Yourlawyer.com (Serevent News)

FDA Panel Wants Restrictions on Two Asthma Drugs

Fri, 12 Dec 2008 00:00:00 -0800

A U.S. Food and Drug Administration (FDA) panel has called for restrictions on two asthma treatments: Serevent and Foradil. Both belong to a class of drugs known as long-acting beta-agonists. Both contain a drug that relaxes muscles around airways, said WHEC TV, but may also mask symptoms that can prompt deadly asthma attacks. Although the expert 27-member panel found Serevent and Foradil drugs present greater risks than benefits and should not be used in the treatment of asthma, the inhaler drugs will likely not be pulled, said WebMD Health News.

The panel suggested the FDA alert physicians to not prescribe Serevent and Foradil as a stand-alone treatment for patients of any age, said WebMD; however, the drugs’ use in chronic obstructive pulmonary disease (COPD) remains unaffected. The panel backed Symbicort and Advair, finding the benefits were greater than the risks, added WebMD.

NBC noted that with 20 million Americans suffering from asthma, it is critical they receive appropriate treatment at the first sign of an attack, noting that the panel was reviewing the benefits and risks—such as hospitalization and death—of a variety of asthma medications.

NBC pointed out that Advair, Serevent, Foradil, and Symbicort are all long-lasting medications that might reduce reliance on rescue inhalers. But, an FDA study found that long-lasting drugs present a two-to-seven times greater risk over other medications for severe complications and death, especially in women, African-Americans, and children under 12. Doctors recommend, said NBC, that these drugs be used in collaboration with inhaled cortico-steroids, which treat inflammation. In Symbicort and Advair, the steroid is built in. Advair was the only one of the four drugs with no increased risk, reported NBC.

Angel Waldron of the Asthma and Allergy Foundation of America told NBC that, “Removing them or limiting access to them would be setting us back about fifteen years in asthma care,“ but not all experts agreed. One recommended Serevent and Foradil be pulled and all four banned for children. Another felt the benefits “far outweighed” the risks, said NBC, which noted of 60,000 patients studied, 20 suffered asthma-related deaths.

Medical guidelines and the drugs' labeling recommend long-acting beta-agonists only be used with inhaled steroids to minimize airway inflammation; the combination lowers risks to levels experts find acceptable, reported WebMD Health News. But studies reveal most asthma patients tend not to use inhaled steroids as prescribed when taking them separately from beta-agonists and patients receive relief from beta-agonist inhalers, leading many to use them alone—a practice called monotherapy—which raises the drugs’ risks, according to the FDA studies, said Web MD.

"I think the label should be greatly strengthened to say that monotherapy for asthma should basically be contraindicated" for Serevent and Foradil, Daniel Notterman, MD, a member of the advisory panel from the department of molecular biology at Princeton University, told Web MD Health News.

Notterman was not alone, and the FDA panel agreed with him in a 17-to-10 vote, saying Serevent and Foradil’s risks outweigh benefits when used alone. The panel found voted unanimously that neither drug be used in younger children four to 11 years old, said Web MD Health News.

"The data is that single use is dangerous," David Schoenfeld, PhD, a panelist and professor of medicine from Massachusetts General Hospital, told Web MD.

Because Advair contains both a beta-agonist and steroids, thus reducing the risk of airway passage inflammation, the pane backed that drug. However, there was disagreement among panel members regarding Advair’s use in children. The fourth drug, Symbicort, is not generally prescribed for children said Web MD.

FDA Considers Heart Risks of Serevent, Foradil, Advair and Symbicort

Thu, 11 Dec 2008 00:00:00 -0800

One expert estimates that long-acting beta-agonists (LABAs) - a class of asthma drugs that includes Serevent, Foradil, Advair, and Symbicort - might be responsible for about 14,000 deaths, Reuters is reporting. The comments were part of a confrontational meeting between the U.S. Food and Drug Administration (FDA) and an advisory panel discussing how to handle increased risks experienced with the inhaled asthma medications called LABAs, said Reuters,

LABAs are used by millions of patients, many of whom are children, noted Reuters. Advair and Symbicort use a LABA with an inhaled steroid; Serevent and Foradil (marketed in the U.S. by Schering-Plough Corp.) only contain LABAs, said Reuters.

