CELEBREX AND BEXTRA: A BETTER WAY TO MAKE THESE DRUGS SAFER.
FDA Advisory Committee Finds COX-2 Drugs Increase Risks of Heart Attacks and Strokes, Advises Stronger Warnings -- But Does Not Require Manufacturer to Market Lower, Safer, Proven-Effective Doses.

     On February 16-18, 2005, a FDA Advisory Committee composed of 32 experts found that the top-selling anti-inflammatory drugs Celebrex, Bextra, and Vioxx -- known as COX-2 inhibitors -- do pose increased risks of heart attacks and strokes.  This was a key decision that once again shows that all new drugs, despite their glossy advertising, carry risks of unrecognized, serious side effects.

     In a close vote, the advisory committee decided to allow Celebrex (celecoxib) and Bextra (valdecoxib) to remain available.  This decision was based on compelling testimony that these drugs can be very important for patients who do not improve or who cannot tolerate other anti-inflammatory drugs.  However, the committee also recommended strong, black-box warnings in the package inserts of Celebrex and Bextra (and Vioxx if it returns).  The committee urged doctors to be much more selective in prescribing Celebrex an Bextra.  "One of the particular problems with COX-2 inhibitors is that they were very widely used almost as soon as they were released," said Dr. Richard Platt, Chairman of the Department of Ambulatory Care and Prevention at Harvard Medical School.¹   Intensive advertising to doctors and consumers drove the overuse of COX-2 drugs.  Now, such advertising for these drugs should cease.

     Are these steps enough?  The medical profession and media seem satisfied.  I am not.  People suffered heart attacks, strokes, and died from these drugs.  Caution is warranted with any new drug, but caution was not heeded with COX-2 inhibitors.  Why not? Moreover, even if the FDA adopts the advisory committee's recommendations, this will not make Celebrex and Bextra safer for the people who require them.

How to Improve the Safety of Celebrex and Bextra

     The FDA committee advised doctors to prescribe the lowest available doses of Celebrex (200 mg/day) and Bextra (10 mg/day).  But how sure are we that these dosages are safe?  We know that 400 mg/day of Celebrex causes heart attacks and strokes; can we be sure that 200 mg doesn't?  We know that 20 mg/day of Bextra causes heart attacks and strokes; can we be sure that 10 mg doesn't?  No, we cannot be sure.  More likely, even at these lower recommended dosages, some risk remains.

     Knowing this, the only rational way to minimize the risks is to ensure that patients receive the smallest amount of Celebrex or Bextra that they require.  Even at 200 mg/day, Celebrex is still a very strong drug -- much stronger than many people need.  Studies have shown that half as much (100 mg/day, given as 50 mg twice-daily) is highly effective.^2,3  My guess is that 50 mg/day (25 mg twice-daily) would work for some people.  Bextra, at 10 mg/day, is also a very strong drug -- much stronger than many people need.  Studies have shown that 5 mg/day and even 2.5 mg/day work.^4-6  Why don't we use these lower, safer doses?  Because the manufacturer doesn't make them.  Drug companies have found that one-size-fits-all drugs sell better, so that's what they market.  That's why, for osteoarthritis (the arthritis of aging or injury), Celebrex and Bextra are one-size-fits-all.  One-size-fits-all dosing doesn't make sense medically, but drug companies are more concerned about sales than about the fact that their methods force people to receive double or quadruple the amount of medication they actually need.

     For many years, the FDA has advised doctors to individualize treatment with anti-inflammatory drugs, so that each patient receives the lowest dosage needed.  This minimizes people's risk, because these drugs' adverse effects (gastrointestinal bleeding, kidney damage, heart attacks) are dose-related.  The higher the dose, the greater the risks.  Individualized dosing is possible with older anti-inflammatory drugs such as ibuprofen (Motrin), diclofenac (Voltaren), and naproxen (Naprosyn).  One-size-fits-all Celebrex and Bextra are as effective as the strongest dose of naproxen, 500 mg twice-daily.  But naproxen comes in three lower twice-daily dosages: 375 mg, 250 mg, and 200 mg (over-the-counter Aleve).  These lower doses work for millions of people, allowing them to obtain pain relief without taking more medication than needed.  This is good medical practice.  In contrast, Celebrex and Bextra are not available at doses equivalent to these lower, safer, effective doses of naproxen.  Instead, everyone who receives Celebrex and Bextra gets the equivalent of the strongest dose of naproxen from the start -- with the increased risks that stronger doses pose.

