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intended only as a reference for use in an ongoing partnership
between doctor and patient in the vigilant management of the
patient's health. It is not a substitute for a doctor's professional
judgment, and serves only as a reminder of concerns that may need
discussion. All users are urged to consult with a physician before
beginning or discontinuing use of any prescription drug or
undertaking any form of self-treatment. This website does not list
every possible adverse reaction, interaction, precaution and effect
of a drug; and all information is presented without guarantees by
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The Food and Drug Administration (FDA) approved aripiprazole (ABILIFY)
in December 2002 for the short-term treatment of schizophrenia.
Aripiprazole is marketed by Bristol-Myers Squibb and Otsuka America
Pharmaceutical, Inc., and brings to six the number of "atypical"
antipsychotics now on the market.
This evaluation is based primarily on the publicly available FDA
reviews of data submitted by Bristol-Myers Squibb/Otsuka to support the
approval of aripiprazole. These reviews are essential in conducting an
independent evaluation of the therapeutic value of a new drug. We can no
longer totally rely on the peer-reviewed medical literature as the gold
standard for the dissemination of scientifically valid information. One
industry insider claims that 50 percent of the medical literature on drugs
is ghostwritten with a positive spin. The editor of the Canadian
Medical Association Journal recently said, "We have no way of
checking. We barely have the resources to do what we're doing, let alone
whether so-and-so is telling us honestly what they did."
The FDA reviews of aripiprazole can be found on the agency's web site
at
www.fda.gov/cder/foi/nda/2002/21-436_Abilify.htm .
All antipsychotics tend to improve symptoms such as hallucinations,
agitation, delusions, suspiciousness and disorganized thinking. The
atypical antipsychotics better improve the negative symptoms of
schizophrenia, such as apathy, emotional withdrawal, lack of pleasure and
disorientation, than older antipsychotics.
Haloperidol
(HALDOL) and
chlorpromazine (THORAZINE) are two examples of older, or typical,
antipsychotics. The newer atypical antipsychotics may be less likely to
cause adverse effects on equilibrium and muscle tone, often called
movement disorders, at moderate doses. However, in higher doses, these
medications can cause serious adverse effects, including elevations in
blood sugar (hyperglycemia). (See
article on drug-induced hyperglycemia with clozapine (CLOZARIL) and
olanzapine (ZYPREXA)).
We have a significant concern about the possibility of eye toxicity with
the use of aripiprazole. The studies done in rats clearly showed
degeneration of the retina in animals receiving aripiprazole. The studies
done in mice and monkeys found no retinal degeneration but they were
invalid studies. The company committed to doing additional post-marketing
research on retinal degeneration in animals as a condition for the
approval of aripiprazole. These are studies that clearly should have been
completed before the drug was approved.
Unfortunately, the drug industry's performance in meeting their
post-marketing study commitments is not good. From 1990 through 1994, a
total of 88 new drugs were approved in which a company had made at least
one post-marketing study commitment. Only 13 percent (11 of the 88) were
classified by the FDA as complete as of December 1999.
The only advice given in the professional product labeling, or package
insert, about the retinal degeneration seen in rats is not very
comforting: "The relevance of this finding to human risk is unknown."
Various rating scales are used to test the efficacy of antipsychotic
drugs. A brief description of these scales can be found at the end this
article. In general, the standard for showing that a drug works (its
efficacy) is that the average scores on the rating scales improve and that
the difference between the averages for those patients receiving a new
antipsychotic, for example, are statistically different from the group of
patients receiving an inactive placebo or another previously approved drug
for treating the same problem.
Five short-term clinical trials were submitted by Bristol-Myers Squibb/Otsuka
to the FDA to support the approval of aripiprazole.
The first trial lasted only four weeks. Altogether, 103 patients with
schizophrenia in acute relapse were randomized to aripiprazole,
haloperidol or placebo. Two rating scales were used, the Brief Psychiatric
Rating Scale (BPRS) and the Clinical Global Impression Severity (CGI-S)
scale. Explanations of these rating scales can be found at the end of this
article. Aripiprazole demonstrated borderline statistical superiority over
placebo on the CGS-S scale only. Haloperidol was superior to placebo on
both the BPRS and CGS-S scales.
The second trial was also a four-week study. This trial involved 414
patients who were given either 15 milligrams or 30 milligrams of
aripiprazole, haloperidol, or placebo per day. In this trial, three rating
scales were used: the CGI-S and the total score and positive subscale of
the Positive and Negative Syndrome Scale (PANSS). Both doses of
aripiprazole were found to be statistically superior to placebo. However,
there appeared to be no therapeutic advantage of the 30 milligram dose
over the 15 milligram dose.
The next trial, again only four weeks in duration, included 404
patients. These patients received either 20 milligrams or 30 milligrams
per day of aripiprazole, the atypical antipsychotic
risperidone (RISPERDAL) or placebo. This study also used the CGI-S and
the total score and positive subscale of the Positive and Negative
Syndrome Scale (PANSS) to evaluate the efficacy of aripiprazole. Both
doses of aripiprazole were found to be better than the placebo.
