All dosages may be repeated every 4 hours, but not more than 5 times daily. Administer to children under 2 years only on the advice of a physician.
Children's acetaminophen Chewable Tablets (80mg): 2-3 years: two tablets. 4-5 years: three tablets. 6-8 years: four tablets. 9-10 years: five tablets. 11-12 years: six tablets
Children's Acetaminophen Elixir and Suspension Liquid (160mg/5ml): (special cup for measuring dosage is provided) 4-11 months: one-half teaspoon. 12-23 months: three-quarters teaspoon. 2-3 years: one teaspoon. 4-5 years: one and one-half teaspoons. 6-8 years: 2 teaspoons. 9-10 years: two and one-half teaspoons. 11-12 years: three teaspoons.
Oral Erythromycin and the Risk of Sudden Death from Cardiac Causes
Wayne A. Ray, Ph.D., Katherine T. Murray, M.D., Sarah Meredith, M.B., B.S., Sukumar Suguna Narasimhulu, M.B., B.S., M.P.H., Kathi Hall, M.S., and C. Michael Stein, M.B., Ch.B.
Background Oral erythromycin prolongs cardiac repolarization and is associated with case reports of torsades de pointes. Because erythromycin is extensively metabolized by cytochrome P-450 3A (CYP3A) isozymes, commonly used medications that inhibit the effects of CYP3A may increase plasma erythromycin concentrations, thereby increasing the risk of ventricular arrhythmias and sudden death. We studied the association between the use of erythromycin and the risk of sudden death from cardiac causes and whether this risk was increased with the concurrent use of strong inhibitors of CYP3A.
Methods We studied a previously identified Tennessee Medicaid cohort that included 1,249,943 person-years of follow-up and 1476 cases of confirmed sudden death from cardiac causes. The CYP3A inhibitors used in the study were nitroimidazole antifungal agents, diltiazem, verapamil, and troleandomycin; each doubles, at least, the area under the time–concentration curve for a CYP3A substrate. Amoxicillin, an antimicrobial agent with similar indications but which does not prolong cardiac repolarization, and former use of erythromycin also were studied, to assess possible confounding by indication.
Results The multivariate adjusted rate of sudden death from cardiac causes among patients currently using erythromycin was twice as high (incidence-rate ratio, 2.01; 95 percent confidence interval, 1.08 to 3.75; P=0.03) as that among those who had not used any of the study antibiotic medications. There was no significant increase in the risk of sudden death among former users of erythromycin (incidence-rate ratio, 0.89; 95 percent confidence interval, 0.72 to 1.09; P=0.26) or among those who were currently using amoxicillin (incidence-rate ratio, 1.18; 95 percent confidence interval, 0.59 to 2.36; P=0.65). The adjusted rate of sudden death from cardiac causes was five times as high (incidence-rate ratio, 5.35; 95 percent confidence interval, 1.72 to 16.64; P=0.004) among those who concurrently used CYP3A inhibitors and erythromycin as that among those who had used neither CYP3A inhibitors nor any of the study antibiotic medications. In contrast, there was no increase in the risk of sudden death among those who concurrently used amoxicillin and CYP3A inhibitors or those currently using any of the study antibiotic medications who had formerly used CYP3A inhibitors.
Conclusions The concurrent use of erythromycin and strong inhibitors of CYP3A should be avoided.
