MEDICATION INFORMATION
USUAL TYLENOL DOSAGE IN children
ALWAYS CHECK WITH THE DOCTOR FIRST
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.
Infants' Acetaminophen Drops and Suspension Drops (80mg/0.8ml): 0-3 months: 0.4 ml. 4-11 months: 0.8 ml. 12-23 months: 1.2 ml. 2-3 years: 1.6 ml. 4-5 years: 2.4ml.
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.
ABSTRACT
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.
Discussion
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 cindy.naron@vanderbilt.edu.
FDA Study Finds Vioxx Increases Heart Attack Risk
By Ransdell Pierson
NEW YORK (Reuters) - Patients taking Merck & Co. Inc.'s Vioxx arthritis drug had a 50 percent greater chance of heart attacks and sudden cardiac death than individuals using Pfizer Inc.'s rival Celebrex medicine, according to a large study financed by the U.S. Food and Drug Administration (news - web sites).
The study, presented at an epidemiologists conference on Wednesday, also found patients taking the highest recommended daily dosage of Vioxx had three times the risk of heart attack and sudden cardiac death as those not taking standard painkillers.
Sudden cardiac death, a sudden electrical disturbance of the heart that is not considered a heart attack, is the biggest cause of death in the United States.
Researchers came up with the potentially damaging findings on Vioxx, a $2.5-billion-a-year blockbuster medicine, after analyzing the medical records of 1.4 million people insured by Kaiser Permanente, the Oakland, California-based health maintenance organization.
Graham said another major finding was that patients taking the typical starting dose of Vioxx had a 50 percent greater chance of heart attack and sudden cardiac death than patients taking any dose of Celebrex.
"Based upon the evidence in this study, I don't think doctors should prescribe high-dosage Vioxx, and patients shouldn't take it," Dr. David Graham, lead investigator for the trial, said in an interview.
Most patients take daily Vioxx doses of 12.5 milligrams and 25 milligrams for arthritis. But a higher dose of 50 milligrams is approved by the FDA (news - web sites) for treatment of pain for no longer than five days.
"The problem is that some patients continue to take it for 30, 60, or 90 days," Graham said, putting themselves at elevated risk of heart attack and sudden cardiac death, Graham said.
Graham, senior scientist for the FDA's Office of Drug Safety, said his own interpretations of the data did not necessarily reflect the views of the FDA.
He presented results of the study on Wednesday at an international meeting of epidemiologists being held in Bordeaux, France.
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
Quinidine Possible toxicity Modest effect
Saquinavir (Invirase; Fortovase) Increase in bioavailability Modest effect, clinical significance unknown
Sertraline (Zoloft) Possible toxicity Clinical importance unclear
Sildenafil (Viagra) Possible sildenafil toxicity; vardenafil (Levitra) and tadalafil (Cialis)may also interact AVOID concurrent use
Simvastatin (Zocor) See HMG-CoA reductase inhibitors
Sirolimus (Rapamune) Possible toxicity AVOID concurrent use
Tacrolimus (Prograf) Possible toxicity Case report of dramatic increase in concentration after patient ate one pomelo; avoid concurrent use
Theophylline Possible decreased effect Modest effect
Verapamil (Calan**) Possible increased toxicity Modest increase in verapamil serum concentrations
Warfarin (Coumadin**) Possible increased anticoagulant effect Single case report (1999); no effect seen in previous report of 10 patients on warfarin
Do Medications Really Expire?
Thomas A. M. Kramer, MD
Medscape General Medicine 5(3), 2003. © 2003 Medscape
Posted 08/21/2003
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
2003
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Group Urges Ban of Antidepressant Serzone
Thu Mar 6, 4:11 PM ET Add Health - AP to My Yahoo!
WASHINGTON - The anti-depressant Serzone, recently pulled off the market in Europe, should be banned here, a consumer advocacy group told the government Thursday — citing 11 deaths from drug-caused liver failure.
Serzone "appears to be one of the most dangerous antidepressants marketed," Dr. Sidney Wolfe of Public Citizen wrote in a petition filed with the Food and Drug Administration (news - web sites).
