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Cox-2 Inhibitors and Rheumatoid Arthritis
A study done by researchers in Hong Kong showed that arthritis sufferers who have had ulcers should not take either Pharmacia/Pfizer's arthritis drug Celebrex, nor AstraZeneca's ulcer medication Prilosec which was given in combination with the generic anti inflammatory drug clofenac.
The study also showed that neither treatment protected as many patients from dangerous kidney complications as past studies had indicated. The study included 287 patients who had a previous bleeding ulcer and so were at high risk of developing another, potentially life-threatening ulcer. It had been hoped that the Cox-2 inhibiting drugs, which do not block the action of the Cox-1 enzyme would therefore not affect the stomach lining. According to Dr. David Y. Graham of the Veterans Affairs Medical Center in Houston: "The results were unexpected. Neither regimen provided a good or even acceptable level of protection from recurrent bleeding."
About 25% of those in the Celebrex group and 31% in the diclofenac/Prilosec group suffered kidney complications, including high blood pressure and swollen ankles; about 6% in each group suffered life-threatening kidney failure.
The FDA has issued a warning in connection with people who develop a rash after having taken Bextra, the next generation of pain killer after Celebrex, manufactured by Pfizer & Co (Pharmacia). If you develop a rash after having taken Bextra, you should stop taking it immediately because it has been linked to some rare but life-threatening skin disease.
The FDA has received about 20 reports of serious reactions, including the skin diseases Stevens-Johnson syndrome, toxic epidermal necrolysis and exfoliative dermatitis as well as allergic reactions among Bextra users since sales began in March. The FDA estimated that between 800,000 to one million people have taken the drug since it first went on sale.
The condition can be life threatening and has already resulted in the hospitalization of some other users of the drug. Pfizer/Pharmacia has written thousands of doctors alerting them to the problem. Bextra is a type of painkiller known as a Cox-2 inhibitor and is used to treat arthritis and menstrual pain.
An advisory panel of the FDA concluded its hearings in regards to the labels on common painkillers such as acetaminophens, ibuprofen, naproxen and aspirins. As a result of these hearings the advisory panel will recommend to the FDA that stronger warning labels are needed for these painkillers. The FDA is expected to act on these recommendations early in 2003. The panel did not question the safety of these products when taken as directed, but questions have arisen in connection with misreading of the labels and overuse of these products.
The panel found evidence that thousands of Americans unwittingly take toxic doses of acetaminophen, which is the main ingredient in almost 200 over-the-counter cold and headache remedies, including Tylenol. The panel voted 23-1 in favor of recommending to the FDA that stronger warnings be required on the labels of all acetoaminophens. Acetaminophen is also found in painkillers such as Percocet and Vicodin.
The panel recommended that every package of a drug that contains acetaminophen states in bold type on the label that it contained the ingredient. It also recommended that the label state in bold letters that taking more than the recommended dosage could result in liver damage. Johnson & Johnson has already undertaken this steps in connection with the labels on Tylenol.
The panel also stated that certain groups of patients, such as the elderly should be warned that they risk stomach bleeding or kidney failure by taking the class of medicines known as nonsteroidal anti-inflammatory drugs known as NSAIDs. Included in the NSAID category are aspirin, ibuprofen, found in Motrin and Advil, and naproxen found in Aleve.
Researchers have noted that acetaminophens (Johnson & Johnson's Tylenol is the best known of these products) can cause liver problems over time, and aspirins can cause gastrointestinal bleeding with prolonged use. John Jenkins, head of the FDA's Office of New Drugs stated that "We'd like to do a better job of preventing some of these (adverse effects)." The advisory panel's recommendation is usually upheld by the final decision of the FDA.
In an interesting side-note to the panel's hearing, each product side in the debate is emphasizing the weakness of the other side, while minimizing the weak points of their own drug. An FDA review of acetaminophen overdoses found that consumer calls to poison-control centers about acetaminophens decreased from 111,175 in 1995 to 108,102 in 1999. Deaths however associated with the drug's overdose rose from 76 to 141 in the same period. The number of deaths included death from suicide as well as from accidental overuse.
