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Life Extension Magazine

LE Magazine March 2003

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Medications side effects

Lower doses recommended by experts

TABLE 4: LOWER INITIAL DOSES OF
ANTIHYPERTENSIVE DRUGS

ACE INHIBITORS PDR PROVEN LOSER
DOSE
Accupril® (quinapril): 10 mg 5 mg
Altace® (ramipril): 2.5 mg 1.25 mg
Capoten® (captopril): 50-75 mg 25 mg
Prinivil®, Zestril® (lisinopril): 10 mg 5 mg

ANGIOTENSIN RECEPTOR BLOCKERS (ARBs)
Cozaar® (losartan): 50 mg 25 mg

BETA BLOCKERS
Inderal® (propanolol): 80 mg 40 mg
Kerlone® (betaxolol): 10 mg 5 mg
Levatol® (penbutolol): 20 mg 10 mg
Lopressor® (Metoprolol): 100 mg 50 mg
Sectral® (acebutolol): 400 mg 200 mg
Tenormin® (atenolol): 50 mg 25 mg
Zebeta® (bisoprolol): 5 mg 2.5 mg

CALCIUM ANTAGONISTS (BLOCKERS)
Calan®, Isoptin®, Verelan® (verapamil): 120-180 mg 90 mg
Cardizem®, Dilacor® (diltiazem): 180-240 mg 120 mg
Norvasc® (amlodipine): 5 mg 2.5 mg
Plendil® (felodipine): 5 mg 2.5 mg

DIURETICS
Demadex® (torsemide): 10 mg 5 mg
Edecrin® (ethacrynic acid): 50 mg 25 mg
HCTZ® (Hydrochlorothiazide): 25 mg 12.5 mg
Lasix® (Furosemide): 80 mg 40 mg
*Spironolactone®: 50 mg 25 mg
Thalitone® (Chlorthalidone): 15 mg 12.5 mg
*Triamterene®: 200 mg 25 mg

Adapted from: Over Dose: The Case Against The Drug Companies. Prescription Drugs, Side Effects and Your Health. Tarcher/Putnam, New York: October 2001.

And from: Cohen, JS. Adverse Drug Effects, Compliance, and the Initial Doses of Antihypertensive Drugs Recommended by the Joint National Committee (JNC) Vs. the Physicians' Desk Reference. Archives of Internal Medicine 2001;161:880-85.

Because most side effects with antihypertensive drugs are dose-related, experts recommend starting with the very lowest effective doses. But what are they? Most doctors turn to the PDR, but the PDR's doses often aren't the lowest. In an analysis I published in the Archives of Internal Medicine in 2001, I found that for 23 of 40 top-selling antihypertensive drugs, the initial doses recommended by the drug companies in the PDR were much higher than recommended by the Joint National Committee-the national board of medical experts on hypertension.21

For example, the manufacturer's initial dose for Norvasc, the fifth most prescribed drug in the U.S. in 2001, is 5 mg. The experts recommend 2.5 mg, 50% less medication. The manufacturer of Capoten (captopril) recommends 50 mg to 75 mg/day initially, 100% to 600% more than the 12.5 mg to 25 mg recommended by experts.

When Tenormin (atenolol) was introduced in 1976, the one-size-fits-all dose was 100 mg. It wasn't until 1980 that a 50 mg dose was available and until 1989 that 25 mg was produced. The manufacturer still recommends 50 mg initially, 100% higher than the 25 mg recommended by the national board.

The manufacturer of Lasix® (furosemide), a commonly prescribed diuretic, recommends 80 mg initially; the national board, 40 mg. The top-selling diuretic hydrochlorothiazide (HCTZ) was recommended at 100 mg initially, but this dose caused serious metabolic problems that affected millions. Yet, it took decades for manufacturers to lower the dose to 25 mg, still 100% higher than the 12.5 mg experts recommend today.

Similar over-dosing is seen with top-sellers Zestril®, Prinivil®, Altace®, Inderal® (propanolol), Cardura®, Cozaar®, and many others (Table 4). Is it any wonder why so many people quit treatment?