Reuters explained that asthma, a chronic disease with symptoms that include restricted breathing and wheezing, can be fatal when untreated or uncontrolled. About 20 million Americans suffer from asthma, according to the National Institutes of Health, said Reuters. LABAs help relax airways to prevent the spasms that cause the attacks and are accompanied with warnings about a link to asthma-related deaths based on findings from a Glaxo study shut down in 2003, said Reuters.

FDA reviewers argued that LABAs should never be prescribed to pediatric asthmatics and asked for revocation of Glaxo's Serevent and Novartis AG's Foradil for all asthma patients, regardless of age, reported Reuters. "We now know with high certainty that LABAs increase asthma mortality. Do the health benefits justify that?" asked FDA drug safety reviewer David Graham, said Reuters, who added that Graham has publicly criticized the FDA’s managing of drug risks. Graham agued that LABAs benefits do not justify its risks, saying that he’s seen little improvement in asthma patients treated with LABAs, noting that as many as 14,000 deaths since 1994 can be linked to LABAs.

The FDA reviewed over 100 clinical trials that involved about 61,000 patients and found that for every 1,000 patients treated with a LABA, nearly three such patients experienced serious asthma-related complications, which included hospitalizations and death, Reuters said. And, added Reuters, although each drug maker argued the benefits of its drugs and against banning LABAs, the advisory panel will vote next regarding the benefits and risks of each of the drugs.

Reuters noted that even if LABA approval for use in the treatment of asthma could face revocation, drugs such as Advair, Serevent, and Foradil could continue to be prescribed for patients suffering from chronic obstructive pulmonary disease (COPD). Meanwhile, AstraZeneca has applied to the FDA for approval of is asthma drug, Symbicort, to be used in the treatment of COPD.

Complications, Deaths Seen with Some Long-Acting Asthma Drugs

Fri, 05 Dec 2008 00:00:00 -0800

Some asthma drugs in a class known as long-acting beta agonists (LABA) can increase the risk of death and complications, a new Food & Drug Administration (FDA) analysis has found. The analysis looked at GlaxoSmithKline PLC's Serevent and Advair, Novartis AG's and Schering-Plough Corp.'s Foradil and AstraZeneca PLC's Symbicort.

The FDA analysis was prepared for an advisory committee meeting next week that is slated to discuss the safety of the drugs, The Wall Street Journal said. At the meeting, FDA advisors will consider whether LABAs should continue to be marketed for children and adults.

LABAs prevent the release of substances in the body that cause inflammation of airways in the lungs. In 2005, the FDA strengthened the warning labels for the asthma drugs to state that they should be reserved for patients who did not respond to other asthma therapies. The label changes came after a study found that patients taking Serevent where four times more likely to suffer an asthma-related death. Others showed that Serevent and Foradil increased asthma exacerbations and hospitalizations in both adults and children.

According to Reuters, the FDA's latest analysis found 2.8 more serious asthma events for every 1,000 asthma patients treated with a LABA. Children ages 4 to 11 "appeared to be at the greatest risk," FDA statisticians said. The risk is lower when the drugs are used together with a steroid to treat underlying inflammation deep inside the airways, Reuters said.

According to The Wall Street Journal, the analysis involved 110 trials and 60,954 patients. The bulk of the patients were from Serevent trials, with about 43,000 patients, the FDA said. The agency said there were 20 asthma-related deaths in the studies and of those, 16 were patients on Serevent and four were patients in the non-LABA group.

The analysis found that only one of the drugs, Advair - which combines an LABA and a steroid in one inhaler - does not appear to increase the risk of a serious event or death, the Journal said. However, Serevent had a significantly higher rate of serious complications than the others.

Asthma Med Serevent Linked to Serious Adverse Events, Death

Fri, 18 Jul 2008 00:00:00 -0700

Researchers have just revealed that patients with chronic asthma who take the asthma medication Serevent—also known generically as Salmeterol—on a daily basis are at increased risk for serious adverse events, including death

The research involved a 12-week review of 32 clinical trials that involved 62,630 patients. In addition to pointing to serious adverse events with daily Serevent use, the research findings also suggest that the collaborative use of inhaled corticosteroids with Serevent may help reduce such adverse effects. It is important to note that the researchers felt that it remains unclear if the addition of corticosteroids with Serevent eliminates the risk entirely. "We found that the biggest increase in risk was seen in people with asthma who were not taking inhaled corticosteroids; however, there is no guarantee that inhaled corticosteroids abolish the risk altogether," lead researcher Dr. Christopher Cates, from Community Health Sciences at St. George's, London, said.