Astra Zeneca announced that it has sent letters to physicians participating in the ongoing Crestor clinical trial program requiring that any remaining patients taking the 80 mg dose be transitioned to lower doses of the drug. There had been two reported cases of kidney damage that may have been associated with the higher dose. There have not been any adverse reactions reported with the lower doses of the drug. This may mean however further delays before the drug receives the approval of the FDA.
Many experts have expressed the thought that one of the reason why Pfizer Inc. has proposed a merger with Pharmacia Inc. is so that it can gain full control over the sales of Celebrex the blockbuster anti-arthritic drugs that both companies are presently co-marketing.
Celebrex garnered over $3.1 billion in sales last year making it the 7th best selling drug in the U.S. in 2001. Please keep in mind also that Pfizer/Pharmacia recently got approval to market Bextra, the next generation of arthritic drug from the companies. Henry McKinnell, Pfizer's chairman and chief executive officer has stated that the company will press more aggressively what he believes is Celebrex's major advantage over Merck & Co's. competing drug Vioxx that it hasn't been linked to any heart problems.
Vioxx on the other hand claims that it has not had the stomach problems that have been associated with those who have been taking Celebrex. Many experts feel that most patients would fare just as well with the cheaper generic pills-including aspirin and ibuprofen-known as NSAIDs. A daily dose of Celebrex costs about $2.39 while a daily dose of Vioxx costs about $2.44. One of the common NSAIDs called diclofenac sells for about $.64 a daily dose and generic naproxen sells for about $.30 cents a daily dose. ( Sources: Drugstorecom; WSJ research)
Through the first five months of this year, the FDA had received just two new drug applications (NDAs). NDAs have been dropping sharply the last few years as shown by the fact that only 24 were made last year down from 53 in 1996. Thus in many ways marketing rather than new research is leading the way for the drug companies to grow their sales.
The two most popular nutritional supplements that some research indicates eases the pain of osteoarthritis are glucosamine and chondroitin sulfate. Although Vioxx may increase the risk of heart attacks and Celebrex's label warns that it may cause stomach ulcers, these two supplements are thought to be free of such side effects.
If you do choose to use these nutritional supplements please keep in mind that the FDA does not regulate the production of supplements the way it regulates the production of drugs. Also choose a reputable brand and look for the letters "USP", which indicates that the manufacturer has followed the guidelines of the US Pharmacopia, a not-for-profit group that sets quality standards for medicines. The recommended dosages are 1,500 milligrams a day for glucosamine and 1,200 milligrams a day for chondroitin sulfate. Please be aware that chondroitin can cause bleeding in people who take blood thinners.
Merck & Co. announced that it would delay its application to refile the NDA for its next generation anti-arthritis drug Arcoxia until the second half of 2003. Arcoxia is Merck's successor to Vioxx as a COX-2 inhibitor drug. This time frame means a delay of more than a year for the introduction of the drug. The FDA had requested additional cardiovascular safety data. Merck also hopes to obtain additional data for the FDA that will show that Arcoxia helps to alleviate acute pain.
Merck will conduct a 6,000 patient study versus diclofenac on osteoarthritis patients for both gastrointestinal and cardiovascular safety data. Arcoxia is only one of several new entrants in the COX-2 battle. Pfizer/Pharmacia's has their new product Bextra already on the market as the successor to its original entrant of Celebrex. AstraZeneca is chomping at the bit with Crestor as its entrant in the COX-2 derby. Novartis's COX-2 entrant, which is awaiting FDA approval, is Prexige, and Abbott Labs' entry in the field for the treatment of rheumatoid arthritis is D2E7.
The FDA ruled that Celebrex must continue to carry a warning on its label that it can cause serious ulcer complications. It also did rule that the revised label could include the fact that the drug did not increase the risk of heart attack or gastrointestinal (GI) attack any more so than generic pain relievers such as ibuprofen or diclofenac. Celebrex is the anti-arthritic drug made by Pfizer and Pharmacia.
Neither Celebrex nor Vioxx, the anti-arthritic drug made by Merck, has been shown to reduce pain better than ibuprofen or other low-cost pain relievers. The FDA requires Merck to carry the warning on the Vioxx label about the potential risk of heart attack, but the agency did state that Vioxx did significantly lower the risk of ulcers more so than did naproxen, an older pain reliever.
