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
http://www.fda.gov/cder/drug/infopage/cox2/default.htm#list.
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.
Non-selective NSAIDs
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
Divisions?
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
in two ways:
20. Where can I get more information?
To find out more about all NSAIDs from FDA:
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Date created: April 7, 2005 |