Postmarket Drug Safety Information for Patients and Providers > Public Health Advisory ...
`
`Page 1 of 4
`
`Archived Content
`The content on this page is provided for reference purposes only. This content has not
`been altered or updated since it was archived.
`
`Home Drugs Drug Safety and Availability Postmarket Drug Safety Information for Patients and Providers
`Drugs
`Public Health Advisory - FDA Announces Important Changes and Additional Warnings for COX-2
`Selective and Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
`4/7/2005
`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:
`(cid:122) 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.
`(cid:122) 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.
`(cid:122) 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.
`(cid:122) Revise the Celebrex label to:
`(cid:122) 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.
`(cid:122) 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.
`
`http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandprovi...
`
`3/23/2015
`
`Patent Owners' Ex. 2062
`IPR2018-00272
`Page 1 of 4
`
`

`

`Postmarket Drug Safety Information for Patients and Providers > Public Health Advisory ...
`
`Page 2 of 4
`
`(cid:122) Encourage practitioners to use the lowest effective dose for the shortest duration consistent with individual
`patient treatment goals.
`(cid:122) 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.
`(cid:122) 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 COX-2 Selective (includes
`Bextra, Celebrex, and Vioxx) and Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)1.
`
`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:
`(cid:122) 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.
`(cid:122) A contraindication for use in patients who have recently undergone coronary artery bypass surgery.
`(cid:122) 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:
`(cid:122) More specific information about the potential CV and GI risks,
`(cid:122) Instructions about which patients should seek the advice of a physician before using these drugs,
`(cid:122) Stronger reminders about limiting the dose and duration of treatment in accordance with package instructions,
`
`http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandprovi...
`
`3/23/2015
`
`Patent Owners' Ex. 2062
`IPR2018-00272
`Page 2 of 4
`
`

`

`Postmarket Drug Safety Information for Patients and Providers > Public Health Advisory ...
`
`Page 3 of 4
`
`unless otherwise advised by a physician, and
`(cid:122) 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 to the MedWatch program, using
`the contact information at the bottom of this page.
`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
`
`Celecoxib
`Valdecoxib
`Rofecoxib
`Non-selective NSAIDs
`Chemical Name
`Diclofenac
`Diflunisal
`Etodolac
`Fenoprofen
`Flurbiprofen
`Ibuprofen**
`
`Indomethacin
`Ketoprofen**
`Ketorolac
`Mefenamic Acid
`Meloxicam
`Nabumetone
`Naproxen**
`
`Oxaprozin
`Piroxicam
`Sulindac
`Tolmetin
`
`Brand Name
`
`Celebrex
`Bextra
`Vioxx
`
`Brand Name
`Cataflam, Voltaren, Arthrotec (combination with misoprostol)
`Dolobid
`Lodine, Lodine XL
`Nalfon, Nalfon 200
`Ansaid
`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
`Toradol
`Ponstel
`Mobic
`Relafen
`Aleve, Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn,
`Naprelan, Naprapac (copackaged with lansoprazole)
`Daypro
`Feldene
`Clinoril
`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.
`
`Related Information
`(cid:122) Nonsteroidal Anti-inflammatory Drugs (NSAIDs)2
`
`Contact FDA
`1-800-332-1088
`1-800-FDA-0178 Fax
`Report a Serious Problem
`MedWatch Online3
`Regular Mail: Use postage-paid FDA Form 35004
`
`http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandprovi...
`
`3/23/2015
`
`Patent Owners' Ex. 2062
`IPR2018-00272
`Page 3 of 4
`
`

`

`Postmarket Drug Safety Information for Patients and Providers > Public Health Advisory ...
`
`Page 4 of 4
`
`Mail to: MedWatch 5600 Fishers Lane
`Rockville, MD 20857
`
`Page Last Updated: 08/16/2013
`Note: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and
`Players.
`Accessibility Contact FDA Careers FDA Basics FOIA No Fear Act Site Map Transparency Website Policies
`
`U.S. Food and Drug Administration
`10903 New Hampshire Avenue
`Silver Spring, MD 20993
`Ph. 1-888-INFO-FDA (1-888-463-6332)
`Contact FDA
`
`For Government For Press
`Combination Products Advisory Committees Science & Research Regulatory Information Safety Emergency
`Preparedness International Programs News & Events Training and Continuing Education Inspections/Compliance
`State & Local Officials Consumers Industry Health Professionals FDA Archive
`
`Links on this page:
`1. ssLINK/ucm103420.htm#list
`2. /Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm103420.htm
`3. https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
`4. http://www.fda.gov/downloads/Safety/MedWatch/DownloadForms/UCM082725.pdf
`
`http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandprovi...
`
`3/23/2015
`
`Patent Owners' Ex. 2062
`IPR2018-00272
`Page 4 of 4
`
`