Some savvy doctors recognize that starting with the lowest dose not only reduces risks, but allows people time to improve their diets, lose weight, start exercising and learn stress reduction or meditation. These methods not only lower blood pressure, but can reduce the amount of medication you need. As one specialist put it, "With blood pressure, it's easy to overshoot the mark. That's why I always start low and give people time to make other changes. Very often, their blood vessels relax over a period of time and you wind up ultimately needing less medication. When I start with standard doses, we spend the rest of our lives combating side effects."

(Editor's note: When it comes to anti-hypertensive drugs, some patients are not taking them frequently enough to maintain continuous blood pressure control. Many anti-hypertensives are sold in "one-per-day" dosing units, but some people need to take these drugs in two divided doses to achieve all-day blood pressure control. Optimal control of hypertension requires blood pressure checks throughout the day. This is the only way to make sure the anti-hypertensive drug is not wearing off and endangering the arterial system.)

Anti-inflammatory drugs

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In package inserts and PDR descriptions of nonsteroidal anti-inflammatory drugs (NSAIDs) such as Motrin®, Voltaren®, Celebrex® and Vioxx®, the FDA specifically requires drug companies to tell doctors to use "the lowest dose for each patient." Why? Because gastrointestinal hemorrhaging and kidney damage from NSAIDs have caused more than 16,000 deaths and 100,000 hospitalizations annually. In 1999, the New England Journal of Medicine reported that NSAIDs were the 15th leading cause of death in the U.S.: "Yet these toxic effects remain largely a 'silent epidemic,' with many physicians and most patients unaware of the magnitude of the problem."22 And they are unaware that these reactions can occur without any warning signs.

These and other NSAIDs side effects are dose-related, yet doctors and patients often aren't informed about the very lowest effective doses, so over-dosing is common.

Motrin® and Voltaren®

When Motrin® (ibuprofen) was introduced in America in 1974, the lowest dose was 300 mg and the most prescribed dose was (and still is) 400 mg. Yet, studies had already proven that 200 mg was effective for osteoarthritis (degenerative arthritis) and rheumatoid arthritis.23-26 Yet, low-dose Motrin® wasn't available for 10 years until over-the-counter Motrin® arrived in 1984. Most doctors still don't know about its effectiveness and instead usually prescribe 400 mg when half as much will do.

The standard dosage of Voltaren® (diclofenac) for osteoarthritis is 50 mg twice or three times daily. Yet, studies before Voltaren's® approval showed that 25 mg three times daily is enough for many patients.27-30

Celebrex® and Bextra®

Dosing with new drugs like Celebrex® and Bextra® is even worse. Both drugs are one-size-fits-all for osteoarthritis, their most common use. This means that the identical amount is prescribed to football players with injury-induced arthritis and to osteoarthritic 90 year-olds weighing 95 pounds and taking nine other drugs.

The standard dose of Celebrex® for osteoarthritis is 100 mg twice-daily. A Mayo Clinic study showed that 50 mg twice-daily works for many people with severe osteoarthritis. Moreover, compared with higher doses, the 50 mg dose not only caused fewer side effects, but wasn't associated with kidney problems.31 Starting at this lower, safer dose would make sense, but the package insert and PDR don't say a word about it, and the smallest Celebrex® pill is a 100 mg capsule. Bextra was effective at half (5 mg) and quarter (2.5 mg) doses in early studies, but this was ignored and only 10 mg is offered for osteoarthritis.

Other drugs

A half dose of the antihistamine Allegra® is effective, but because the drug is one-size-fits-all and the pill is a capsule, a half dose is difficult to get. Half doses of Claritin®, especially Claritin-D®, work for some people, but for others even full-dose Claritin® isn't enough. In fact, the FDA wanted Claritin® produced at 20 mg, but this dose could cause sedation, which would hamper advertising. So doctors and patients are stuck with a one-size-fits-all 10 mg dose that is inadequate for as many as 50% of patients.32

Half doses of Zantac®, Axid® and Pepcid® were proven effective long before they were first marketed in the 1980s. It was only a decade later, when the drugs were marketed over-the-counter, that lower doses became available. Until then, people with mild heartburn got the same strong doses as people with bleeding ulcers.