AstraZenaca announced that it had received an "approvable" letter from the FDA for its cholesterol-lowering drug Crestor several weeks earlier than had been expected. The company and the FDA will follow this approval with discussions about the labeling for the drug.
It usually takes several months for this matter to be settled, so the new drug will probably not be available until early next year. Many experts feel that Crestor sales will sharply impact Vioxx and Celebrex. The big question in connection with the labeling will be the effect of Crestor in regards to whether or not it increases the risk for heart problems.
There is an editorial written by Dr. Pere Juni, a senior researcher at the University of Berne, in Switzerland, and two other doctors, that appeared in the June 1 issue of The British Medical Journal, they harshly criticizes one of the main studies used by Pharmacia to promote its best selling arthritis drug Celebrex.
The study in question concluded that Celebrex was safer than other widely used arthritis drugs, because it caused fewer ulcers had "serious irregularities". A spokesman for Pharmacia, Dr. Steve Geis, a vice-president for clinical research said that the company stands by the previously announced conclusions.
The study in question was reported on in 2000 in the Journal of the American Medical Association. The study concluded that patients taking Celebrex suffered fewer serious ulcer complications that those taking ibuprofen or diclofenac. The Washington Post later published an article stating that the published data only covered the first 6 months of the test rather than the full year data for which time period the study lasted for. According to Dr. Juni and his colleagues, much of the safety data that appeared for the first 6 months of the trial disappeared when considered on the full year basis.
Pharmacia and the doctors it hired for the study said they omitted the last 6 months of data because many patients dropped out in the latter half of the study, skewing the results. The high-drop out rate left more high-risk ulcer patients in the Celebrex test group than there were in the other groups. Dr.Juni and his colleagues feel that Pharmacia has a responsibility to the medical and scientific community to point out all the details of the study, not only that part which is most favorable to the drug.
One of the most difficult problems to evaluate whenever a new drug is introduced deals with the effect the drug may have on other areas of the patient's health. A drug may be very good for one purpose and yet it may cause some serious problems in other areas. In our article below we originally examined some of the results of the new COX-2 inhibitors in the battle against arthritis pain. Recently however there are more and more indications that some of the drugs that have been effective in treating Rheumatoid Arthritis may also be effective in the fight against colon cancer.
Ron Winslow wrote an article in the May 22 edition of the Wall Street Journal entitled " Arthritis Drug Celebrex Shows Promise as Cancer Weapon". The article reported on the results of a small study whose results were announced at the recently concluded meeting of the American Society of Clinical Oncology. More studies continue to show that COX-2 is present in high quantities in a wide range of tumors.
According to Andrew Dannenberg, director of cancer prevention at New York Presbyterian Hopitals's Cornell campus, an overabundance of COX-2 can interfere with the normal life cycle of cells by preventing their natural death, thus resulting in the uncontrolled growth of cancer cells. COX-2 may also promote growth of blood vessels that feed tumors, and may also regulate the process associated with metastasis. No one is claiming that COX-2 inhibitors prevent cancer, it is possible that in combination with other drugs, they may be used to prevent the growth of cancerous cells.
The December, 1999 edition of Nature Study looked at the results of a study done by some researchers at the Veterans Affairs Medical Center in Long Beach, Calif. The study was done on rats who had been administered the older arthritis drug indomethacin and the newer COX-2 inhibitor drugs. It concluded that both slowed the development of new blood vessels in rat cells. By slowing the growth of new blood vessels you can therefore slow the growth of cancerous tumors.
One of the negatives that this study showed was that the latest generation of arthritis pain drugs would also slow the ulcer healing process. An article in the New York Times by Gina Kolata on January 18th, 2000 stated that the National Health Institute would oversee tests to see if the COX-2 inhibitors can prevent colon cancer as well as treat Rheumatoid Arthritis. It was determined that the older drugs slowed the development of new blood vessels in rat cells to a greater extent than did the COX-2 inhibitors. We caution you by pointing out that these tests were not performed on humans.
