Pharmacy Division Ramathibodi Hospital


News 08/04/2544

Read critiques of the December 21, 2000, NEJM study linking PPA to increased risk of stroke.

Gabapentin at 2400 mg/day is an effective prophylactic agent for patients with migraine headaches.

For most children with acute sinusitis, antimicrobial treatment offers no significant clinical benefit.

Low-dose beta-blockers appear to retard the rate of progression of carotid intima-media thickness in healthy middle-aged asymptomatic adults with carotid plaque.

Phenylpropanolamine Linked to Increased Risk of Stroke

Updated April 5, 2001

An ingredient in dozens of over-the-counter cold and allergy medicines, as well as in appetite suppressants and other weight loss drugs, has been found to increase the risk of hemorrhagic stroke in women, according to an early release of a New England Journal of Medicine article. Men were not shown to be affected. In an attempt to remove all over-the-counter medications containing phenylpropanolamine (PPA), the US Food and Drug Administration has asked all drug manufactuers to voluntarily cease production of products containing PPA.

Phenylpropanolamine, Ephedra Linked to Serious Adverse Effects

Reuters Health Nov 7 - Over-the-counter appetite suppressants pose significant risk of cerebrovascular events, according to two reports which have been released early by the New England Journal of Medicine because of their "potential public health implications."

The first report finds a high risk of hemorrhagic stroke in women associated with use of phenylpropanolamine.

Dr. Walter Kernan, of Yale University School of Medicine, and associates compared 702 adult patients below age 50 from 43 hospitals across the US who had experienced a subarachnoid hemorrhage or an intracerebral hemorrhage with 1376 control subjects. Fifty-five percent of the patients were women.

After adjusting for race, hypertension, and current smoking status, the odds ratio for hemorrhagic stroke for women within 3 days of using phenylpropanolamine in appetite suppressants was 16.58, and with first use of a product containing phenylpropanolamine it was 3.13.

Dr. Kernan's group observed no increased risk of hemorrhagic stroke in men associated with use of the drug in cough or cold remedies. None of the men, however, had used appetite suppressants.

The second report adds support to the contention by the US Food and Drug Administration that consumption of ephedra alkaloids poses significant health risks to some users.

Drs. Neal L. Benowitz and Christine A. Haller, of the University of California, San Francisco, reviewed 140 reports of adverse events related to the use of dietary supplements containing ephedra that had been submitted to the FDA between 1997 and 1999.

They evaluated the probability that an adverse event was related to the use of the supplements based on "the timing of the event in relation to the dose and duration of use; an assessment of the pattern of response to determine whether it constituted a recognized reaction to the substance on the basis of previous reports of ephedrine or similar stimulants in the medical literature; and a determination of the contribution of any underlying diseases or medical conditions."

Forty-three events were considered to be definitely or probably related to the use of the supplements, and 44 possibly related. Cardiovascular symptoms were involved in 47% of these, while cerebrovascular adverse events were involved in 18%.

Ten events resulted in death and 13 in permanent impairment. Nine serious adverse events occurred after subjects had used relatively low doses (12 to 36 mg/day) of ephedra alkaloids. Eleven sudden catastrophic events occurred in previously healthy individuals. Some of the adverse events followed the use of caffeine and ephedra combined.

Drs. Benowitz and Haller write, "The risks of taking ephedra alkaloids as a dietary supplement...are difficult to justify because the alkaloids have no demonstrated benefit."

N Engl J Med 2000; November 6, 2000.

FDA Takes Steps to Remove PPA From OTC Products

Reuters Health Nov 7 - US regulators on Monday said that they are taking steps to remove from the market a common ingredient in over-the-counter diet drugs and decongestants amid concerns that it is linked to a higher risk of strokes.

The ingredient, phenylpropanolamine (PPA) is found in dozens of nonprescription products, including cold medicine Dimetapp and weight-loss drugs, such as Dexatrim and Acutrim.

The US Food and Drug Administration (FDA) said that it has asked all drug companies voluntarily to stop marketing products containing PPA. Makers would have the option to reformulate the products with other ingredients.

The agency also is writing a proposal that would make the sale of PPA products, both prescription and over-the-counter, illegal. That process is likely to take several months.

The FDA recommended that consumers stop using PPA-containing products, which are still available on store shelves and may be in their medicine cabinets. Regulators determined that PPA appears to be linked to "very rare" cases of strokes in adults under age 50, said Dr. Charles Ganley, head of the FDA's division of over-the-counter drugs.

"We do believe there is some association between (PPA) and the risk for this event," Ganley said in an interview.

"We don't want to be alarmist. It is a very rare occurrence, but when you develop it, it could be devastating," he added.

Industry groups have disputed a Yale University study, part of the FDA's basis for the proposals, as inconclusive.

Other products that contain PPA include some versions of Alka-Seltzer Plus, Comtrex, Contac, Coricidin, Tavist-D and Triaminic.