The studies in the review all involved clinical trials in which participants were randomly assigned to either regular Serevent, a placebo, or the medication Salbutamol. Of all of the patients involved, 2380 were children. Serevent is a long-acting, beta2-adrenergic receptor agonist that is delivered as a dry powder and is administered with a special inhaler. Serevent is the trade name and Salmeterol is the drug’s generic name. Salbutamol is the generic name for the drug marketed as Albuterol, an asthma medication that relaxes the smooth muscle in the lungs and opens airways to improve breathing. In addition to treating asthma, Albuterol treats chronic bronchitis, emphysema, and is also used to prevent exercise-related asthma.

Using data from two large surveillance studies, the researchers found that regular Serevent use increased the risk of asthma-related mortality in patients who did not also use inhaled steroids. Also, the mortality from any cause was higher with Serevent than with placebo. And, Serevent did increase the risk of non-fatal serious events. The researchers calculate that one extra serious event arose over 28 weeks for every 188 patients who used Serevent on a daily basis. More research is needed to determine if Serevent use is more or less risky in children as compared with adults.

For those patients whose asthma is not adequately controlled by moderate doses of inhaled corticosteroids, the addition of Serevent can relieve symptoms; however, the authors warn that this relief, "… may be at the expense of an increased risk of serious adverse events and asthma-related mortality; risks which are not clearly abolished by inhaled corticosteroid."

Serevent is prescribed for long-term, twice-daily use for the treatment of bronchospasm associated with Chronic Obstructive Pulmonary Disease (COPD), including emphysema and chronic bronchitis and is also prescribed for long-term, twice-daily use in the maintenance treatment of asthma in patients four years of age and older. Also, Serevent is used for the prevention of exercise-induced bronchospasm (EIB) in patients four years of age and older.

Serevent side effects include throat irritation; sinus headache; nausea; oral “musosal abnormality”; joint pain; sleep disturbance and paresthesia, or tingling; contact dermatitis and eczema; and pyrexia, or increase in body temperature.

FDA Seeks Info on Serevent, Advair, Foradil As Part of Safety Review

Thu, 06 Mar 2008 00:00:00 -0800

Asthma drugs, including Serevent, Advair, Foradil, are the subject of a Food & Drug Administration (FDA) safety review. The FDA has requested information from the manufacturers of the asthma medications as part of an ongoing safety review of the drugs in children.

Serevent, Advair and Foradil are long-acting beta 2-adrenergic agonists that prevent the release of substances in the body that cause inflammation of airways in the lungs. In 2005, the FDA strengthened the warning labels for the asthma drugs to state that they should be reserved for patients who did not respond to other asthma therapies. The label changes came after a study found that patients taking Serevent where four times more likely to suffer an asthma-related death. Others showed that Serevent and Foradil increased asthma exacerbations and hospitalizations in both adults and children.

Asthma is a chronic disease marked by restricted breathing and wheezing, and often made worse by exercise, cigarette smoke and other factors. About 20 million people in the United States have asthma, according to the National Institutes of Health.

In November, prior to an FDA pediatric advisory panel meeting on the medications' use in children, the agency posted documents detailing nine patients under the age of 16 where injured while taking Serevent, and five died since the medication was approved for children in 2006. The FDA reviewers who posted the Serevent and Advair information did not identify whether the adverse events cited in the documents where unique to children, but they did write that Serevent might carry more risks than benefits for young users. The FDA report said that a study to assess the benefits and risks of Serevent and Advair might be needed, however, it conceded that would be difficult to find enough children to participate in such a clinical trial. Instead, the FDA report recommended that a more “formal” analysis of data regarding Serevent and Advair be conducted. The FDA's pediatric advisory panel ultimately recommended that the drugs' labels needed new language more specific to children.

The FDA said it plans to ask a panel of outside advisers to review the drugs' risks and benefits in adults and children in the fall or winter of 2008.

Serevent Should Have Stronger Warnings About Fatal Side Effects in Children, FDA Panel Says

Thu, 29 Nov 2007 00:00:00 -0800

Serevent, a top selling asthma drug, needs stronger safety warnings, a Food & Drug Advisory (FDA) panel said yesterday. The FDA panel's Serevent recommendation came after five children died while using the drug. If adopted, the new warnings could have serious implications for Serevent sales, and for those of another GlaxoSmithKline asthma medication, Advair. Serevent is an active ingredient in Advair.