In 1991 the New England Journal of Medicine published the results of a landmark study begun in 1983. The conclusion of that study was that people who took 16 or more aspirins a month for at least a year had about 1/2 the risk of death from colon cancer as people who didn't regularly use aspirin. A study involving 104,217 people in the Tennessee Medicaid program also showed that there were far fewer cases of colon cancer in elderly people who used aspirin regularly to treat their arthritis than amongst those who did not use aspirin regularly.
Please keep in mind that since aspirin and the NSAIDS such as Advil and Aleve are all off patent there is no financial inducement for the drug companies to investigate the possibilities of their anti-cancer properties.
Many of us, including this writer, have taken aspirin for many years as a heart failure preventive. This interesting finding may now also come into play in the fight against rheumatoid arthritis and colon cancer. Scientists at both Merck & Co. and alsoat the Searle division of Monsanto Co. believe that their new anti-arthritic drugs may also be useful in the fight against colon cancer.
Colon cancer killed about 48,000 people last year, which was second only to lung cancer. The F.D.A has now approved Celebrex, a non-steroidal drug to be marketed for treatment of certain polyps, which greatly increases the risk of developing colon and rectal cancer at an early age. The mechanism of action was related to the drug acting as an anti-inflammatory agent. Now the FDA has approved its use for the treatment of a rare genetic disorder that causes intestinal polyps.
The condition is called familial adenomatous polyposis (FAP). It increases the risk factor for developing colon and rectal cancer. The FDA made it clear that this medication should only be used in addition to current treatments, which usually involve removal of the lower intestine. The study cited for approving Celebrex for use in FAP involved 83 patients and showed that those patients using Celebrex developed 28 percent fewer polyps than those who used a placebo did. In this study, the main side effects of Celebrex were indigestion and diarrhea. The FDA is also requiring Searle to undertake more studies to determine whether reducing polyps was in fact beneficial to patients. Consult your physician for further information on this medication.
Both aspirin and these 2 drugs block the action of the natural enzyme referred to as COX-2 that is involved in some manner with inflammations. Many researchers feel that COX-2 enzyme affects the cell growth occurring excessively in cancer. If both aspirin and these 2 drugs can turn off the switch that produces the excess cell growth in colon cancer it may do the same for other cancers. Both these companies and Bayer are presently engaged in extensive testing to see if this preventive action will affect colon cancer. Both Merck and Searle are also presently testing COX-2 inhibitors to see the affect it may have on Alzheimer's disease.
Merck & Co. announced that it had withdrawn its application for approval with the FDA for its next generation rheumatoid arthritis drug Arcoxia, its successor to Vioxx. Merck said it would re-file its application after it has acquired some additional data that the commission was requesting. On the other hand Pfizer and Pharmacia launched Bextra, their next generation version of Celebrex the week of April 15th.
The FDA did grant Merck approval to add to the label of Vioxx the fact that the drug seems to protect the user against ulcers. The label must however add as a precaution that it may increase the risk of heat attack. Vioxx has won approval to include on its label that it treats rheumatoid arthritis, osteoarthritis, acute pain and menstrual pain.
It is estimated that there are about 100,000 hospitalizations, and 16,500 deaths each year due to some extent to the usage of standard pain pills such aspirin and ibuprofen in connection with ulcers.
Some analysts suggested that the Arcoxia application was withdrawn because of concern over the drug's potential cardiovascular risks. A spokesman for Merck did not indicate a timetable for resubmission of the application. The advisory panel for the FDA will be meeting some time in May to review the safety of the Cox-2 inhibitors. Sales of Vioxx were $2.1 billion in 2001 making it the 6th best-selling drug, compared to Celebrex, which had $2.4 billion in sales in 2001 making it the 3rd best-selling drug.
Pharmacia Inc. and Pfizer have begun co-marketing Bextra, which is their next generation drug to Celebrex. The FDA has approved the drug for treating the signs and symptoms of osteoarthritis and adult rheumatoid arthritis and primary dysmenorrhera (painful menstrual cramping). It has not been approved for acute pain as of this date.
