Health Canada Approves Changes to Vioxx (Rofecoxib) Label to Reflect GI Safety Data from Landmark Study

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Health Canada Approves Changes to Vioxx (Rofecoxib) Label to Reflect GI

Safety Data from Landmark Study

" Good news for physicians and their patients concerned about NSAID-induced

ulcers "

MONTREAL, QC -- August 21, 2002 -- Merck Frosst Canada Ltd. announced today

that Health Canada has approved changes to the prescribing information for

Vioxx® (rofecoxib) to include results from the landmark 8,000-patient VIGOR

(Vioxx® Gastrointestinal Outcomes Research) study.

Rofecoxib is now the first and only medicine that selectively inhibits the

COX-2 enzyme that is proven to reduce the risk of developing clinically

important gastrointestinal (GI) side effects in patients with or without

risk factors for such GI side effects compared to the non-steroidal

anti-inflammatory drug (NSAID) naproxen.

" It is clear that COX-2 inhibitors offer a significant advantage over other

existing therapies such as the use of NSAIDs, " said Dr. Hunt,

professor of medicine, McMaster University Medical Centre, Hamilton,

Ontario. " NSAIDs are often prescribed to reduce pain and inflammation in

patients with arthritis. However, use of non-selective NSAIDs, especially

among older persons, can significantly increase morbidity, including the

risk of perforations, ulcers and bleeds which can also result in a

measurable mortality. "

New prescribing information now includes VIOXX* GI safety data The

prescribing information for rofecoxib has been revised to include the data

from the VIGOR study that was originally published in the November 23, 2000

issue of The New England Journal of Medicine. Patients enrolled in the study

were all diagnosed with rheumatoid arthritis (RA) and had required NSAIDs

for at least one year. While rofecoxib is not indicated in Canada to treat

RA, the study was conducted in this population because RA patients have a

higher risk for GI side effects, making this a particularly rigorous test of

the medication's GI safety.

Findings of VIGOR showed that rofecoxib 50 mg once daily (two-to-four times

higher than the recommended daily dose for chronic use in osteoarthritis)

significantly reduced the risk of serious GI events by 54 per cent and the

risk of complicated GI events by 57 percent compared to naproxen 500 mg

twice daily. This GI safety benefit now appears as a modification to the

rofecoxib prescribing information that is currently available to physicians.

" This is good news for physicians and patients concerned about NSAID-induced

perforations, ulcers and bleeds, " said Dr. Bombardier,

rheumatologist, professor of medicine, University of Toronto and Director,

Healthcare Research Division, Autoimmune Research Center, Toronto Hospital.

" With the revised labelling, the GI safety benefit of VIOXX® is confirmed. "

One of the leading causes of gastrointestinal ulceration are bacterial

infection with H. pylori and is the use of NSAIDs. Of all patients who take

NSAIDs, approximately 80 percent will experience endoscopic lesions and

about 25 percent of NSAID users will go on to have a gastric ulcer(1). Four

out of five people who develop a serious GI side effect while taking a NSAID

do not have any warning symptoms.

Approximately 10 million prescriptions for NSAIDs are written in Canada

every year(2). The total annual costs of NSAID-induced GI complications for

elderly Canadians in Quebec is $18 million(3).

Clinical importance of the VIGOR study

The VIGOR study, a randomized, double-blind outcomes trial, involved 8,076

patients with rheumatoid arthritis in 22 countries (including 18 sites in

Canada) is considered by experts to be of critical importance because of the

potentially devastating side effects of traditional arthritis medications,

or NSAIDs. These side effects can occur at any time during the course of

treatment - even within the first few days. While some patients are at

increased risk for these potentially life-threatening consequences of NSAID

treatment, perforations, ulcers, obstructions and bleeds can - and do -

occur without warning in patients not considered to be at risk.

Other pertinent data from VIGOR

· Reduction in GI events was seen in all patient groups, including

patients considered to be at higher risk because of individual risk factors

such as age, prior history of a GI side effect, use of steroids and H.

pylori.