It's impossible to predict which patient will get Serzone-caused liver failure, "nor is there any way to guarantee that once diagnosed, patients' lives can be saved," he said.
Public Citizen counted 53 cases of liver injury, including the 11 deaths, among Serzone users reported to an FDA monitoring system since the drug began selling in 1994. The FDA estimates its monitoring system counts fewer than 10 percent of the side effects caused by medications.
Antidepressants cause a variety of side effects, but Wolfe contends there are numerous equally effective but safer alternatives to Serzone.
The FDA will seriously consider the petition, said spokeswoman Susan Cruzan.
Cases of liver failure among Serzone users are very rare and "we don't know why they're happening," said Rob Hutchinson, a spokesman for manufacturer Bristol-Myers Squibb Co. But he said rates of liver problems have not changed over the years, suggesting no need for renewed concern.
Bristol-Myers quit selling Serzone in Europe in January, saying it made the decision because of low European sales, not safety questions. But some foreign regulators cited concern about fatal liver failure at the time, and Wolfe told the FDA that several had been pursuing stronger safety measures.
Wolfe said Serzone inhibits an enzyme key to drug metabolism, allowing the anti-depressant to build to toxic levels in the liver. That enzyme also metabolizes numerous other drugs, meaning patients taking multiple medications could be at higher risk, he said.
In 2001, the FDA added its strongest warning possible to Serzone's label, bold print inside a black box stating that one side effect is potentially fatal liver failure. FDA's Cruzan would not say if reports of liver damage have dropped since the stricter warning appeared.
Britain Warns Kids, Teens on Drug Paxil
1 hour, 25 minutes ago Add Health - AP to My Yahoo!
By EMMA ROSS, AP Medical Writer
LONDON - Children and adolescents should not be given the anti-depressant Paxil, British health regulators said Tuesday after new research indicated that the risk of suicidal thoughts and self harm is higher in youngsters taking the drug.
The drug, which is called Seroxat outside the United States and is made by British-based GlaxoSmithKline, is not licensed for use in children and teenagers anywhere in the world. However, some doctors give it to treat depression, based on their own judgment.
The new research, provided to Britain's Medicines and Healthcare products Regulatory Agency by GlaxoSmithKline, does not apply to adults, the regulators said.
Britain's Department of Health said the evidence provided by the drug company, from nine studies based on more than 1,000 youngsters, shows there is an increase in the rate of self harm and potentially suicidal behavior in those under 18 taking Paxil.
GlaxoSmithKline spokesman David Mawdsley said the rate of a collection of emotional side-effects, ranging from mood swings and increased crying, to suicidal thoughts and self-harm, was twice as high in the Paxil group as in those taking a fake pill. A total of 3.2 percent of patients on Paxil had the emotional side-effects, compared with 1.5 percent of those taking the dummy pill.
"It has become clear that the benefits of Seroxat in children for the treatment of depressive illness do not outweigh these risks," the government said in a statement. "Young people under 18 years currently taking Seroxat for depression should consult their doctor."
Alasdair Breckenridge, chairman of the regulatory agency, said the benefits for adults of taking Seroxat for depression were well known.
"It is important that patients who are benefiting from Seroxat should not be alarmed by the announcement and should continue their treatment," he said.
An expert advisory panel was set up last month to look into the effects of Paxil and other medications in its class, known as selective serotonin reuptake inhibitors, or SSRIs.
"The expert group will be examining urgently what implications, if any, these new findings have for the use of Seroxat in adults," said the panel's chairman, Ian Weller. "At present the evidence is not sufficient to confirm a causal association between SSRIs and suicidal behavior in adults."
It is estimated that almost 17 million people worldwide have been treated with Paxil.
Beta-Blockers Alone or in Combination With Thiazide Diuretics Reduce Risk of Fractures
Yael Waknine Medscape Medical News 2004. © 2004 Medscape
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.
JAMA. 2004;292:1326-1332
Reviewed by Gary D. Vogin, MD
Pfizer says Bextra, heart problems linked
Last Updated: 2004-10-15 14:49:21 -0400 (Reuters Health)
By Toni Clarke
NEW YORK (Reuters) - Pfizer Inc. on Friday said two small clinical trials showed heart bypass surgery patients taking Bextra, an anti-inflammatory in the same class as the recently withdrawn drug Vioxx, had a higher risk of stroke and heart attack.
