'Black Box' Warning for Acetaminophen Prescription Combos

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'Black Box' Warning for Acetaminophen Prescription Combos

FDA Panel Backs 'Black Box' Warning for Acetaminophen Prescription Combos

By Emily P. Walker, Washington Correspondent, MedPage Today
Published: June 30, 2009

ADELPHI, Md. June 30 -- An FDA advisory panel voted 36 to 1 to recommend a "black box" warning for prescription medications that combine acetaminophen with another drug.

If the FDA follows the advice, it would slap its strictest warning on prescription pain medications that combine acetaminophen with hydrocodone (Vicodin), oxycodone (Percocet), or codeine (Tylenol 3).

A joint panel of the Drug Safety and Risk Management Advisory Committee, Nonprescription Drugs Advisory Committee, and the Anesthetic and Life Support Drugs Advisory Committee voted for the warning after two days of hearings on ways to reduce acetaminophen's liver damage risk.

"History has been that some of these medications have [seemed] safe and effective and now we're saying they're not," said committee chairman Lewis Nelson, MD, an emergency medicine physician at New York University Medical Center.

The FDA does not have to follow the advice of its advisory committees, but it usually does -- particularly when there is a substantial majority behind a proposal.

About 42,000 people visit emergency departments each year with acetaminophen overdoses, half of which are accidental. They often occur when a consumer unknowingly takes more than one acetaminophen product.

One advisory panelist attributed 10% of fatalities from acetaminophen overdoses to combination products.

In a far less decisive vote, the committee voted 20 to 17 in favor of a more extreme recommendation to pull all prescription products containing acetaminophen from the market.

Because the split was so close, it is unclear whether the FDA will adopt the recommendation, but if it did, some options would be eliminated for pain patients. For instance, patients taking Vicodin would not have an acetaminophen-free option because there is no hydrocodone-only formula.

In addition, removing the acetaminophen from the Vicodin would move the drug into the more-strictly regulated "class II" schedule of narcotics from its current classification as a class III drug, creating additional barriers for physicians prescribing the drug to patients.

Sandra Kweder, MD, deputy director of the Office of New Drugs at the FDA, said that some patients increase their dosage of prescription narcotics, such as Vicodin, over time to get more of an effect from the hydrocodone. That, she said, could eventually deliver toxic doses of acetaminophen along with the narcotic.

"As many patients with chronic pain rely on these medications on a daily basis, the amounts of total acetaminophen consumed can be staggering," said Timothy Collins, MD, a pain specialist at Duke University Medical Center, who was not on the panel.

That may help explain why the committee came down on prescription acetaminophen drugs much harder than on over-the-counter combinations. It voted 24 to 13 against recommending that the FDA remove over-the-counter combination drugs from the shelves.

The prescription acetaminophen drugs may present a higher risk for liver damage than over-the-counter drugs because people tend to take the prescription drugs for longer periods of time said Dr. Kweder.

Lowering Doses and Limiting Options

Although it appears they'll keep their combination products on the shelves, makers of over-the-counter drugs were unhappy when the panel voted 21-16 to recommend that the FDA lower the maximum daily dose for acetaminophen below its current 4,000 mg.

The panel also recommended that the maximum single adult dose be lowered to 650 mg instead of 1,000 mg.

While there is a 650 mg extended-release acetaminophen tablet, the most common form is the 325 mg pill, so patients would be instructed to take no more than two at a time.

"We're disappointed that the panel chose to recommend lowering the dose," said Linda Suydam, president of the Consumer Healthcare Products Association, which represents makers of over-the-counter drugs.

"I think the committee voted in opposition to the data," she said.

Although the committee saw little data indicating smaller doses would protect against liver damage, the drug companies failed to present convincing data showing that a larger dose worked any better than the smaller one.

The committee voted 24 to 13 to recommend making the 500 mg pill available by prescription only. So, in order to get former maximum dose of 1,000 mg of acetaminophen at one time, a patient would need a prescription.

On the other hand, as a pediatric gastroenterologist and liver specialist pointed out, a patient could just take three of the 325 mg pills.

"I do not think this requirement for the 1,000 mg dose as a prescription product will have much impact since people will just use the 350 mg [times] three rather than 500 [times] two," said James Heubi, MD, of Cincinnati Children's Hospital Medical Center, when asked about the vote.

Dr. Heubi was not on the advisory committee.

If it chooses to accept the panel's recommendations, the FDA would have to go through its usual rule-changing process, including soliciting public comment, prior to changing dosing for acetaminophen products.

In a day of votes that represented little consensus among the diverse group of advisers, the committee unequivocally agreed on two things: the black box measure, and that parents are all too confused by the variety of liquid acetaminophen doses available for sick children.

So, the committee voted 36 to 1 to winnow the available liquid doses down to just one.

Committee Rejects Shrinking Containers

Despite testimony from British physicians who favored requiring acetaminophen pills to be sold in smaller packages, the committee wasn't convinced. In another close (20-17) vote, it rejected a proposal requiring manufacturers to downsize their pill packs and bottles.

The largest bottle of Tylenol that Johnson & Johnson's McNeil subsidiary sells contains 325 tablets, but some generic brands come in bulk bottles with as many as 1,000 pills.

Several of the panelist felt the giant bottles of pills sent a message that acetaminophen is safer than it is.

"I hope the committee doesn't take this 'no' vote as we support selling 1,000 pill containers at Costco," said Judith Kramer, MD, associate professor of medicine at Duke University Medical Center.

In the United Kingdom, when package size was reduced, overdoses decreased modestly, a London toxicologist told the panel. But the committee was not convinced that reducing the package size here would have a measurable effect on those who accidentally overdose.

The panel also voted against recommending that manufactures move to "unit-of-use" packaging, which measures out the exact amount a patient might need prior to delivering the drug to the pharmacy.

The FDA may also consider other changes on which the committee did not agree, such as stronger warnings against mixing alcohol and acetaminophen or lowering the amount of acetaminophen in prescription products.

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