Celebrex
Pfizer Statement on New Information Regarding Cardiovascular Safety of Celebrex
Dosing in Long-Term Cancer Studies Suspended Due to Increased Cardiovascular Risk in One Study; Preliminary Analysis of Second Long-Term Cancer Study Shows No Increased Cardiovascular Risks
(from the webpage http://www.pfizer.com/are/investors_releases/2004pr/mn_2004_1217.cfm)
NEW YORK, December 17 -- Pfizer Inc said it received new information last night about the cardiovascular safety of its COX-2 inhibitor Celebrex (celecoxib) based on an analysis of two long-term cancer trials.
As reported to Pfizer by the Data Safety and Monitoring Board, one of the studies (the APC cancer trial) demonstrated an increased cardiovascular risk over placebo, while the other trial (the PreSAP cancer trial) revealed no greater cardiovascular risk than placebo.
“These clinical trial results are new. The cardiovascular findings in one of the studies (APC) are unexpected and not consistent with the reported findings in the second study (PreSAP). Pfizer is taking immediate steps to fully understand the results and rapidly communicate new information to regulators, physicians and patients around the world,” said Hank McKinnell, Pfizer chairman and chief executive officer.
Celebrex is approved for use in the United States for the treatment of arthritis and pain, at recommended doses of 100mg to 200mg daily for osteoarthritis and 200mg to 400mg a day for rheumatoid arthritis. It is also approved for a rare condition called familial adenomatous polyposis in doses up to 800mg per day. The APC cancer trial studied Celebrex at doses of 400mg to 800mg per day. In the PreSAP cancer trial the dose was 400mg per day.
“In placing this new information in context, it is important to understand that the APC trial results differ from both the PreSAP cardiovascular results as well as the large body of data that we and others have accumulated over time, in which an increased risk of serious cardiovascular events in arthritis patients, even at higher-than-recommended doses, had not been seen,” said Dr. Joseph Feczko, president of worldwide development for Pfizer.
“Celebrex is an important medicine that provides necessary pain relief to many patients. Patients being treated with Celebrex should discuss appropriate treatment options with their healthcare professionals. Physicians should factor this new information, as well as ulcer risks and gastrointestinal bleeding seen with traditional NSAIDs, into their prescribing decision.”
In the Adenoma Prevention with Celecoxib (APC) trial, patients taking 400mg and 800mg of Celebrex daily had an approximately 2.5 fold increase in their risk of experiencing a major fatal or non-fatal cardiovascular event compared to those patients taking placebo, according to the National Cancer Institute (NCI). Based on these statistically significant findings, the sponsor of the trial, the NCI, has suspended the dosing of Celebrex in the study.
In a separate long-term study, the Prevention of Spontaneous Adenomatopus Polyps (PreSAP) trial, there has been no increased risk for Celebrex patients taking 400mg daily compared with those taking placebo. These findings are based on an identical analysis used to assess cardiovascular risk in the APC trial and conducted by the same independent safety review board. The information from this Pfizer sponsored trial was also received by Pfizer last night and, as with the APC information, was immediately shared by the company with the U.S. Food and Drug Administration.
The two studies, which are following patients over a five-year period, have enrolled a total of about 3,600 patients, some of whom have participated for more than four years. Pfizer estimates that about 2,400 patients evaluated in the cardiovascular analysis have completed two years of treatment.
A third long-term study involving Celebrex in patients at high-risk for Alzheimer’s disease is also under way with about 2,000 patients enrolled, about 750 of whom are on 400mg per day of Celebrex. As with the cancer studies, this study is monitored by independent safety experts who meet regularly to assess adverse events. A review by this board as recent as December 10 did not result in any recommendations to change the conduct of this study.
In September and October, the Data Safety and Monitoring Boards of the APC and PreSAP cancer trials conducted a preliminary review of all the then-available data and determined to proceed with the studies. With the cooperation of Pfizer, the safety review boards convened a panel of cardiovascular experts to conduct additional reviews and analyses of the data from these two trials. Last evening, Pfizer received preliminary information resulting from the reviews. The company has not yet received the full analyses of these studies.
As previously announced, Pfizer will continue to work with FDA on the company’s plans to sponsor a major clinical study to further assess Celebrex in osteoarthritis patients at high-risk for cardiovascular disease.
January 11, 2005 Special Edition: American Academy of Orthopedic Surgery Headline News
Use of Pain Medication/NSAIDs
Recent information about pharmaceutical and over-the-counter (OTC) pain medication used to treat arthritis and other musculoskeletal disorders has caused some concern in the medical community regarding patient use. There currently is conflicting research data on several of the drug agents. The Food and Drug Administration (FDA) will hold an advisory committee meeting on February 16-17, 2005, to discuss the analysis of data on non-steroidal anti-inflammatory drugs (NSAIDs) in response to this controversy. The American Academy of Orthopaedic Surgeons (AAOS) will update its membership with all relevant scientific information as it becomes available.
