WASHINGTON, April 12-The FDA has issued a "black box" warning on all atypical antipsychotic drugs on the basis of evidence that their use leads to excess mortality for elderly patients.
These drugs are typically used off-label in nursing homes to control "sundowning." In this condition patients with dementia wander the halls and develop agitation during nighttime hours.
In its public health advisory, which was issued late yesterday, the FDA noted that the drugs are approved for treatment of schizophrenia and mania, but "clinical studies of these drugs to treat behavioral disorders in elderly patients with dementia have shown a higher death rate associated with their use compared to patients receiving a placebo."
Action Points
- Agitation is a common symptom among elderly patients with dementia, but there is no FDA-approved treatment for agitation associated with dementia.
- Caregivers and family members who are dealing with dementia patients should be advised about non-pharmacological approaches to treating agitation, including a thorough assessment for comorbities such as urinary tract infection that may trigger agitation.
- Patients receiving atypical antipsychotic agents for control of behavioral symptoms associated with dementia should be carefully monitored taking into account the FDA advisory of a higher death rate associated with therapy.
The drug agency analyzed data from 17 placebo-controlled studies of four drugs in this class and determined that the rate of death for elderly dementia patients treated with an atypical antipsychotic drug was roughly 1.6 to 1.7 times that of placebo. The most common causes of death were heart-related (heart failure or sudden cardiac death) or pneumonia.
Atypical antipsychotics fall into three drug classes on the basis of their chemical structure, but the FDA says that excess mortality was seen across all classes. As a result, the agency concluded that "the effect is probably related to the common pharmacologic effects of all atypical antipsychotic medications, including those that have not been studied in the dementia population."
The advisory applies to these atypical antipsychotic agents:
- Abilify (aripiparozole)
- Zyprexa (olanzapine)
- Seroquel (quetiapine)
- Risperdal (risperidone)
- Clozaril (clozapine)
- Geodon (ziprasidone).
The FDA also included Symbyax, which is a combination of Zyprexa and Prozac (fluoxetine) that is approved for treatment of depressive episodes associated with dipolar disorder.
The FDA instructed the manufacturers to add a "boxed warning to their drug labeling to describe the risk." The so-called black box will also state that the drug is "not approved for the treatment of behavioral symptoms in elderly patients with dementia."
The FDA action comes less than a year after Alzheimer's disease researchers reported that compared with placebo, 60% of patients randomized to Seroquel at doses of 200 mg/day had significant improvement in agitation associated with dementia (P<0.05).
The randomized, placebo controlled trial, which was reported in July 2004 at the International Conference on Alzheimer's Disease and Related Disorders, compared two Seroquel doses -- 100 mg/day and 200 mg/day -- with placebo in 333 nursing home patients with probable Alzheimer's disease and/or vascular dementia.
When the results were reported, senior investigator Pierre Tariot, M.D., a professor of psychiatry, neurology, aging, and developmental biology at the University of Rochester in New York, said Seroquel was well tolerated with no increase in cerebrovascular events -- which many Alzheimer's disease researchers consider the most significant risk when prescribing atypical antipsychotic agents for patients with dementia.
In Dr. Taroit's study the hazard ratio for cerebrovascular events in patients receiving Seroquel was 0.15 (95% confidence interval [CI], 0.02 - 1.34). This compares favorably with the risk ratio range for Risperdal (2.3 - 3.3) and Zyprexa (3.0 - 4.87), Dr. Tariot said, but he noted that the confidence intervals were broad.
At the Alzheimer's research meeting, William Thies, PhD, vice president of medical and scientific affairs for the Alzheimer's Association, said that even though agitation is a major treatment problem in Alzheimer's disease, there were little data to support any specific treatments for agitation. He said the Seroquel study was "a major finding, and I think it is one of the most significant studies presented at this meeting."
Importantly, this study has only been presented at this meeting in abstract form and has not been published in a peer reviewed journal. For this reason, the study was not one of the ones reviewed by the FDA and the conclusions must be considered to be preliminary. They should not form the basis of clinical recommendations.
Finally, the FDA said it is also considering adding a warning to the labeling of older antipsychotic medications because limited data also suggest a similar increase in mortality for these drugs. But the agency is awaiting results from an ongoing review of those older drugs.
Related articles:
- Dementia Drug Treatment Still Elusive
- Cardiovascular Risk Factors Linked to Dementia
- Mild Cognitive Impairment Flagged as Possible Early Sign of Alzheimer's Disease, Stroke
- Moderate Alcohol Consumption Appears to Slow Cognitive Decline in Older Women
Primary Source
Food and Drug Administration Talk Paper. FDA Issues Public Health Advisory for Antipsychotic Drugs Used for Treatment of Behavioral Disorders in Elderly Patients
Secondary Source
9th International Conference on Alzheimer's Disease and Related Disorders, Philadelphia, July 17-22, 2004. Pierre Tariot, MD, University of Rochester, New York. William Thies, Alzheimer's Association, Chicago.