Drug warnings outline danger

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FYI

DeSiena

Drug warnings outline danger

By Rita Rubin, USA TODAY 4-26-2005

When the Food and Drug Administration wants to get a

message across loud and clear about a prescription

drug's risk, it tells the manufacturer to add a

black-box warning to the label.

Celebrex is one of several high-profile drugs to

receive the FDA's new black-box warnings.

File, Getty Images

Several high-profile drugs in recent months have been

given new black-box warnings — named for the narrow

outline of a rectangle that surrounds their boldface

text.

But some observers suggest that the federal agency may

be relying too heavily on the label warnings and

accompanying printed materials.

And some question whether, in the case of at least one

drug, the FDA went overboard, preventing patients who

could benefit from getting a prescription.

Recent FDA decisions to add black-box warnings have

generated a good deal of publicity:

• Antidepressants now warn of a possible link to

suicidal behavior.

• Prescription non-steroidal anti-inflammatory drugs

(NSAIDs), a group of pain relievers that includes

ibuprofen and naproxen as well as the blockbuster

Celebrex, will have to carry a black-box warning

highlighting the increased risk of heart attacks,

strokes and bleeding of the digestive tract.

• At the recommendation of an advisory panel in

February, the FDA is working on a black-box warning

for Elidel and Protopic, two eczema creams linked to

cancer in animals.

When pharmacists dispense these drugs, they'll hand

out consumer-friendly MedGuides explaining risks and

benefits.

The FDA uses such tools to ensure that the only

patients who take potentially dangerous drugs are

those for whom the benefits outweigh the risks. But

even FDA officials acknowledge that they really don't

know how effective black-box warnings and MedGuides

are in maximizing safe prescribing.

" You know, evaluations of the effectiveness of any of

these programs are really limited, " Ann Trontell,

deputy director of the agency's Office of Drug Safety,

told an FDA advisory panel in February.

Clearly, the track record of black-box warnings,

MedGuides and " Dear Health Care Professional " letters

— often sent to doctors and pharmacists when a new

warning is added to a drug label — is uneven.

" There are a lot of examples that, at best, don't

provide you with much reassurance that labeling

changes work, " Alastair Wood, a pharmacologist at

Nashville's Vanderbilt University and chairman of the

NSAIDs advisory panel, said at the February meeting.

" That is not to say we shouldn't do them, but

certainly, just labeling changes on their own have not

been extraordinarily effective. "

The antihistamine Seldane, pain reliever Duract,

heartburn drug Propulsid and diabetes drug Rezulin all

came off the market because multiple revisions in

their labels failed to adequately reduce what the FDA

considered inappropriate prescribing.

There do appear to be some success stories, depending

on your perspective. Safety concerns led

GlaxoKline in 2000 to stop selling Lotronex,

approved for women with diarrhea-predominant irritable

bowel syndrome. Two years later, the FDA took the

unprecedented step of allowing it back on the market,

but with a 21-line black-box warning and a new

risk-management program.

Appropriate candidates

Before doctors can prescribe Lotronex, they must

attest that they have the necessary knowledge to

diagnose patients and treat them with the drug. They

then receive stickers to place on prescriptions,

confirming to pharmacists that a patient is an

appropriate candidate for the drug.

Far fewer doctors prescribe the drug now than before

it came off the market, says s of the

Research Triangle Institute in North Carolina.

s, a former Glaxo scientist, is now lead

investigator on a Lotronex patient survey.

" Is that program so restrictive that patients who

really could benefit aren't? " s asks. " The

patients who have the most severe symptoms are the

only ones getting the drug. "

Ketorolac, an NSAID for moderately severe pain,

carries a black-box warning against taking it for more

than five days because the risk of drug-related liver

problems rises over time. According to an August 2004

memo from FDA officials Mark Avignan and Gerald Dal

Pan, the average length of prescriptions for ketorolac

was a fairly consistent five to seven days over the

five-year period ending in May 2004.

Still, the authors acknowledged, they did not know

whether the drug's labeling deserved all the credit

for the short-term prescribing. Health plan reminders

that excess days on ketorolac wouldn't be covered also

might have prompted pharmacists to dispense the drug

frugally.

The FDA does not have the authority to dictate medical

practice, only to influence it, points out

Temple, associate director for medical policy at the

FDA's Center for Drug Evaluation and Research.

" I think sometimes people just don't agree with you, "

Temple says. " There's a recommendation (a boldface but

not boxed label warning) for periodic liver testing

for all the statins, and I don't think everybody's

doing that.

" You could probably have a debate about whether it's

really worth it, " he says. " They might be right, they

might be wrong. "

Cholesterol-lowering statins present a relatively low

risk of liver problems compared with, for example,

Rezulin. What Temple says really worries him is when

doctors ignore warnings about clear, severe risks.

" That's a different problem, " he says. " They're just

not getting the message. "

In the three years Rezulin was on the market

(1997-2000), the manufacturer distributed four " Dear

Doctor " letters to licensed U.S. physicians about

labeling revisions. But Pamela Heaton, assistant

professor of pharmacy practice at the University of

Cincinnati College of Pharmacy, calls such letters

" probably a relatively ineffective way to get a

message across to physicians. They're just getting

lost in the shuffle of business. "

Heaton is the co-author of a study in the January

issue of Pharmacoepidemiology and Drug Safety that

focused on Ohio Medicaid claims for Rezulin

prescriptions.

Before the first " Dear Doctor " letter was sent, about

9% of patients who received Rezulin prescriptions had

their liver enzymes checked first. After the first two

letters went out, that proportion peaked at 26%. But

after the fourth letter went out, the percentage of

patients who had their liver enzymes tested before

starting treatment actually dropped, to 18%.

" I don't think black-box warnings are going to be any

more effective than 'Dear Doctor' letters, " says the

study's lead author, Cluxton Jr., an associate

professor of pharmacy practice and family medicine at

the Cincinnati pharmacy college.

Cluxton says the FDA needs to be more proactive to

counter drug company marketing. " Even if the FDA would

just go to the major (medical) meetings — like go to

the major arthritis meetings — and do a special

session, " he says. " Physicians want to understand what

is going on. They just don't want a very brief

message: 'You should do this because we think so.' "

Physicians are only one part of the problem, Heaton

and Cluxton say. " From my perspective, we need to get

people other than the doctors involved in this, "

Cluxton says. " It's got to be the pharmacist, and it's

got to be the patient. "

Not only do physicians need to be ordering the

necessary tests to monitor drug safety, Heaton says,

but " we need pharmacists to be asking patients if

they've had these tests done. And we need patients to

realize if the physician ordered the test, they need

to get the test done. "

A need for discussion

Simply handing patients a MedGuide might not be

enough, says Lee Rucker of AARP's Public Policy

Institute. " I think sometimes what's missing is that

it's all just on the paper, " Rucker says. " There seems

to be a need for that face-to-face discussion before

the patient is sent out the door. "

Negative publicity, as opposed to the new black-box

warning, may make patients and doctors more cautious

about NSAIDs, says Arthur Levin, the only member of

the FDA advisory panel to vote in favor of taking

Celebrex off the market.

" I don't think this will be a true test, frankly, of

the benefits or lack thereof of increasing warning

labels, " says Levin, director of the New York-based

Center for Medical Consumers. " It's hard for people to

understand that something can be approved, can be

advertised, can be prescribed for you by a doctor and

still not be safe. "

Dr. DeSiena, D.C.

Washington Street Chiropractic Center, L.L.C.

771 Washington Street

Eugene, OR 97401

(541) 686-BACK (2225)

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