Erythromycin is a commonly used macrolide antimicrobial agent with a long history of use, and it is considered largely free of serious toxicity. However, there have been case reports of torsades de pointes in patients receiving both oral and intravenous erythromycin.1,2,3,4 An increase in the risk of torsades de pointes is consistent with the effects of erythromycin on cardiac electrophysiology; studies have shown prolongation of the QT interval5,6 and blockade of the potassium channel encoded by the human ether-a-go-go–related gene (HERG).7
There are important clinical questions that these case reports have not addressed. Although there is an association between erythromycin and serious ventricular tachyarrhythmias, the magnitude of the risk of ventricular tachyarrhythmia has not been quantified in population-based studies. Studies of the association of erythromycin and arrhythmia have focused on the intravenous use of the drug,1,6 perhaps because this use is involved in the majority of the reported cases1,3 and because the rapid rise to peak concentrations may increase the risk of arrhythmia. However, in clinical practice, this drug is usually administered orally, and the perception that oral use is not associated with arrhythmias is unsupported by data. Pharmacokinetic drug–drug interactions also may increase the risk of sudden death from cardiac causes among patients using erythromycin. Erythromycin is extensively metabolized by cytochrome P-450 3A (CYP3A) isozymes.8 Many other commonly used medications inhibit the metabolism of drugs that is mediated by CYP3A, including nitroimidazole antifungal agents, certain calcium-channel blockers, and some antidepressant drugs. Although there have been reports of prolonged QT intervals9 and torsades de pointes4 among patients who were concurrently receiving oral erythromycin and CYP3A inhibitors, the clinical importance of this possible drug–drug interaction remains unclear.
In our population-based study, we sought to quantify the association between oral erythromycin and the risk of sudden death from cardiac causes, usually as the result of ventricular tachyarrhythmia. The primary questions posed in the study were whether the risk of sudden death was increased among those using oral erythromycin and whether this risk was altered by the concurrent use of erythromycin and potent inhibitors of CYP3A. To assess possible confounding by the indications for antimicrobial use, we also studied patients who were currently using amoxicillin, an antibiotic drug that is used in clinical circumstances similar to those in which erythromycin is used.
Case reports have long suggested that erythromycin is associated with an increase in the risk of torsades de pointes. Two reviews of data from the Adverse Drug Event reporting system of the Food and Drug Administration identified 346 reports of cardiac arrhythmias2 and 82 reports consistent with torsades de pointes3 in which erythromycin was mentioned. The present controlled study provides confirmatory evidence: the rate of sudden death from cardiac causes was twice as high among patients who were current users of oral erythromycin as among those who had not used any of the study antibiotic drugs. In contrast, those who had formerly used erythromycin or were currently using amoxicillin had no significant increase in risk. A key finding was that the risk was greatest among those concomitantly using erythromycin and the study drugs that were likely to inhibit its metabolism. Among such patients, the risk of sudden death from cardiac causes was five times as high as that among those who were not using any of the study antibiotic drugs or CYP3A inhibitors. These findings were not affected by the concurrent use of other drugs known to increase the risk of ventricular arrhythmias the metabolism of which is inhibited by erythromycin or by use of other potentially arrhythmogenic drugs.
There were several limitations to the study. Although the cohort included both a large number of subjects who had used the study antibiotic drugs and a large number of sudden deaths from cardiac causes, there were only 194 person-years of follow-up for the concurrent use of erythromycin and the study CYP3A inhibitors, with three sudden deaths from cardiac causes. Nevertheless, given the low incidence of sudden death from cardiac causes among members of the study cohort (1.2 per 1000 person-years of follow-up), this finding was significant (P=0.004) and, thus, unlikely to be due to chance. Indeed, in a similar group of patients (who were concurrently using amoxicillin and CYP3A inhibitors or were currently using amoxicillin or erythromycin and had formerly used CYP3A inhibitors), with a total of 778 person-years of follow-up, there were no sudden deaths from cardiac causes.
The study data did not include information on a variety of behavioral risk factors that are associated with cardiovascular disease, including smoking, higher body-mass index, high consumption of saturated fats, and lack of physical activity. We addressed this potential confounding in several ways. First, adverse effects of these risk factors are likely to be mediated to a large extent by other variables, such as the presence of hyperlipidemia, hypertension, diabetes mellitus, and preexisting cardiovascular disease, such as heart failure, angina, and myocardial infarction. If such conditions were diagnosed and treated, they were controlled for in the statistical analysis. Second, the study included several control groups that, with regard to unmeasured confounders, should be very similar to the group that used erythromycin and the group that used the study CYP3A inhibitors. These control groups included concurrent users of amoxicillin and the CYP3A inhibitors, current users of erythromycin and former, not current, users of CYP3A inhibitors, and current users of erythromycin and calcium-channel blockers that do not affect CYP3A metabolism. None of these groups had an increase in the risk of sudden death from cardiac causes.
