MONDAY June 16, 2008 (foodconsumer.org) -- The U.S. Food and Drug Administration today announced its decision to have boxed warnings added on the label of "conventional" antipsychotic drugs to indicate that increased risk of death has been associated with the off-label use of these medications to treat behavioral problems in older people with dementia.

Boxed warnings are the strongest ones that the FDA can give under the Food and Drug Administration Amendments Act of 2007 (FDAAA).   In 2005, the agency already demanded similar labeling changes for "atypical" antipsychotic drugs due to similar association with elevated death risk.

The warning for both classes of drugs is to say that clinical trials suggest that antipsychotic drugs of both types are linked with an increased risk of death when used in elderly patients treated for dementia-related psychosis.

"It is important that health care professionals and consumers have the most up-to-date drug safety information," said Thomas Laughren, M.D., director of the FDA's Division of Psychiatry Products in the Center for Drug Evaluation and Research.

"The prescribing information for all antipsychotic drugs will be updated to describe the risk of death in elderly patients being treated for symptoms associated with dementia."

Both classes of drugs are dopamine receptor antagonists that block the action of naturally occurring dopamine in the brain. Abnormally high dopamine action has been linked to psychosis and schizophrenia.

The difference is primarily in their side effects.   Atypical antipsychotic drugs have a lower incidence of neurological side effects such as involuntary movements or "tics".

Neither class is approved for use in the treatment of dementia-related symptoms including forgetfulness, poor memory, and an inability to recognize familiar objects, sounds, or people.

The FDA approves the drugs primarily for the treatment of symptoms associated with schizophrenia.  But the agency leaves the door open for doctors to use antipsychotic medications in treatment of patients with symptoms of dementia, a practice called "off-label" use that the FDA allows.

Two recent observational epidemiological studies examined the risk of death in elderly patients with dementia who were treated with conventional antipsychotic drugs and found that the death rates were comparable between those taking atypical antipsychotic and those using conventional antipsychotic drugs.

These studies, along with the earlier evidence for atypical antipsychotic drugs, indicate that both types of drugs should be considered to have an increased risk of death when used in the elderly treated for dementia-related psychosis, justifying the labeling of the boxed warnings, the FDA has concluded.

The FDA today issued letters to the manufacturers of both types of antipsychotic drugs, informing the manufacturers of its decision that they should make changes to drug labeling to indicate the risk. They were asked to change labeling in a way that all of the drugs carry uniform warning language.   The drug makers have 30 days to respond.

The affected conventional antipsychotic drugs include Compazine (prochlorperazine), Haldol (haloperidol), Loxitane (loxapine), Mellaril (thioridazine), Moban (molindrone), Navane (thithixene), Orap (pimozide), Prolixin (fluphenazine), Stelazine (trifluoperazine), Thorazine (chlorpromazine), and Trilafon (perphenazine).

Atypical antipsychotic drugs that have been required to carry a boxed warning include Clozaril (clozapine) , FazaClo (clozapine), Geodon (ziprasidone), Invega (paliperidone), Risperdal (risperidone), Seroquel (quetiapine), Zyprexa (olanzapine), and Symbyax (olanzapine and fluoxetine).

The FDA asked healthcare providers to consider the following when deciding whether or not to use any antipsychotic drug in elderly dementia patients.

Elderly patients with dementia-related psychosis treated with conventional or atypical antipsychotic drugs are at an increased risk of death.

Antipsychotic drugs are not approved for the treatment of dementia-related psychosis.   Furthermore, there is no approved drug for the treatment of dementia-related psychosis.   Healthcare professionals should consider other management options.

Physicians who prescribe antipsychotics to elderly patients with dementia-related psychosis should discuss this risk of increased mortality with their patients, patients’ families, and caregivers.

In the meantime, the FDA advised that "people taking antipsychotic drugs should not abruptly stop taking them. Caregivers and patients should talk to the patient's health care professionals about any concerns."

Below is some background about antipsychotics for healthcare professionals, cited from the FDA website.

Information for Healthcare Professionals

Antipsychotics

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FDA ALERT [6/16/2008]:   FDA is notifying healthcare professionals that both conventional and atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis.  