Another question has now come to the forefront to cast another shadow of doubt about Merck's anti-arthritic drug Vioxx. The problem boils down to a question as to whether or not prolonged use of Vioxx causes damage to the user's liver.
A kidney disease known at segmental sclerosis has affected two well-known basketball players, Alonzo Mourning of the Miami Heat and Sean Elliot of the San Antonio Spurs. In the case of Mourning, he had to sit out one-year because of the problem and Elliot had to undergo a kidney transplant operation and is no longer playing pro ball.
Many pro athletes take nonsteroidal anti-inflammatory drugs like ibuprofen and aspirin as well as the prescription drugs Vioxx and Indocin to help overcome arthritic or other painful conditions that may prevent them from playing that day. It is common knowledge that most professional basketball and football players use these drugs. Mourning believes that his long-term use of the drugs over his 12-year career contributed to his disease.
Dr. Gerald Chodak, a clinical professor of urology at the University of Chicago stated as follows: " Decreased kidney function is a known side effect with almost every anti-inflammatory you can think of."
Merck revealed at an drug analysts meeting that the company was disappointed with the recent sales trend of its anti-arthritic drug Vioxx. While sales this year for the drug should total about $2.5 billion, its growth rate has slowed perceptably lately.The sales rate slowdown has been effected by the August article in the Journal of the American Medical Association which questioned whether the drug increases the risk of heart attacks. The other reason for the sales rate slowdown has been the fact that large managed-care groups are not allowing its members easy access to the drug. The HMO executives do not feel that the drug relieves arthritic pain any better than some less expensive anti-arthritic drugs.
Pharmacia Corp. and Pfizer Inc. announced that the FDA had approved Bextra (R) (valdecoxib tablets), a COX-2 specific inhibitor, for treating the signs and symptoms of osteoarthritis, adult rheumatoid arthritis and the treatment of pain associated with menstrual cramps. In global clinical trials involving more than 5,000 patients, Bextra became the third drug in the class of medicines called COX-2 inhibitors that relieve pain as well as aspirin does, but without causing as many gastrointestinal side effects. It thus joins Pfizer's Celebrex and Merck's Vioxx in the battle against arthritis.
Arthritis affects more than 23 million Americans. Osteoarthritis (OA) is the more prevalent one, affecting 21 million, while rheumatoid arthritis (RA) affects more than 2.1 million. RA is an autoimmune disease that affects joint lining, cartilage and bones. OA is a chronic disorder that causes pain and stiffness, because of the degeneratrion of joint cartilage and adjacent bones.
According to the announcement from Pharmacia "We do not see any evidence of increased risk for any kind of serious cardiovascular problems,". The most common side affects seen in the clinical tests of Bextra were headache, abdominal pain, upset stomach and nausea. Pharmacia said that it planned to begin selling Bextra in conjunction with Pfizer early next year. The clinical studies had lasted between 3 to 6 months time. The company's announcement further stated that neither Bextra nor Celebrex should be given to patients who suffer from asthma or suffered allergic reactions after taking aspirin or conventional NSAIDS.
Per the October update to the Red Book, Merck increased the price of Vioxx by
9.3%, or 13.5% year over year. The prices of all dosages of Vioxx were
increased. No price increase was seen for Pfizer's Celebrex. The Red Book is a
pharmacist's resource for drug pricing based on "average wholesaler prices".
Once again we ask how accurate is the "average wholesale price" listing when as,
Merck is doing with Vioxx, a drug company increases the price of a drug whose
sales is slowing in the marketplace. Could it be that the strategy is to
increase the price, so it would appear that a sharper percentage discount is
seemingly given when the price is cut? Pfizer has not changed its pricing for
Celebrex whose sales is holding up better right now than is Vioxx. Pharmacia did
announce however that the FDA has approved the use of Celebrex to include
treatment of acute and menstrual pain in adults.
An analysis of the raw data for the research done by Merck & Co. on Vioxx and by
Pharmacia/Pfizer & Co. for Celebrex by Eric J. Topol and Steven E. Nissen,
chairman and vice-chairman, respectively, of cardiovascular medicine at the
Cleveland Clinic concluded that "Current data would suggest that use of these so
called 'COX-2 inhibitors' might lead to increased cardiovascular events."