Drugs that have the potential to interact with erythromycin were restricted to the inhibitors of CYP3A for which a prospective study showed a doubling or more of the AUC of a recognized CYP3A substrate. Thus, cimetidine26 and several other less potent CYP3A inhibitors were not included in the study. We reasoned that the increase in the risk of sudden death from cardiac causes would be mediated by the increase in plasma erythromycin concentrations. Hence, drug interactions that result in small increases in erythromycin concentrations would be less likely to cause adverse clinical outcomes and thus more difficult to detect. Because erythromycin is an old drug, there are a limited number of studies on potential CYP-mediated drug–drug interactions. We thus inferred an effect of the study CYP3A inhibitors on erythromycin from their effects on other well-recognized CYP3A substrates. This inference is reasonable, since the mechanism of the interaction is understood and its effects are predictable.
The study provided no direct data with regard to the mechanisms by which the concomitant use of erythromycin and the study CYP3A inhibitors increased the risk of sudden death from cardiac causes. We believe that the most probable explanation is that the concurrent use resulted in an increase in the plasma erythromycin concentrations, thereby increasing the risk of QT prolongation (a known, dose-associated effect of erythromycin6) and thus of serious ventricular arrhythmias. However, other factors may be involved. Two calcium-channel blockers, verapamil and diltiazem, accounted for nearly all the use of CYP3A inhibitors in the study. Both drugs are CYP3A substrates, and erythromycin, a CYP3A inhibitor, is likely to increase their plasma concentrations. Furthermore, erythromycin and verapamil are also substrates and inhibitors of P-glycoprotein, a drug-efflux pump, and each could therefore alter the other's concentration. Well-recognized consequences of an overdose of a calcium-channel blocker are bradycardia, hypotension, and heart block, which can provoke sudden death from cardiac causes.45
The cohort had limited use of clarithromycin and several other drugs that prolong the QT interval and are metabolized by CYP3A.36,37,38,39,40 Although the absence of such drugs from the study did not confound the association between erythromycin and the risk of sudden death from cardiac causes, the sample size was insufficient to study the independent association of these drugs with an increase in risk. Further investigations are needed.
In conclusion, patients who used both erythromycin and the study CYP3A inhibitors had a risk of sudden death from cardiac causes that was five times as great as that among patients who had not used these drugs. Given that there are alternatives to erythromycin and to most CYP3A inhibitors, the use of this combination should be avoided in clinical practice.Source Information
From the Division of Pharmacoepidemiology, Department of Preventive Medicine (W.A.R., S.M., K.H.), and the Departments of Medicine and Pharmacology, Divisions of Cardiology (K.T.M.), Clinical Pharmacology (K.T.M., S.S.N., C.M.S.), and Rheumatology (C.M.S.), Vanderbilt University School of Medicine; and the Geriatric Research, Education, and Clinical Center, Nashville Veterans Affairs Medical Center (W.A.R.) — both in Nashville.
Address reprint requests to Dr. Ray at email@example.com.
DRUG INTERACTIONS WITH GRAPEFRUIT JUICE
The ability of grapefruit juice to increase serum concentrations of drugs was first discovered
during a study of the effect of ethanol on felodipine (Plendil) pharmacokinetics. Double-strength
grapefruit juice used to disguise the taste of ethanol resulted in higher than expected serum concentrations
of felodipine (DG Bailey et al, Clin Invest Med 1989; 12:357).