In April 2005, FDA notified healthcare professionals that patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death.   Since issuing that notification, FDA has reviewed additional information that indicates the risk is also associated with conventional antipsychotics.

Antipsychotics are not indicated for the treatment of dementia-related psychosis.   

This information reflects FDA’s current analysis of data available to FDA concerning these drugs. FDA intends to update this sheet when additional information or analyses become available.

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To report any unexpected adverse or serious events associated with the use of these drugs, please contact the FDA MedWatch program and complete a form on line at http://www.fda.gov/medwatch/report/hcp.htm or report by fax to 1-800-FDA-0178, by mail using the postage-paid address form provided on line, or by telephone to 1-800-FDA-1088.

FDA is requiring the manufacturers of conventional antipsychotic drugs to add a Boxed Warning and Warning to the drugs’ prescribing information about the risk of mortality in elderly patients treated for dementia-related psychosis similar to the Boxed Warning and Warning added to the prescribing information of the atypical antipsychotic drugs in 2005.*   See the last page of this document for a list of conventional and atypical antipsychotic drugs.

Considerations for Healthcare Professionals

Elderly patients with dementia-related psychosis treated with conventional or atypical antipsychotic drugs are at an increased risk of death.

Antipsychotic drugs are not approved for the treatment of dementia-related psychosis.   Furthermore, there is no approved drug for the treatment of dementia-related psychosis.   Healthcare professionals should consider other management options.

Physicians who prescribe antipsychotics to elderly patients with dementia-related psychosis should discuss this risk of increased mortality with their patients, patients’ families, and caregivers.

Background Information and Data

Previously, in April 2005, FDA informed healthcare professionals and the public about the increased risk of mortality in elderly patients receiving atypical antipsychotic drugs to treat dementia-related psychosis (April 2005 Public Health Advisory and Information for Healthcare Professionals).   At that time, the analyses of 17 placebo-controlled trials that enrolled 5377 elderly patients with dementia-related behavioral disorders revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients.   Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g. pneumonia) in nature.   Based on this analysis, FDA requested that the manufacturers of atypical antipsychotic drugs include information about this risk in a Boxed Warning and the Warnings section of the drugs’ prescribing information.

Recently, two observational epidemiological studies1,2 were published that examined the   risk of death in patients who were treated with conventional antipsychotic drugs.

Gill et al.1 performed a retrospective cohort study in Ontario, Canada of 27,259 adults, 66 years of age or older, with a diagnosis of dementia between April 1997 and March 2002.   The investigators compared the risk for death with use of an atypical antipsychotic versus no antipsychotic and the risk for death with use of a conventional antipsychotic versus an atypical antipsychotic. They found that   atypical antipsychotics were associated with increased mortality as compared to no antipsychotic use as early as 30 days and persisting until study end at 180 days. The investigators found that conventional antipsychotic use showed a marginally higher risk of death compared with atypical antipsychotic use. The causes of death were not reported in this study.  

Schneeweiss et al.2 performed a retrospective cohort study in British Columbia, Canada of 37,241 adults, 65 years of age or older, who were prescribed conventional (12,882) or atypical (24,359) antipsychotic medications for any reason between January 1996 and December 2004. The investigators compared the 180-day all cause mortality with use of a conventional antipsychotic versus an atypical antipsychotic. They found that the risk of death in the group of patients treated with conventional antipsychotic medications was comparable to, or possibly greater than, the risk of death in the group of patients treated with atypical antipsychotic medications. The causes of death with the highest relative risk were cancer and cardiac disease.  

FDA considers that the methodological limitations in these two studies preclude any conclusion   that conventional antipsychotics have a greater risk of death with use than atypical antipsychotics. FDA has determined, however, that the overall weight of evidence, including these studies, indicates that the conventional antipsychotics share the increased risk of death in elderly patients with dementia-related psychosis that has been observed for the atypical antipsychotics.   The prescribing information for all antipsychotic drugs will now include the same information about this risk in a Boxed Warning and the Warnings section.

References

1.   Gill SS et al.   Antipsychotic drug use and mortality in older adults with dementia.   Ann Intern Med.   2007;146:775-786

2.   Schneeweiss S et al.   Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients.   CMAJ.   2007;176:627-632.