Debabrata Mukherjee, now of the University of Michigan collaborated on the
analysis, whose findings were published in the Journal of the American Medical
Association.
When the FDA originally approved the drugs, they required both Merck and Pharmacia/Pfizer to include on the label that 2% to 4% of those using the drugs for at least a year could get ulcers. In order to have this labelling changed both companies undertook large studies whose results they presented to the FDA in order to have the warning removed from the labels. This turned into a very embarrassing attempt by Pharmacia because the FDA disclosed that Pharmacia had an additional half-year Celbrex data beyond what it had published.
The 12-month data showed worse results regarding ulcers than did the 6-month data whose results had been published in JAMA. Jay Goldstein, professor of medicine at the University of Illinois at Chicago who was one of the Celebrex's study authors stated that the extra data was not included because a high number of patients dropped out during the study's second six monts. The authors worried that JAMA would not publish the study with such suspect data according to Dr. Goldstein. JAMA's editor, Catherine D. DeAngelis says that Pharmacia and the authors should have told JAMA about the extra data so that the journal would have had all the facts on the matter.
In examing the data presented for the benefit of the FDA in connection with the ulcer matter, the agency became alarmed about the apparently high rate of cardiac events, especially in respect to Vioxx. The agency enlisted Dr. Nissen of the Cleveland Clinic to help evaluate the heart data. Drs. Nissen and Topol determined that according to Dr. Topol, "I wouldn't say this was buried , but the appropriate cautionary flag wasn't raised."
The largest Vioxx study analyzed by the Cleveland Clinic authors included 8,076 rheumatoid-arthritis patients treated for up to 13-months with either Vioxx or naproxen. Forty-five Vioxx patients suffered a serious clot-related event during the study, compared to 20 in the naproxen group. In Pharmacia's yearlong study of 8,059 patients, there was "no significant difference" in cardiac events between patients on Celebrex and those taking other low cost NSAIDs, diclofenac and ibuprofen. The NSAIDs are painkillers that include aspirin, Advil and Aleve.
The Cleveland Clinic researchers compared the rate of cardiac events among Vioxx and Celebrex patients with that in 23,407 medium-risk cardiac patients given a placebo in various heart-attack prevention trials. The annualized heart attack rate in the placebo patients was 0.52%, with Vioxx it was 0.74%, and with Celebrex it was 0.80%.
The study did show that the Vioxx users had half the rate of ulcers and bowel perforations as those taking naproxen. The Celebrex study did not show such positive results re ulcers and bowel perforations. This could be because the Celebrex participants were also taking aspirin. Celebrex failed to prove that it reduced pain quickly, something the Vioxx studies proved. According to Sharon Levine, associate director of the Permanente Medical Group at Kaiser Permanente, " Consumers are paying millions and millions for drugs that, for most of them, appear to have not clinical benefit" over much cheaper pills.
If you look at just the cost factor in comparing Celebrex, Vioxx and ibuprofen or naproxen it is a no-brainer. A prescription for ibuprofen or naproxen costs about $20 versus about $77 for Vioxx and $87 for Celebrex. As we all know however cost is not the sole criteria in evaluation the total cost-effectiveness of a drug.
In the ongoing battle between Celebrx and Vioxx, a study presented at the American College of Cardiology's meeting in Orlando, showed that elderly hypertensive osteoarthritis patient's taking Merck's Vioxx had an increase in mean systolic blood pressure compared with those taking Pharmacia's Celebrex, who showed no increase in mean systolic blood pressure.
Celebrex was first introduced to the market in 1999 and its introduction was the most successful drug launch in history. Last year the drug had over $2.6 billion in sales. Vioxx was introduced about 5 months later and it was the 2nd most successful drug launch in history. According to the latest figures Vioxx had over $2.2 billion in sales last year.
Both Vioxx and Celebrex cost about $3 a day, versus their generic competitors which cost about 10 cents per day. One of the ow-cost generic drugs used to treat rheumatoid arthritis is called methotrexate. If the cost for the generics is less you may then ask why use the COX-2 inhibitors? If however they can be proven to be non-harmful to the stomach and not increase the risk of ulcers the answer would swing largely in their favor.