MECHANISMS ? Grapefruit juice inhibits the activity of the cytochrome P450 isozyme
CYP3A4, which is involved in the metabolism of about half of all drugs currently prescribed (Medical
Letter 2003; 45:46). The results of several studies suggest that it affects intestinal but not hepatic
CYP3A4; repeated dosing (three times a day) of large amounts (200-240 mL, double-strength) over
several days can inhibit hepatic CYP3A4 as well (JJ Lilja et al, Eur J Clin Pharmacol 2000; 56:411;
ML Veronese et al, J Clin Pharmacol 2003; 43:831). Drugs that undergo extensive first-pass metabolism
in the gut wall, such as lovastatin ( Mevacor, and others), may be particularly affected.
Grapefruit juice contains the furanocoumarins bergamottin and 6?7?-dihydroxybergamottin, both of
which inhibit CYP3A4, but it is likely that other substances are also involved (DJ Bailey, Clin
Pharmacol Ther 2003; 73:529). Grapefruit juice probably has little effect on the drug efflux transporter
P-glycoprotein, required for the elimination of many drugs, but does appear to inhibit organic
anion transporting polypeptide (OATP), which aids absorption of certain drugs (RB Parker et al,
Pharmacotherapy 2003; 23:979; L Becquemont et al, Clin Pharmacol Ther 2001; 70:311; GK Dresser
et al, Clin Pharmacol Ther 2002; 71:11).
TIME COURSE ? Because grapefruit juice is at least partly an irreversible (mechanismbased)
inhibitor of CYP3A4, the activity of the enzyme does not immediately return to normal after
the juice has moved through the intestine. Interactions with drugs, therefore, cannot be fully avoided
by taking them at a different time. The recovery half-life for CYP3A4 activity after a single glass of
grapefruit juice appears to be about one day, and after 3 days little inhibitory effect remains (DJ
Greenblatt et al, Clin Pharmacol Ther 2003; 74:121; J Lundahl et al, Eur J Clin Pharmacol 1995; 49:61).
AMOUNT AND TYPE OF GRAPEFRUIT JUICE ?The amount of grapefruit ingested substantially
affects the magnitude of drug interactions. One glass a day for 3 days doubled serum concentrations
of lovastatin; three glasses a day of double-strength grapefruit juice for 3 days resulted
in 15-fold increases in serum concentrations of lovastatin and simvastatin (Zocor)(JD Rogers et al,
Clin Pharmacol Ther 1999; 66:358; JJ Lilja et al, Clin Pharmacol Ther 1998; 64:477, 655; T Kantola et
al, Clin Pharmacol Ther 1998; 63:397). Package inserts for some CYP3A4-metabolized drugs, simvastatin
for example, state that the patient can drink up to one quart of grapefruit juice per day without
an effect, but marked inhibition of enteric CYP3A4 is known to occur with such amounts.
Drug Effect Comments
The capacity to inhibit CYP3A4 may vary depending on whether the grapefruit is white or pink, where
and when it was harvested, and whether it is consumed in the form of a whole grapefruit or as fresh
or frozen juice. Variations in the concentrations of the presumed-3A4-inhibiting furanocoumarins
have been detected even in different lots of the same brand of grapefruit juice (P Schmiedlin-Ren et
al, Drug Metab Dispos 1997; 25:1228). Although most grapefruit drug interaction studies used reconstituted
frozen juice, fresh grapefruit also contains CYP3A4 inhibitors (DG Bailey et al, Clin
Pharmacol Ther 2000; 68:468).
OTHER CITRUS JUICES ? Seville (sour) oranges, like grapefruit, contain bergamottin and
6?7?-dihydroxybergamottin, and can interact with drugs metabolized by CYP3A4 (S Malhotra et al,
Clin Pharmacol Ther 2001; 69:14). Pomelos are a form of grapefruit native to India and some other
Asian countries, and they may also inhibit CYP3A4 (K Egashira et al, Transplantation 2003; 75:1057).
