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.
Jay S. Cohen, M.D
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.
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!
(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.
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).
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.
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)."
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
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.
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).
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
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.
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
One-Size-Fits-All: A Worsening Trend
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
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
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.
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
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.
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.
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.
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.
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
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.
Physicians' Desk Reference, 53th Edition. Montvale, N.J.: Medical Economics Company,
Wolfe, MM, Lichtenstein, DR, Singh, G. Gastrointestinal toxicity of nonsteroidal
anti-inflammatory drugs. New England Journal of Medicine 1999;1340(24):1888-99.
Ahmad, SR, Kortepeter, C, Brinker, A, et al. Renal failure associated with the
use of celecoxib and rofecoxib. Drug Safety 2002;25:537-544.
Bing, RJ. Cyclooxygenase-2 inhibitors: is there an association with coronary or
renal events? Current Atherosclerosis Reports 2003;5:114-7.
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.
Montamat, SC, Cusack, BJ, Vestal, RE. Management of drug therapy in the elderly.
New England Journal of Medicine 1989;321(5):303-9.
Recchia, AG, Shear, NH. Organization And Function Of An Adverse Drug Reaction
Clinic. Journal Of Clinical Psychiatry, 1994;34:68-79.
Cohen, JS. Over Dose: The Case Against The Drug Companies. Prescription Drugs,
Side Effects, and Your Health. Tarcher/Putnam, New York: October 2001.
Williams, RD. Medications and older adults. FDA Consumer Magazine, Sept.-Oct.
Celebrex Package Insert. Searle & Co., 1999.
Physicians' Desk Reference, 57th Edition. Montvale, N.J.: Medical Economics Company,
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.
Melmon, KL, Morrelli, HF, Hoffman, BB, Nierenberg, DW. Melmon and Morrelli's Clinical
Pharmacology: Basic Principles in Therapeutics. (3rd Edition). New York: McGraw-Hill,
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.
Hubbard, R, Geis, GS, Woods, E, et al.
Efficacy, tolerability, and safety
of celecoxib, a specific Cox-2 inhibitor, in osteoarthritis. Arthritis and Rheumatism,
Cohen, JS. Why Aren't Lower, Effective, OTC Doses Available Earlier by Prescription?
Annals of Pharmacotherapy 2003;37(1):136-142.
2003, Jay S. Cohen, M.D. All rights
have my permission to copy and disseminate all or part of these articles if it
is clearly identified as the work of: Jay S. Cohen, M.D., The Free Underground
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