If one of the drug companies could prove that its drug was less harmful than the other, that would be a big plus in helping it gain a bigger share of this huge market for the drug. Only about 2 % to 4 % of NSAID users develop stomach problems such as ulcers, but there are millions of people who use either the NSAIDs or the COX-2 inhibitors. It is estimated that about 100,000 patients are hospitalized each year as a result of the NSAIDs of whom about 15,000 will die. In the case of the elderly who intake low-dose aspirin to prevent or deal with heart problems the answer to the question becomes quite relevant.
The advisory committee turned down the Pharmacia/Pfizer application to change the warning label but did allow Merck to include the fact on the label that the results were still open re the question of increasing the risk of ulcers.
Merck originally announced the preliminary results of its gastrointestinal (GI) trial of Vioxx done under the study name of VIGOR in a letter to investigators in late March 2000. The results of the study were publicly released May 24, 2000. The trial was based on comparisons on 8,076 patients with rheumatoid arthritis who were administered 50 mg of Vioxx once daily, or 500 mg of the generic naproxen twice daily.
The trial began in January 1999 and ended earlier than expected. Merck submitted the data to the FDA hoping to gain removal of the current NSAID GI warning. Vioxx showed a statistically significant reduction in perforations, ulcerations, obstructions and bleeds vs. naproxen. Vioxx users had 54% fewer painful ulcers, stomach holes and gut bleeding than those taking naproxen.
The rate of bad side effects was 4.5% per year in the naproxen patients, campared with 2.1% among the Vioxx users.Vioxx reduced the most severe side effects, including stomach blockages and severe bleeding by 57%. Unexpectedly, Vioxx had a higher rate of cardiovascular side effects (such as thromboembolic events) than naproxen. Because of these results, Merck will allow patients to use low-dose aspirin in future clinical trials for Vioxx as well as when their new generation COX-2 inhibitor, MK-663 is used. The aspirin is used to help prevent formation of blood clots that can cause heart attacks and strokes.
In the Pharmacia/Pfizer study, called CLASS, 22 % of the patients took aspirin, 78 % did not, along with the drug Celebrex. The results indicated that Celebrex was not associated with thromboembolic events, even in the patients who did not take the low dose aspirin. The Celebrex did not show superior results for the GI profile than did the NSAID comparators, ibuprofen and diclofenac.Thus further testing will be required on this matter.
Vioxx, the trade name for rofecoxib is an inhibitor of cyloxygenase-2 or COX-2, an enzyme in the body believed to be at the root of pain and inflammation. This non-steroid anti-inflammatory drug (NSAID) is approved for relief of signs and symptoms of osteo-arthritis, the management of acute pain and for the treatment of dysmenorrhea. It is comparable to other NSAID, but has a narrower range of side effects, especially lower incidence of GI effects.
Many researchers are becoming more aware of the possible side effects that occur when COX-2 inhibitors are used by patients suffering from rheumatoid arthritis. COX-2 inhibitors caused fewer stomach ulcers than many other pain relievers, but as they have had a higher, though relatively low, risk of heart attacks than patients taking the older pain relievers. The F.D.A. is considering whether to add infomation on possible cardiovascular side effects to both drugs' labels. Several doctors said that they are worried about the possibility of heart attacks because many of the arthritis patients taking the drugs are elderly, and have a higher risk of cardiovascular problems to begin with. Thus we come back to the same question as to whether or not aspirin should be used in connection with COX-2 inhibitors?
In addition some new research seems to give further support to the theory that people who take aspirin regularly to reduce the risk of heart attack may also be substantially extending their lives. Dr. Patricia Gum of the Cleveland Clinic led the study group that found that in addition to reducing the risk of heart attack those individuals who took an aspirin every other day seemed to also benefit by extending their longevity.
The results of the study appeared in The Journal of the American Medical Association. The study evaluated 2,310 people who were taking about one aspirin daily or every other day at test time, and 3,864 who were not taking any aspirin at all on a regular basis. The average age of the aspirin using group was 62, while the average age of the non-users was 56. There was a total of 276 deaths in about three years of follow-up. There were about an equal number of total deaths in both groups, but since the aspirin using group was an older grouping to begin with, the researchers found that the aspirin users were 33% less likely to die than those who were not taking aspirin.