Sweet oranges (used to make orange juice) and tangerines do not inhibit CYP3A4 (DG Bailey et al,
Lancet 1991; 337:268; JT Backman et al, Clin Pharmacol Ther 2000; 67:382). Lime juice was reported
to increase felodipine serum concentrations in some people, but the amount used (250 mL quarterstrength)
was unusually large (DG Bailey et al, Clin Pharmacol Ther 2003; 73:529). Whether lemon
juice interacts with drugs is unknown.
CONCLUSION ? Grapefruit is a well-documented inhibitor of intestinal CYP3A4 and interacts
with many drugs. Ingestion of grapefruit juice at a different time from the drug does not fully
circumvent the interaction. Since hepatic CYP3A4 generally is not affected, the magnitude of drug
interactions involving grapefruit juice tends to be less than that observed with drug inhibitors of
CYP3A4. Nevertheless, for drugs requiring careful control of serum concentrations, such as amiodarone
( Cordarone, and others), carbamazepine ( Tegretol, and others), cyclosporine ( Sandimmune,
and others), sirolimus (Rapamune)or tacrolimus (Prograf), it would be prudent to advise patients to
avoid grapefruit juice, grapefruit, pomelos and Seville oranges. For most CYP3A4-metabolized
drugs, limiting daily intake to one 8-oz glass of juice or one half of a fresh grapefruit would probably
avoid any adverse drug interactions.
SOME DRUGS AFFECTED BY GRAPEFRUIT JUICE*
Albendazole (Albenza) Possible increased effect
Amiodarone (Cordarone**) Possible toxicity AVOID concurrent use
Benzodiazepines Increased effect with triazolam, oral midazolam;
theoretically alprazolam, diazepam also AVOID concurrent use
Budesonide (Entocort EC) Possible toxicity Systemic exposure doubled
Buspirone (BuSpar) Possible toxicity AVOID concurrent use
Carbamazepine ( Tegretol**) Possible toxicity Monitor concentrations
Cyclosporine ( Sandimmune, Neoral**) Possible toxicity Monitor concentrations
Dextromethorphan Increased risk of toxicity Modest effect
Diltiazem (Cardizem**) Possible toxicity Modest effect
Erythromycin Possible increased toxicity Modest effect
Estrogens Increased ethinyl estradiol and 17?-estradiol effect
Etoposide (VePesid**) Possible decreased effect AVOID concurrent use
Felodipine (Plendil) Possible toxicity Larger effect with multiple doses;
amlodipine is minimally affected
Fexofenadine (Allegra) Possible decreased effect Large amount; apple and orange juice had similar effect
Fluoxetine (Prozac**) Possible serotonin syndrome Single case report; patient also
taking trazodone which could have contributed
Fluvoxamine Possible increased toxicity Based on study in healthy subjects HMG-CoA reductase inhibitors
Possible increased lovastatin, simvastatin or (less likely) atorvastatin toxicity Effect may last = 24 hrs; unlikely with pravastatin, fluvastatin and rosuvastatin
Indinavir (Crixivan) Possible decreased effect Conflicting results; clinical importance not established
Itraconazole (Sporanox) Possible decreased effect AVOID concurrent use
Lovastatin (Mevacor**) See HMG-CoA reductase inhibitors
Methylprednisolone (Medrol**) Possible increased effects Large amounts
Nicardipine (Cardene**) Possible increased toxicity Little change in hemodynamic effect
Nifedipine (Procardia**) Increased risk of toxicity AVOID concurrent use
Nimodipine (Nimotop) Possible toxicity AVOID concurrent use
Nisoldipine (Sular) Possible increased toxicity AVOID concurrent use
Praziquantel (Biltricide) Possible toxicity Based on study in healthy subjects
This month's Psychopharmacology Today column will be our second guest column. It is a piece that has been available on the Web for about a year but was brought to my attention recently. It answers a question that I have asked and been asked multiple times. Before I found this, no one had ever given me a straight answer about what the expiration dates on medications mean and how seriously they should be taken. This is an important issue, and I think that psychopharmacologists, if not all practitioners and patients, will find this column immensely helpful. It is well researched, well written, and I wish that I had written it myself.