     This means that with Celebrex and Bextra, the same strong doses would be prescribed for the arthritis of a 90 year-old woman who weighs 90 pounds and takes 9 other medications and for the arthritic toe of Shaquille O'Neil.  This makes no sense.  We know that people vary in their medication needs and tolerances.  Drugs that do not allow doctors to select dosages based on a patient's age, weight, state of health, use of other medications, or a history of medication reactions, make it impossible to avoid problems.  My book Over Dose: The Case Against The Drug Companies (2001), written long before the COX-2 problems emerged, describes the failure of the drug industry and FDA to provide safe drugs.  Chapter Two discusses anti-inflammatory drugs including Celebrex,  and how to use these drugs more safely.  Here are some quotes from Over Dose and other sources that are relevant to the current problems with Celebrex and Bextra:

        "Historically, drugs have often been initially marketed at what were later recognized as excessive doses. ... Any given dose provides a mixture of desirable and undesirable effects, with no single dose necessarily optimal for all patients."  Drug manufacturers should "identify a reasonable starting dose, ideally with adjustments for patient size, gender, age, concomitant illness, and concomitant therapy."  U.S. Food and Drug Administration .⁷

       "Many adverse reactions arise from the failure to tailor the dosage of drugs to widely different individual needs."  Goth's Medical Pharmacology.⁸

       "Many drugs have been introduced at doses that later were found to be too high; and usually years have passed, with unnecessary toxicity, before action was taken."  British Medical Journal.⁹

       "You run into patients all of the time who don't tolerate standard doses."  Holly Whitcomb, owner of four pharmacies in the Seattle area¹⁰.

       "To think that the same dose will do the same thing to all patients is absurd.  Patients need to be titrated, starting with the lowest possible dose that could have the desired effect." Dr. Raymond Woosley, former chairman of the department of pharmacology at the Georgetown University Medical Center.¹⁰

     Drugs that do not allow doctors to seek the lowest dosage for each individual place patients at unnecessary risk of side effects.  The manufacturer of Celebrex and Bextra should be required to undertake the actions necessary to market lower, safer, proven-effective dosages of these drugs.  In the meantime, if you require Celebrex or Bextra, ask your doctor about starting at a one-half or one-quarter dosage.  These dosages can be obtained by prescription from some of the compounding pharmacies across America.

[For more information on these issues, please see my previous articles on Celebrex and Bextra in the Oct.-Dec. newsletters in 2004 and 2003.  Over Dose offers information about scores of top-selling drugs, the underlying problems in the drug industry and FDA, and what doctors and consumers can do to use medications with fewer risks.  For more information about Over Dose and a table of contents.  Over Dose can be ordered through online and standard bookstores.]

References
1.  FDA advisors warn: COX-2 inhibitors increase risk of heart attack and stroke.  BMJ 2004;330:bmj.com.
2.  Bensen, WG, Fiechtner, JJ, McMillen, JI, et al.  Treatment of osteoarthritis with celecoxib: a randomized controlled trial.  Mayo Clinic Proceedings 1999;74(11):1095?]105.
3.  Hubbard, R, Geis, GS, Woods, E, Yu, S, ZHao, W.  Efficacy, tolerability, and safety of celecoxib, a specific Cox-2 inhibitor, in osteoarthritis.  Arthritis and Rheumatism 1998;41(9 suppl):S196 [abstract].
4.  Kivitz, A, Eisen, G, Zhao, WW, Bevirt, T, Recker, DP.  Randomized placebo-controlled trial comparing efficacy and safety of valdecoxib with naproxen in patients with osteoarthritis.  Journal of Family Practice 2002;51(6):530-7.
5.  Makarowski, W, Zhao, WW, Bevirt, T, Recker, DP.  Efficacy and safety of the COX-2 specific inhibitor valdecoxib in the management of osteoarthritis of the hip: a randomized, double-blind, placebo-controlled comparison with naproxen.  Osteoarthritis & Cartilage 2002;10(4):290-6. 
6.  Ormrod, D, Wellington, K, Wagstaff, AJ.  Valdecoxib.  Drugs 2002;62(14):2059-71.
7.  Food and Drug Administration.  Guideline for industry: Dose-response information to support drug registration.  U.S. Food and Drug Administration, www.fda.gov/cder/guidance/iche4.pdf:Nov. 1994 (checked Feb. 22, 2003).
8.  Clark, WG,  Brater, DC, Johnson, AR.  Goth's Medical Pharmacology.  13th Edition.  St. Louis: The C.V. Mosby Company, 1992.
9.  Herxheimer, A.  Dosage needs systematic and critical review.  BMJ 2001;323:253.
10.  Gebhart, F.  Is Standard Dosing to Blame for Adverse Drug Reactions?  Drug Therapy, Jan. 17, 2000;34.

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