Straight Talk About Selective COX-2 Inhibitors and NSAIDs

May 2005

AF President's letter to the FDA

The developments over the past several months related to selective COX-2 inhibitors and nonsteroidal anti-inflammory drugs (NSAIDs) have confused the public and shaken its confidence in an important class of drugs used to relieve arthritis pain. In response to evidence that selective COX-2 inhibitors increase the risk of cardiovascular (CV) complications, two selective COX-2 inhibitors – Vioxx (rofecoxib) and Bextra (valdecoxib) – have been taken off the market. The selective COX-2 inhibitor Celebrex (celecoxib) will have a strong warning regarding the potential for serious CV complications associated with use of the drug, and similar warnings about the potential for CV complications will be required for all NSAIDs (excluding aspirin).
We have responded below to many of the questions that people with arthritis have about these decisions and the impact these will have on their lives. The Arthritis Foundation believes that this discussion has failed to take into account the potential benefits from these drugs and their contribution to improving the lives of millions of people with arthritis. We will continue to express our strong opinion about the importance of informed patient choice with regard to arthritis drugs. People with arthritis have the right to make their own decisions about treatments to alleviate their pain and minimize the risk of serious limitations from arthritis – the nation’s number one cause of disability.

Q. What was included in the FDA’s recent announcement about NSAIDs?
A. On Thursday, April 7, 2005, the U.S. Food and Drug Administration (FDA) asked Pfizer Inc. to voluntarily withdraw the COX-2 inhibitor Bextra from the market. It also required the placement of a strong “black box” warning on the label of the COX-2 inhibitor Celebrex regarding the risk of CV events such as heart attacks and strokes from the drug. In addition, it strengthened warning labels for all prescription and over-the-counter (OTC) NSAIDs to add the risk of serious CV events in addition to gastrointestinal (GI) bleeding. The FDA called for additional clinical studies to learn more about the long-term benefit and safety of these drugs in arthritis. Previously, Vioxx, another COX-2 inhibitor, was voluntarily withdrawn from the market by its manufacturer, Merck, due to CV side effects.

Q. I thought the FDA previously said that both Celebrex and Bextra could remain on the market with appropriate warnings? Why the change?
A. A committee of medical experts that advises the FDA (FDA Advisory Committee) reviewed extensive data and heard testimony in February and subsequently recommended to the FDA that both Celebrex and Bextra remain available with stronger warnings about side effects. While the FDA carefully considers the recommendations of its advisory committees, it is under no obligation to follow the recommendations. In this case, the decisions by the FDA differ from the recommendations of its advisory committee in both removing Bextra from the market and extending more significant warnings to all NSAIDs.

Q. How can I reduce my risk of complications from these drugs?
A. Since the risk of side effects appears to be related to the dose of these drugs, the advisory committee and FDA recommended that patients take the lowest dose possible of NSAIDs and Celebrex that best controls their symptoms. The dose needed varies from person to person. In no instance should someone take more than the prescribed or recommended dose of these medications. The Arthritis Foundation advises that patients not abruptly stop their medication or alter their dosage without first speaking with their doctor.

Q. Why did the FDA ask Pfizer to withdraw Bextra from the market?
A. The FDA concluded that the overall risk versus benefit profile of Bextra is unfavorable based on the following:
The lack of adequate data on the CV safety of long-term use of Bextra and the increased risk of adverse CV events in short-term coronary artery bypass surgery trials.
Reports of serious and potentially life-threatening skin reactions, including deaths, in patients using Bextra.
Bextra has not been shown to offer any advantages over the existing NSAIDs.
Q. I am currently taking Bextra. What should I do?
A. Since Bextra will no longer be available, you need to talk with your doctor about discontinuing Bextra and learning more about other treatment options for your arthritis. You and your doctor should work together to develop a treatment plan based on your symptoms and the impact of arthritis on your life.

Q. Given all the talk about side effects, what other medication(s) should I consider if I was previously taking Bextra or Vioxx?

A. There are a number of different NSAIDs available, including both prescription and OTC drugs. These as well as analgesic drugs (pain relievers) such as acetaminophen are very important drugs for relief of pain and to allow people with arthritis to better use their joints. NSAIDs are often used with a proton pump inhibitor such as Nexium or (esomeprazole) or Prilosec (omeprazole), to help limit the risk of GI bleeding. Celebrex remains a COX-2 option to offer pain relief and a reduced risk of GI complications. The best medication and dosage for you needs to be discussed with your physician and based on consideration of your symptoms, the limitations caused by your arthritis, your response to previous drugs, and most importantly your risk tolerance.