Last month, an FDA advisory committee recommended that the agency reclassify PPA as unsafe. The committee's recommendation was based primarily on the Yale study, which was funded by the Consumer Healthcare Products Association.

Britain Launches Inquiry into OTC Drug Ingredient Linked to Stroke

LONDON (Reuters) Nov 8 - Britain's Health Ministry on Tuesday said it had launched an investigation into an ingredient commonly used in non-prescription cold and cough medicines after a US study found it can increase the risk of certain strokes in people under the age of 50.

The ingredient, phenylpropanolamine (PPA), is a chemical used mainly as a decongestant and is found in dozens of over-the-counter (OTC) products. The US Food and Drug Administration (FDA) on Monday said that it has asked all drug companies who make products that contain PPA voluntarily to stop marketing those products. Makers would have the option to reformulate the products with other ingredients, the agency said.

The FDA, which also warned consumers not to use products containing PPA, called for the ban after a Yale University study linked the ingredient to 500 strokes a year in people aged 18 to 50 years.

The agency said it also is writing a proposal that would make illegal the sale of prescription and OTC products that contain PPA. That process is likely to take several months, the FDA said.

Britain's Health Ministry, which has not withdrawn the drug, said: "We are aware of the situation in America and the Committee on the Safety of Medicines are reviewing the situation in the UK and will make recommendations."

"Patients with concerns about products containing PPA should contact their pharmacist," the agency added.

While 98% of PPA dosages in the US are found in decongestant medicines, a small amount is found in some appetite suppressants and weight-loss drugs.

Dr. Charles Ganley, head of the FDA's OTC drugs division, said that after reviewing a study carried out by Yale University, regulators determined that PPA seemed tied to "very rare" cases of hemorrhagic, or bleeding, strokes in adults under age 50, particularly women.

"We do believe there is some association between [PPA] and the risk for this event," Dr. Ganley said in an interview with Reuters. "We don't want to be alarmist. It is a very rare occurrence, but when you develop it, it could be devastating," causing disability or death, he said.

Dr. Ganley said it was hard to determine how much PPA might elevate stroke risk. At an advisory committee meeting last month, FDA officials estimated PPA might cause between 200 and 500 hemorrhagic strokes per year in patients aged 18 to 49.

Last year US consumers bought about 6 billion doses of drugs that contained the chemical.

In the Yale study, hemorrhagic strokes occurred within three days after people took products with PPA. "You could not predict who it would occur in," Dr. Ganley said, adding that men as well as women could be at risk.

The FDA panel recommended that PPA should no longer be "generally recognised as safe," a requirement for OTC drugs.

British pharmaceutical company SmithKline Beecham said it was halting production and shipment of Contac 12-hour cold capsules, the only formulation of Contac that contains PPA.

The company also said it had asked retailers to remove the product from US shelves.

Warner-Lambert Co., the consumer products division of US drug company Pfizer Inc., said none of its cough, cold, sinus or allergy medicines made in the United States contained PPA.

The New England Journal of Medicine released findings from the Yale study on its Web site on Monday because of its "potential public health implications" and said it would publish the results in its December 21st issue.

Phenylpropanolamine Class Action Suits Target Drugmakers

NEW YORK (Reuters Health) Mar 02 - The first national class actions involving the substance phenylpropanolamine (PPA) — a common but potentially dangerous ingredient found in many over-the-counter medications — were filed this week against six major drug manufacturers.

Cohen, Milstein, Hausfeld & Toll PLLC, a national class action law firm, filed the six suits on behalf of the millions of consumers who purchased over-the-counter cold, flu and allergy medications containing PPA.

The complaints accuse American Home Products Corp., Schering-Plough Corp., Bayer Corp., SmithKline Beecham Corp., Bristol-Myers Squibb Co. and Novartis Corp. of having known about PPA's side effects for more than 20 years.

The US Food and Drug Administration warned consumers last November to stop taking products containing PPA, which has been linked to a higher risk of stroke. The FDA also said it would be taking steps to remove PPA from all drug products and asked that all drug companies discontinue marketing products with PPA.

"It's very clear that PPA is a dangerous ingredient. We also think that it's clear that consumers and healthcare professionals have not been fully informed about its dangerous effects," said Stephen D. Annand, head of Cohen, Milstein's healthcare practice group in Washington, DC. "We believe that the relief that we have requested is of critical importance as a public heath issue," he told Reuters Health.

The lawsuits, filed in US District Court in Seattle, call for manufacturers to inform healthcare providers nationwide that some of their patients may have suffered brain, heart or other injuries from taking PPA-containing products and to educate consumers about the dangers of PPA.

The suits also seek refunds to consumers for the purchase price of medications that contained PPA, and propose that funds be set aside for additional PPA research on adverse side effects and for improving ways of treating injuries caused by PPA.

"We believe that the manufacturers knew for many years of the dangerous effects, that they stalled FDA efforts to get to the bottom of it, [and] that they caused the process to move so slowly that the products were on the market much, much longer than they should have been," Annand said.