September 9, 2002
DO MEDICATIONS REALLY EXPIRE?
Try An Experiment With Your Mother-In-Law
By Richard Altschuler
Does the expiration date on a bottle of a medication mean anything? If a bottle of Tylenol, for example, says something like "Do not use after June 1998," and it is August 2002, should you take the Tylenol? Should you discard it? Can you get hurt if you take it? Will it simply have lost its potency and do you no good?
In other words, are drug manufacturers being honest with us when they put an expiration date on their medications, or is the practice of dating just another drug industry scam, to get us to buy new medications when the old ones that purportedly have "expired" are still perfectly good?
These are the pressing questions I investigated after my mother-in-law recently said to me, "It doesn't mean anything," when I pointed out that the Tylenol she was about to take had "expired" 4 years and a few months ago. I was a bit mocking in my pronouncement -- feeling superior that I had noticed the chemical corpse in her cabinet -- but she was equally adamant in her reply, and is generally very sage about medical issues.
So I gave her a glass of water with the purportedly "dead" drug, of which she took 2 capsules for a pain in the upper back. About a half hour later she reported the pain seemed to have eased up a bit. I said "You could be having a placebo effect," not wanting to simply concede she was right about the drug, and also not actually knowing what I was talking about. I was just happy to hear that her pain had eased, even before we had our evening cocktails and hot tub dip (we were in "Leisure World," near Laguna Beach, California, where the hot tub is bigger than most Manhattan apartments, and "Heaven," as generally portrayed, would be raucous by comparison).
Upon my return to NYC and high-speed connection, I immediately scoured the medical databases and general literature for the answer to my question about drug expiration labeling. And voila, no sooner than I could say "Screwed again by the pharmaceutical industry," I had my answer. Here are the simple facts:
First, the expiration date, required by law in the United States, beginning in 1979, specifies only the date the manufacturer guarantees the full potency and safety of the drug -- it does not mean how long the drug is actually "good" or safe to use. Second, medical authorities uniformly say it is safe to take drugs past their expiration date -- no matter how "expired" the drugs purportedly are. Except for possibly the rarest of exceptions, you won't get hurt and you certainly won't get killed. A contested example of a rare exception is a case of renal tubular damage purportedly caused by expired tetracycline (reported by G. W. Frimpter and colleagues in JAMA, 1963;184:111). This outcome (disputed by other scientists) was supposedly caused by a chemical transformation of the active ingredient. Third, studies show that expired drugs may lose some of their potency over time, from as little as 5% or less to 50% or more (though usually much less than the latter). Even 10 years after the "expiration date," most drugs have a good deal of their original potency. So wisdom dictates that if your life does depend on an expired drug, and you must have 100% or so of its original strength, you should probably toss it and get a refill, in accordance with the cliché, "better safe than sorry." If your life does not depend on an expired drug -- such as that for headache, hay fever, or menstrual cramps -- take it and see what happens.
One of the largest studies ever conducted that supports the above points about "expired drug" labeling was done by the US military 15 years ago, according to a feature story in the Wall Street Journal (March 29, 2000), reported by Laurie P. Cohen. The military was sitting on a $1 billion stockpile of drugs and facing the daunting process of destroying and replacing its supply every 2 to 3 years, so it began a testing program to see if it could extend the life of its inventory. The testing, conducted by the US Food and Drug Administration (FDA), ultimately covered more than 100 drugs, prescription and over-the-counter. The results showed that about 90% of them were safe and effective as far as 15 years past their original expiration date.