Prilosec® is effective at a half dose of 10 mg, but there's scant information about it in the PDR, so doctors rarely prescribe it. Over-the-counter 10 mg Prilosec will finally allow people to take a lower, safer dose for mild conditions.
Viagra® has been linked with more than 500 deaths and 1,500 heart attacks, strokes and other vascular events.33 The manufacturer and FDA blame this on patients' age, health or sexual activity, but many deaths have occurred in men with no major medical problems and before they even had sex. Suspicion remains that Viagra® may affect blood pressure or cause a cardiac arrhythmia in rare individuals. The standard starting dose is 50 mg for all men ages 18 to 65, but I've suggested starting with a half dose, especially in middle-age men,34 the group in which many reactions have occurred. A half dose works for some men; if it isn't enough, it can be easily increased.

Lotronex® generated a controversy that did not have to happen. Lotronex® is effective for irritable bowel syndrome, a nasty disorder that limits people's lives, but the condition isn't an emergency requiring immediate powerful dosing. Yet, Lotronex was released one-size-fits-all, and after causing hospitalizations and deaths, was withdrawn. As I told the FDA, one-size-fits-all drugs tie doctors' hands by keeping them from matching doses to patients' needs or reducing doses when side effects emerge. Belatedly, after unnecessary harm and a public furor, Lotronex® was re-released in 2002-at a half dose.

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Dosage is key with the widely used heart drug digoxin because excessive doses can cause cardiac arrhythmias. For years, the recommended starting dose was 0.25 mg. However, a half dose works. A 1997 study showed that 0.125 mg of digoxin improved congestive heart failure, whereas higher doses produced diminishing improvement and greater toxicity.35

Sleep medicines such as Ambien® and Halcion® (triazolam) are often effective at half doses. Halcion® is another drug released at excessive doses that, after undue harm, widespread controversy, and being banned in many countries, had its dose lowered.

The neuroleptic Risperdal® was marketed in 1993 at 2 mg/day, which was rapidly increased to 6 mg within three days. Doctors quickly learned-from patients' adverse reactions-that these doses were excessive, and the manufacturer now recommends 1 mg the first day, increasing to 3 mg in three days. That's 50% less medication. Still, doctors start some patients at 0.25 mg or 0.5 mg. Similar patterns have occurred with Haldol® and other drugs.

Because Xenical®, a weight-loss drug, works by blocking fat absorption, it can cause embarrassing side effects. Dosage is key, yet whether you are slightly overweight or massively obese, whether you eat a little or a lot, you get the same dose of one-size-fits-all Xenical®: 120 mg three-times-a-day. A half dose was proven effective in studies, but the manufacturer does not market it.

Zyban®, widely advertised for smoking cessation, is started at 150 mg, then doubled to 300 mg in three days, but even at this strong dose long-term cessation rates aren't impressive. Some people taking Zyban® can tolerate only 150 mg, and others tolerate even less. In 2001, British regulators issued warnings about seizures with Zyban® at the standard dosage.36 To obtain lower doses, some doctors prescribe Wellbutrin®, an antidepressant that's identical to Zyban® but comes in lower doses.

In 2001, users of inhaled steroids for asthma or allergies learned that these drugs had been discovered to cause bone loss. "The message really is, we need to use inhaled corticosteroids at the lowest doses that we can," Dr. Elliott Israel told the San Diego Union-Tribune.37 But why weren't they doing so from the start?

The list goes on and on (Table 5). Repeated discoveries of dose-related toxicities years after people have started medications is not satisfactory. We know that most side effects are dose-related, which means that many are preventable by defining the lowest, safest doses initially, not years or decades later after problems inevitably emerge or drugs go over-the-counter.

TABLE 5: LOWER, SAFER, EFFECTIVE DOSES FOR 36 OTHER FREQUENTLY PRESCRIBED DRUGS THAT YOU WON'T FIND IN THE PDR OR MOST OTHER DRUG REFERENCES

Even if a drug isn't listed here, a lower dose may still work. Many drugs are never tested at lower doses or the research isn't published, but a lower initial dose may be appropriate in some situations. Work with your doctor. Do not change doses without medical direction; undertreatment can be harmful.

