Drug Profile

Do Not Use: These drugs are known as COX-2 inhibitors. Like all nonsteroidal anti-inflammatory drugs (NSAIDs), they work by inhibiting the COX enzyme. Two forms of COX are known to exist: COX-1 and COX-2. In theory, blocking these enzymes reduces the symptoms of arthritis, but this also leads to the adverse gastrointestinal (GI) effects associated with NSAIDs. It was thought that if COX-2 was selectively blocked, arthritis pain would be relieved without the serious GI adverse effects seen with other NSAIDs. However, COX-2 inhibitors are no more effective than other older NSAIDs, most have not been shown to have a lower rate of ulcers than related drugs and some have been shown to cause heart disease.

Concern about the cardiovascular safety of the COX-2 inhibitors dates back to the November 2000 publication of the Vioxx GI Clinical Outcomes Research (VIGOR) study.[7] That study found a fourfold to fivefold increase in heart attacks in people using rofecoxib (VIOXX) compared with people using the older NSAID naproxen (ALEVE, NAPROSYN). Despite this evidence, a concerted advertising effort by the companies selling COX-2 inhibitors resulted in increasing sales. Then, in September 2004, the manufacturer voluntarily removed VIOXX from the market after a subsequent study confirmed the cardiovascular risks. The Adenomatous Polyp Prevention on Vioxx (APPROVe) trial, a three-year study involving 2,600 patients, investigated the efficacy of rofecoxib for prevention of colon polyps when compared with a placebo. After 18 or more months of treatment, patients taking rofecoxib had twice the risk of a heart attack than those receiving a placebo (3.5% versus 1.9%).[8],[9]

VIOXX was not the only COX-2 inhibitor to fall under suspicion. The Celecoxib Long-Term Arthritis Safety Study (CLASS) had shown an increase in chest pain for patients taking celecoxib (CELEBREX) compared with those taking two other NSAIDs, although this effect was not statistically significant.[10] However, in January 2005, Public Citizen revealed that CELEBREX's manufacturer, Pfizer, had failed to publish the results of a randomized, placebo-controlled study that had been completed four years before and that showed a significantly increased (3.6-fold) rate of serious cardiovascular adverse events and a more than doubled rate of cardiovascular deaths in people taking celecoxib compared with those taking a placebo.[11]

Adverse effects

The BMJ published a meta-analysis (a study that combines data from many other studies) examining the use of NSAIDs and cardiovascular safety. The authors of the article stated that there is a risk of cardiovascular adverse effects associated with these drugs, and this risk must be considered when treating patients.[12]

Interactions

Studies suggest a possible harmful interaction between NSAIDs and a class of osteoporosis drugs called bisphosphonates. Patients need to be alert to the fact that the combination can result in an increased risk of ulcers and other GI adverse effects. Read more in the July 2010 issue of Worst Pills, Best Pills News.

Combining NSAIDs with anticoagulants (blood thinners for preventing blood clots) increases the risk of serious bleeding complications.[13]

Regulatory action surrounding COX-2 inhibitors

2005: In January, Public Citizen filed a petition with the Food and Drug Administration (FDA) requesting the banning of celecoxib and valdecoxib (BEXTRA, another COX-2 inhibitor for which evidence of cardiovascular toxicity existed),[14] arguing that such toxicity was an adverse effect of all COX-2 inhibitors.

In April, the FDA announced that BEXTRA would be removed from the market, although the agency cited skin reactions as the reason for its removal. It also announced an expanded warning on cardiovascular dangers (see "Warnings" box at top of page), although it applied the warning to all NSAIDs, not just the COX-2 inhibitors. (Aspirin is not required to carry the warning.)

2015: The FDA announced that the agency is strengthening the existing warning for all non-aspirin NSAIDs concerning an increased risk of heart attack and stroke.[15]

Celecoxib

Celecoxib exploded onto the market in early 1999, successfully marketed as "super-aspirin," a "breakthrough" drug as effective as the older NSAIDs but supposedly without the same risk of GI toxicity, the adverse effect that is the most serious concern with the use of NSAIDs. Public Citizen has designated celecoxib as a Do Not Use drug because there is no evidence that it is safer or more effective than some of the older NSAIDs, such as naproxen and ibuprofen.

