Merck Announces"Voluntary" Withdraw of Vioxx® from market

WHITEHOUSE STATION, N. J., Sept. 30, 2004—Merck & Co., Inc. today announced a voluntary worldwide withdrawal of VIOXX® (rofecoxib), its arthritis and acute pain medication. The company’s decision, which is effective immediately, is based on new, three-year data from a prospective, randomized, placebo-controlled clinical trial, the APPROVe (Adenomatous Polyp Prevention on VIOXX) trial.

The trial, which is being stopped, was designed to evaluate if VIOXX 25 mg was effective in preventing the reoccurrence of polyps in the rectum and colons of patients having previous adenomas (pre cancerous tumor) in the colon and rectum. This would be a new use for VIOXX®

In this study, there was an increased relative risk for confirmed cardiovascular events, such as heart attack and stroke, beginning after 18 months of treatment in the patients taking VIOXX compared to those taking placebo. The results for the first 18 months of the APPROVe study did not show any increased risk of confirmed cardiovascular events on VIOXX, and in this respect, are similar to the results of two placebo-controlled studies described in the current U.S. labeling for VIOXX.

The trial enrolled 2,600 patients and compared VIOXX 25 mg to placebo. The trial began enrollment in 2000. Results of the VIGOR (VIOXX Gastrointestinal Outcomes Research) study, released in March 2000, demonstrated that the risk of gastrointestinal toxicity with VIOXX was less than with naproxen, but indicated an increased risk of cardiovascular events versus naproxen.

However, in other studies including Merck’s Phase III studies that were the basis of regulatory approval of the product, there was not an increased risk of cardiovascular events with VIOXX compared with placebo or VIOXX compared with other non-naproxen non-steroidal anti-inflammatory drugs (NSAID's). Merck began long-term randomized clinical trials to evaluate the cardiovascular safety profile of VIOXX after the drug had already been approved by the FDA for sale by prescription.

Merck has informed the U.S. Food and Drug Administration and regulatory authorities in other countries of its decision. The company also is in the process of notifying health care practitioners in the United States and other countries where VIOXX is marketed. Patients who are currently taking VIOXX should contact their health care providers to discuss discontinuing use of VIOXX and possible alternative treatments. In addition, patients and health care professionals may obtain information from www.merck.com and www.vioxx.com, or may call (888) 36-VIOXX (1-888-368-4699).

"The results of clinical studies with one molecule in a given class are not necessarily applicable to others in the class. Therefore, the clinical significance of the APPROVe trial, if any, for the long-term use of other drugs in this class, consisting of COX-2 specific inhibitors and NSAID's, is unknown. The company will work with regulatory authorities in the 47 countries where ARCOXIA is approved to assess whether changes to the prescribing information for this class of drugs, including ARCOXIA, are warranted. Merck is continuing to seek approval for ARCOXIA in other countries, including the United States." (1)

Brief History of anti inflammatory/ analgesic medications

Vioxx is an anti inflammatory and analgesic drug belonging to a class of medications known as COX 2 inhibitors. This means it works for conditions causing both inflammation and pain. Anti inflammatory analgesics have enormous use for a wide variety of conditions including:

Aspirin was the first anti inflammatory analgesic widely used and marketed. It was the mainstay of therapy until a class of newer medications, known as NSAIDS (non-steroidal anti inflammatory drugs), emerged and largely replaced aspirin for most purposes in the early 1980's. The two most commonly prescribed NSAIDS that emerged were Ibuprofen (Motrin®, Advil®, Nuprin®) and Naproxen (Naprosyn ®, Alleve®). The NSAIDS generally have a higher therapeutic to side effect ratio than Aspirin and have essentially replaced Aspirin for all purposes except the use of low dose Aspirin for prevention of heart attack and stroke. A higher "therapeutic to side effect ratio" means that the dose of the drug likely to be effective is much less likely to be near the dose of that drug that is associated with increasing side effects.

NSAIDS work by inhibiting the production of a chemical compound called cyclooxygenase that is made by the body in response to tissue injury or inflammation. Cyclooxygenase is necessary for the production of a class of other chemicals called prostaglandins. Prostaglandins have a variety of effects in the body depending on the type of prostaglandin and what part of the body the prostaglandin is made in. Inflammatory prostaglandins produced in response to tissue injury or irritation enhance the release of other chemicals in the body that cause tissue swelling and pain.

