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Ziprasidone is an atypical antipsychotic that may offer
important clinical benefits to the approximately 1%-2% of
the population that suffer from the devastating effects
of acute and chronic schizophrenia and schizoaffective disorder.
This document summarizes safety and efficacy data available
for ziprasidone with particular emphasis on ECG findings
and other important cardiovascular risk factors.
Ziprasidone Is an Effective and Well-Tolerated Agent for
the Short-Term and Long-Term Management of Psychosis. In
short-term (4 to 6 week), double-blind, fixed-dose, placebo-controlled
trials ziprasidone was superior to placebo in treating the
positive, negative, and depressive symptoms associated with
an acute exacerbation of schizophrenia or schizoaffective
disorder. In a one-year, double-blind, placebo-controlled
maintenance trial, ziprasidone significantly reduced the
risk of recurrence of acute exacerbation in hospitalized
patients with chronic or subchronic schizophrenia. Ziprasidone
was also effective in treating the negative symptoms of
schizophrenia.
Ziprasidone was well tolerated in both the short-term and
long-term placebo-controlled trials, with a low overall
incidence of adverse events. Ziprasidone demonstrated a
particularly low liability for movement disorder adverse
events as evidenced by a low rate of spontaneous reports
and by specific rating scales. Ziprasidone treatment was
not associated with any laboratory test abnormalities
indicative of clinically relevant toxicity.
Pharmacokinetics of Ziprasidone have been Extensively Studied
in Individual Trials as well as in a Large Population Pharmacokinetic
Database.
Ziprasidone displays linear pharmacokinetics over the recommended
dose range (80 to 160 mg daily) and has a mean half-life
of 6.6 hrs. Its relative oral bioavailability is increased
by up to 100% in the presence of food. In multiple dose
studies, the Cmax typically occurs at approximately 6 hrs
after dosing in the fed state, with steady-state attained
within 1 to 3 days. Ziprasidone is extensively metabolized
by both aldehyde oxidase and P-450 mixed function oxidases
(predominantly CYP3A4). One circulating metabolite of ziprasidone,
S-methyl-
dihydroziprasidone (M9), may contribute to its pharmacologic
effects.
Co-administration of CYP3A4 inhibitors or inducers with
ziprasidone results in limited (35%) increases/decreases
in ziprasidone exposure. No other clinically significant
drug-drug interactions have been observed. The Effect of
Ziprasidone on the QTc is Modest and Well Characterized.
In the short-term, double-blind, placebo-controlled trials
submitted with the NDA, doses of ziprasidone from 80 to
160 mg daily were associated with a mean increase in QTc
relative to baseline of 5.9 to 9.7 msec (Bazett correction)
or 4.4 to 9.3 msec (Baseline correction).
The FDA issued a not-approvable letter for oral ziprasidone
in June of 1998, characterizing the decision as a “very
close” one. The sponsor was asked to conduct further evaluation
of the compound with respect to QT effects. Study 054 was
designed, in consultation with the Agency, to measure the
effects, at peak drug exposure after dosing, of ziprasidone,
risperidone, olanzapine, quetiapine, thioridazine and haloperidol
on the QTc. Electrocardiograms were recorded under fasting
conditions and at the time of estimated maximum exposure
to each study drug, in the absence and presence of a metabolic
inhibitor. QT interval measurements were made using standardized
12-lead ECG methodology. A mean prolongation of QTc was
measured for every antipsychotic agent tested, a finding
that is consistent with preclinical properties of these
agents. Although selected as a comparator in part because
it was expected to have no effect on QTc, a relationship
between concentration and QTc effect was detected for haloperidol,
providing evidence of the capacity of that drug to prolong
QTc at a therapeutic dose. The QTc effect of ziprasidone
160 mg was found to be approximately 10 msec greater than
the effects of four of the comparative antipsychotics (haloperidol,
quetiapine, risperidone and olanzapine) and 10 msec less
than the QTc effect of thioridazine 300 mg.
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