FDA Urges Prominent Warning Label For Antibiotic Ketek

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FDA Urges Prominent Warning Label For Antibiotic

http://www.therapeuticsdaily.com/news/article.cfm?contentvalue=916378 & contenttyp\

e=sentryarticle & %20channelID=31

Dow - May. 19, 2006

(From THE WALL STREET JOURNAL)

By Wilde Mathews

FOOD AND DRUG Administration safety reviewers have linked the antibiotic

Ketek to 12 cases of liver failure, including four deaths, and they are

recommending adding a prominent new label warning that " severe,

life-threatening, and in some cases fatal " liver toxicity has been

reported in patients taking the drug.

The findings, in a confidential May 16 memorandum by the FDA's Division

of Drug Risk Evaluation reviewed by The Wall Street Journal, raise new

questions about the Sanofi-Aventis SA antibiotic. They also put more

pressure on the FDA as Congress carries out investigations of the

agency's handling of Ketek.

Senate Finance Committee Chairman Grassley, an Iowa Republican,

and House Democrats Markey of Massachusetts and Henry Waxman of

California want to know more about a large clinical trial that was

designed to demonstrate the drug's safety but was dogged by fraud and

other problems. The FDA ended up discounting the study but approved

Ketek anyway in April 2004. The lawmakers are also examining ongoing

clinical trials of Ketek in children.

Last year, Ketek was prescribed 3.35 million times in the U.S. and had

sales of $193 million, according to IMS Health. A strong label warning

would probably depress sales of the drug, but the agency doesn't always

follow recommendations from its drug-safety office. In a statement, an

FDA spokeswoman said that the memo reflects the drug-safety office's

" interpretation of adverse-event data " and recommends " labeling

revisions be considered but not product withdrawal. "

Calling some of the liver-failure cases " clinically remarkable, " the

memo describes " profound " liver injury that set in as soon as a few days

after some patients took Ketek and had a " signature of rapid onset and

tempo. " The document says that many of the 12 cases appeared to have few

other possible causes and occurred in people who were " generally

healthy. " Besides the four deaths, one patient had a liver transplant

and three others were considered for transplants but recovered.

In a statement, Sanofi-Aventis said it " continues to believe that Ketek

is safe and effective when used as directed. " It said that it is engaged

in " ongoing discussions with the FDA regarding a detailed medical

evaluation of hepatic events " reported in connection with Ketek use and

that it is evaluating the data with leading experts. The company said a

detailed response to the findings in the memo would be inappropriate

while it is in discussions with the agency.

The internal FDA memo analyzes incidents reported through the end of

April in people in the U.S. who were prescribed Ketek after the drug won

FDA approval. The reviewers found 23 reported cases of serious liver

injury, as well as the 12 liver failures, that were " associated " with

Ketek. The FDA also got reports of 44 liver-related events that weren't

serious.

The overall estimated rate of reported liver failures tied to Ketek,

known generically as telithromycin, was 23 per 10 million prescriptions.

That compares with a reported rate of 6.6 per 10 million prescriptions

for Avelox, six for Tequin and 2.1 for Levaquin. For two antibiotics in

a class similar to Ketek -- Biaxin and Zithromax -- the rates were 4.2

and 3.7. Use of an older antibiotic, Trovan, was sharply restricted in

1999 after the FDA received reports of 14 liver failures, which

translates into an estimated reporting rate of 58 per 10 million

prescriptions. The rates include any generic versions of the drugs.

The memo cautioned that such comparisons aren't definitive, because they

may at least partly reflect differences in how likely health-care

providers and others were to report events. The rates were also

calculated based on different time frames. The memo says the rate of

liver-event filings about Ketek rose after the January publication

online of a medical-journal article on liver damage in people who took

the drug. By some estimates, the FDA gets reports of only 10% or less of

potential drug side-effects. Despite the system's flaws, such reports

have been a major factor in the withdrawal of several drugs.

The FDA spokeswoman said that the safety reviewers found " the numerical

risk appears higher in the Ketek database " but " they are not able to

conclude greater risk for liver injury in patients receiving Ketek than

other drugs in the category. " The finding will be " carefully considered

along with all other sources of expert review " in the FDA's final

assessment of Ketek, she said.

Calculated a different way, the rate of reported liver failures in

people who took Ketek was 167 per one million person-years of use of the

drug (a person-year is a year of one patient taking the drug), the FDA

document says. Even before the medical-journal article stimulated more

reports, the rate was 89, the memo says, well above the liver-failure

rate for the general population, which is about one per one million

person-years. The document concludes that the Ketek rates are

" consistent with an association " between the drug and liver failure.

The memo says it is from an FDA safety evaluator named Wassel and

a team leader, Brinker. Mark Avigan, director of the

drug-risk-evaluation division, signed off on the memo as well. The

document is addressed to Janice Soreth, the head of the FDA division

that approves antibiotics, which is likely to spearhead any negotiations

the agency has with Sanofi-Aventis about adding warnings to the label.

The congressional investigations are focusing on a large clinical safety

trial of more than 24,000 people. The study -- whose problems were

detailed in the Journal May 1 -- was conducted by the drug maker after

the FDA initially refused to approve the medication because of lingering

concerns about liver damage and other potential risks.

Despite the worries about the safety study, the FDA approved Ketek to

treat sinusitis, bronchitis and pneumonia acquired outside a hospital.

FDA officials wrote at the time that there was a " systemic failure " of

the safety study's monitoring program to " detect data integrity problems

when they clearly existed. " But they wrote that they were " able to rely

on the post-marketing experience " outside the U.S., where there was a

low rate of side-effect reports tied to Ketek, " to conclude there was

substantial evidence of safety. " After 3.7 million overseas

prescriptions, there had been one death related to a liver reaction, and

it wasn't clearly linked to Ketek.

But according to the new drug-safety reviewers' memorandum, the number

of U.S. reports of liver failures among Ketek users is far higher than

those the agency has received from overseas. The memo cites just two

reports of possible liver failure in other countries, both from Japan,

even though the drug was approved in Europe in 2001. The reason for the

discrepancy isn't clear.

Currently, Ketek's label carries a mildly worded caution that liver

dysfunction " has been reported with the use of Ketek " and that " these

events were generally reversible. " When the medical-journal report came

out, the FDA urged doctors to watch for signs of liver damage. But the

agency said that based on the information it had when it approved Ketek,

including the large safety study, the liver risk tied to the drug

appeared similar to that of other antibiotics.

The drug-safety memo recommended that the Ketek label carry a warning

about liver risk set apart by bold type or a black box, which is

reserved for the most serious safety concerns. Among other things, the

proposed warning would mention reports of liver necrosis and liver

failure, and say that in some cases liver injury " progressed rapidly and

occurred after administration of a few doses of Ketek. " The suggested

labeling would also warn doctors to watch patients for signs of hepatitis.

(END) Dow Newswires

May 19, 2006 04:00 ET (08:00 GMT)

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