Risperidone was also found to be statistically superior compared to
placebo on the three rating scales.
In the fourth trial, a total of 420 patients were assigned to receive
either 10, 15 or 20 milligrams per day of aripiprazole or placebo. This
was the longest of the five trials, but lasted only six weeks. The main
rating scale used in this trial was the PANSS total score. The three
different doses of aripiprazole were found to be superior to placebo.
There was no clear advantage of the 15 milligram and 20 milligram doses
over the 10 milligram dose.
The last trial studied 307 patients given aripiprazole, haloperidol or
placebo. Neither aripiprazole nor haloperidol demonstrated superiority
over placebo. This is known as a failed trial.
In summary, three of the five short-term trials lasting four or six
weeks showed the efficacy of aripiprazole in doses ranging from 10
milligrams to 30 milligrams per day. There appeared to be no therapeutic
advantage of the 30 milligram dose over the lower doses. The FDA-approved
dose for the drug ranges from 10 milligrams to 15 milligrams per day. Of
the two remaining studies, aripiprazole could not be differentiated from
placebo in one, and the other trial failed.
These trials were not conducted in a way to make direct comparisons
between aripiprazole and haloperidol or respiridone. And nothing in these
five trials can lead one to believe that aripiprazole is a meaningful
advancement in the treatment of schizophrenia.
There are additional findings from the FDA's safety review of
aripiprazole that are important. An alteration in the electrical
conduction of the heart known as QT prolongation is an important safety
issue with both old and new antipsychotic drugs. QT prolongation can lead
to life-threatening heart rhythm disturbance. (See previous articles on
Ziprasidone
(GEODON) AND
Thioridazine (MELLARIL).)
There was no evidence of QT prolongation with aripiprazole at doses up
to 30 milligrams per day. However, in a special study that explored doses
of the drug up to 90 milligrams per day, there was substantial
prolongation the QT interval at doses of 75 milligrams and 90 milligrams
per day.
Again, the FDA-approved dose of this drug ranges from 10 milligrams to
15 milligrams per day, but there is nothing to prevent a physician from
prescribing the drug in a much higher dose except the knowledge of the
patient. Undoubtedly, many physicians will. The FDA is allowing
Bristol-Myers Squibb/Otsuka to sell aripiprazole in 10 milligram, 15
milligram, 20 milligram and 30 milligram tablets. Generally, as a drug's
dose increases, so does the risk of adverse drug reactions.
In the short-term trials discussed above, drowsiness occurred in 15.3
percent of the patients treated with 30 milligrams of aripiprazole per
day. Involuntary movement disorders are always a concern with
antipsychotic drugs. The incidence of extrapyramidal symptoms in these
trials were similar to placebo except for akathisia, a syndrome
characterized by an inability to remain in a sitting position, with
restlessness and a feeling of muscular quivering. Akathisia occurred in 10
percent of the aripiprazole treated patients compared to 6.8 percent of
those receiving placebo.
A drop in blood pressure on standing (orthostatic hypotension) was seen
in 14 percent of the patients receiving aripiprazole compared to 11.9
percent of those getting placebo. This can present a risk for falls.
Weight gain has also been a problem with the antipsychotic drugs,
particularly with the atypical anti-psychotics. In the short-term trials,
there was a small difference in average weight gain between aripiprazole
and placebo patients. The patients given aripiprazole gained on average
1.5 pounds while the placebo patients lost 0.1 pounds on average. The
proportion of patients gaining more than seven percent of their body
weight who were taking aripiprazole was eight percent, compared to three
percent of the placebo patients.
There are a number of potentially important drug interactions with
aripiprazole. Because the primary effect of aripiprazole is on the central
nervous system (CNS), patients should avoid alcohol and use caution if
they are taking other drugs that effect the CNS. Aripiprazole also has the
potential to enhance the effect of some high blood pressure-lowering
drugs.
Carbamazepine (TEGRETOL), a drug used frequently in combination with
antipsychotic medications, can induce the liver enzyme that is responsible
for the breakdown (metabolism) of aripiprazole. This may result in faster
elimination of the drug and a lower therapeutic effect.
Ketoconazole (NIZORAL), quinidine (DURAQUIN, QUINAGLUTE DURA-TABS,
QUNIDEX),
fluoxetine (PROZAC) or
paroxetine (PAXIL) can inhibit the liver enzymes that breakdown
aripiprazole. This can lead to higher blood levels of the drug and greater
risk of adverse drug reactions.
The editors of the highly respected Medical Letter on Drugs and
Therapeutics concluded in their February 13, 2003 evaluation of
aripiprazole that "published comparisons with other atypical
antipsychotics are needed to determine its relative efficacy and safety."
The lack of comparative studies with other antipsychotics is sufficient
reason to wait before using this drug.
What You Can Do
You should follow the Health Research Group's Seven Year Rule with
aripiprazole and wait to use this drug as there is no evidence to suggest
that it is a "breakthrough" drug.
