Jay S. Cohen M.D.       http://medicationsense.com      1337 Camino Del Mar   Suite C       Del Mar, CA 92014       Phone: 858.345.1760       Fax: 858.509.8944


Seniors, Side Effects, and Celebrex: Does This Strong, One-Size-Fits-All Drug Put Seniors, Women, And Others At Unnecessary Risk?

How Medication Marketing Overrides Medical Science

Celebrex, the powerful, top-selling anti-inflammatory drug, symbolizes the good and bad of medication therapy today. On the one hand, Celebrex helps millions of people. On the other, it's one-size-fits-all dosage for degenerative arthritis (osteoarthritis) is unnecessarily strong for many people, placing them at extra risk of major side effects such as gastrointestinal hemorrhage, kidney injury, and death.

The risks aren't small. Anti-inflammatory drugs cause more than 16,000 deaths and 100,000 hospitalizations each year. The Physicians' Desk Reference states: "Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation, can occur at any time, with or without warning symptoms, in patients treated chronically with nonsteroidal anti-inflammatory drugs (1)." Yet, as the New England Journal of Medicine warned: "These toxic effects remain largely a `silent epidemic,' with many physicians and most patients unaware of the magnitude of the problem (2)." The risk of gastrointestinal bleeding is somewhat less with newer anti-inflammatory drugs like Celebrex, but the risk of kidney failure isn't (2A), and the newer drugs have also been associated with cardiovascular events (2B).

Seniors and Women, Beware!
Seniors (and women) are impacted the most. Why? One major reason is that although seniors are more vulnerable to the toxic effects of anti-inflammatory drugs, they routinely receive the same strong doses as younger, bigger, healthier people. Such methods defy medical sense and common sense, yet the same 100-mg twice-daily dose of Celebrex is indicated for Shaquille O'Neal's arthritic toe, Ally McBeal's tennis elbow arthritis, and Grandma Moses' arthritic fingers, even if Grandma is 90 years old, weighs 90 pounds, and takes nine other drugs.

Medication side effects are a huge problem for seniors, most of whom rely on prescription drugs. Overall, seniors account for about 20% of the population, yet they sustain 39% of drug side effects requiring hospitalization and 51% causing death (3,4). That's why experts repeatedly advise doctors to use caution when treating seniors and, except in acute situations, to start with the lowest, safest medication doses. In my book Over Dose (5), I quote experts, medical journals and textbooks on this point, but here one statement will suffice, because it's from the U.S. Food and Drug Administration:


"There is evidence that older adults tend to be more sensitive to drugs than younger adults, due to their generally slower metabolisms and organ functions. ... The old adage, `Start low and go slow,' applies especially to the elderly (FDA Consumer Magazine, 1997)(6)."


You need to go no farther than Celebrex, an arthritis drug commonly prescribed for seniors. The 1999 Celebrex package insert states that "the incidence of adverse experiences tended to be higher in elderly patients (7)." The 2003 package insert states that "there have been more spontaneous post-marketing reports of fatal gastrointestinal events and acute renal failure" with Celebrex in seniors (8).

Here's another reason why seniors should take lower doses of Celebrex: blood levels of Celebrex rise higher in seniors, 40%-50% higher on average than in younger adults (8). Higher blood levels mean greater risks. Seniors don't need higher blood levels of Celebrex for it to work. With a lower dose, they could get the same blood levels and effectiveness as younger adults. This is important because seniors are more vulnerable than younger adults to the serious side effects of anti-inflammatory drugs.

Women are also impacted by these issues. Celebrex blood levels rise higher in older women than older men, which the manufacturer attributes to women's lower weight. Thus, the package inserts recommends that "for patients of less than 50 kg [110 pounds] in body weight, initiate therapy at the lowest recommended dose (8)."

That's a good idea, but for osteoarthritis, the recommended dose is one-size-fits-all. There is no lower dose.

The Devil Is in the Dosage
Why is it so important to use the lowest effective doses of medications? Because 75%-80% of all side effects are dose-related (9,10). Just like with coffee and alcohol, most side effects are a function of the amounts taken, not of the drugs themselves.

Lower medication doses usually have fewer risks and are sometimes surprisingly effective. In fact, many seniors with arthritis do fine with the very low doses in the over-the-counter anti-inflammatories Aleve, Orudis, or Motrin (ibuprofen).

So what is my concern about Celebrex? The Celebrex package insert advises, "For osteoarthritis and rheumatoid arthritis, the lowest dose of Celebrex should be sought for each patient (8)." But how can you do this if the dosage is one-size-fits-all?

Lower doses of Celebrex actually work (11,12), but because they aren't marketed, most doctors and patients don't know this. For example, in a large Mayo Clinic study, 50 mg twice-daily of Celebrex was significantly effective (11). That's 50% less medication than the standard dose -- and considerably less risk.

Most of the people in this study had severe arthritis. This suggests that an even lower Celebrex dosage, 25 mg perhaps, would be enough for people with mild arthritis. In fact, in a decade or so we'll probably see low-dose Celebrex as an over-the-counter drug. That's exactly what happened with Motrin, Orudis, and Aleve (naproxen). But why must we wait a decade to obtain the lowest, safest, effective anti-inflammatory doses? That's exactly what I asked in my 2003 article in the Annals of Pharmacotherapy: "Why Aren't Lower, Effective, Over-The-Counter Doses Available Earlier by Prescription (13)?"