· A sub-analysis of the VIGOR study compared rofecoxib and naproxen for

the rates of usage of GI protective agents (drugs prescribed by physicians

to help protect the patients' stomach), GI diagnostic procedures and

hospitalizations due to complicated GI events. Patients treated with

rofecoxib were hospitalized less often than naproxen for complicated GI

events, had fewer GI procedures and required fewer GI protective agents.

Cardiovascular data also included in prescribing information

The prescribing information for rofecoxib has also been revised to include

cardiovascular data from VIGOR. In this study, a statistically significant

higher incidence of serious cardiovascular thrombotic events was seen in

patients receiving rofecoxib 50 mg once daily compared to patients treated

with naproxen 500 mg twice daily. A total of 45 serious cardiovascular

thrombotic events occurred among 4,047 patients taking rofecoxib compared to

19 among 4,029 taking naproxen. This was largely due to a difference in the

incidence of non-fatal heart attacks: 18 for rofecoxib and 4 for naproxen.

The number of cardiovascular thrombotic deaths was similar in patients

treated with rofecoxib (n=7) compared to naproxen (n=6).

Also included in the prescribing information are data from a

placebo-controlled database derived from two studies with a total of 2,142

elderly patients (mean age 75; rofecoxib n=1,067, placebo n=1,075). The

median exposure in these studies was approximately 14 months. The number of

patients with a serious cardiovascular thrombotic event was 21 for patients

treated with rofecoxib 25 mg once daily versus 35 for patients receiving

placebo. In these same two placebo-controlled studies, mortality due to

cardiovascular thrombotic events was 8 versus 3 for rofecoxib versus

placebo, respectively. The significance of the cardiovascular findings from

these three studies (VIGOR and the placebo-controlled studies) is unknown.

Prospective studies with rofecoxib to compare the incidence of serious

cardiovascular events to NSAID comparators or placebo have not been

performed.

As with all other NSAIDs, fluid retention, edema and hypertension have been

observed in some patients taking rofecoxib. Rofecoxib should be used with

caution and should be introduced at the lowest recommended dose in patients

with fluid retention, hypertension or heart failure. The prescribing

information states that all of this information should be taken into

consideration and caution should be exercised when rofecoxib is prescribed

to patients with a medical history of ischemic heart disease (including

patients with a history of angina or heart attack). Rofecoxib is not a

substitute for ASA(aspirin) to prevent cardiovascular events because of its

lack of effect on platelets.

Merck Frosst Canada & Co. is one of the country's leading research-based

pharmaceutical companies. The Merck Frosst Centre for Therapeutic Research,

one of the largest biomedical research facilities in Canada, has a mandate

to discover new therapies for the treatment of respiratory, inflammatory and

other diseases. In 2001, the company invested nearly $120 million in

research and development in Canada. For its part, Merck Frosst Canada Ltd.

markets an extensive line of cardiovascular products for high blood

pressure, elevated cholesterol and heart failure as well as a broad range of

vaccines.

Merck Frosst is a recognized leader in the treatment of arthritis, asthma,

osteoporosis, HIV/AIDS, glaucoma, prostate disease, migraines and infectious

diseases. Based in Montréal, Quebec, Merck Frosst employs approximately

1,900 people including 300 of the world's leading scientific personnel. It

is also firmly committed to science education and sponsors a number of

programs designed to spark young people's interest in science. Merck Frosst

Canada & Co. and Merck Frosst Canada Ltd. are affiliated companies of Merck

& Co., Inc. of Whitehouse Station, New Jersey. Merck & Co., Inc. is a

publicly traded company on the New York Stock Exchange under the symbol MRK.

References:

1. Singh, G., Recent considerations in NSAID gastropathy, American Journal

of Medicine, July 1998.

2. Pan American Congress of Gastroenterology and Endoscopy, 1999.

3. , R.A., Rheumatology 2002;41 (suppl.1): 7-15.

®Registered trademark of Merck & Co., Inc. Used under license.

SOURCE: Merck Frosst Canada Ltd.