Serevent and Advair are inhalation powders used to prevent asthma attacks. Asthma is a chronic lung disease that causes inflammation and narrowing of the airways in the lungs. Asthma attacks cause shortness of breath, cough, chest pain and other symptoms. Serevent and Advair contain long-acting beta 2-adrenergic agonists that prevent the release of substances in the body that cause inflammation of airways in the lungs. Both Serevent and Advair are used to prevent asthma attacks, and do not work if an asthma attack has already begun. Advair and Serevent are also used to treat chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis.

The FDA advisory panel met yesterday to review nine new adverse event reports involving pediatric Serevent patients. Those reports included five deaths over a period of about a year. The panel also looked at several others studies that indicated increased hospitalizations and deaths in children using Serevent. Panel members were obviously disturbed by the Serevent side-effect reports, with two panel members arguing that Serevent should actually be pulled from the market. "The data is very troubling because both the increase in hospitalization and in mortality is so different" from what doctors currently believe, said panel member Thomas Newman, an epidemiologist at the University of California, San Francisco.

Serevent problems first came to light a few years back. Consumer group Public Citizen lists both Serevent and Advair on its "worst drugs" list. Since the fatal side effects where first reported, Serevent sales have plummeted, but Advair is still a blockbuster for Glaxo.

The FDA will consider the safety of other drugs in Serevent's class, including Advair, at a future advisory panel meeting. It is theorized that a steroid used as an ingredient in Advair, but not Serevent, provided protection against serious complications, but the FDA panel rejected that notion, saying there was no real evidence to support it.

In 2005, the FDA strengthened the warning labels for Serevent and Advair, as well as Foradil, a similar drug made by Novartis AG, warning that these asthma drugs should be reserved for patients who did not respond to other asthma therapies. The label changes came after a study found that patients taking Serevent where four times more likely to suffer an asthma-related death. Others showed that Serevent and Foradil increased asthma exacerbations and hospitalizations in both adults and children.

In a statement, GlaxoSmithKline said that it remained confident that Serevent and Advair are safe drugs, and their benefits outweigh any risks. Serevent and Advair are the second best-selling medications in the world, with sales of more than $6 billion.

Serevent and Advair May Cause Injury, Death in Children, FDA Report Says

Mon, 26 Nov 2007 00:00:00 -0800

Serevent and Advair, top-selling asthma drugs, will take center stage this week, when a Food & Drug Administration (FDA) panel meets to discuss the use of these medications in children. A report prepared by FDA staffers and posted on the agency's website indicate that both Serevent and Advair can have rare but deadly side-effects when used in children.

Serevent and Advair, both manufactured by GlaxoSmithKline, are inhalation powders used to prevent asthma attacks. Asthma is a chronic lung disease that causes inflammation and narrowing of the airways in the lungs. Asthma attacks cause shortness of breath, cough, chest pain and other symptoms. Serevent and Advair contain long-acting beta 2-adrenergic agonists that prevent the release of substances in the body that cause inflammation of airways in the lungs. Both Serevent and Advair are used to prevent asthma attacks, and do not work if an asthma attack that has already begun. Advair and Serevent are also used to treat chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis.

At a meeting that begins tomorrow, the FDA Pediatric Advisory Committee will discuss the use of Advair and Serevent in children. According to documents posted on the FDA website last week, nine patients under the age of 16 where injured while taking Serevent, and five died since the medication was approved for children in 2006. The FDA reviewers who posted the Serevent and Advair information did not identify whether the adverse events cited in the documents where unique to children, but they did write that Serevent might carry more risks than benefits for young users. The FDA report said that a study to assess the benefits and risks of Serevent and Advair might be needed, however, it conceded that would be difficult to find enough children to participate in such a clinical trial. Instead, the FDA report recommended that a more "formal" analysis of data regarding Serevent and Advair be conducted.

Researchers Say "Killer" Asthma Inhalers Should Be Recalled

Tue, 20 Jun 2006 00:00:00 -0700

Researchers from Cornell and Stanford universities have concluded three common asthma inhalers containing the drugs salmeterol or formoterol may be causing four out of five U.S. asthma-related deaths per year and should be taken off the market.

The researchers made their recommendation after concluding a search of medical literature.

