Do Not Use Until February 2004
Celecoxib (CELEBREX) - Another Nonsteroidal Anti-Inflammatory Drug (NSAID)

Celecoxib (CELEBREX), approved by the Food and Drug Administration (FDA) for the symptomatic relief of osteoarthritis and rheumatoid arthritis, becomes the 20th member of the family known as nonsteroidal anti-inflammatory drugs, or NSAIDs for short. This family includes such well-known prescription and nonprescription products as ibuprofen (MOTRIN, MOTRIN IB), nabumetone (RELAFEN), ketoprofen (ORUDIS, ORUDIS KT) and piroxicam (FELDENE). Celecoxib is not approved by the FDA for the treatment of acute pain. Although the drug's manufacturer, G.D. Searle and Company, a part of chemical giant Monsanto, sought approval for the treatment of acute pain, celecoxib failed to meet the standard for an effective painkiller.

The safety and effectiveness of celecoxib has not been evaluated in children under 18 years of age.

The most common serious adverse effect of NSAIDs is gastrointestinal (GI) toxicity that can cause ulcers, perforations, and bleeding that can lead to hospitalization and even death. Other potentially serious effects of the NSAIDs are liver and kidney toxicity and an alteration in the blood's ability to clot.

All NSAIDs, including celecoxib, work by inhibiting an enzyme called cyclooxygenase, or COX for short. Two forms of COX are known to exist, COX-1 and COX-2. In theory, blocking both of these reduces the symptoms of arthritis but also leads to the adverse effects associated with NSAIDs. In theory it is thought that if COX-2 is selectively blocked, arthritis pain would be relieved without the adverse effects seen with other NSAIDs. This is a nice, neat mechanism that is simple and easy to understand, and sells a lot of drugs to uncritical doctors and patients. It also makes doctors and pharmacists think they know more than they really do about the way drugs work.

Not frequently discussed in news media is the fact that COX-2 may have other important physiological functions in addition to its role in inflammation. These include GI tract tissue repair, cell integrity, kidney function, fetal kidney development during pregnancy, ovarian function and fertility, and cartilage repair. New drugs such as celecoxib and other COX-2 drugs in the pipeline offer not only new mechanisms of action, but also new mechanisms of potential toxicity and the possibility of a new spectrum of adverse effects.

Since 1996, celecoxib's manufacturer has been trying to distance its product from the host of other NSAIDs by publicizing it not as an NSAID, but as a selective COX-2 inhibitor "without the side effects associated with currently available agents"--meaning other NSAIDs. This is a game drug companies often play; they begin planting positive images for new products in the minds of doctors and the public long before they get FDA marketing clearance. In the year before celecoxib was reviewed by the FDA's Arthritis Drugs Advisory Committee, according to the Dow Jones News Retrieval database, there had been 700 different stories written about COX-2 inhibitors. Image building involves promoting the positive aspects of unpublished company-sponsored clinical studies, presented at scientific meetings, and making sure that there is wide coverage of these meetings by uncritical news media. The image that Searle is building for celecoxib is one of a breakthrough class of new drugs called selective COX-2 inhibitors rather than as just another NSAID. Distancing celecoxib from the NSAIDs by calling it a COX-2 inhibitor rather than an NSAID gives the impression of greater safety, particularly GI safety.

When the news media rely on drug company press releases as a source of information, they become a platform for de facto direct-to-consumer prescription drug advertising. This is done to create demand for a new drug before it is approved by the FDA, and it works. Celecoxib is now the second fastest selling new drug in history, right behind sildenafil (VIAGRA), the wildly popular drug for sexual dysfunction that also received the full advance-promotion treatment.

Searle attempted to convince the FDA that celecoxib should not carry the same warning about GI toxicity as the 19 other NSAIDs. This would have allowed the company to promote it as being safer than other NSAIDs. Searle presented studies to the FDA showing that the occurrence of ulcers seen through an endoscope, a device used to view the lining of the stomach, was less with celecoxib than with other NSAIDs. This type of ulcer is often shallow and often heals by itself. It is not known if fewer ulcers seen through an endoscope will translate into fewer bleeding ulcers and hospitalizations or deaths for patients that use COX-2 drugs. Because of this the FDA made the right decision and celecoxib carries the following warning, just like every other NSAID:

Gastrointestinal (GI) Effects- Risk of GI Ulceration, Bleeding, and Perforation: Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, can occur at any time, with or without warning symptoms, in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Minor upper gastrointestinal problems, such as dyspepsia [upset stomach], are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding, even in the absence of previous GI tract symptoms. Patients should be informed about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.

COX-2 drugs are not necessarily safer than other NSAIDs. Meloxicam (MOBIC), an NSAID that has been available in the United Kingdom since September 1996, was promoted as a selective COX-2 inhibitor, safer than the other drugs in its class. Last year, the British Journal of Clinical Pharmacology published a study of healthy people given meloxicam, a dummy placebo pill, or piroxicam (FELDENE) for 28 days that found that, using an endoscope again, "no significant mucosal damage" (damage to the lining of the stomach) occurred in either the placebo or the meloxicam group. But recently, the British Government required a major strengthening of warnings on this drug because of severe gastrointestinal effects. In August 1998 the British Medicines Control Agency and the Committee on Safety of Medicines reported on the first 21 months of marketing experience with Boehringer-Ingelheim's meloxicam. Of a total of 1,339 adverse reactions reported to the government for the drug, 41 percent or 549 were GI adverse effects with 18 percent of these, or 99, being reports of perforations, ulcers or bleeding, including five deaths.

