FDA is asking manufacturers of atypical antipsychotics to add a "black box" warning to labeling on an increased mortality risk associated with the drugs' off-label use to treat dementia-related behavioral disorders.

FDA issued a ¹ public health advisory discussing deaths with use of antipsychotics in elderly patients with behavioral disturbances on April 11.

The agency also put out an ² alert for healthcare professionals for seven antipsychotic drug products: Lilly's Zyprexa (olanzapine) and Symbyax (olanzapine/fluoxetine); Novartis' Clozaril (clozapine); AstraZeneca's Seroquel (quetiapine); Bristol-Myers Squibb/Otsuka's Abilify (aripiprazole); Johnson & Johnson's Risperdal (risperidone); and Pfizer's Geodon (ziprasidone).

"FDA has determined that patients with dementia-related psychosis treated with atypical (second generation) antipsychotic medications are at an increased risk of death compared to placebo," the alert states.

"Based on currently available data, FDA has requested that the package insert for [atypical antipsychotics] be revised to include a black box warning describing this risk and noting that this drug is not approved for this indication."

FDA's advisory notes that while all the atypical antipsychotics are approved for treatment of schizophrenia, none is approved for treatment of behavioral disorders in patients with dementia.

Zyprexa already carries a warning on an increased incidence of death in elderly patients treated for dementia-related psychosis (³ 'The Pink Sheet' Feb. 23, 2004, In Brief).

Labeling for Zyprexa also includes a warning regarding an increase in cerebrovascular events when used to treat dementia-related psychosis. Symbyax, Abilify and Risperdal labeling include similar warnings.

The warnings note that the products are not approved for treatment of patients with dementia-related psychosis.

FDA has been considering expanding the cerebrovascular warning to the entire class (⁴ Also see "Antipsychotic Class Warning On Cerebrovascular Events Under FDA Review" - Pink Sheet, 4 April, 2005., p. 32).

The agency's request for a black box is based on results of 17 placebo-controlled trials of Zyprexa, Abilify, Risperdal and Seroquel that enrolled a total of 5,106 elderly patients with dementia-related behavioral disorders.

Analyses of the trials showed a risk of death in the antipsychotic-treated patients that was 1.6 to 1.7 times the risk with placebo. The rate of death in antipsychotic-treated patients was about 4.5%, compared to 2.6% in the placebo group.

Most deaths were due to cardiovascular events such as heart failure and sudden death or infections, most commonly pneumonia.

"Because the increase in mortality was seen with atypical antipsychotic medications in all three chemical classes, the agency has concluded that the effect is probably related to the common pharmacologic effects of all atypical antipsychotic medications, including those that have not been systematically studied in the dementia population," the advisory says.

The letters requesting the changes give the manufacturers 30 days to respond, after which negotiations about specific warning language will continue.

As a result, FDA said the process "will likely take several months to complete."

The issue of FDA/company negotiations over drug warnings has gained attention in Congress. Sen. Edward Kennedy (D-Mass.) is pushing for drug safety legislation that would give the agency authority to mandate specific warning language (⁵ [A#00670100004], p. 7).

The advisory says FDA is considering adding a warning about use for dementia-related psychosis to labeling for older antipsychotics as well.

"The limited data available suggest a similar increase in mortality for these drugs," the document states.

Antipsychotic Boxed Warning Will Caution Against Off-Label Use In Dementia

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