However, NSAIDS also inhibit the production of Prostaglandin E which normally helps protect the stomach lining.

In the late 1990's a newer class of NSAIDS, the COX 2 inhibitors, were developed that in theory were less likely to cause gastrointestinal side effects. These medications are thought to bind cyclooxygenase 2 receptors (not involved in Prostaglandin E production) and are less likely to bind other cyclooxygenase receptors that are involved in Prostaglandin E production.

VIOXX was launched in the United States in 1999 and has been marketed in more than 80 countries. In some countries, the product is marketed under the trademark CEOXX. Worldwide sales of VIOXX in 2003 were $2.5 billion.

With the politics of deregulation pushed by both the Clinton and Bush administrations intended to speed new drugs to market these medications appeared relatively quickly. Many of the older NSAIDS were no longer patented and were available without a prescription at very reasonable cost. A month supply of Motrin or Naprosyn might range from $5 to $15. COX 2 inhibitors, on the other hand, were likely to cost about $100 for a month supply.

Acetaminophen (Tylenol™) is an analgesic (pain reliever) but not an anti inflammatory medication. It has an excellent safety profile when used at appropriate dosages and is the recommended starting medication for patients that have chronic painful conditions such as arthritis. However, it is not as effective as NSAIDS for more severe pain and for conditions that involve inflammation (rheumatoid arthritis, burns, soft tissue swelling).

Who Wins?

Pfizer, maker of the COX 2 inhibitor Celebrex® (Celecoxib) and Bextra® (Valdecoxib), appears poised to take advantage of Vioxx's misfortune assuming new studies do not show the same problems associated with Vioxx™. However, as of 10/15/2004 new informational alerts from Pfizer indicate that Bextra appears to be associated with a higher incidence of cardiovascular side effects, including heart attack and stroke, when used in post operative patients

" NEW YORK, OCTOBER 15 : PFIZER Inc. on Friday said two clinical trials showed patients taking its anti-inflammatory drug Bextra, had a higher risk of cardiovascular events during high-risk coronary bypass surgery.

Pfizer did not say what the cardiovascular events were, but often, this term refers to heart attack, blood clots and stroke. Bextra—an arthritis drug—is not approved for use in surgical settings in the United States.

Pfizer said, in the two trials of patients undergoing the surgery, an increase in cardiovascular events was seen in patients taking Bextra.

Pfizer also said that it is changing the label on Bextra, in order to strengthen a warning about a rare but serious skin reaction that can occur mainly within the first two weeks of therapy." (2)

Additionally, Pfizer has recently noted that Bextra is associated with a rare allergic skin reaction that can be life threatening. This may be due to the presence of a sulfa component in Bextra. Sulfa containing drugs are associated with a risk of skin disorders ranging from mild rashes to life threatening sloughing off of the skin. Persons taking Bextra and noticing any new skin rash or itching should immediately discontinue this medication and notify their physician.

Another potential beneficiary are makers of older anti inflammatories. The COX2 inhibitors have never been shown to be more effective than Ibuprofen or other nonspecific NSAIDS. Although Ibuprofen has the highest number of total patients experiencing side effects, primarily gastrointestinal/ stomach irritation, it is by far the most commonly used NSAID. For short term use of 2 weeks or less studies have shown no higher incidence of gastrointestinal side effects than COX 2 inhibitors with both having a 15 to 20 % incidence of reported side effects.

Recommendations

Patients taking VIOXX need to consult their physician about discontinuing this medication and finding an acceptable alternative! Because on drug has bad side effects does not necessarily mean that another similar, but different, drug will have the same bad side effects. This is true only if the drugs in question have been thoroughly examined in randomized placebo controlled double blinded studies of sufficient duration (in the case of VIOXX this meant at least 18 months). It is not clear that either Celebrex or Bextra have met these requirements!

We at DoctorsCorner stress that these concerns must be discussed with a patient's physician. Certainly persons with cardiovascular risk factors (high blood pressure, prior heart attack/ coronary artery disease, stroke, smoking) or family history of such risk factors must be especially concerned about the use of COX-2 inhibitors. We do not recommend their use unless absolutely necessary and no other effective alternative is available.