The Drug and Therapeutics Bulletin, the British equivalent of our Medical Letter, which is sent to all British physicians, said in its August 1998 issue that "There is no convincing evidence that the risk of the severest adverse gastrointestinal events, namely peptic ulceration, perforation and bleeding, is lower with meloxicam than with other NSAIDs when given at equi-effective doses....Meloxicam has not been compared with ibuprofen...which comes out best in most safety assessments."

All members of the NSAID family of drugs can cause gastrointestinal toxicity that can lead to bleeding and hospitalization or death. The risk of gastrointestinal toxicity from these drugs increases with increasing doses and length of treatment. If these symptoms develop while you are taking an NSAID, stop the drug immediately and contact your doctor: severe abdominal or stomach pain, cramping, or burning; severe and continuing nausea, heartburn, or indigestion; bloody or black, tarry stools; vomiting blood or material that looks like coffee grounds; or spitting up blood.

In studies testing celecoxib for the treatment of osteoarthritis, the drug was found to be better than a placebo. At doses of 100 milligrams or 200 milligrams given twice daily the effectiveness of celecoxib was comparable to 500 milligrams of naproxen (NAPROSYN) also given twice daily.

At a Washington DC chain pharmacy the retail price for a month's supply of celecoxib 100 milligram is $107.99 and for a month's supply of the 200-milligram dosage is $168.99, while a month's supply of generic naproxen at the same pharmacy is only $37.09. The American College of Rheumatology Guidelines for the Medical Management of Osteoarthritis recommends that acetaminophen (TYLENOL) be tried before an NSAID at a maximum dose up to 4,000 milligrams (4 grams) a day. A bottle of 250 generic acetaminophen tablets in the 500-milligram strength costs $7.69 at our local chain pharmacy. At the maximum dose recommended by the American College Rheumatology for osteoarthritis this bottle of 250 tablets would last a month.

In the trials evaluating the effectiveness of celecoxib in rheumatoid arthritis in the same doses used in the osteoarthritis trials the drug proved better than the placebo, and similar in effectiveness to 500 milligrams of naproxen given twice a day.

Celecoxib shares a chemical similarity to the sulfa drugs and should not be taken by people who are allergic to them. Celecoxib should not be taken by people who have experienced asthma, hives, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, allergic reactions to NSAIDs have been reported in such people.

Long-term use of NSAIDs has resulted in kidney damage. People at greatest risk of this reaction are those with impaired kidney function, heart failure, liver dysfunction, and those taking diuretics (water pills) such as hydrochlorothiazide (HYDRODIURIL) and angiotensin converting enzyme (ACE) inhibitors, of which captopril (CAPOTEN) and enalapril (VASOTEC) are examples. The elderly are also at greater risk of kidney damage from NSAIDs. Clinical trials with celecoxib have shown kidney effects similar to those observed with other NSAIDs.

Cases of severe liver reactions, including jaundice (yellowing of the skin or whites of the eyes) and fatal hepatitis (inflammation of the liver), and liver failure (some with fatal outcomes) have been reported with NSAIDs. The symptoms of drug-induced liver toxicity are non-specific and may mimic many other illnesses. They include rash, loss of appetite, tiredness, pain on the right side just below the rib cage (the location of the liver), dark urine or a yellowing of the skin or whites of the eyes (jaundice). The symptoms of liver toxicity may also include fever. The main treatment for drug-induced liver damage is stopping the drug.

NSAIDs may diminish the blood-pressure-lowering effect of ACE inhibitors. This interaction should be given consideration in patients taking celecoxib along with an ACE inhibitor. NSAIDs can also reduce the effects of water pills. Use of the antifungal drug fluconazole (DIFLUCAN) resulted in a two-fold increase in celecoxib levels in the blood. Lithium (LITHOBID) blood levels increased approximately 17 percent when celecoxib was given. Patients on lithium treatment should be closely watched when celecoxib is introduced or withdrawn.

The editors of the highly regarded Medical Letter On Drugs and Therapeutics, written for doctors and pharmacists, concluded their review of celecoxib by saying: "Whether serious gastrointestinal bleeding will occur less frequently with celecoxib remains to be established." Because of the uncertainty about safety that always accompanies the release of any new drug and the fact that celecoxib has not been shown to be any more effective than older NSAIDs you should wait at least five years, until February 2004, to take celecoxib.

We recommend that you should always wait at least five years from the date of release to take any new drug unless it is one of those rare "breakthrough" drugs that offers a documented therapeutic advantage over older, proven drugs. New drugs are tested in a relatively small number of people before being approved, and serious adverse effects or life-threatening drug interactions may not be detected until the new drug has been taken by hundreds of thousands of people. A number of new drugs have been withdrawn usually within five years after a drug's release. Also, serious new adverse reaction warnings have been added to the labeling of a number of drugs, or new interactions have been detected, usually within five years after a drug's release.

What You Can Do

You should wait at least five years to take celecoxib. It is an expensive new drug that may be no more effective and no safer than acetaminophen or older NSAIDs at a fraction of the cost.