They base these conclusions on a statistical analysis of 19 published trials involving 33,826 patients. This so-called meta-analysis found that patients who inhaled the long-acting beta-agonists salmeterol (trade names Serevent and Advair, both made by GlaxoSmithKline) or formoterol (trade name Foradil, made by Novartis Pharmaceuticals) were 3.5 times more likely to die from asthma and 2.5 times more likely to be hospitalized (whether or not death resulted), compared with those taking a placebo.

The reason, say the researchers, is because although these medications relieve asthma symptoms, they also promote bronchial inflammation and sensitivity without warning.

Asthma death is relatively rare, 15 patients in the meta-analysis who were taking the beta-agonists died, compared with three in the placebo group, over a six-month period.

"In total, there are about 5,000 deaths a year due to asthma, whether or not a person is taking a long-acting beta-agonist," said Edwin Salpeter, the J.G. White Distinguished Professor of Physical Sciences Emeritus at Cornell, who led the statistical analysis in the study.

An eminent astrophysicist, Salpeter has more recently focused his attention on medical statistics.

"We can show that overall it is statistically significant that, compared to patients taking a placebo, these long-acting beta-agonists kill a lot of people," he said.

"These asthma deaths are generally in healthy young adults," said his daughter, Shelley Salpeter, the lead author of the paper appearing online and in the June 20 issue of Annals of Internal Medicine. She is a clinical professor of medicine at Stanford's School of Medicine and a physician at Santa Clara Valley Medical Center in San Jose, Calif.

"We estimate that approximately 4,000 out of the 5,000 asthma deaths that occur in the U.S. each year are actually caused by these long-acting beta-agonists, and we urge that these agents be taken off the market," she added.

Adding an anti-inflammatory drug to a long-acting beta-agonist adds little benefit, report the Salpeters.

Advair, for example, (the fourth bestselling drug in the world with $5.6 billion in annual sales), combines salmeterol with an anti-inflammatory drug to provide some protection against bronchial inflammation associated with beta-agonists. But hospitalizations still doubled for patients inhaling a long-acting beta-agonist combined with an anti-inflammatory drug compared with asthma patients taking a placebo and an anti-inflammatory drug by itself.

Of the 19 studies surveyed in the meta-analysis, the largest the Salmeterol Multicenter Asthma Research Trial with 26,000 participants reported a fourfold increased risk for asthma-related deaths and a twofold increase in life-threatening asthma events in patients using salmeterol.

If older people who also suffered from chronic obstructive pulmonary disease were removed from the analysis, the Salpeters report, salmeterol would be associated with a six times greater risk for asthma-related deaths.

The meta-analysis found that 53 of 3,083 patients inhaling beta-agonists were hospitalized for an asthma attack compared with 12 of 2,008 patients who received a placebo, meaning that there was one hospitalization for every 71 patients treated with a long-acting beta-agonist per year.

The Salpeters say that these two long-acting beta-agonists can result in death because tolerance to them develops over time.

"These agents can improve symptoms through bronchodilation at the same time as increasing underlying inflammation and bronchial hyper-responsiveness, thus worsening asthma control without any warning of increased symptoms," said Shelley Salpeter.

"It is particularly frightening that long-acting beta-agonists are detrimental, whether salmeterol or formoterol, whether taken alone or with anti-inflammatory drugs, both for children and for adults," said Ed Salpeter.

Asthma inhalers causing deaths - study

Tue, 20 Jun 2006 00:00:00 -0700

Three asthma inhalers with salmeterol or formoterol may cause 80 percent of U.S. asthma deaths annually, says a new study.

Because of the possible health risks, these products sold as GlaxoSmithKline's Serevent and Advair, and Novartis' Foradil should be recalled, said researchers at Cornell University and Stanford University.

"These asthma deaths are generally (occurring) in healthy young adults," said Stanford researcher Shelly Salpeter. "We estimate that approximately 4,000 of the 5,000 asthma deaths that occur in the U.S. each year are caused by these long-acting beta-agonists, and we urge that (they) be taken of the market."

The researchers conducted a statistical analysis of 19 published asthma trials involving 33,826 patients and found that people who used salmeterol-based asthma inhalers (Serevent and Advair) or inhalers containing formoterol (Foradil) were 3.5 times more likely to die from asthma.

The team also saw that these same patients were 2.5 times more likely to be hospitalized than asthma patients using a placebo inhaler.

Both drugs are in a drug class known as long-acting beta-agonists.

