NEWS - FDA committees recommend naproxen as first-line therapy over COX-2s

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FDA committees recommend naproxen as first-line therapy over coxibs

Rheumawire

Feb 19, 2005

Gandey

Gaithersburg, MD - The US Food and Drug Administration committees have

formally recognized the cardiovascular and cerebrovascular risk of COX-2

selective agents. Members of the Arthritis Advisory Committee and the Drug

Safety and Risk Management Advisory Committee voted overwhelmingly in favor

of naproxen with a proton pump inhibitor as first-line therapy over coxibs

and most called for black box warnings, additional physician and patient

education materials, and better post-marketing surveillance.

" One of the clearest signals from all of the trials is the relative safety

of naproxen, " Dr Shafer (Stanford University VA Palo Alto Health

Service Care System, CA) told rheumawire. " And many trialsin fact all of the

trialsthat compared drugs to naproxen consistently found improved safety

with naproxen. " When asked whether he personally would recommend the

over-the-counter product, Shafer responded with a laugh, " I actually have it

with me now. I took an informal poll among committee members at dinner, " he

added, " and all of them had brought an NSAID, and without exception, they

brought naproxen as their NSAID of choice. "

The panel voted unanimously in favor of recognizing the cardiovascular

effects of the three COX-2 inhibitors available in the UScelecoxib,

valdecoxib, and until recently, rofecoxib. All but one panel member voted in

favor of the overall risk-to-benefit profile supporting the continued

marketing of celecoxib (Celebrex, Pfizer).

Panel okays celecoxib, but with stricter warnings

Recommendations for celecoxib:

Initiate black box warning

Halt direct-to-consumer advertising

Add education materials

Call for lower 200 mg dose

The committee as a whole decided that while celecoxib should continue to be

available, stricter cautions are in order including a strongly worded black

box warning about thrombotic risk and education materials such as a 'Dear

Healthcare Professional' letter and patient education materials. The

committees also talked about dose-dependent toxicity and tended to err on

the side of doses of 200 mg. A number of panelists also urged that

direct-to-consumer advertising of celecoxib be halted.

Arthur Levin, an expert in health policy and a committee member representing

consumers, was the one panelist who voted against the continued marketing of

celecoxib. " It takes forever in this negotiated process to get the things in

place that are recommended and then accepted by the FDA. I am very concerned

about the timeline, " he said, noting that similar meetings raising concerns

about Roche's isotretinoin (Accutane) have been dragging on for at least a

year. " Based on prior experience, you are not going to see this in the next

couple of months. "

The meeting chair Dr Alastair Wood (Vanderbilt University Medical Center,

Nashville, TN) responded, " I think one of the jobs of the committee should

be to provide a guideline for a time frame and light a fire under these

guys. " The other option, he added, could be to impose such severe

restrictions on products that companies have an incentive to work to have

them removed.

Speaking on behalf of the FDA, Dr Temple from the office of drug

evaluation, responded, " We're committed to making our decision on your

recommendations about these products very quickly after this meeting and we

will do everything we can to implement whatever changes there are as quickly

as possiblerecognizing that there are sometimes certain logistical issues

that have to be worked through but we are committed to working as quickly as

possible. "

Divided over rofecoxib: Merck has decision to make

Recommendations for rofecoxib:

Initiate stronger black box warning than celecoxib

Prohibit direct-to-consumer advertising

Add education materials

Cut dosing from 25 mg to 12.5 and virtually eliminate 50 mg

Commence patient informed consent (possibly)

The panel was split over whether or not the overall risk-to-benefit profile

supports the renewed marketing of rofecoxib (Vioxx, Merck). The final vote

was 17 committee members in favor and 15 against.

" The data are very compelling, " Wood said. " There is a clear signal that

rofecoxib is substantially worse than other drugs. I don't think there's any

reason to keep it on the market, " he said. But other committee members

argued in favor of marketing based on the drug's indication as the only

coxib available for juvenile rheumatoid arthritis (RA). Shafer noted that

rofecoxib has demonstrated the strongest GI benefit, is available in once

daily dosing, and is the only coxib available for patients with allergies to

sulfonamide.

During the discussion following the divided vote, the committees decided to

implement stronger variations of the warnings they recommended for

celecoxib. They also opted to dramatically reduce doses of rofecoxib. The

committees recommended largely eliminating the 50 mg dose favoring instead

to cut the standard 25 mg dose to 12.5 mg.

