnormal Behavior in Children and Adolescents?
At the present time, the FDA does not have a complete explanation for the association seen between oseltamivir and abnormal behavior. It is unclear if these reports are related to the drug, manifestations of the flu alone, or a combination oseltamivir and the flu. The majority of adverse event reports continue to come from Japan. That may suggest some genetic predisposition in the Japanese population for the development of abnormal behavior with the use of oseltamivir.

The FDA commented that due to the fact that numerous reporting physicians stated in these reports that their patient’s abnormal behavior was associated with oseltamivir treatment and that the peculiar characteristics of these adverse events are different from the usual flu-related central nervous system symptoms, the agency cannot rule out the possible contribution of oseltamivir to abnormal behavior over and above the adverse symptoms that may result from the flu.

What You Can Do
Oseltamivir should be stopped immediately if the person taking this drug develops abnormal behavior, delirium, hallucinations, delusions, aggression, suicidal ideation and/or other mental status changes while taking the drug to treat the flu. The safest option, until more is known about this possible dangerous side effects with oseltamivir, is then to take the individual experiencing abnormal behavior to the emergency room for evaluation. The patient’s physician should be contacted as soon as possible.