Background:
* Results from the APPROVe (Adenomatous Polyp Prevention on Vioxx®) clinical trial determined that there was an increased relative risk for confirmed cardiovascular events, such as heart attack and stroke, beginning after 18 months of treatment in patients taking Vioxx compared with those taking a placebo. Merck & Co., Inc., the drug's manufacturer, announced a worldwide withdrawal of Vioxx on September 30, 2004.
* On December 9, 2004, the FDA announced label modifications for Bextra®, a Cox-2 inhibitor, requiring that the drug labeling be updated to include warnings for cardiovascular risk and severe skin reactions. A recent study demonstrated an increased cardiovascular risk in patients treated with Bextra compared to placebo. The bolded warning states contraindications for the use of Bextra in patients undergoing coronary artery bypass graft surgery.
* On December 17, 2004, the National Institutes of Health (NIH) announced that it suspended the use of a Cox-2 inhibitor, Celebrex (celecoxib), for all participants in a large colorectal cancer prevention trial conducted by the National Cancer Institute (NCI). The Adenoma Prevention with Celecoxib (APC) trial was halted after analysis showed a 2.5-fold increased risk of cardiovascular events for participants taking the drug compared to those receiving a placebo.
* On December 20, 2004, the FDA announced that preliminary information from the clinical trial involving NSAIDs and patients at risk of developing Alzheimer's disease showed an increased risk of cardiovascular events with the use of naproxen, when compared to placebo. The FDA advises that patients currently taking over-the-counter naproxen products should carefully follow the instructions on the label. Patients should not exceed the recommended doses for naproxen. Patients also should not take naproxen for longer than 10 days unless otherwise directed by a physician.
Recent Governmental Recommendations
On December 23, 2004, the FDA made the following interim recommendations on NSAIDs:
* Physicians prescribing Celebrex (celecoxib) or Bextra (valdecoxib) should consider emerging information when weighing the benefits against risks for individual patients. Patients who are at a high risk for gastrointestinal bleeding, have a history of intolerance to non-selective NSAIDs, or are not doing well on non-selective NSAIDs may be appropriate candidates for Cox-2 selective agents.
* Individual patient risk for cardiovascular events and other risks commonly associated with NSAIDs should be taken into account for each prescribing situation.
* Consumers are advised that all OTC pain medications, including NSAIDs, should be used in strict accordance with the label directions. If use of an OTC NSAID is needed for more than 10 days, a physician should be consulted.
In addition, the AAOS recommends the following:
The use of medication involves a risk/benefit ratio and should be assessed by physicians in conjunction with their patient and in light of their patient's specific condition. The AAOS encourages its Fellows to monitor new research and developments in these therapies because new information continues to develop rapidly. Because NSAID use has been associated with gastrointestinal symptoms, physicians may want to consider therapies that provide protection for the stomach, in addition to those that provide for pain relief. Physical therapy, exercise, and acupuncture may also provide pain relief for some patients. (See list of Additional Resources below for a link to the NIH acupuncture study.)
A selection of additional resources:
The FDA urges health care providers and patients to report adverse event information to FDA via the MedWatch program by phone (1-800-FDA-1088), by fax (1-800-FDA-0178), or by the Internet: http://www.fda.gov/medwatch/index.html.
Vioxx (rofecoxib)
http://www.fda.gov/cder/drug/infopage/vioxx/default.htm
Bextra Label Updated with Boxed Warning Concerning Severe Skin Reactions and Warning Regarding Cardiovascular Risk
http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01331.html
FDA Statement on the Halting of a Clinical Trial of the Cox-2 Inhibitor Celebrex
http://www.fda.gov/bbs/topics/news/2004/new01144.html
Use of Non-Steroidal Anti-Inflammatory Drugs Suspended in Large Alzheimer's Disease Prevention Trial
http://www.nih.gov/news/pr/dec2004/od-20.htm
Naproxen Information
http://www.fda.gov/cder/drug/infopage/naproxen/default.htm
FDA Issues Public Health Advisory Recommending Limited Use of Cox-2 Inhibitors
http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01336.html
NIH Press Release: Acupuncture Relieves Pain and Improves Function in Knee Osteoarthritis
http://www.nih.gov/news/pr/dec2004/nccam-20.htm
NSAIDS
FDA Public Health Advisory on the use of NSAIDS
http://www.fda.gov/cder/drug/advisory/nsaids.htm
Safe Use of Over-the-Counter Pain Relievers (analgesics) and Fever Reducers (antipyretics)
http://www.fda.gov/cder/drug/analgesics/default.htm
See Celebrex.com for further information.