While the group opted to maintain the product's indication for juvenile RA,

members raised concerns. " I am worried about the potential silent and

insidious effect this could have on children, " said Dr Stuart Hoffman

(Cleveland Clinic Foundation, OH). Some panelists recommended allowing

rofecoxib for children with parent informed consent and largely disallowing

the product for adults except in specific compassionate use circumstances.

Panelists react to lack of valdecoxib data

Recommendations for valdecoxib:

Initiate stronger black box warning than celecoxib

Halt direct-to-consumer advertising

Add education materials

Contraindicate in cardiac surgery

Committee members questioned whether valdecoxib (Bextra, Pfizer) should have

ever been approved at all considering the " paucity of data " and the

additional concern over adverse skin reactions. " It seems almost

inconceivable to me that someone would prescribe this drug instead of

celecoxib, " Wood said. He added that with such a lack of data, there is no

evidence that it is safer or more harmful.

Dr Curt Furberg (Wake Forest University, Winston-Salem, NC) said that in the

absence of strong evidence, the committees need to reconsider whether or not

valdecoxib should remain on the market. " Perhaps we have to face up to this

and take it off the market, " he said.

But in the end, the committees voted narrowly in favor of the overall

risk-to-benefit profile supporting the continued marketing of valdecoxib.

Seventeen members voted for, 13 against, and 2 abstained. " The panel clearly

was concerned over the lack of long-term safety data and that reflected in

the unenthusiastic vote for retaining valdecoxib on the market, " Shafer told

rheumawire in an interview following the meeting.

Members called for a strong black box warning, education materials such as a

Dear Healthcare Professional letter and patient education materials, no

direct-to-consumer advertising as well as a contraindication for cardiac

surgery.

COMBINATION THERAPY WITH ASPIRIN AND COX-2 SELECTIVE AGENTS ILL-ADVISED,

GROUP SAYS

Panelists discussed the role of the concomitant use of low-dose aspirin in

reducing cardiovascular risk in patients treated with COX-2 inhibitors.

While many members complained of a lack of data, the group as a whole, voted

against combination therapy. Many expressed concern that aspirin would

offset the GI benefits of the selective agent and that physicians should

therefore opt instead for a nonselective product.

" I've looked at all of the data and there's just no compelling evidence, "

said Dr Nissen (Cleveland Clinic Cardiovascular Coordinating Center,

OH). " It goes both ways, and this is actually one of the biggest

disappointments for the whole class because when this hypothesis was raised,

there were people who said, 'Don't worry about these drugs, just give

everybody a baby aspirin everyday and you can reverse the toxicity of COX-2

inhibitors.' And it turns out that that hypothesis appears to be wrong. I've

always said that the road to hell is paved with biological plausibility. "

But, Nissen adds, the data on which to base this decision remains limited.

" It would be useful, if this class of drugs were to survive in the long run,

to study this in a more formal way with larger sample sizes. "

Panel didn't stop at the coxibs; made recommendations for nonselective

NSAIDs too

The committees recognized that their proposals to the FDA would likely

result in a market shift to other products such as nonselective NSAIDs or

even selective products not currently marketed as coxibs, such as meloxicam

(Mobic, Boehringer Ingelheim). The group expressed concern that its

decisions could instigate unintended consequences and they therefore opted

to inform physicians and the public about concerns over other products as

well. " We don't want people to switch to another drug and gain a false

reassurance that there isn't a problem with that product too, " Nissen said.

The group decided that while warnings for all NSAIDs would be appropriate,

it would be a mistake to issue identical blanket warnings and risk further

confusing physicians and patients. " We need to attach appropriately graded

warnings, " Shafer argued.

The committees voted unanimously in favor of issuing black box warnings for

nonselective NSAIDs. And they opted for an individualized approach for each

drug. In a press conference following the meeting, , the FDA's

director of the office of new drugs admitted that the committees' suggestion

will be logistically complicated. " The more gradients there are in the

recommendations, the more difficult it will be to do in a timely manner, " he

said.

Public reaction

" Even before the meeting was adjourned, the top story online in was,

'Panel recommends pain drugs remain on the market,' " Shafer said. " This is

correct, but it does not reflect the panel's very graded response to the

risks of rofecoxib, the perceived relative safety of celecoxib compared to

rofecoxib, and the concerns over the COX-2 selective NSAIDs, and reassuring

data of naproxen. " Shafer told rheumawire, " I'm afraid that the shades of

gray that people heard during the meeting will be left out of the press

announcement. "

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org