In light of these results, a former director of the testing program, Francis Flaherty, said he concluded that expiration dates put on by manufacturers typically have no bearing on whether a drug is usable for longer. Mr. Flaherty noted that a drug maker is required to prove only that a drug is still good on whatever expiration date the company chooses to set. The expiration date doesn't mean, or even suggest, that the drug will stop being effective after that, nor that it will become harmful. "Manufacturers put expiration dates on for marketing, rather than scientific, reasons," said Mr. Flaherty, a pharmacist at the FDA until his retirement in 1999. "It's not profitable for them to have products on a shelf for 10 years. They want turnover."
The FDA cautioned there isn't enough evidence from the program, which is weighted toward drugs used during combat, to conclude most drugs in consumers' medicine cabinets are potent beyond the expiration date. Joel Davis, however, a former FDA expiration-date compliance chief, said that with a handful of exceptions -- notably nitroglycerin, insulin, and some liquid antibiotics -- most drugs are probably as durable as those the agency has tested for the military. "Most drugs degrade very slowly," he said. "In all likelihood, you can take a product you have at home and keep it for many years, especially if it's in the refrigerator." Consider aspirin. Bayer AG puts 2-year or 3-year dates on aspirin and says that it should be discarded after that. However, Chris Allen, a vice president at the Bayer unit that makes aspirin, said the dating is "pretty conservative"; when Bayer has tested 4-year-old aspirin, it remained 100% effective, he said. So why doesn't Bayer set a 4-year expiration date? Because the company often changes packaging, and it undertakes "continuous improvement programs," Mr. Allen said. Each change triggers a need for more expiration-date testing, and testing each time for a 4-year life would be impractical. Bayer has never tested aspirin beyond 4 years, Mr. Allen said. But Jens Carstensen has. Dr. Carstensen, professor emeritus at the University of Wisconsin's pharmacy school, who wrote what is considered the main text on drug stability, said, "I did a study of different aspirins, and after 5 years, Bayer was still excellent. Aspirin, if made correctly, is very stable.
Okay, I concede. My mother-in-law was right, once again. And I was wrong, once again, and with a wiseacre attitude to boot. Sorry mom. Now I think I'll take a swig of the 10-year dead package of Alka Seltzer in my medicine chest -- to ease the nausea I'm feeling from calculating how many billions of dollars the pharmaceutical industry bilks out of unknowing consumers every year who discard perfectly good drugs and buy new ones because they trust the industry's "expiration date labeling."
Reprinted with permission of Redflagsdaily
Beta-Blockers Alone or in Combination With Thiazide Diuretics Reduce Risk of Fractures
Sept. 14, 2004 — Beta-blocker therapy is associated with a significantly reduced risk of fractures when prescribed alone or in combination with thiazide diuretics, according to the results of a large, retrospective, population-based study published in the Sept. 15 issue of JAMA.
"Animal studies suggest that the ?-blocker propanolol increases bone formation, but data on whether use of ?-blockers (with or without concomitant use of thiazide diuretics) is associated with reduced fracture risk in humans are limited," writes Raymond G. Schlienger, PhD, MPH, from the University Hospital Basel in Switzerland, and colleagues, noting that thiazide diuretics are thought to protect against bone loss by reducing urinary calcium excretion.
Using the U.K. General Practice Research Database (GPRD), investigators identified the records of 30,601 patients aged 30 to 79 years with an incident fracture diagnosis between 1993 and 1999. Control subjects (n = 120,819) had not sustained a fracture and matched the case patients with respect to age, sex, calendar time, and general practice attended.
Current users of beta-blockers, thiazides, or thiazide-like diuretics were defined as those having received a prescription within 60 days prior to the date of fracture. Long-term users were defined as those having received at least 20 prescriptions, each representing one to three months of therapy.
Fractures of the hand/lower arm (42.0%) and foot (15.1%) were most common. Data analysis correlating fracture incidence with drug therapy included adjustments for smoking, body mass index, number of practice visits, and use of calcium channel blockers, angiotensin-converting enzyme inhibitors, antipsychotics, antidepressants, statins, antiepileptics, benzodiazepines, corticosteroids, and estrogens.
