FDA
NSAID Warning
FDA Announces Important Changes and Additional Warnings for
COX-2 Selective and Non-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 populations.
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 overall risk-benefit.
Specifically, FDA is requesting the actions
listed below and will work closely with the manufacturers
to ensure their timely implementation.
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 celecoxib.
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 duration
possible.
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 physician.
Non-Selective NSAIDs
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 at:
http://www.fda.gov/cder/drug/infopage/cox2/default.htm#list.
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 individual patient.
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 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 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 information.
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 http://www.fda.gov/medwatch/index.html.
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)
COX-2
Selective NSAIDs |
| Chemical Name |
Brand Name |
| Celecoxib |
Celebrex |
| Valdecoxib |
Bextra |
| Rofecoxib |
Vioxx |
Non-selective
NSAIDs |
| Diclofenac |
Cataflam, Voltaren, Arthrotec
(combination with misoprostol) |
| Diflunisal |
Dolobid |
| Etodolac |
Lodine, Lodine XL |
| Fenoprofen |
Nalfon, Nalfon 200 |
| Flurbiprofen |
Ansaid |
| Ibuprofen** |
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) |
| Indomethacin |
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
|
| Ketoprofen** |
Oruvail, Orudis, Actron |
| Ketorolac |
Toradol |
| Mefenamic |
Acid Ponstel |
| Meloxicam |
Mobic |
| Nabumetone |
Relafen |
| Naproxen** |
Aleve, Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn,
Naprelan, Naprapac (copackaged with lansoprazole) |
| Nabumetone |
Relafen |
| Oxaprozin |
Daypro |
| Piroxicam |
Feldene |
| Nabumetone |
Relafen |
| Salsalate |
Disalcid |
| Sulindac |
Clinoril |
| Tolmetin |
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.
**There are over-the-counter versions of these prescription
medications.
Information provided by The U.S. Food and Drug Administration
(www.fda.gov) |
