COX II WARNING

By: Marilynn Marchione, Associated Press

11/13/2006

CHICAGO -- The first published studies of Arcoxia, the drug that Merck & Co. hopes will take the place of its withdrawn painkiller Vioxx, are getting mixed reviews from doctors, some of whom say the results do not make a case for the medication's approval.

The critics cite not just Arcoxia's side effects but also that Merck tested it against diclofenac, an older painkiller known to raise heart risks. A fairer comparison would have been to a medicine that does not do that, such as naproxen, sold as Aleve, they say.

"The development program for Arcoxia is fatally flawed," said Dr. Steven Nissen, a Cleveland Clinic cardiologist who formerly headed the Food and Drug Administration's cardiac drug advisory panel. "My advice to the FDA is that they should not approve this drug."

Dr. David Graham, an FDA drug safety expert who has criticized his agency's handling of Vioxx, agreed. "It's my own suspicion that this study was intentionally designed to minimize the possibility of their having a repeat of what happened with VIGOR," the study that revealed Vioxx's heart risks, he said.

The new research "raises red flags," Graham said, and gave his personal opinion that the drug should not be approved. "There's every reason to think it suffers from the same problems" as Vioxx, he said.

Vioxx was a blockbuster arthritis drug when Merck pulled it from the market in September 2004 over safety concerns. Like Arcoxia, it is a cox-2 inhibitor, a class of drugs originally developed to be gentler on the stomach and hopefully easier to take long-term than traditional pain relievers. Arcoxia already is widely used in other countries, and Merck has been seeking approval to sell it in the United States. In August, the company said preliminary data from unpublished studies showed that Arcoxia did not increase heart risks more than diclofenac, sold as Cataflam and Voltaren by Switzerland-based Novartis AG.

On Monday, pooled results of three studies of Arcoxia were to be published in the British journal The Lancet and presented at an American Heart Association conference in Chicago. They involved 34,701 arthritis patients, average age 63, in the United States and 37 other countries. One-third had heart disease or multiple risk factors for it.

After an average of 18 months on either drug, clot-related heart problems were statistically similar — 320 among the 17,412 who started the study on Arcoxia, and 323 among the 17,289 on diclofenac, said lead author Dr. Christopher Cannon of Brigham and Women's Hospital in Boston. About one percent of each group suffered a heart attack, stroke or death within a year of starting on their drug. That rose to about 2.5 percent three years later.

Arcoxia users were 30 percent less likely to have ulcers, stomach bleeding or other gastrointestinal problems (176 cases versus 246 on diclofenac), but the rate of serious problems was similar.

"Most of the GI bleeding in this study was probably microscopic, meaning it wasn't clinically important," the FDA's Graham said.

Slightly more than half of each group stopped taking whichever drug they had been assigned. Side effects were the reason for 20 percent of the discontinuations. More people quit Arcoxia because of high blood pressure; more stopped diclofenac because of stomach or liver problems. Congestive heart failure was rare but more common among those receiving a higher dose of Arcoxia than among those on a lower dose or diclofenac. Cannon consults for Merck and other drug makers. Nissen currently heads a large study funded by Merck's chief rival in this field, Pfizer Inc., though he said he gets no salary from it and that all research revenue goes to the Cleveland Clinic Foundation.

The Arcoxia study "isn't the answer to everything" about painkillers, but it provides one piece of the puzzle, Cannon said.

"A picture is emerging here," said co-author Garret FitzGerald, a University of Pennsylvania scientist who believes that all cox-2 drugs bring additional heart and stroke risks because they work through a common mechanism.

"If you have people that are at risk of heart disease ... you stay away from these drugs at the cox-2 end of the spectrum and tilt towards the other end, where naproxen lies," he said. Conversely, if someone's risk of ulcer or stomach bleeding is high, a cox-2 might make more sense, he said.

Pfizer's Celebrex is the only one still on the market in the U.S.

Why was Vioxx pulled from the market?

The immediate withdrawal of Vioxx was based on data from a three-year trial designed to evaluate the possible effectiveness of this drug in preventing the recurrence of colon polyps. In comparing people taking Vioxx with those taking a placebo — an inactive medication — those taking Vioxx had an increased risk of cardiovascular problems, such as heart attack and stroke, after 18 months. Although the risk of a Vioxx-related heart attack or stroke is very small, the degree of risk depends on how much Vioxx you took and for how long.

What are the alternatives to Vioxx?

You can take the COX-2 inhibitor Celebrex or switch to a traditional nonsteroidal anti-inflammatory drug, such as naproxen (Aleve). Until recently, you could also take the COX-2 inhibitor Bextra.

Why was Bextra taken off the market?

According to the Food and Drug Administration (FDA), Bextra was taken off the market because of:

Is Celebrex safe?

