6/21/2018
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`Postmarket Drug Safety Information for Patients and Providers > Public Health Advisory - FDA Announces Important Changes and Additi…
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`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 ris
`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 wit
`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
`
`
` 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.
`
`
`
` A
`
`http://wayback.archive-it.org/7993/20161024015703/http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/u… 1/3
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`Page 1 of 3
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`Patent Owner Ex. 2071
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`Postmarket Drug Safety Information for Patients and Providers > Public Health Advisory - FDA Announces Important Changes and Additi…
`6/21/2018
`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 fo
`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 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
`
`Celebrex
`Bextra
`Vioxx
`
`Brand Name
`
`Celecoxib
`Valdecoxib
`Rofecoxib
`Non-selective NSAIDs
`Chemical Name
`
`Diclofenac
`Diflunisal
`Etodolac
`Fenoprofen
`Flurbiprofen
`Ibuprofen**
`
`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
`Oxaprozin
`Feldene
`Piroxicam
`Sulindac
`Clinoril
`http://wayback.archive-it.org/7993/20161024015703/http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/u… 2/3
`
`Indomethacin
`Ketoprofen**
`Ketorolac
`Mefenamic Acid
`Meloxicam
`Nabumetone
`Naproxen**
`
`Page 2 of 3
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`Patent Owner Ex. 2071
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`Postmarket Drug Safety Information for Patients and Providers > Public Health Advisory - FDA Announces Important Changes and Additi…
`Tolectin, Tolectin DS, Tolectin 600
`
`6/21/2018
`Tolmetin
`
`*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
`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
`Mail to: MedWatch 5600 Fishers Lane
`Rockville, MD 20857
`
`Page Last Updated: 08/16/2013
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`Links on this page:
`1. ssLINK/ucm103420.htm#list
`2. /7993/20161024015703/http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm103420.htm
`3. http://wayback.archive-it.org/7993/20161024015703/https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
`4. http://wayback.archive-
`it.org/7993/20161024015703/http://www.fda.gov/downloads/Safety/MedWatch/DownloadForms/UCM082725.pdf
`
`http://wayback.archive-it.org/7993/20161024015703/http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/u… 3/3
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`Page 3 of 3
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`Patent Owner Ex. 2071
`Mylan v. Pozen
`IPR2017-01995
`
`