The company also updated its warning that Bextra can cause a rare, but sometimes fatal, skin disorder called Stevens-Johnson syndrome to note that cases of the condition are being seen more often with Bextra than with other drugs in the same class.
Pfizer's shares fell nearly 4 percent on the New York Stock Exchange.
Bextra is approved to treat pain from arthritis and, like Merck & Co.'s Vioxx, is a COX-2 inhibitor. A recent trial showed Vioxx doubled the risk of heart attack and stroke in arthritis patients who took the drug for more than 18 months.
The Vioxx withdrawal has cast a cloud over the entire class of COX-2 inhibitors, which includes Bextra, Celebrex and an experimental drug from Novartis AG called Prexige.
However, Pfizer said that following the Vioxx withdrawal it re-examined its clinical data base of 8,000 patients with rheumatoid arthritis and osteoarthritis and found no increased risk of dangerous heart events in patients taking Bextra for up to a year. The company also found no increased risk in a trial of patients taking Bextra in a general surgery setting.
Doctors said it is too early to quantify the potential risk of Bextra or of Pfizer's other COX-2 inhibitor Celebrex as neither have tested for long enough. Pfizer said it is conducting longer term trials in arthritis patients.
The coronary bypass trials are ones that Dr. Eric Topol of the Cleveland Clinic Foundation and an early and outspoken critic of Vioxx, said he finds concerning as they show a cluster of heart attacks and strokes. But he said the danger signal does not appear to be as strong as it was with Vioxx.
"Celebrex and Bextra do appear safer than Vioxx but whether they are really safe, especially in patients with heart risk, that's an open question," Topol said.
Pfizer has updated the label on several occasions since it was approved in 2001 to reflect the risk of Stevens Johnson syndrome, a form of allergic reaction often caused by certain types of drug. Symptoms usually begin as a blistering of the mouth and lips, spreading to the throat, tongue and other parts of the body. The blisters sometimes become so extensive as to be fatal. The company also updated its warning that Bextra can cause a rare, but sometimes fatal, skin disorder called Stevens-Johnson syndrome to note that cases of the condition are being seen more often with Bextra than with other drugs in the same class.
Pfizer's shares fell nearly 4 percent on the New York Stock Exchange.
Bextra is approved to treat pain from arthritis and, like Merck & Co.'s Vioxx, is a COX-2 inhibitor. A recent trial showed Vioxx doubled the risk of heart attack and stroke in arthritis patients who took the drug for more than 18 months.
The Vioxx withdrawal has cast a cloud over the entire class of COX-2 inhibitors, which includes Bextra, Celebrex and an experimental drug from Novartis AG called Prexige.
However, Pfizer said that following the Vioxx withdrawal it re-examined its clinical data base of 8,000 patients with rheumatoid arthritis and osteoarthritis and found no increased risk of dangerous heart events in patients taking Bextra for up to a year. The company also found no increased risk in a trial of patients taking Bextra in a general surgery setting.
Doctors said it is too early to quantify the potential risk of Bextra or of Pfizer's other COX-2 inhibitor Celebrex as neither have tested for long enough. Pfizer said it is conducting longer term trials in arthritis patients.
The coronary bypass trials are ones that Dr. Eric Topol of the Cleveland Clinic Foundation and an early and outspoken critic of Vioxx, said he finds concerning as they show a cluster of heart attacks and strokes. But he said the danger signal does not appear to be as strong as it was with Vioxx.
"Celebrex and Bextra do appear safer than Vioxx but whether they are really safe, especially in patients with heart risk, that's an open question," Topol said.
Pfizer has updated the label on several occasions since it was approved in 2001 to reflect the risk of Stevens Johnson syndrome, a form of allergic reaction often caused by certain types of drug. Symptoms usually begin as a blistering of the mouth and lips, spreading to the throat, tongue and other parts of the body. The blisters sometimes become so extensive as to be fatal. The company also updated its warning that Bextra can cause a rare, but sometimes fatal, skin disorder called Stevens-Johnson syndrome to note that cases of the condition are being seen more often with Bextra than with other drugs in the same class.
