Psychiatric News August 19, 2005
Volume 40 Number 16
© 2005 American Psychiatric Association
p. 15
Generic Antipsychotic Is Equivalent To Brand Product, Data Show
Jim Rosack
Generic versions of clozapine continue to be plagued by rumors of low
quality or lack of bioequivalence to the brand-name product, in spite of data
and FDA determinations to the contrary.
When patients taking Novartis's Clozaril were switched to a generic
clozapine, no statistically significant changes were seen in a wide array of
outcomes measuring patient stability and resource utilization, according to a
study published in the August Community Mental Health Journal.
Concerns about the bioequivalence of generic and brand-name clozapine have
existed nearly as long as the generic versions of the second-generation
antipsychotic have been available. The first generic version of Clozaril was
approved by the U.S. Food and Drug Administration (FDA) on November 26, 1997.
Within roughly a year, clinicians were expressing concerns that that first
generic, made by Zenith-Goldline Pharmaceuticals, was not, in fact,
bioequivalent to the brand-name product. There were numerous reports of
patients whose symptoms became worse and even some reports of full relapse
after being switched from the branded product to the generic.
The issue became so heated that Novartis and Ivax Corp. (which makes the
Zenith-Goldline brand of generic products) threatened reciprocal legal action
in 2000 (Psychiatric News, December 15, 2000). By February 2001, the
FDA publicly stated that the data the agency had seen indicated there was no
bioequivalence problem. The FDA also said, however, that it would continue to
monitor reports of bioequivalence problems and recommended that Ivax conduct a
new complete bioequivalence study. Ivax subsequently did so, and the FDA
confirmed the drug's AB bioequivalence rating to Clozaril.
"These data demonstrate that there was no increase in service
utilization by patients converted to generic clozapine."
The latest study, completed by Daniel Healy, M.D., a clinical assistant
professor of psychiatry at the University of Michigan, and his colleagues,
looked at 108 adult patients aged 18 and above in a clozapine clinic at the
Washtenaw County Community Mental Health Center (CMHC) in Michigan. These 108
patients constituted all the patients being followed in the clozapine clinic
at the time.
In an attempt to reduce pharmaceutical costs, the CMHC, along with the
University of Michigan Pharmacy Service, decided to switch patients from
Clozaril to a specific generic equivalent, made by Mylan Pharmaceuticals. The
CMHC chose Mylan, the researchers noted, because of the company's strong data
on bioequivalence.
For each patient, serum clozapine levels were obtained two weeks before and
after the switch from brand to generic. A one-year retrospective examination
of each patient's records was completed prior to the switch.
Information about outpatient psychiatric visits, emergency room visits,
inpatient hospitalizations, partial-hospital or day-program utilization,
crisis-center utilization, dose of clozapine, and use of any adjunct
antipsychotic medications were collected for each patient. The same
information was collected for one year following the patients' switch to
clozapine.
Of the 108 patients, 62 were men and 46 women, and the average age was 42.5
years. The patient sample was overwhelmingly Caucasian; only two were
Hispanic, and 14 African American. The average daily dose of Clozaril taken by
patients prior to the switch was 452 mg (+/- 177 mg). The average dose of
clozapine after the switch was 451 mg (=/- 176 mg). No statistically
significant differences were found in serum blood levels achieved with oral
doses of clozapine compared with Clozaril.
In the year after the switch, 16 patients required an increase in dose, and
11 required a decrease in dose. Nine patients required the addition of an
adjunct antipsychotic, and three patients who were already on a second
antipsychotic had to be changed to a different antipsychotic.
Overall, there were no statistically significant differences between
Novartis's Clozaril and Mylan's clozapine as measured by inpatient hospital
days, crisis-center utilization, admissions for inpatient treatment, and
outpatient psychiatric visits for the periods studied—that is, one year
before the switch and one year after the switch. The only statistically
significant finding was a decrease in psychiatric emergency room
visits—69 for Clozaril compared with 32 for clozapine.
"These data demonstrate that there was no increase in service
utilization by patients converted to generic clozapine. In fact, all of our
measures of utilization decreased, although the decrease was significant only
for ER visits," the authors concluded.
Healy and his colleagues suggested that the lack of increase in service
utilization and the significant decline of ER use "may reflect gradual
stabilization of these patients over time or the gradual reductions of
patients using inpatient or psychiatric emergency room services in
general."
The switch, they added, "was cost-effective, as the reduction in
pharmacy costs was not offset by increased utilization costs."
The researchers conceded that they used "proxy measures of
utilization" that "did not reflect increasing symptoms." The
researchers also noted that because patients' clinical status was not assessed
before and after the switch, "it is possible that patients did exhibit
symptom change with the switch."
An abstract of "Clinical Equivalence of Generic
Clozapine" can be accessed at
<springerlink.metapress.com>
by clicking on "Browse Publications," "C,"
"Community Mental Health Journal," and
"August." 
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