Public Health Advisory
FDA Announces Important Changes and Additional Warnings
for COX-2 Selective
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Today, the Food and Drug Administration (FDA) is
announcing that it has asked Pfizer, Inc. to voluntarily withdraw
Bextra (valdecoxib) from the market. Pfizer has agreed to suspend
sales and marketing of Bextra in the U.S., pending further
discussions with the agency. FDA is also asking
manufacturers of all marketed prescription NSAIDs, including
Celebrex (celecoxib), a COX-2 selective NSAID, to 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 with
these drugs and the well-described, serious, and potentially
life-threatening gastrointestinal (GI) bleeding associated with
their use. The Medication Guide will accompany every prescription
NSAID at the time it is dispensed to better inform patients about
the CV and GI risks. Finally, FDA is asking manufacturers of
non-prescription (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
announcement does not apply to aspirin as it has clearly been shown
to reduce the risk of serious adverse CV events in certain patient
In reaching these decisions, FDA has carefully considered the
available data on all of the NSAIDs. The Agency has also considered
presentations, discussions, and votes from the joint public meeting
of the FDA Arthritis Advisory Committee and the Drug Safety and Risk
Management Advisory Committee held on February 16, 17, and 18, 2005
to discuss the CV safety concerns for these drugs along with their
Specifically, FDA is requesting the actions listed below and will
work closely with the manufacturers to ensure their timely
BEXTRA (valdecoxib tablets)
FDA has concluded that the overall risk versus benefit profile is
unfavorable and has requested that Pfizer, the manufacturer of
Bextra, 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 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.
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.
Patients currently taking Bextra should contact
their physicians to consider alternative treatments.
CELEBREX (celecoxib tablets)
FDA has concluded that the benefits of Celebrex outweigh the
potential risks in properly selected and informed patients.
Accordingly, FDA will allow Celebrex to remain on the market 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 (see below) about CV and GI
risk, plus specific information on the controlled clinical trial
data that demonstrate an increased risk of adverse CV events for
Encourage prescribers to discuss with patients the
potential benefits and risks of Celebrex and other treatment options
before a decision is made to use Celebrex.
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
Commit to conduct a long-term study to
address the safety of Celebrex compared to naproxen and other
appropriate drugs. FDA will work with Pfizer to design this
long-term study and ensure its timely initiation and completion.
Patients who are taking CELEBREX should
discuss questions or concerns about this new information with their
A number of non-selective NSAIDs (prescription and non-prescription
(over-the-counter (OTC)) are approved for marketing in the United
States. A list of these products is attached and is also available
Long-term controlled clinical trials have not been conducted with
most of these NSAIDs. However, the available data suggest that use
of these drugs may increase CV risk. It is very difficult to draw
conclusions about the relative CV risk among the COX-2 selective and
non-selective NSAIDs with the data available.
All sponsors of non-selective NSAIDs will be asked to conduct and
submit to FDA a comprehensive review and analysis of available
controlled clinical trial databases pertaining to their NSAID
product(s) to which they have access to further evaluate the
potential for increased CV risk.
FDA will work closely with sponsors and other interested
stakeholders (e.g., NIH) to encourage additional long-term
controlled clinical trials of non-selective NSAIDs to further
evaluate the potential for increased CV risk.
In addition, FDA is requesting labeling changes for both
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
FDA will request that manufacturers of all
prescription products containing non-selective NSAIDs 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 regarding the
potential for CV and GI adverse events associated with the use of
this class of drugs. The Medication Guide will be required to be
given to patients at the time each prescription is dispensed. The
Medication Guide will also 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 for an
Patients who are taking a prescription
non-selective NSAID should discuss questions or concerns about this
new information with their physician.
OTC Non-Selective NSAIDs
The available data do not suggest an increased risk of serious CV
events for the short-term, low-dose use of the NSAIDs available over
the counter. FDA will allow these products to remain on the market,
but will request changes to the label to better inform consumers
regarding the safe use of these products.
FDA will ask manufacturers of all OTC 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
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 package instructions,
unless otherwise advised by a physician, and
A warning about potential skin reactions.
Patients who are taking an OTC NSAID should
carefully follow the labeled directions, particularly with regard to
dose and duration of use, and should contact their physician
regarding any questions or concerns they may have about this new
Note: Aspirin is a nonselective NSAID. However, aspirin is also a
platelet inhibitor and has been shown in clinical trials to
reduce the risk of CV events. Patients taking aspirin to prevent
CV events should NOT stop taking it, unless specifically advised to
do so by their physician.
FDA expects that these actions will further
encourage the safe and effective use of these products. FDA will
continue to notify health care providers and patients in a timely
fashion as new information becomes available.
FDA urges health care providers and patients to report adverse event
information the MedWatch program by phone (1-800-FDA-1088), by fax
(1-800-FDA-0178), or by the Internet at
COX-2 Selective Non-steroidal
Anti-inflammatory Drugs (NSAIDs) and
Prescription and Over-the-Counter (OTC) Non-selective NSAIDs
Approved Under New Drug Application (NDA) Abbreviated New
Drug Application (ANDA)
||Cataflam, Voltaren, Arthrotec (combination with
||Lodine, Lodine XL
||Nalfon, Nalfon 200
||Motrin, Motrin IB, Motrin Migraine Pain, Advil,
Advil Migraine Liqui-gels, Ibu-Tab 200, Medipren, Cap-Profen,
Tab-Profen, Profen, Ibuprohm, Children’s Elixsure
*, Vicoprofen (combination with
hydrocodone), Combunox (combination with oxycodone)
||Indocin, Indocin SR, Indo-Lemmon, Indomethagan
||Oruvail, Orudis, Actron
||Aleve, Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn,
Naprelan, Naprapac (copackaged with lansoprazole)
Tolectin, Tolectin DS, Tolectin 600
*There are many
OTC Combinations with ibuprofen: Advil Cold And Sinus, Advil
Cold, Advil Allergy Sinus, Children’s Advil Allergy Sinus,
Ibuprohm Cold and Sinus, Sine-Aid IB, Children’s Motrin Cold.
over-the-counter versions of these prescription medications.
Back to COX2
Date created: April 7, 2005