One-Size-Fits-All: A Worsening Trend
Anti-inflammatory drugs introduced in the 1970s and 1980s came in multiple sizes. Motrin came in 300, 400, 600, and 800 mg sizes. Naproxen: 250, 375, and 500 mg. Naproxen 250 mg twice-daily worked for most of my patients. Naproxen 375 mg twice-daily was enough for most of the rest. Only a small percentage required the 500 mg twice-daily dosage.

Studies show that Celebrex is as effective as naproxen. In fact, it's as effective as the 500 mg dose of naproxen (11). So Celebrex is very powerful. The problem is, all patients are started with this powerful dose, the equivalent of the strongest, riskiest dose of naproxen. You don't get the choice of starting Celebrex at a dose that's equivalent to 250 or 375 mg of naproxen. Therein lies the problem, because these drugs' worst toxicities are dose-related, and even the FDA urges doctors to prescribe the lowest, safest, effective doses.

Marketing over Medical Science. Why is this happening? That's discussed at length in Over Dose, but in short, drug companies market to doctors, who prefer drugs that are easy to prescribe, allowing them to finish quickly and move on. Meanwhile, doctors assume that if a drug is recommended one-size-fits-all, it's okay, because the drug companies have researched it and the FDA has approved it. This assumption is dead wrong. The system has no direction, regulation is weak, and marketing factors frequently override medical science.

Such methods may work with other, less vital commodities, but with medications it has a distinct downside: more than 106,000 deaths and 2,000,000 severe, often disabling side effects in U.S. hospitals annually (9). If outpatients were included, the numbers would be even higher. Moreover, side effects drive millions of people from badly needed treatment every year.


Informed Consent Means Possessing Enough Information to Make an Intelligent Choice

Medications, including Celebrex, help millions of people. But medications are also a leading cause of death and disability. Much of this harm is preventable by using the lowest effective doses that each person requires.

Lower doses don't work for everyone. Some people require standard doses. Some people require high doses. But many people respond to lower, safer doses if given the chance. And in my experience, most people would prefer to at least start with a lower dose; if it isn't effective, the dosage can always be raised. This is what I call precision prescribing. This model doesn't apply to some drugs (e.g., some anti-infectives and anti-cancer drugs), but it applies to most drugs.

However, you and your doctor can't consider a lower, safer dose of Celebrex if you don't know about it. And you won't learn about it in the package insert or Physicians' Desk Reference, which are written by the drug companies. My purpose in publishing Over Dose and this newsletter is to provide scientifically-sound information about lower, safer doses of scores of top-selling drugs, information you won't get from package inserts, the PDR, or the drug industry's saturation advertising or 90,000 sales reps. Newspaper and magazine articles sometimes provide good information, but often read more like infomercials.

Most people don't like taking medications. If they must, they prefer taking as little medication as possible. But unless the healthcare system makes this possible, we will continue over-dosing millions of people and perpetuating the decades-long epidemic of side effects. Prevention begins with good information.

If you and your doctor want to try low-dose Celebrex (do not alter doses yourself), you cannot split the 100-mg capsule. You and your doctor could consider using Celebrex once-daily instead of twice-daily, but the effects might not last twenty-four hours.

Another approach is to have a compounding pharmacy make lower dose capsules. For a fee, many compounding pharmacies will do this with a doctor's order. If you or your doctor don't have a local compounding pharmacy, the Professional Compounding Centers of America (800-331-2498; 281-933-6948) will help you find one.

References
1. Physicians' Desk Reference, 53th Edition. Montvale, N.J.: Medical Economics Company, 1999.
2. Wolfe, MM, Lichtenstein, DR, Singh, G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. New England Journal of Medicine 1999;1340(24):1888-99.
2A. Ahmad, SR, Kortepeter, C, Brinker, A, et al. Renal failure associated with the use of celecoxib and rofecoxib. Drug Safety 2002;25:537-544.
2B. Bing, RJ. Cyclooxygenase-2 inhibitors: is there an association with coronary or renal events? Current Atherosclerosis Reports 2003;5:114-7.
3. Smucker, WD, Kontak, JR. Adverse drug reactions causing hospital admission in an elderly population: experience with a decision algorithm. Journal of the American Board of Family Practice 1990;3(2):105-9.
3A. Montamat, SC, Cusack, BJ, Vestal, RE. Management of drug therapy in the elderly. New England Journal of Medicine 1989;321(5):303-9.
4. Recchia, AG, Shear, NH. Organization And Function Of An Adverse Drug Reaction Clinic. Journal Of Clinical Psychiatry, 1994;34:68-79.
5. Cohen, JS. Over Dose: The Case Against The Drug Companies. Prescription Drugs, Side Effects, and Your Health. Tarcher/Putnam, New York: October 2001.
6. Williams, RD. Medications and older adults. FDA Consumer Magazine, Sept.-Oct. 1997.
7. Celebrex Package Insert. Searle & Co., 1999.
8. Physicians' Desk Reference, 57th Edition. Montvale, N.J.: Medical Economics Company, 2003.
9. Lazarou, J, Pomeranz, BH, Corey, PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279(15):1200-5.
10. Melmon, KL, Morrelli, HF, Hoffman, BB, Nierenberg, DW. Melmon and Morrelli's Clinical Pharmacology: Basic Principles in Therapeutics. (3rd Edition). New York: McGraw-Hill, Inc., 1993.
11. 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.
12. Hubbard, R, Geis, GS, Woods, E, et al.
Efficacy, tolerability, and safety of celecoxib, a specific Cox-2 inhibitor, in osteoarthritis. Arthritis and Rheumatism, 1998;41(9 suppl):S196[abstract].
13. Cohen, JS. Why Aren't Lower, Effective, OTC Doses Available Earlier by Prescription? Annals of Pharmacotherapy 2003;37(1):136-142.





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