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A case of telithromycin-related
liver damage
Mrs Henderson — not her
real name — had a cough that just wouldn't
go away. She'd had pneumonia twice before, so
she headed to a clinic for an x-ray to make sure
her lungs were OK. The doctor told her she had
bronchitis and gave her a prescription.
Shortly before the end of the
course, she began to feel tired, then lost her
appetite entirely. Her abdomen was tender and
her cough had not improved. She went back to the
doctor, who drew some blood for tests. He called
her back that afternoon to say there were some
abnormalities in her liver function, and that
he wanted her to come back the next day.
Within 48 hours, she'd been
admitted. She had a fever and her transaminases
were skyrocketing. They did an MRI to look for
stones and went in with a scope when they couldn't
find any. Still nothing. Four days later, unable
to figure out what was going on, her gastroenterologist
went over her history for the hundredth time.
He asked her the name of the antibiotic she had
been given two weeks earlier. Her husband had
to call the pharmacy, because she couldn't remember.
Telithromycin, they told him. "That may be it,"
the doctor said. "We've had some reports."
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On February 12, the FDA announced
it was limiting the approved uses of telithromycin to
community-acquired pneumonia (CAP) — removing the
indications for chronic bronchitis and sinusitis —
because of concerns of liver toxicity. The announcement
was only the latest in a series of controversies involving
the antibiotic, which has been implicated in two FDA
reviews and a US Senate investigation since its April
2004 approval.
Things have been quieter here in
Canada, where the drug was approved for the same indications
a year earlier than in the US. Health Canada has posted
a couple of warnings about liver toxicity, including
a "Dear Health Professional" letter released by manufacturer
Sanofi-Aventis in October 2006, but has not yet followed
suit in narrowing the drug's approved indications.
Adverse events happen. And while
the patients who survive them are outraged at the thought
that something that was supposed to make them better
may have almost killed them, the reality is that it's
hard to establish whether a given drug is to blame.
WASTED
WARNINGS
The case of telithromycin is an unusual one. The principle
investigator involved in the main pre-approval clinical
trial has been sentenced to prison for falsifying records,
and the FDA is currently knee-deep in a senatorial investigation
over its approval of the drug.
But it also illustrates how the
healthcare system is poorly equipped to handle post-marketing
reports of adverse events (AEs), particularly the dissemination
of these reports among healthcare professionals. "They're
pretty much useless," says Dr Jack Uetrecht, who holds
a Canada Research Chair in adverse drug reactions. "It's
part of human psychology. If you've prescribed a drug
many times and nothing happened, you'd say 'oh that's
nonsense'. And if you prescribe a drug one time and
your patient dies, you'll think it's a terrible drug,
even if the incidence of AEs is one in a million."
Dr Paul Coolican, an FP in Morrisburg,
ON, says he prescribed telithromycin for sinusitis,
CAP and acute exacerbations of COPD without difficulty
— until he got wind of the FDA reported liver toxicity
as a serious but rare event. "My perception, which may
be inaccurate, is that Health Canada does not have a
reliable and timely system for dispensing such information.
When they do, it usually comes after we have heard of
the issue from the FDA," he wrote in an email. He says
he heard about the toxicity warning from his pharma
rep well before he got Health Canada's warning.
Dr Dan Ezekiel, a Vancouver FP,
first heard about problems with telithromycin about
a year-and-a-half ago from colleagues. "I used it a
dozen times, mostly for bronchitis, and it was always
fine," he recalls. But when he heard there had been
reports of liver problems, he says he stopped prescribing
it immediately, adding that he had lots of other options
to choose from.
ON
REPORT
Concerns over telithromycin's safety first began circulating
after a letter documenting three cases of severe liver
injury was published online in the Annals of Internal
Medicine on January 20, 2006. One patient recovered,
one needed a transplant and the third died.
A few weeks later, Health Canada
issued a warning to alert physicians to the possibility
of liver toxicity associated with telithromycin —
one that most Canadian doctors have probably never laid
eyes on.
The agency has received a total
of 104 domestic reports of AE, 19 of which involved
liver toxicity. Of those, "seven instances of serious
liver injury were deemed possibly or probably caused
by [telithromycin]," says Dr Suzanne Bayly, an evaluator
with the Marketed Health Products Directorate at Health
Canada.
"I think there's no question that
it causes liver toxicity, the class in general does,"
says Dr Uetrecht. "Whether it's more dangerous than
other macrolides is not totally clear at this point,
but I wouldn't use it unless there's a very strong indication."
Health Canada has not yet decided
whether it will follow suit with the US' restrictions
on telithromycin's approved uses. "We are in the process
of completing an overall review, and we haven't decided
what our final actions will be," says Dr Bayly. In Europe,
she points out, the regulatory agency completed a similar
assessment last fall and decided not to restrict the
drug's indications. "Of course," she adds, "new information
could always prompt a change of mind."
THE
MISSING LINK
That's another problem, according to Dr Uetrecht —
it's well known that only a handful of AEs ever get
reported. "There's no way to force physicians to do
something like this, and if they're busy, then the quality
of the information is poor and it's useless," he explains.
He's reviewed hundreds, if not thousands of AE reports,
most of which he says are uninterpretable. "Health Canada
is getting all these forms, and they can't do anything
about them."
Establishing with any sort of certainty
that the drug caused the event takes a lot more than
will, especially in the case of suspected liver toxicity.
"You have to know all other possible diseases the patient
has, their alcohol consumption — which patients
often lie about — and any other medications they're
taking," explains Dr Uetrecht. Even then, you're far
from out of the woods. One study he mentioned found
that in 17% of cases of acute liver injury, no cause
could be found. "It can happen that the liver fails
for no obvious reason," he says. "The most you can do
is try to fit the event to a pattern that the drug is
known to be associated with, but you can't really be
sure."
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