Overlooked by uncritical journalists, too many health care professionals and a duped public was the fact that celecoxib was approved by the FDA with exactly the same warnings about risks of GI bleeding and death as the other 19 NSAIDs on the market at that time.[16] Celecoxib's manufacturer could not prove, and has not proved, to the FDA that its drug is any safer than the legion of other NSAIDs already available (at much lower cost) as far as GI toxicity is concerned.

Celecoxib is remarkable in one respect: Despite the fact that it is an unremarkable treatment for arthritis and pain, it generated $1 billion in sales before a single clinical trial was published comparing it to an existing drug for the treatment of arthritis.[17] In recent years, the core business of the pharmaceutical industry has been marketing, not research, and celecoxib is the foremost example of how successful marketing can be, even for a drug that is no better or safer (just more expensive) than drugs already on the market.

In December 1998, Public Citizen's Health Research Group testified before the FDA's Arthritis Drugs Advisory Committee, which was reviewing celecoxib. The Health Research Group representative cautioned that the COX-2 enzyme may affect other important physiological functions, including GI tract tissue repair, cell integrity, kidney function, kidney development in the fetus during pregnancy, ovarian function and fertility, and cartilage repair. New drugs such as celecoxib, and other COX-2 drugs in the pipeline, offered not only new mechanisms of action but also new mechanisms of potential toxicity and the possibility of a new spectrum of adverse effects.[18]

The manufacturer scored an egregious advertising coup with the publication of the CLASS study in the Sept. 13, 2000, issue of the Journal of the American Medical Association (JAMA).[19] The results of this six-month-long study were spun to say that celecoxib was safer on the GI tract than other NSAIDs. A cautiously optimistic editorial about the therapeutic benefits of celecoxib accompanied the publication of the study.[20]

The FDA's Arthritis Advisory Committee met on Feb. 7, 2001, to review a request by celecoxib's manufacturer to change the drug's labeling to indicate that it is a GI-safe NSAID, based on the results of the study. A company must prove to the FDA any claim of superiority of its drug over other drugs before the claim can legally be made. At this meeting, it was revealed that the company actually had data on the safety of celecoxib for as long as 16 months, rather than just the six months of results published in JAMA.

The FDA medical officer who reviewed the study for the February advisory committee meeting concluded that the company had failed to show a statistically significant lower rate of serious GI adverse reactions compared with the other drugs included in the study. The other NSAIDs were usual doses of ibuprofen (MOTRIN) and diclofenac (VOLTAREN).[20]

In February 2005, the FDA warned that new evidence indicated that long-term administration of NSAIDs resulted in renal papillary necrosis (the death of certain kidney tissue) and other kidney injury. Patients at greatest risk of this reaction include those with impaired renal function, heart failure or liver dysfunction; those taking diuretics and ACE inhibitors; and the elderly. Kidney injury symptoms usually subside with discontinuation of NSAID therapy. Clinical trials with Celebrex have shown renal effects akin to those observed with similar NSAIDs. No information is available from controlled clinical studies regarding the use of Celebrex in patients with advanced renal disease. Therefore, treatment with Celebrex is not recommended in these patients.[21]

In addition, the FDA warns that Celebrex is a sulfonamide and can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, which can be fatal. These serious effects can occur without warning and in patients without a previously known sulfa allergy. Patients should be informed about the signs and symptoms of serious skin manifestations, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.[21]

Because celecoxib is chemically related to the sulfonamides, it must not be taken by those who have had an allergic reaction to a sulfa drug.

More recent research has shown that celecoxib increases the risk of heart attacks, stroke and other adverse cardiovascular events.[22]

In 2016, Health Canada, a regulatory agency similar to the FDA, issued safety information that when celecoxib is used at dosages higher than 200 mg per day, there may be an increased risk of heart attack and stroke.[23]

Meloxicam (MOBIC)

The NSAID meloxicam was approved in April 2000 by the FDA, making it the 23rd NSAID on the U.S. market. Public Citizen has listed meloxicam as a Do Not Use drug because there is no evidence that it is safer or more effective than some of the older NSAIDs such as naproxen and ibuprofen.

Meloxicam is approved only for the relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis.

Meloxicam is by no means a new drug; it joins the list of drugs first marketed in other countries and then recycled in the U.S. Meloxicam has been available in the U.K. since September 1996 and has been promoted there as a selective, and thus supposedly safer, NSAID for the GI tract. GI adverse effects are the most serious reactions seen with the NSAIDs.

