The Fluoroquinolone Toxicity Research Foundation

 
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Heart and Cardiovascular Research                     See downloads for: Adobe Files



QUOTES FROM THE HEARING:
Committee Doc A: I'm going to say no, and I'm going to say no
because of the following reasons. I think when the drug is marketed,
no matter what kind of warning you put in it, it's going to be used
in substantially
different ways than it's been used in the trials. And, I think that
this is exactly the kind of place that you get into trouble with,
when a drug is approved, it's carefully studied in a trial, people
are carefully excluded who have prolonged QT intervals, are carefully
excluded who are on drugs that can be additive with it in terms of
the effect, and it's used for a very short interval of time, and so
it's not clear -- I am absolutely convinced
that the drug will be used differently once it's marketed frequently.
And, I think there are enough things that really haven't been
answered. I don't know if the drug effects potassium and magnesium
excretion, and whether it somehow is additive with other drugs that
produces increased loss of electrolytes through the kidneys, because
that has not been looked at. It seems to possibly cause or increase
the incidence of atrial fibrillation, and we don't have real drug
levels from real patients
correlated with QT times.
So, I don't know, I'm just somewhat concerned.
The other issue with safety, obviously, is the risk benefit
ratio, and I'm not sure I see what this drug adds to drugs that we
already have that's so unique that we need this drug, that we
absolutely need it, and we need it now for some indication. There are
other drugs that you can use. They may have the same problem, but
given that they haven't been studied in
this way, I don't know that's the case.

------
COMMITTEE DOC B: Well, I guess I'd have to say no, the data on
safety are not convincing. It seems to me, based on the discussion,
that the QT facts are clinically relevant, steady state
concentrations needs to be studied further. In addition, the concern
about people using the drug for longer than 12 days, I don't think we
have enough information on that, and I believe that that may occur,
even though that probably would not necessarily be what
we would recommend.The other concerns about other drugs that might
prolong the QT interval, the problems with hypokalemia, the problems
with death after the drug was discontinued, and, again, the age-old
problem, the use of this drug in children, I think we need to study
the drug and the pharmacokinetics, and we also need to study the
safety in the pediatric population. We need data on that, because
although it was not studied, and although it won't be
approved for children, I'm afraid it will be used in this population
and I'm concerned about that.


<< COMMITTEE DOC C: I was prepared to vote for safety with an
appropriate change in the label, but the two that have talked about
all the things that we don't know about, you know, the behavior of
this drug have swayed me. I think I shall have to vote against, I
don't believe we know enough yet about
the safety because of the cardiac problems.---------

Guest Expert Doc A: I was -- I thought Dr. A's summary captured a
lot of my concerns, and I think that on balance we don't know enough
now to conclude that it's safe.I think the other thing that gives me
pause is the fact that this is
a drug that may be very widely used, so even if the estimates of one
to two percent, which I think are very conservative, of meaningful QT
prolongations are correct, that might be tens or hundreds of
thousands of people who would experience those. So, it seems to me
that knowing more would be necessary for me to say yes, so I think if
I had a vote I would probably say no for now.ACTING CHAIRMAN : And
finally, I'd like to make sure that there are
no other comments that the voting members of the committee would like
to make.
Committee Doc D: I just have one comment, which also echoes a little
bit what Dr. A said, which is that although I think this drug is
safe, I think we also have to consider the other drugs, other
antibiotics that are out there, and whether the risk benefit ratio is
as good as other comparators
or similar drugs that are there. And, I think in balance thi
probably
doesn't add a terrible -- it doesn't add very much to the antibiotic
armamentarium that we currently have.
------
Dr. A: I'm a little confused by what we are voting on. I mean, my
answer is still no from before. I agree that if the drug is approved
that it has to have a warning label similar to what's been
described. I also wonder whether
it shouldn't include something about the possibility that it may
induce atrial fibrillation in patients, particularly, patients at
high risk for that arrhythmia. And, you know, whether it should
contain information about the drug effect on QT may be aggravated by
hypokalemia and, therefore, potassium
levels, particularly, on patients who are on drugs that cause
hypokalemia should be monitored, or at least baseline checked.I mean,
I think there may be other things that need to go into the
warning label to caution people. I would also suggest that it say
something about the fact that in the
trials prolonged use of the drug, in terms of its cardiovascular
safety, were
not assessed, you know, by giving it longer than stated You know, in
terms of the other drugs that have been approved, I
guess one of the problems that the pharmaceutical company has here is
that, you know, they were, perhaps, the first to come along, take a
drug with this issue and evaluate it so thoroughly, so it's
probably, you know, raised as
many questions as it has answered.
DR. A: Do you have data on how this drug affects potassium and
magnesium excretion from the kidney? The second question, in terms
of the accumulation of this drug in tissues, over what time period
does that occur? What is the half life in tissues? Is it likely if
people use the drug for longer periods of time that the drug would
continue to accumulate and levels would continue
to rise in tissues?
DRUG CO. DOC: We do have some tissue accumulation studies in
Phase I and Phase II and in small numbers of patients multiple time
points. We also have a dialysis and skeletal muscle study. Most of
those studies, however,
were done with a single dose administration of very short term.There
is, as Dr. __showed you, considerable accumulation in pulmonary
tissues which is helpful in this sort of setting. Our data for
skeletal muscle is that the concentrations reached in skeletal
muscle are about 80 percent of the plasma concentrations of the drug.
We don't have data to address the possibility of long-term
accumulation in tissues but for skeletal muscle the ratios are less
than plasma concentrations.
-------
So less than 8 weeks after this hearing where all these issues
were
raised, it was approved...(Bayer also makes Cipro)



http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3558t2.rtf