The September 4, 2001 edition of the N.Y.Times has an interesting 1 1/3rd page ad from Boehringer Ingelheim Pharmaceuticals, Inc.with the bold headlines of the ad reading "Attention Vioxx and Celebrex Users: Are You Dissatisfied? If so, ask your doctor about MOBIC(meloxican). It's the osteoarthritis medicine with proven safety and efficacy used by 45 million patients in 100 countries for over five years." The ad contains a coupon for a free 30 day supply of MOBIC when presented to a participating pharmacy along with the coupon and a prescription for MOBIC. Thus, by innuendo, the ad seems to attack both Vioxx and Celebrex, while at the same time telling the reader to ask his/her physician for a prescription for MOBIC. How many readers will notice that this drug deals with osteoarthritis versus the rheumatoid arthritis that Celebrex and Vioxx are aimed at.
Pharmacia released Phase III data on parecoxib (COX-2 inhibitor) at the American Pain Society meeting. Results showed that the administration of parecoxib sodium, the first investigational injectable COX-2 specificanalgesic, significantly reduced the amount of morphine consumed by patients while improving overall pain relief.
On March 23, 2001 Pharmacia announced that it had filed its NDA for valdecoxib, its second-generation oral COX-2 inhibitor. Pfizer will co-market valdecoxib with Pharmacia as was the case with Celebrex. Pharmacia further stated that it expected the standard 10-12 month FDA review, and therefore thought it could have the FDA approval sometime in the first quarter of 2002. Early indications are that valdecoxib has a faster onset of action and faster pain relief than does Celebrex. More will be unveiled in connection with the new drug at the medical meetings beginning with the Digestive Disease Week meetings from May 19-23, 2001.
Searle is presently testing Celebrex in people with a form of genetically based colon disease called FAP (familial adenomatous polyposis). The FDA has put this test on a fast track basis meaning that they will announce their decision within 6 months. Scientists have determined an extremely excessive amount of COX-2 in patients with not only colon cancer, but also in patients with pancreatic cancer and head and neck cancers.
A key advantages of the new COX-2 inhibitors is that they relieve the pain from arthritis with less risk of causing or irritating ulcers associated with the older anti-inflammatory drugs such as ibuprofen and suilind ac. Vioxx was launched in the U.S. about 5 months later than Celebrex. It accounted for about $373 in revenue in 1999. Celebrex generated about $1.5 billion in sales in its first year, making it the best selling first year prescription drug. Although these new drugs cost about $750 per year more than generic anti-inflammatory drugs they have been deemed more appropriate for the elderly patients who have a higher risk of ulcers.
The University of Rochester has announced that it has filed a patent infringement suit against Searle and Pfizer the manufacturer and co-marketers of Celebrex. 17.5 million prescriptions were written for Celebrex last year. Officials of the university stated that the purpose of their suit is to negotiate royalties rather than have the drug removed from the market.
The patent was based on the work of Dr. Donald Young a professor of biochemistry and medicine, assisted by Michael K. O'Banion and Virginia D. Winn while at the university. Nonsteroidal anti-inflammatory drugs, aspirin, and ibuprofen work by blocking both the COX-1 and COX-2 enzyme. They also have a negative affect because usage can lead to ulcers and gastrointestinal bleeding.
The cyclo-oxygenase (COX) enzyme is involved in pain and inflammation. The COX-1 enzyme is involved in protecting the lining of the stomach from acids. The patent application was filed in 1992. Scientists from 2 other universities were making the same discoveries at just about the same time. They were the University of California, under Dr. Harvey R. Herschman, and Brigham Young University under Professor Daniel L Simmons. Lawyers for the university said they had not started any negotiations with Merck the manufacturer of Vioxx since they wanted to concentrate their action against Celebrex the bigger selling drug. COX-2 inhibitors alleviate pain while minimizing side affects such as ulcers and gastrointestinal disorders.
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