Questions and Answers FDA Regulatory Actions for the COX-2 Selective and Non-Selective Non-Steroidal Anti-inflammatory drugs (NSAIDs)
1. What is FDA announcing today?
In follow-up to the February 16-18, 2005, joint meeting of FDA’s Arthritis and Drug Safety and Risk Management Advisory Committees, convened to discuss the safety of the “COX-2 selective nonsteroidal anti-inflammatory drugs and related agents,” we are announcing our planned regulatory actions for Bextra, Celebrex, and the non-selective prescription and over-the-counter (OTC) non-steroidal anti-inflammatory drugs (NSAIDs).
We have concluded that the overall risk versus benefit profile for Bextra is unfavorable and we have requested that Pfizer, the manufacturer, voluntarily withdraw the drug from the market. Pfizer has agreed to suspend sales and marketing of Bextra in the U.S., pendng further discussions with the agency. We are requesting that manufacturers of all marketed prescription NSAIDs, including Celebrex, a COX-2 selective NSAID, revise the labeling (package insert) for their products to include a boxed warning and a Medication Guide. The boxed warning will highlight the potential for increased risk of cardiovascular (CV) events and the well-described, serious, and potentially life threatening gastrointestinal (GI) bleeding associated with these drugs.
We are asking manufacturers of OTC NSAIDs to revise their labeling to include more specific information about the potential GI and CV risks, and 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.
We anticipate that our actions will lead to careful and appropriate use of these drugs to maximize their potential benefits and minimize their risks.
2. To what products does FDA’s decision apply and what is being requested?
The decision applies to the marketed COX-2 selective drugs (Bextra and Celebrex) as well as the non-selective NSAIDs. A detailed chart listing the chemical name and trade names for the products affected by this announcement is attached and also can be found at Table of Drug Products.
For the COX-2 selective inhibitor drugs, we have determined the following:
Bextra (valdecoxib tablets): FDA has concluded that the overall risk versus benefit profile is unfavorable at this time and has requested the manufacturer of Bextra, Pfizer, Inc., to voluntarily withdraw Bextra from the market. This request is based on:
the lack of adequate data on the cardiovascular safety of long-term use of Bextra, along with the increased risk of adverse CV events in short-term coronary artery bypass surgery (CABG) trials that FDA believes may be relevant to chronic use,
reports of serious and potentially life-threatening skin reactions, including deaths, in patients using Bextra. The risk of these serious skin 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, and
the lack of any demonstrated advantages for Bextra compared with other NSAIDs.
Pfizer has agreed to suspend sales and marketing of Bextra in the U.S. pending further discussions with the agency.
Celebrex (celecoxib tablets): We have concluded that the benefits of Celebrex outweigh the potential risks in properly selected and informed patients. FDA has decided to allow Celebrex to remain and has asked Pfizer to take the actions listed below:
Revise the Celebrex label to include a boxed 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 practitioners to use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.
Include a Medication Guide as part of the labeling. It 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 appropriate drugs.
Vioxx (rofecoxib tablets and suspension): Vioxx was voluntarily removed from the market by Merck in September 2004. FDA will carefully review any proposal from Merck for resumption of marketing of Vioxx, and would likely discuss the review with the new FDA Drug Safety Oversight Board and an Advisory Committee before making a final decision.
Based upon the available data, FDA has concluded that an increased risk of CV events may be a class effect for NSAIDs. There are a number of non-selective NSAIDs currently approved for marketing in the United States. Long term controlled clinical trials have not been conducted with most of these NSAIDs. However, the available data suggests that use of these drugs may increase CV risk.
To further evaluate the potential for increased CV risk, all sponsors of non-selective NSAIDs will be asked to conduct and submit to FDA a comprehensive review and analysis of pertinent available controlled clinical trial databases.
In addition, FDA is requesting labeling changes for prescription and OTC non-selective NSAIDs. Because the use and labeling for the prescription products is different from those available without a prescription, they are addressed separately.
Prescription Non-Selective NSAIDs
Based on the available data, the FDA will request the manufacturers of all prescription products containing non-selective NSAIDs to revise their product labeling to include:
A boxed warning regarding the potential serious adverse CV events and the serious, and potentially life-threatening GI adverse events associated with the use of this class of drugs.
A contraindication for use in patients who have recently undergone coronary artery bypass surgery.