The researchers said that, although beta-agonists relieve bronchial spasm, they also promote bronchial inflammation and sensitivity without warning. Although Advair contains an anti-inflammatory to correct this problem, hospitalizations of patients taking Advair were still double those of people who took a placebo plus an anti-inflammatory, the team noted.

The study authors, whose paper appears in the June 20 issue of the Annals of Internal Medicine, noted that asthma death is relatively rare. Only 15 study patients who were taking the drugs died, compared to three in the placebo group over a six-month period, they said.

Common Asthma Inhalers Cause Up to 80% of Asthma-Related Deaths, Cornell and Stanford Researchers Assert

Fri, 09 Jun 2006 00:00:00 -0700

Three common asthma inhalers containing the drugs salmeterol or formoterol may be causing four out of five U.S. asthma-related deaths per year and should be taken off the market, researchers from Cornell and Stanford universities have concluded after a search of medical literature.

They base these conclusions on a statistical analysis of 19 published trials involving 33,826 patients. This so-called meta-analysis found that patients who inhaled the long-acting beta-agonists salmeterol (trade names Serevent and Advair, both made by GlaxoSmithKline) or formoterol (trade name Foradil, made by Novartis Pharmaceuticals) were 3.5 times more likely to die from asthma and 2.5 times more likely to be hospitalized (whether or not death resulted), compared with those taking a placebo.

The reason, say the researchers, is because although these medications relieve asthma symptoms, they also promote bronchial inflammation and sensitivity without warning.

Nevertheless, asthma death is relatively rare 15 patients in the meta-analysis who were taking the beta-agonists died, compared with three in the placebo group, over a six-month period.

"In total, there are about 5,000 deaths a year due to asthma, whether or not a person is taking a long-acting beta-agonist," said Edwin Salpeter, the J.G. White Distinguished Professor of Physical Sciences Emeritus at Cornell, who led the statistical analysis in the study. An eminent astrophysicist, Salpeter has more recently focused his attention on medical statistics. "We can show that overall it is statistically significant that, compared to patients taking a placebo, these long-acting beta-agonists kill a lot of people," he said.

"These asthma deaths are generally in healthy young adults," said his daughter, Shelley Salpeter, the lead author of the paper appearing online and in the June 20 issue of Annals of Internal Medicine. She is a clinical professor of medicine at Stanford's School of Medicine and a physician at Santa Clara Valley Medical Center in San Jose, Calif.

"We estimate that approximately 4,000 out of the 5,000 asthma deaths that occur in the U.S. each year are actually caused by these long-acting beta-agonists, and we urge that these agents be taken off the market," she added.

Adding an anti-inflammatory drug to a long-acting beta-agonist adds little benefit, report the Salpeters. Advair, for example, (the fourth bestselling drug in the world with $5.6 billion in annual sales), combines salmeterol with an anti-inflammatory drug to provide some protection against bronchial inflammation associated with beta-agonists. But hospitalizations still doubled for patients inhaling a long-acting beta-agonist combined with an anti-inflammatory drug compared with asthma patients taking a placebo and an anti-inflammatory drug by itself.

Of the 19 studies surveyed in the meta-analysis, the largest the Salmeterol Multicenter Asthma Research Trial with 26,000 participants reported a fourfold increased risk for asthma-related deaths and a twofold increase in life-threatening asthma events in patients using salmeterol. If older people who also suffered from chronic obstructive pulmonary disease were removed from the analysis, the Salpeters report, salmeterol would be associated with a six times greater risk for asthma-related deaths.

The meta-analysis found that 53 of 3,083 patients inhaling beta-agonists were hospitalized for an asthma attack compared with 12 of 2,008 patients who received a placebo, meaning that there was one hospitalization for every 71 patients treated with a long-acting beta-agonist per year.

The Salpeters say that these two long-acting beta-agonists can result in death because tolerance to them develops over time.

"These agents can improve symptoms through bronchodilation at the same time as increasing underlying inflammation and bronchial hyper-responsiveness, thus worsening asthma control without any warning of increased symptoms," said Shelley Salpeter.

"It is particularly frightening that long-acting beta-agonists are detrimental, whether salmeterol or formoterol, whether taken alone or with anti-inflammatory drugs, both for children and for adults," said Ed Salpeter.

Co-authors of the study include Shelley Salpeter's son, Nicholas Buckley, a student at Sequoia High School in Redwood City, Calif., and Thomas Ormiston, a physician at Santa Clara Valley Medical Center in San Jose, Calif.

