The U.S. Food and Drug Administration (FDA) has ordered manufacturers of
atypical, or second-generation, antipsychotic medications to add a new warning
to already existing black-box warnings noting that the drugs are associated
with an increased risk of death related to psychosis and behavioral problems
in elderly patients with dementia.
Although none of the newer antipsychotic medications is approved to treat
behavioral disturbances associated with dementia, the use of the drugs in the
elderly has been widely studied. Both industry executives and regulators
acknowledge that the popular medications are commonly prescribed off-label for
older patients—particularly those with Alzheimer's disease—who
exhibit aggressive or agitated behaviors.
The FDA said last month that an agency review of placebo-controlled trials
involving the use of four of the drugs in elderly patients with
dementia-related behavioral problems found numerical increases in the rate of
death in patients taking the medications compared with patients taking
placebo. Of the studies included in the agency analysis, 15 of the 17 trials
showed increased death rates associated with olanzapine (Zyprexa),
aripiprazole (Abilify), risperidone (Risperdal), and quetiapine
While no studies on clozapine (Clozaril) or ziprasidone (Geodon) use in
elderly populations have been completed, the FDA mandated that they, too,
carry the new warning.
The agency noted that the six drugs fall into three different chemical
classes, and the increased risk was seen with drugs in each of the three
classes. Therefore, the FDA said, "The agency has concluded that the
effect is probably related to the common pharmacologic effects of all atypical
medications, including those that have not been systematically studied in the
The reviewed studies, the FDA said, included 5,106 patients, and several
analyses demonstrated "an approximately 1.6- to 1.7-fold increase in
mortality in these [combined] studies."
In the FDA-reviewed studies, which averaged 10 weeks in duration, the rate
of death in drug-treated patients was about 4.5 percent, compared with a rate
of 2.6 percent in the patients taking placebo.
Examination of the specific causes of these deaths revealed that most were
due to either heart-related events (for example, heart failure or sudden
death) or infections (mostly respiratory, including pneumonia).
In addition to the six antipsychotics, the olanzapine/fluoxetine
combination (Symbyax) will carry the new black-box
The agency also noted it may require the older, typical antipsychotic
medications to carry similar warning language "because the limited data
available suggest a similar increase in mortality for these drugs."
However, the review of data on the older drugs is ongoing, the FDA said.
While the newly required warning will appear in a black box, the message
itself isn't entirely new. In fact, since last year olanzapine and risperidone
have included in their labeling information regarding increased risk of death
in elderly patients. Moreover, questions and concerns have followed each of
the second-generation antipsychotics since their individual arrivals in the
Clozapine, the oldest of the newer medications, is associated with serious
blood dyscrasias, including agranulocytosis, that has resulted in patient
deaths. Clozapine also carries a black-box warning regarding cardiac toxicity
leading to potentially fatal myocarditis.
Both risperidone and olanzapine carry a warning about potential increased
risk of cerebrovascular events, including stroke and an increased risk of
death from stroke. A similar warning was added to the label of aripiprazole at
the end of last year.
Ziprasidone was required at approval to carry a warning regarding the
drug's propensity to prolong the heart's QT interval and potentially to induce
fatal cardiac arrhythmias.
But the most studied adverse effect of the newer generation antipsychotics
is their association with hyperglycemia, in some cases leading to
ketoacidosis, coma, or death. A black-box warning was added to the labels of
all six drugs in 2003 alerting prescribers and patients to the possibility of
the drugs' leading to the development of potentially fatal diabetes
More information on the newly required warnings is posted online at<www.fda.gov/cder/drug/advisory/antipsychotics.htm>.▪