Question #1) What is FDA announcing?
In follow-up to the February 16-18, 2005, joint meeting of the FDA’s Arthritis and Drug Safety and Risk Management Advisory Committees, which 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.
Question #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. This includes these COX-2 Selective NSAIDs:
This also includes Non-selective NSAIDs including:
- Diclofenac brand names Cataflam, Voltaren, Arthrotec (combination with misoprostol)
- Diflunisal brand name Dolobid
- Etodolac brand names Lodine, Lodine XL
- Fenoprofen brand names Nalfon, Nalfon 200
- Flurbiprofen brand name Ansaid
- Ibuprofen brand names 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), Note: there are over-the-counter versions of ibuprofen and also many OTC Combinations with ibuprofen such as: 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
- Indomethacin brand names Indocin, Indocin SR, Indo-Lemmon, Indomethegan
- Ketoprofen brand names Oruvail, Orudis, Actron, Note: there are over-the-counter versions of ketoprofen.
- Ketorolac brand name Toradol
- Mefenamic Acid brand name Ponstel
- Meloxicam brand name Mobic
- Nabumetone brand name Relafen
- Naproxen brand names Aleve, Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole), Note: there are over-the-counter versions of naproxen.
- Oxaprozin brand name Daypro
- Piroxicam brand name Feldene
- Salsalate brand name Disalcid
- Sulindac brand name Clinoril
- Tolmetin brand names Tolectin, Tolectin DS, Tolectin 600
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.