A Medication Guide for patients to help make them aware of the potential for CV and GI adverse events associated with the use of this class of drugs. 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 if treatment with an NSAID is warranted in an individual patient.
OTC Non-Selective NSAIDs
The available data do not appear to suggest an increased risk of serious CV events for the short-term, low-dose use of the NSAIDs available over the counter. FDA will request changes to the label to better inform consumers regarding the safe use of these products.
FDA will ask the manufacturers of all non-prescription products containing ibuprofen (Motrin, Advil, Ibu-Tab 200, Medipren, Cap-Profen, Tab-Profen, Profen, Ibuprohm), naproxen (Aleve), and ketoprofen (Orudis, Actron) to revise their labeling to include:
More specific information about the potential CV and GI risks,
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.
3. What information did FDA review to arrive at its decisions?
FDA’s Center for Drug Evaluation and Research (CDER) considered the risk/benefit profile for each of the drugs Cox-2 selective drugs, and the CV risks of NSAIDs as a class. We reviewed the regulatory histories and NDA databases of the various NSAIDs, FDA and sponsor background documents prepared for the joint Advisory Committee meeting, all materials and data submitted by other stakeholders to the Advisory Committee meeting, presentations made at the joint meeting, the discussions held by the Committee members during the meeting, and the specific votes and recommendations of the joint Committee.
4. What offices within the Center for Drug Evaluation and Research had input into the decisions?
Participants in the CDER decision-making process included staff from the Office of New Drugs (i.e., the Division of Anti-Inflammatory, Analgesic, and Ophthalmic Drug Products, the Division of Over-the-Counter Drug Products, and the Offices of Drug Evaluation II and V), the Office of Drug Safety, Office of Pharmacoepidemiology and Statistical Science, the Office of Medical Policy, the Office of Regulatory Policy, and the Office of the Center Director.
5. Does the Office of Drug Safety agree with the Office of New Drugs and the
The management of the Offices of Drug Safety and New Drugs are in full agreement regarding the actions announced by FDA today.
6. Why has FDA requested Pfizer to voluntarily withdraw Bextra from the market?
We have concluded that, from a public health perspective, we must assume that Bextra has an increased risk of CV events with long-term use. This conclusion is strongly supported by the significant increase in CV risk seen in those patients who had just undergone heart surgery and the fact that other COX-2 selective NSAIDs have demonstrated such increased CV risk in long-term studies. What is not known is how large that risk is in outpatient long-term use, because the studies have not been done. However, the CV risk is likely to be no less than that of other Cox-2 selective inhibitors. In addition, Bextra already carries a boxed warning related to its increased risk of serious, life-threatening skin reactions, which have been reported at a much higher rate than for other COX-2 selective inhibitors. Finally, there are no data to suggest that Bextra has benefits that would outweigh these risks (e.g., GI safety or better efficacy). Bextra has not been shown to offer any advantages over other existing NSAIDs. Therefore, we have concluded that the overall risk versus benefit profile of Bextra is unfavorable.
7. The Advisory Committee votes were split on Bextra. Why didn’t FDA go with the recommendation of the majority?
The Advisory Committees were closely divided on whether Bextra should remain on the market (17 voted yes, 13 voted no, with 2 abstentions). Advisory Committee votes are recommendations to FDA, and are not binding on the agency. In all cases, but particularly in cases where its Advisory Committees are closely divided, FDA has the responsibility to weigh all the evidence and determine what, if any, regulatory action is appropriate. After weighing all the evidence, as described in question 6 above, FDA decided to seek the withdrawal of Bextra from the market.
8. It was reported in the New York Times that the members of the FDA Arthritis and Drugs Safety and Risk Management Advisory Committees reviewing the safety risks of COX-2 inhibitors were not obligated to disclose their potential conflicts of interest. Were there any conflicts of interest for any of the members, and did this have an effect on the members’ recommendations?
For each advisory committee meeting, the Center for Drug Evaluation and Research (CDER) collects financial interest information for advisory committee members and consultants prior to their participation in order to determine whether the members or consultants have any financial interests that pose conflicts of interest.
All members of this joint committee and consultants who participated as discussants and/or voted at the meeting responded to detailed questions regarding their interests in all entities with a financial interest in the meeting topic. After conducting a review of the potential conflicts of interest for all of the members on the advisory committee examining COX-2 inhibitors, conflicts of interest were found. However, these conflicts were not deemed to be of sufficient magnitude to outweigh the need for the members’ and consultants’ expertise for this meeting. Waivers were written and approved consistent with the federal ethics and conflict of interest laws for 19 participants.
