Psychiatr News July 18, 2008
Volume 43, Number 14, page 1
© 2008 American Psychiatric Association
FDA Extends Black-Box Warning to All Antipsychotics
Jun Yan
New studies and label warnings about the risks of all antipsychotics
have not made clinical decisions any easier for physicians, patients, and
caregivers.
Three years after the Food and Drug Administration (FDA) instituted a
black-box warning for all second-generation antipsychotic (SGA) medications
about increased risk of death in elderly dementia patients, a similar warning
is being added to the labels of first-generation antipsychotics (FGAs) such as
haloperidol and perphenazine.
The FDA announced its decision in mid-June after reviewing two
epidemiological studies, both conducted in Canada, that were published in
2007. The two studies found mortality rates in elderly patients taking FGAs to
be comparable to or higher than the rates in patients taking SGAs.
In a study by Sebastian Schneeweiss, M.D., and colleagues, the mortality
hazard ratio in the FGA-treated elderly patients was 1.47 times that of
SGA-treated patients within 180 days after starting the antipsychotic
prescription. Included in this study were more than 37,000 people in British
Columbia aged 65 and older who were started on antipsychotic medications.
About one-third of these patients received FGA prescriptions, and the rest
were given the newer SGAs. The study was published in the February 2007
Canadian Medical Association Journal.
The other study, reported by Sudeep Gill, M.D., M.Sc., and colleagues and
published in the June 5, 2007, Annals of Internal Medicine, was
conducted in patients with dementia aged 66 years and older in the province of
Ontario. From public health databases, the authors constructed and compared
three cohorts of FGA users, SGA users, and nonusers of antipsychotics based on
dementia patients' status as community-dwelling or long-term-care residents.
They ended up with a total of 27,259 pairs of antipsychotic-using and nonusing
patients who were matched in demographics and clinical status.
New use of SGAs was associated with a significantly higher mortality rate
than no antipsychotic use from 30 days to 180 days after the initial
prescription (hazard ratio 1.31 in community-dwelling elderly patients and
1.55 in long-term-care patients). In addition, the mortality risk was slightly
higher in FGA users than SGA users.
The prescribing labels of all antipsychotics are now required to carry a
standard warning. "The boxed warning will say that elderly patients with
dementia-related psychosis and treated with antipsychotics have an increased
risk of death," said Thomas Laughren, M.D., director of the Division of
Psychiatry Products at the FDA's Center for Drug Evaluation and Research, at a
June 16 press conference. The revised labels were to be finalized within 30
days of the mandate.
According to the "Information for Healthcare Professionals"
bulletin posted on the FDA's Web site, "the methodological limitations
in these two studies preclude any conclusion that conventional antipsychotics
have a greater risk of death with use than atypical antipsychotics." In
other words, the agency chose not to differentiate the mortality risks of FGAs
and SGAs on the basis of the two retrospective, nonrandomized, observational
studies. The 2005 black-box warning for SGAs about increased risk of death in
elderly dementia patients was based on the FDA's review of data from
randomized, placebo-controlled clinical trials.
The FDA's decision "reflects the fact that enough information has
emerged to warrant comparable language required for first-generation and
second-generation antipsychotics," Jeffery Lieberman, M.D., chair of the
APA Council on Research, told Psychiatric News. He pointed out that
the widespread use of SGAs in elderly dementia patients in the past decade had
led to the accumulation of randomized clinical trial results that suggest an
increased mortality risk compared with placebo. The risk with use of FGAs had
been suspected, but not well studied, mainly because SGAs have been considered
to cause fewer movement side effects and thus prescribed far more frequently
for frail elderly patients.
"The lesson for clinicians is that these drugs carry certain
liabilities, including potentially lethal consequences," Lieberman said.
Although the increase in risk is small, it is important to individual
patients. Nonetheless, he acknowledged that physicians have very limited
options in treating dementia-related psychosis and related behavioral
symptoms.
No antipsychotics have been approved for treating psychosis or agitation in
elderly patients with dementia. In fact, no drug has been approved for these
symptoms. Laughren also emphasized that the black-box warning is not a
contraindication, and clinicians still have the option of using these drugs
for dementia patients at their discretion.
In a white paper released in July 2007, the American College of
Neuropsychopharmacology (ACNP) reviewed clinical evidence and found that
"clinicians, patients, and caregivers are left with unclear choices of
treatment for dementia patients with psychosis and/or severe agitation,"
which often "cause considerable caregiver distress and hasten
institutionalization of patients."
Despite the risks associated with antipsychotic drugs, "there is
insufficient evidence to suggest that psychotropics other than antipsychotics
represent an overall effective and safe, let alone better, treatment choice
for psychosis or agitation in dementia," said the white paper.
Possible reasons for the association between antipsychotics and increased
death rate remain unknown. The causes of death in studies of this relationship
ranged from cancer to cardiovascular diseases, Laughren said.
The ACNP white paper recommended that physicians carefully determine the
cause of psychosis and behavioral symptoms in dementia and discuss treatment
options, including behavioral treatment strategies, with patients and
families.
The FDA Information for Healthcare Professionals brochure is posted
at
<www.fda.gov/cder/drug/InfoSheets/HCP/antipsychotics_conventional.htm>.
"ACNP White Paper: Update on Use of Antipsychotic Drugs in Elderly
Persons With Dementia" is posted at
<www.acnp.org/asset.axd?id=40ed5fbf-b74e-444e-a926-49b4c5bc7069>.
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