Results showed that current beta-blocker users had a significantly reduced risk of fracture (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.72 - 0.83), as did current users of thiazides (OR, 0.80; 95% CI, 0.74 - 0.86) compared with nonusers of beta-blockers or thiazides. Current users of both beta-blockers and thiazides had the lowest relative risk of fracture (OR, 0.71; 95% CI, 0.64 - 0.79) compared with nonusers.
Long-term use of beta-blockers had a stronger protective effect against fractures in men (OR, 0.69) than in women (OR, 0.92) after adjustments for number of practice visits (indicative of health status), medical attention, and number of drugs used. "[T]he differences in drug use between men and women may not explain the differences in effect size with longer-term ?-blocker use," the authors comment. "This difference should be explored in future studies.
"[T]he present large case-control analysis provides evidence that use of ?-blockers — alone or in combination with thiazide diuretics — is associated with a significantly decreased fracture risk," the authors write, noting that additional observational studies and controlled trials are needed to confirm these findings.
"Many elderly patients with hypertension who are at risk of developing osteoporosis may potentially benefit from combined therapy with [relatively inexpensive] ?-blockers and thiazides," the authors conclude.
One of the authors is the recipient of a grant from the Swiss National Science Foundation.
Reviewed by Gary D. Vogin, MD
Expired Medications May Maintain Potency for Decades
Ricki Lewis, PhD
Oct 08, 2012
October 8, 2012 — An analysis of 8 medications indicates that most of the active ingredients they contain were present in adequate amounts decades after the drugs' expiration dates, according to results from a study published online October 8 in the Archives of Internal Medicine.
Lee Cantrell, PharmD, from the California Poison Control System, San Diego Division, University of California San Francisco School of Pharmacy, and colleagues used liquid chromatography/mass spectrometry to measure the amounts of the active ingredients in the medications. The medicines, which had expired 28 to 40 years ago, were found in a retail pharmacy in their original, unopened packaging.
To meet US Food and Drug Administration (FDA) standards, an active ingredient must be present in 90% to 110% of the amount indicated on the label. Drug expiration dates are set for 12 to 60 months after production, even though many compounds can persist far longer.
In the new analysis, 12 of the 14 active ingredients persisted in concentrations that were 90% or greater of the amount indicated on the label. These 12 compounds retained their full potency for 336 months or longer. Eight of them retained potency for at least 480 months. Dr. Cantrell’s team was unable to find a standard for homatropine, 1 of the 15 ingredients.
Only aspirin and amphetamine fell below the 90% cutoff. Phenacetin was present at greater than the cutoff in Fiorinal (butalbital, aspirin, caffeine, and codeine phosphate, but was considerably less in Codempiral No. 3. The authors attribute the deficit in Codempiral to conditions that led to preferential degradation of phenacetin because of its amide group, compared with codeine, which is also in Codempiral but is more chemically stable.
Three compounds persisted in greater than 110% of the labeled contents: methaqualone (in Somnafac), meprobamate (in Bamadex), and pentobarbital (in Nebralin). These relatively high amounts may reflect degradation of other components of the compounded drug, the fact that the samples were produced before FDA-instituted quality control measures in 1963, or inconsistencies of the analytical techniques between when the drugs were compounded and now.
The new findings are consistent with the efforts of the Shelf-Life Extension Program, which has extended the expiration dates on 88% of 122 drugs tested so far. Extensions range from 66 to 278 months.
"[O]ur results support the effectiveness of broadly extending expiration dates for many drugs," the researchers conclude. They also point out that extending shelf life can significantly lower costs to consumers.
Limitations of the analysis, the investigators write, include an inability to confirm the storage conditions of the drug samples, as well as imprecise dating of the samples.
The authors have disclosed no relevant financial relationships.
Arch Intern Med. Published online October 8, 2012. Abstract