We do not believe that any of the conflicts of interest affected members’ recommendations.
9. Why isn’t FDA requesting that Celebrex also be withdrawn?
The Advisory Committees were unanimous in their conclusion that an increased risk of CV adverse events has been demonstrated for Celebrex (as for all the Cox-2 selective inhibitors) but strongly supported the continued marketing of the drug. FDA has concluded, based on the available data, that the benefits of Celebrex outweigh its potential risks in properly selected and informed patients. This conclusion is based on our review of the available safety data and the long-term controlled clinical trial comparisons of Celebrex to non-selective NSAIDs. While it appears that Celebrex is associated with an increased risk of serious CV adverse events, the available data do not support a conclusion that Celebrex is significantly worse than the non-selective NSAIDs. The NSAID class boxed warning regarding increased CV and GI risks will be applied to Celebrex, and in addition the labeling will include additional information as described in question 2 above that will inform physicians and patients of the potential risks and allow for informed prescribing decisions.
10. Does FDA anticipate that Vioxx will return to the market at some point?
Vioxx was voluntarily removed from the market by Merck in September 2004. FDA will carefully review any proposal from Merck for resumption of marketing of Vioxx, and would likely discuss the review with the new FDA Drug Safety Oversight Board and an Advisory Committee before making a final decision.
11. Will Bextra be available to patients on a compassionate use basis?
If the sponsor proposes a program to provide limited access to those patients who believe that this drug is the best option for them, FDA would be willing to consider this.
12. Are there other examples of drug products that have boxed warnings on the prescription indications, but are also available at an OTC dose?
We believe that this is the first time that a product with a boxed warning on the prescription version will also be available for non-prescription use. We believe that the available data support a conclusion that short-term use of low doses of the available OTC NSAIDs is not associated with any increased serious CV risk. When used according to their labeled instructions, we believe that OTC NSAIDs continue to have a very favorable risk benefit profile, and we believe it is important to maintain a range of therapeutic options for the short-term relief of pain in the OTC market.
13. Who may be at higher risk when taking these products?
Those at higher risk would include patients immediately post-operative from cardiovascular bypass surgery (CABG) and people who have coronary artery disease (people who have known angina or who have had a heart attack), people who have cerebrovascular disease (people who have had a stroke or who currently have episodes known as TIA (transient ischemic attacks)), and people with a history of stomach ulcers.
14. Did FDA consult the newly identified Drug Safety Board (DSB) that was to be established by the Agency?
No. The Board has not yet been convened.
15. Is Naproxen safe from a CV standpoint? How does it compare to the COX-2s?
Based on the currently available data FDA has concluded that the potential for increased risk of serious CV adverse events is a class effect of NSAIDs. This conclusion applies to naproxen. As with other members of the NSAID class, additional data from long-term, controlled clinical trials is needed to more definitively determine the magnitude of increased risk, if any, of naproxen over placebo and in relation to other NSAIDs.
16. Some NSAIDs have been associated with serious, potentially life-threatening skin reactions, such as Stevens-Johnson syndrome (SJS). What is FDA doing to warn patients about this risk?
FDA has determined that the labeling for all non-prescription NSAIDs should be updated to warn of the potential for skin reactions. Accordingly, along with the changes to the label to address CV risks, the agency will ask manufacturers of non-prescription NSAIDs to make these changes. 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, FDA will determine whether additional labeling changes with regard to skin reactions are warranted.
17. If I’m taking Bextra, what should I do?
We encourage people taking Bextra to contact their physician to discuss discontinuing use and alternative treatments. Any decision about which drug product to take to treat your symptoms should be made in consultation with your physician based on an assessment of your specific treatment needs.
18. If I have rheumatoid arthritis, what pain medication does FDA recommend?
You should consult your doctor to discuss the best course of action.
19. How can I report serious side effects with COX-2 selective and non-selective NSAIDs to FDA?
FDA encourages anyone aware of a serious adverse reaction to make a MedWatch report. You can report an adverse event using the contact information at the bottom of this page.
20. Where can I get more information?
To find out more about all NSAIDs from FDA:
Visit our Drug Information web page
Call Drug Information at: 888-INFO-FDA (888-463-6332)