Q. How concerned should I be about the side effects of these drugs?
A. All medications have side effects that you must consider and accept when you decide to take the medication. With any medication, you and your physician must determine the appropriate trade-off between the benefits of the medication and the risk of possible side effects. This is a very individual and personal decision because only you know the impact arthritis has on your life and what risk you are willing to tolerate.

Q. What changes did the FDA make for Celebrex?
A. After concluding that the benefits of Celebrex outweigh the potential risks in properly selected and informed patients, the FDA has allowed Celebrex to remain on the market and has asked Pfizer to take the actions listed below:

Revise the Celebrex label to include a highlighted warning containing the class NSAID warnings and contraindication about CV and GI risk, plus specific information on the controlled clinical trial data that demonstrate an increased risk of adverse CV events for celecoxib.

Encourage physicians and patients to use the lowest dose that controls symptoms and for the shortest period of time.

Include a Medication Guide as part of the labeling, which will be required to be given at the time the drug is dispensed to inform patients of the potential for CV and GI risk associated with NSAIDs, in general, and Celebrex specifically. The Medication Guide will inform patients of the need to discuss with their doctor the risks and benefits of using NSAIDs and the importance of using the lowest effective dose for the shortest duration possible.

Commit to conduct a long-term study of the safety of Celebrex compared to naproxen and other similar drugs.

Q. I’m currently taking or considering taking Celebrex. Should I be concerned?

A. The Arthritis Foundation believes the new warnings being required for Celebrex are justified and help to better inform people with arthritis about the potential side effects from the drug. However, if used appropriately and monitored carefully, Celebrex remains an important and effective drug for the treatment of arthritis, particularly for persons who have failed to respond to other NSAIDs or those at high risk for NSAID-ulcers. Individuals with high blood pressure, congestive heart failure, angina pectoris or previous stroke or heart attack are at the highest risk of CV side effects from Celebrex and should only use the drug as last resort.

Q. Even OTC NSAID medications are coming under fire, but I have been taking them for years … am I in danger?
OTC NSAIDs are safe and effective when used as directed on the label. The FDA has asked manufacturers of OTC NSAIDs (with the exception of aspirin) to revise their labeling to include more additional information about the potential for GI and CV risks, and provide information to assist consumers in the safe use of the drug. This includes instructions about which patients should seek the advice of a physician before using these drugs, stronger reminders about limiting the dose and duration of treatment in accordance with the package instructions unless otherwise advised by a physician, and a warning about potential skin reactions. While the FDA has required stronger risk warning labeling for all OTC NSAIDs, the GI risks including bleeding and ulcers for these medications have been known for years and are not new. The Arthritis Foundation believes the new FDA requirement to add warnings of CV side effects to OTC NSAIDs may be overly cautious since we are not aware of any conclusive data that provide clear evidence of CV risk from these NSAIDs. Additional studies to learn more about the potential for CV risks from these drugs are needed.

Q. Naproxen made headlines late last year when the NIH-sponsored Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT) was halted. What are the CV and other risks associated with naproxen?

A. At the FDA Advisory Panel Hearing in February, it was concluded that naproxen was not associated with an increased CV risk and that the ADAPT study was stopped for reasons other than concerns over naproxen safety. Naproxen continues to be a safe and effective drug when used as directed. However, like all of the traditional NSAIDs, it does have the potential for causing GI side effects.

Q. Is acetaminophen associated with CV risks and what is its role in arthritis treatment?
A. Acetaminophen is an analgesic (pain relieving) drug, and has no effects on inflammation. It is not part of the NSAID class of drugs and is not associated with either GI or CV risks. Acetaminophen does, however, have the potential to cause liver damage if used in high doses or combined with excessive alcohol consumption. Acetaminophen continues to be an important, cost-effective and safe drug for arthritis pain relief, particularly for people with mild to moderate arthritis symptoms.

Q. Some NSAIDs have been associated with rare serious and potentially life-threatening skin reactions, such as Stevens-Johnson syndrome (SJS). What is being done to warn patients about this risk?
A. The FDA is asking manufacturers of OTC NSAIDs to include a warning about potential skin reactions. The labeling of prescription NSAIDs already addresses potential skin reactions. The FDA also has recently received a Citizens Petition regarding the risk of SJS with ibuprofen (received February 15, 2005). The petition is still under review. After reviewing the data submitted with the petition, the FDA will determine whether additional labeling changes with regard to skin reactions are warranted.

Q. Will Vioxx be returned to the market at some point?
A. Vioxx was voluntarily removed from the market by Merck in September 2004. The FDA has indicated that it would be willing to consider a proposal from Merck for resumption of marketing of Vioxx. This would likely be carefully reviewed with the new FDA Drug Safety Oversight Board and an advisory committee before a decision would be made.