A spokesman for the Whitehall-Robins division of American Home Products, one of the defendants, told Reuters Health that the company "does not comment" on matters of ongoing litigation.

Gabapentin Reduces Frequency of Migraine Headaches

WESTPORT, CT (Reuters Health) Mar 30 - Gabapentin at 2400 mg/day is an effective prophylactic agent for patients with migraine headaches, according to results of a multicenter trial.
Dr. Leslie Magnus of Parke-Davis Medical Research in Morris Plains, New Jersey recruited patients who had three to eight migraines per month and had not received, or had failed, previous prophylactic therapy. The trial included a 4-week placebo baseline period, a 4-week titration phase, and an 8-week stable-dosing phase.

During the titration phase, 98 patients started at 300 mg/day and were increased to 1800 mg/day or 2400 mg/day. Forty-five patients were in the placebo arm of the study. The results appear in the February issue of Headache.

The mean number of days with headache pain per 4 weeks was 3.4 days in the treatment group and 5.0 days in the placebo group. A minimum 50% reduction in headache rate was experienced by 46.4% of subjects receiving 2400 mg/day gabapentin, compared with 16.1% of those in the placebo group. Adverse drug effects included somnolence, dizziness, and asthenia, which are known side effects of gabapentin.

Increases in GABA or modulated intracellular calcium influx caused by gabapentin may act to reduce the central neuronal hyperexcitability associated with migraine, the investigators theorize.

Headache 2001;41:119-128.

Antibiotic Treatment Unnecessary for Most Children With Acute Sinusitis

WESTPORT, CT (Reuters Health) Apr 02 - For most children with acute sinusitis, antimicrobial treatment offers no significant clinical benefit, researchers report in the April issue of the journal Pediatrics. The vast majority of these children will get better on their own if given enough time, they conclude.

Dr. Jane M. Garbutt, of Washington University School of Medicine in St. Louis, Missouri, and colleagues, randomized 188 children, who had acute sinusitis for between 10 to 28 days, to amoxicillin, amoxicillin-clavulanate or placebo for 2 weeks.

No significant differences between the groups emerged in "overall symptom resolution, duration of symptoms, recovery to usual functional status, days missed from school or childcare, or relapse and recurrence of sinus symptoms," the authors report.

"Children with clinically diagnosed acute sinusitis with 10 days of persistent symptoms, specifically, cough and discharge, who are not improving, do not appear to benefit from antimicrobial treatment," Dr. Garbutt told Reuters Health. "Our findings would suggest that it is appropriate to wait another 7 days before antibiotics are started."

Delaying the start of antimicrobial therapy for 3 weeks after the onset of symptoms may decrease unnecessary antibiotic use. In this study, between 0 and 21 days, 87% of children got better regardless of treatment, "so the suggestion is you have to wait a bit longer," Dr. Garbutt said.

Placebo-treated subjects fared no better or worse than antibiotic-treated subjects did. "Clinical outcomes for patients who were treated with amoxicillin and amoxicillin-clavulanate were the same and equivalent to placebo," the researchers report in the journal. If antibiotic treatment is started after 10 days of sinus symptoms, they favor amoxicillin rather than amoxicillin-clavulanate.

"It is hard to identify the causative organism for acute sinusitis, so we don't have a lot of information about bacteriology," Dr. Garbutt added, "but the estimate is that 20 to 200 times more infections are caused by viruses than bacteria."

Pediatrics 2001;107:619-625.

Beta-Blockade Reduces Carotid Thickening, Indicating Anti-Atherosclerotic Effect

WESTPORT, CT (Reuters Health) Apr 02 - Low-dose beta-blockers appear to retard the rate of progression of carotid intima-media thickness in healthy middle-aged asymptomatic adults with carotid plaque, according to a report in Circulation for April 3.

"This is the first randomized trial to show that metoprolol CR/XL has an anti-atherosclerotic effect in humans," lead author Dr. Bo Hedblad from Malmo University Hospital said in a journal statement.

Dr. Hedblad and colleagues randomly assigned 793 men and women, who participated in the Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS), to 25-mg metoprolol CR/XL once daily, or 40-mg fluvastatin once daily, or a combination of metoprolol CR/XL and fluvastatin, or placebo.

Among subjects receiving metoprolol, the rate of progression of intima-media thickness in the carotid bulb was reduced at 18 months (-0.058 mm/y) and 36 months (-0.023 mm/y). The rate of progression in the common carotid was also reduced among the patients in the fluvastatin group at 36 months (-0.009 mm/y), Dr. Hedblad's group says.

In addition, during the 36 months of followup there were fewer cardiovascular events, including myocardial infarction and stroke, among patients receiving metoprolol CR/XL than among patients in the fluvastatin group (5 versus 13).

Before the clinical implications of beta-blockers in the early treatment of atherosclerosis are known, more study is needed. "Further experimental studies need to be conducted to understand the mechanism of the anti-atherosclerotic effect of metoprolol CR/XL," said Dr. Hedblad.

Circulation 2001;103:1721-1726.

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