In the August 1998 issue of Current Problems in Pharmacovigilance, a newsletter published by Britain's Medicines Control Agency and the Committee on Safety of Medicines, it was reported that in the first year and nine months of marketing experience with meloxicam in that country, there had been a total of 1,339 adverse reactions reported to the government for the drug. Of these, 41%, or 549, were GI adverse effects, 99 being reports of perforations, ulcers or bleeding, including five deaths. The British drug regulatory authorities required a major revision in the warnings for meloxicam because of these severe GI adverse effects.[24]

The internationally respected Drug and Therapeutics Bulletin, the U.K.'s equivalent of the American Medical Letter on Drugs and Therapeutics, said the following in its August 1998 issue: "There is no convincing evidence that the risk of the severest GI 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."[25]

In March 2012, the FDA added the following information to the drug product label of Mobic concerning its use in women trying to conceive: Data from studies have shown that NSAIDs, including Mobic, may be associated with a reversible delay in ovulation. Mobic is not recommended for women who have difficulties conceiving or who are undergoing investigation of infertility.[26]

Rofecoxib

Rofecoxib was a heavily promoted, overpriced NSAID that was taken off the market on Sept. 30, 2004, because it caused an increase in heart attack and stroke. The drug was approved by the FDA for the management of osteoarthritis, rheumatoid arthritis, acute pain and painful menstrual periods.

Valdecoxib

Valdecoxib was another redundant "me too" drug in the crowded NSAID family of drugs. This drug is chemically similar to celecoxib, and both valdecoxib and celecoxib are produced by the same manufacturer, Pfizer. Public Citizen has listed valdecoxib as a Do Not Use drug because there is no evidence that it is safer or more effective than some of the older NSAIDs, such as naproxen and ibuprofen.

On April 7, 2005, after concluding that the overall risk versus benefit profile of valdecoxib was unfavorable, the FDA requested Pfizer Inc. to voluntarily withdraw valdecoxib from the market. This request was based on:

The lack of adequate data on the cardiovascular safety of long-term use of valdecoxib, along with the increased risk of adverse cardiovascular events in short-term coronary artery bypass surgery trials that FDA believes may be relevant to chronic use.

There have been reports of serious and potentially life-threatening skin reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme), including deaths. The risk of these reactions in individual patients is unpredictable, occurring in patients with and without a prior history of sulfa allergy, and after both short- and long-term use.

This NSAID carried the same product label warning about GI toxicity as all other drugs in the NSAID family.[27]

Valdecoxib was to be the second prong of a two-pronged marketing strategy that would begin with parecoxib, an injectable form of valdecoxib that breaks down to valdecoxib in the body. The plan was to have both an injectable and an oral drug. In October 2000, the manufacturer submitted its application to the FDA for the approval of parecoxib for the management of acute pain.[28] The FDA informed Pharmacia (bought by Pfizer) in July 2001 that parecoxib was "not approvable." The company did not reveal why the application for parecoxib was rejected.[29]

The manufacturer filed its application for valdecoxib's FDA marketing clearance in March 2001, asking that it be approved for the treatment of osteoarthritis, rheumatoid arthritis, acute pain and painful menstrual periods.[30] When valdecoxib was approved in November 2001, the drug had failed to gain FDA approval for acute pain and is still not approved to treat acute pain.[27]

Pfizer did not let valdecoxib's failure to gain FDA approval for acute pain deter it from making the drug a marketing success. The New York Times reported on Nov. 22, 2002, that an article published in The Journal of the American Dental Association[31] concluded that valdecoxib was effective for acute pain following dental surgery. This was six months after the FDA rejected the drug for acute pain.[32]

2020: The FDA and Health Canada (an agency in Canada similar to the FDA) warned that use of NSAIDs at about 20 weeks or later in pregnancy rarely causes serious kidney problems in an unborn baby.[33],[34] These kidney problems can lead to oligohydramnios, a condition in which there are low levels of amniotic fluid surrounding the baby. Amniotic fluid normally provides a protective cushion and plays an important role in the development of a baby’s lungs, digestive system and muscles. Oligohydramnios in turn can lead to decreased range of motion in a baby’s arms and legs and delayed lung maturation.