MEDICATION DRUG COMPANY INITAL DOSAGE EFFECTIVE, LOWER DOSAGE
ALLEGRA® (FEXOFENADINE) 60 mg twice-daily 20 mg three-times-a-day, or 40 mg twice-daily1
AMBIEN® (ZOLPIDEM) 10 mg 5 or 7.5 mg at bedtime2
AXID® (NIZATIDINE) 150 mg twice-daily 25-75 mg twice-daily or 300 mg at bedtime 100 mg at bedtime3
CELEBREX® (CELECOXIB) 100 mg twice-daily 50 mg twice-daily
COLCHICINE® 0.6 mg twice-daily 0.3 mg twice-daily
CYTOTEC® (MISOPROSTOL) 200 mcg 50 or 100 mcg four-times-a-day four-times-a-day4
DALMANE® (FLURAZEPAM) 30 mg at bedtime 15 mg at bedtime5
DESYREL® (TRAZODONE) 150 mg/day 25-100 mg/day6
EFFEXOR® (VENLAFAXINE) 75 mg/day 37.5 or 50 mg/day7
ELAVIL® (AMITRIPTYLINE) 50-75 mg/day 10-25 mg/day8
ESTRACE® (ORAL ESTRADIOL) 1-2 mg/day 0.5 mg/day9
ESTRADERM® (TRANSDERMAL ESTRADIOL) 0.05-0.1 mg/day 0.02-0.025 mg/day10
ESTRATAB® (ESTERIFIED ESTROGENS) 1.25 mg/day 0.3-0.625 mg/day11
LIPITOR® (ATORVASTATIN) 10 mg/day 2.5 or 5 mg/day
MEVACOR® (LOVASTATIN) 20 mg/day 10 mg/day
MOTRIN® (IBUPROFEN) 300-400 mg three- 200 mg three- or four-times-a-day times-a-day
NORPRAMIN® (DESIPRAMINE) 100 mg/day* 10 or 25 mg/day
PAMELOR® (NORTRIPTYLINE) 50-75 mg/day 10 or 25 mg/day12
PEPCID® (FAMOTIDINE) 20 mg twice-daily 10 mg twice-daily or or 40 mg at bedtime 20 mg at bedtime13
PRAVACHOL® (PRAVASTATIN) 10-20 mg/day 5-10 mg/day
PREMARIN® (CONJUGATED ESTROGENS),for vasomotor symptoms or osteoporosis: 0.625 mg/day 0.3 mg/day
PRILOSEC® (OMEPRAZOLE) 20 mg/day 10 mg/day14
PROZAC® (FLUOXETINE) 20 mg/day 2.5, 5, or 10 mg/day
RISPERDAL® (RISPERIDONE) 1-2 mg/day 0.5 mg/day15
SERZONE® (NEFAZODONE) 100 mg twice-daily 50 mg once or twice daily 16,17
SINEQUAN® (DOXEPIN) 75 mg/day 10, 25, or 50 mg/day18
TAGAMET® (CIMETIDINE) 800 mg at bedtime 400 mg at bedtime
TOFRANIL® (IMIPRAMINE) 75 mg/day 10-25 mg/day19
VASOTEC® (ENALAPRIL) 5 mg/day 2.5 mg/day**20
VOLTAREN® (DICLOFENAC) 50 mg two-, three-,or four-times-a-day 25 mg three- times-a-day
WELLBUTRIN® (BUPROPION) 100 mg twice-daily 50 mg twice-daily21
XENICAL® (ORLISTAT) 120 mg 3 times daily 60 mg 3 times daily22
ZANTAC® (RANITIDINE) 150 mg twice-daily 100 mg twice-daily23 or 300 mg at bedtime
ZOCOR® (SIMVASTATIN) 10-20 mg/day 2.5, 5, or 10 mg/day24,25
ZOFRAN® (ONDANSETRON) 8 mg twice-daily 1-4 mg three-times-a-day26
ZOLOFT® (SETRALINE)
50 mg/day 25 mg/day

* The manufacturer recommends starting with a lower dose, but doesn't specify.
** The manufacturer does recommend 2.5 mg for people on a diuretic, but this lower initial dose may also be useful for small, elderly, or other people.

Adapted from: Cohen, JS. Over Dose: The Case Against The Drug Companies. Prescription Drugs, Side Effects, and Your Health. Tarcher/Putnam, New York: October 2001.

References for Table 5 at the end.

Continued on Page 4 of 6

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