Q. Will Bextra be available to patients on a compassionate use basis?
A. The FDA has indicated that it would be willing to consider a proposal from Pfizer for a program to provide limited access to those patients who believe that Bextra is the best option for them.

Q. What are possible alternatives to medications for treating arthritis?
A. While medications are a very important part of a total treatment plan for managing arthritis and maintaining an active life, they are just one part of a total treatment plan. The Arthritis Foundation encourages people to learn as much as possible about all treatment options, and to work closely with their doctor to develop a comprehensive treatment plan that is best suited for them. In addition to medications, the Arthritis Foundation stresses the importance of weight control, exercise and physical activity, joint injections, the use of orthotic and assistive devices and surgical options for the management of pain and functional limitations caused by arthritis.

Q. Why were selective COX-2 inhibitors developed in the first place?
A. COX-2 inhibitors were originally developed to reduce the risk of GI complications associated with traditional NSAIDs, including serious bleeding and even death. NSAIDs block two different forms of COX enzymes -- the COX-2 enzymes which are responsible for pain and inflammation as well as COX-1 enzymes which act to protect the stomach. The development of drugs that selectively block the COX-2 enzymes relieve the pain and inflammation of arthritis, but have little or no effect on the gastroprotective COX-1 enzymes. A number of clinical studies have clearly shown that selective COX-2 inhibitors are associated with significantly fewer GI side effects as compared to conventional NSAIDs.

Q. Can I return my unused Bextra for a refund?
A. You may take your unused Bextra tablets to your local pharmacy and request a refund. Or you may contact the National Notification Center (NNC) at 1-866-608-3935 to receive a patient product return kit by mail. NNC will process your refund on Pfizer's behalf.

Q. Where can I get more information about NSAIDs?
A. To find out more about all NSAIDs:

Request a free Arthritis Today Drug Guide

Visit FDA’s Drug Information Web page

Visit the American College of Rheumatology Web site

Call Drug Information at: 888-INFO-FDA (888-463-6332).

Q. As the voice for millions of people with arthritis, what is the Arthritis Foundation’s view of these decisions?
A. The Arthritis Foundation believes that most of the decisions made by the FDA serve to improve and protect the health of people with arthritis. However, the Arthritis Foundation is concerned that the voice of millions of people with arthritis who use and benefit from these drugs to maintain an active life has neither been sufficiently brought into the discussions nor heard in making these decisions.

All medications have risks and benefits. The Arthritis Foundation supports efforts to better and more fully inform the public about the risks associated with selective COX-2 inhibitors. This will allow the consumer to more effectively work with their doctor to make individual treatment decisions that best meet their needs.

The Arthritis Foundation urges the FDA and Merck to review their decisions on Vioxx and Bextra and to reconsider putting these drugs back on the market. We believe that selective COX-2 inhibitors are an important and valuable class of drugs for many people with arthritis; that a very large number stand to benefit from these drugs, and will decide to use them and fully accept the risks.

Additionally, the Arthritis Foundation asks the FDA to reconsider the decision to place warnings about CV risks on OTC non-selective NSAIDs. We do not believe that there is currently sufficient nor conclusive evidence to justify this action. This is a very valuable and cost-effective class of drugs used by millions of people with arthritis to relieve pain.

The Arthritis Foundation fully supports efforts to increase surveillance of drugs once they are approved and available in the marketplace to better understand the risks of side effects from the drugs and communicate these risks clearly and quickly to the public and healthcare providers.

The Arthritis Foundation supports efforts to improve the educational content of direct-to-consumer advertising of drugs so that the public has a realistic expectation of benefit and risk. We regard appropriate direct-to-consumer advertising as a valuable resource for people with arthritis to help initiate a dialogue with their physician about potential treatments.

The Arthritis Foundation believes continued study is needed to learn more about the benefits and risks of long-term use of drugs in people with arthritis. Most forms of arthritis are chronic and people typically use these drugs for months or even years.

The Arthritis Foundation encourages greater efforts to inform people about all available treatment options when making treatment decisions.

Q. How can I let the FDA know how its decisions have impacted me?

A. The Arthritis Foundation encourages consumers impacted by these decisions to make their voices heard. The FDA's Center for Drug Evaluation and Research (CDER) is responsible for the approval of new drugs and post-market reviews for safety. The Arthritis Foundation has information on its Web site that tells how to contact CDER. To contact the FDA by mail, write to:

Lester M. Crawford, DVM, PhD
Acting Commissioner
U.S. Food and Drug Administration
Parklawn Building
5600 Fishers Lane, Room 14-71
Rockville, MD 20857

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