SOURCE: Cornell University

Study Cites Increased Death Risk From Asthma Drugs

Tue, 06 Jun 2006 00:00:00 -0700

Popular and long-acting asthma medicines such as Advair and Serevent pose a substantially increased risk of hospitalization and death to users compared with placebos, according to a new analysis of 19 studies on the subject.

The analysis also found that the increased risks of the long-acting bronchodilators affect a broad range of users more than doubling the rate at which asthma patients had to be hospitalized. Most experts have believed that the powerful bronchodilators are harmful only to a small number of people genetically predisposed to having a negative reaction.

"What we have here is a drug that increases the number of people who will die from the disease it is treating," said lead author Shelley Salpeter of Stanford University. "The long-acting bronchodilators can help reduce symptoms for many people, but we think the price in terms of serious side effects and deaths is unacceptable."

The Food and Drug Administration has voiced concerns about the widely used medicines, and last fall it required drugmakers to prepare stiff new warnings to the package label. But the new analysis, published in the journal Annals of Internal Medicine, raises the possibility that the drug should be taken off the market if it continues to be so widely used.

"The use of long-acting [bronchodilators] could be associated with a clinically significant number of unnecessary hospitalizations, intensive care unit admissions and deaths each year," the authors wrote. "Black box warnings on the labeling for these agents clearly outline the increased risk for asthma-related deaths associated with their use, but these warnings have not changed prescribing practices of physicians."

One of the long-lasting bronchodilators is Advair Diskus, made by GlaxoSmithKline. It brought in $3.4 billion last year for the company, making it the nation's fifth biggest-selling drug, according to IMS Health, which tracks health data.

More than 3.5 million patients use the drug. In the new analysis, the authors estimated that Advair "may be responsible" for as many as 4,000 of the 5,000 asthma-related deaths each year in the United States.

Glaxo spokeswoman Mary Anne Rhyne disputed that figure and said the Centers for Disease Control and Prevention has found a decline in asthma-related deaths since the long-acting bronchodilators came on the market in the mid-1990s.

Rhyne said Advair has been recommended for use in treatment guidelines for asthma from the National Institutes of Health because it reduces symptoms and allows asthma sufferers to sleep through the night, exercise and generally resume normal lives.

"The author's conclusions are inconsistent with a large body of evidence and experience of patients," she said.

She also said doctors have written more than 68 million prescriptions for Advair in the United States since 2001, so there is extensive experience with its benefits and risks.

The new generation of bronchodilators, known as long-acting beta-agonists or LABAs, have been both popular and controversial for some time. The FDA added a black-box warning about their risks in 2003, and last year additional concerns led to an FDA advisory panel meeting to discuss whether they should be taken off the market. The panel concluded that they should not.

As a result of the meeting, however, the agency demanded stronger language in the black-box warning and issued a public health advisory in November that said: "Even though LABAs decrease the frequency of asthma episodes, these medicines may make asthma episodes more severe when they occur. . . . LABAs should not be the first medicine used to treat asthma. LABAs should be added to the asthma treatment plan only if other medicines do not control asthma, including the use of low-or-medium dose corticosteroids."

The new meta-analysis looked at results of 19 trials that studied 33,826 asthma sufferers given either the long-acting bronchodilators or inactive placebos. (Slightly half of both groups were also taking inhaled steroids.) Salpeter said the results found that people on the long-acting medication were four to six times more likely to die of asthma-related causes than those on placebo.

Inhaled steroids, which have long been used to treat asthma, work by reducing the hypersensitivity in the lungs that leads to inflammation and narrowing of the airways. LABAs work by helping to relax the muscles around the airways in the lungs and thereby reduce wheezing. In addition to Advair, Glaxo sells another LABA drug, Serevent, and Novartis sells Foradil.

Glaxo and the FDA have long sparred over how to describe the potential risks of Advair and Serevent. When the agency said last November that the black-box warning needed to be made tougher, Glaxo publicly opposed the move. The tougher warning that the drug could increase the risk of asthma-related death was approved in March. It also said Advair should be prescribed only when other drugs have proved insufficient.

Some research has suggested that LABAs are more likely to harm African Americans than other groups.

Advair, Other Asthma Drug Get Label Alerts

Mon, 06 Mar 2006 00:00:00 -0800

The asthma medication Advair and a related drug will bear stronger warnings of an increased risk of death associated with one of their ingredients.