Pfizer's shares fell nearly 4 percent on the New York Stock Exchange.
Bextra is approved to treat pain from arthritis and, like Merck & Co.'s Vioxx, is a COX-2 inhibitor. A recent trial showed Vioxx doubled the risk of heart attack and stroke in arthritis patients who took the drug for more than 18 months.
The Vioxx withdrawal has cast a cloud over the entire class of COX-2 inhibitors, which includes Bextra, Celebrex and an experimental drug from Novartis AG called Prexige.
However, Pfizer said that following the Vioxx withdrawal it re-examined its clinical data base of 8,000 patients with rheumatoid arthritis and osteoarthritis and found no increased risk of dangerous heart events in patients taking Bextra for up to a year. The company also found no increased risk in a trial of patients taking Bextra in a general surgery setting.
Doctors said it is too early to quantify the potential risk of Bextra or of Pfizer's other COX-2 inhibitor Celebrex as neither have tested for long enough. Pfizer said it is conducting longer term trials in arthritis patients.
The coronary bypass trials are ones that Dr. Eric Topol of the Cleveland Clinic Foundation and an early and outspoken critic of Vioxx, said he finds concerning as they show a cluster of heart attacks and strokes. But he said the danger signal does not appear to be as strong as it was with Vioxx.
"Celebrex and Bextra do appear safer than Vioxx but whether they are really safe, especially in patients with heart risk, that's an open question," Topol said.
Pfizer has updated the label on several occasions since it was approved in 2001 to reflect the risk of Stevens Johnson syndrome, a form of allergic reaction often caused by certain types of drug. Symptoms usually begin as a blistering of the mouth and lips, spreading to the throat, tongue and other parts of the body. The blisters sometimes become so extensive as to be fatal. The company also updated its warning that Bextra can cause a rare, but sometimes fatal, skin disorder called Stevens-Johnson syndrome to note that cases of the condition are being seen more often with Bextra than with other drugs in the same class.
Pfizer's shares fell nearly 4 percent on the New York Stock Exchange.
Bextra is approved to treat pain from arthritis and, like Merck & Co.'s Vioxx, is a COX-2 inhibitor. A recent trial showed Vioxx doubled the risk of heart attack and stroke in arthritis patients who took the drug for more than 18 months.
The Vioxx withdrawal has cast a cloud over the entire class of COX-2 inhibitors, which includes Bextra, Celebrex and an experimental drug from Novartis AG called Prexige.
However, Pfizer said that following the Vioxx withdrawal it re-examined its clinical data base of 8,000 patients with rheumatoid arthritis and osteoarthritis and found no increased risk of dangerous heart events in patients taking Bextra for up to a year. The company also found no increased risk in a trial of patients taking Bextra in a general surgery setting.
Doctors said it is too early to quantify the potential risk of Bextra or of Pfizer's other COX-2 inhibitor Celebrex as neither have tested for long enough. Pfizer said it is conducting longer term trials in arthritis patients.
The coronary bypass trials are ones that Dr. Eric Topol of the Cleveland Clinic Foundation and an early and outspoken critic of Vioxx, said he finds concerning as they show a cluster of heart attacks and strokes. But he said the danger signal does not appear to be as strong as it was with Vioxx.
"Celebrex and Bextra do appear safer than Vioxx but whether they are really safe, especially in patients with heart risk, that's an open question," Topol said.
Pfizer has updated the label on several occasions since it was approved in 2001 to reflect the risk of Stevens Johnson syndrome, a form of allergic reaction often caused by certain types of drug. Symptoms usually begin as a blistering of the mouth and lips, spreading to the throat, tongue and other parts of the body. The blisters sometimes become so extensive as to be fatal.
Shares of Pfizer fell $1.08, or 3.7 percent, to $28.00 in early afternoon trading on the New York Stock Exchange.
(Additional reporting by Ransdell Pierson in New York and Julie Steenhuysen in Chicago)
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