Celebrex, like Vioxx and Bextra, is a COX-2 inhibitor. COX-2 inhibitors don't cause the stomach bleeding and ulcers that traditional nonsteroidal anti-inflammatory drugs (NSAIDs) might. If you're susceptible to gastrointestinal bleeding or ulcers, Celebrex may be a safe and appropriate treatment for you. Celebrex also might be an appropriate choice if you take drugs that contain prednisone. Those drugs, like NSAIDs, can cause stomach bleeding. To take traditional NSAIDs on top of those drugs would further increase your risk of bleeding.

If you've been taking a COX-2 inhibitor because of your history of stomach bleeding or ulcers, don't assume that Celebrex is automatically the right choice. Celebrex can cause kidney problems, hypertension and fluid retention. Although the risk of stomach bleeding may be lower if you take Celebrex than if you take a traditional NSAID, it's important to realize that stomach bleeding can still occur. Older patients may be at higher risk for all of these side effects.

In addition, you shouldn't take Celebrex if you have sulfa allergies.

Because of concerns that Celebrex, like Vioxx and Bextra, may pose an increased risk of heart attack and stroke, the FDA has asked the drug manufacturer to revise its drug label to include a warning of the medication's cardiovascular and gastrointestinal risks. The FDA is also encouraging doctors to prescribe the lowest effective dose for the shortest duration possible, in accordance with an individual's treatment plan.

Are traditional NSAIDs safe?

If you aren't at risk of stomach bleeding, your first choice for arthritis pain relief should be a traditional NSAID, such as ibuprofen (Advil, Motrin, others). In general, traditional NSAIDs are just as effective as COX-2 inhibitors for reducing pain and inflammation, although as with any group of drugs, there are individual patients who find one drug more effective than another.

If you switch from a COX-2 inhibitor to a traditional NSAID, be aware that some can cause stomach bleeding in a small percentage of people. If you're concerned about stomach bleeding, consider taking a traditional NSAID along with a proton pump inhibitor, which helps protect your stomach and reduces your risk of ulcers and bleeding. Be aware that NSAIDs also can cause kidney problems, hypertension and fluid retention in some patients.

The FDA has also called for manufacturers of over-the-counter NSAIDs to revise their labels to include more information about their possible risk of cardiovascular events and gastrointestinal bleeding. These label changes don't apply to aspirin, though, because the evidence clearly shows that aspirin reduces the risk of heart attack and stroke in certain people. However, aspirin, like other NSAIDs, is associated with an increased risk of stomach bleeding.

Aleve has also been in the news. Is it safe?

A recent study of the NSAID naproxen (Aleve, others) for prevention of Alzheimer's disease has raised concerns that it, too, may be associated with an increased risk of heart attack. If there is an increased risk, this risk is likely small. It has not emerged as a concern in the roughly 30 years that the drug has been available. It's very possible that the other nonsteroidal anti-inflammatory drugs, such as ibuprofen, pose this same risk. Most patients who are doing well with these drugs can continue to take them.

At this point, the exact degree of increased risk for such problems as heart attack and stroke seems to be low for most patients but higher for others. The FDA has called for the manufacturers of naproxen to revise their labeling, the same as for other NSAIDs.

What should you take if you have arthritis pain but not inflammation?

If you have pain but you don't have inflammation, you could try over-the-counter or prescription pain relievers such as acetaminophen (Tylenol, others), tramadol (Ultram) and nonaspirin salicylate products (Disalcid, Trilisate, others).

What if Vioxx or Bextra was the only medication that worked for you? What do you do then?

You may need to consider combining other drugs to get the relief you need. Also consider nondrug alternatives, such as physical therapy, acupuncture and massage, to help with your pain and inflammation.

Vioxx was extremely popular. Will this medication eventually return to the market, but with a stronger label warning? What about Bextra?

The FDA has stated that it will review any proposal by the manufacturer for resumption of the sale of Vioxx, with a stronger warning label. The manufacturer has not stated if or when it plans to submit such a proposal. The FDA has stated that the manufacturer of Bextra must further study the drug's risks before considering resumption of its sale.

In the light of new information from the producer, Pfizer, the European Medicines Agency’s (EMEA) scientific Committee for Human Medicinal Products (CHMP) has reassessed the safety of using parecoxib and valdecoxib. The following warnings apply to both medicinal products:

Parecoxib/valdecoxib must not be used as pain treatment for patients undergoing coronary artery bypass graft (CABG) surgery. Two studies have shown a higher incidence of blood clots in heart and brain compared to a placebo (inactive medicine) in such patients. It is not yet clarified whether the risk also applies to patients who have undergone other kinds of coronary artery procedures, for instance coronary balloon angioplasty.

Compared to other COX-2 inhibitors, parecoxib/valdecoxib have been connected to incidences of very serious skin reactions – some with fatal outcome. The reactions appeared early in the course of treatment and symptoms from skin or mucous membranes (such as itching, blisters, bullae or sores) should result in immediate discontinuation of treatment.

On 22 December, Pfizer sent further information to Danish anaesthetists, doctors dealing with pain relief, surgeons as well as hospital pharmacies. The product information of Dynastat® has been updated and can be found both via EMEA’s press statement and in the fact box to the right (in Danish).