The revised warnings apply to Advair and Serevent, Food and Drug Administration spokeswoman Laura Alvey said Monday. Advair is GlaxoSmithKline's best-selling product, and Serevent is another of the British company's drugs.

The updated versions of the "black-box" warnings on both drugs caution that salmeterol, one of the active ingredients in Advair and the active ingredient in Serevent, may increase the risk of asthma-related death. Black-box warnings are the most severe warnings the FDA can require of prescription drugs.

Advair should be used only by patients when other asthma drugs, such as low- to medium-dose inhaled corticosteroids, don't work or if their asthma is severe enough to merit use of two medications, the revised warning says.

As for Serevent, it should only be used as an additional medication when the low- to medium-dose inhaled corticosteroids aren't sufficient or, again, if the asthma is serious enough to merit use of two drugs.

The FDA in November asked that the labels be updated for the two drugs, along with a third, Foradil.

Foradil's manufacturer, Novartis, remains in talks with the FDA and no final decision has been reached, said Julie Lux, a spokeswoman for Schering-Plough Corp., which markets Foradil in the United States.

GlaxoSmithKline said in a statement that it was pleased to reach an agreement with the FDA on the label changes to its two drugs.

"The new product labels communicate the benefit-risk profile of Serevent and Advair and help guide physicians in making appropriate prescribing decisions," the company said. In November, however, it maintained that the drugs already came with sufficient warning. The company reported in February that sales of Advair, sold as Seretide in the United Kingdom, rose 22 percent last year to $5.2 billion.

The FDA last Friday released new medications guides for patients using the two GlaxoSmithKline drugs. The letters urge asthmatics using the drugs to talk to their doctors about the relative risks and benefits of the medicines.

The agency said a large U.S. study found that more people using the asthma drugs died from their asthma compared with those taking dummy medication. The number of asthma deaths in the study was small, however: just 13 out of 13,176 patients.

The drugs help with long-term control and prevention of asthma symptoms like wheezing and shortness of breath. They help the muscles around the airways in the lungs stay relaxed.

Top Asthma Drugs Get Stronger Warning

Mon, 06 Mar 2006 00:00:00 -0800

The asthma medication Advair and Serevent will now carry the strongest warnings the FDA can require of prescription drugs.

The "black-box" warnings on both drugs caution that key ingredient salmeterol may increase the risk of asthma-related death.

The revised warning cautions that Advair should be used only by patients when other asthma drugs, such as low- to medium-dose inhaled corticosteroids, don't work or if their asthma is severe enough to merit use of two medications.

As for Serevent, it should only be used as an additional medication when the low- to medium-dose inhaled corticosteroids aren't sufficient or, again, if the asthma is serious enough to merit use of two drugs.

In a statement, drug maker GlaxoSmithKline said it was pleased to reach an agreement with the FDA on the label changes to its two drugs.

A third asthma drug, Foradil, manufactured by Novartis, remains in talks with the FDA and could receive a similar black box warning.

In making the ruling, the FDA cites a large U.S. study that found that more people using the asthma drugs died from their asthma compared with those taking dummy medication. The number of asthma deaths in the study was small, however: just 13 out of 13,176 patients.

The drugs assist with long-term control and prevention of asthma symptoms such as wheezing and shortness of breath by relaxing muscles around the airways in the lungs.

Serevent Exposes Blacks to Higher Risk of Asthma-Related Death – Study

Wed, 22 Feb 2006 00:00:00 -0800

A new study has found that GlaxoSmithKline’s (GSK) popular asthma drug, Serevent, (salmeterol), exposes African-American patients to a higher risk of asthma-related death.

The study was led by Dr. Harold S. Nelson, professor of medicine, allergy and immunology at the National Jewish Medical and Research Center in Denver, Colorado.

Serevent is a member of the beta agonist class of asthma medications, which treat asthma symptoms by relaxing inflamed airways.
According to Dr. Nelson: "The bottom line is that in a very large study in which salmeterol or a placebo was added to whatever treatment patients already were on, there was an increased number of severe asthma attacks, including fatal attacks.

The researchers analyzed data from 1996 to 2003, looking at the harmful side effects of salmeterol among more than 26,000 males and females over 12 years of age.

All subjects were asthma sufferers already taking some form of asthma medication other than inhaled beta antagonists. In the year before the study, over 25% of the subjects had visited an emergency room as a result of an asthma attack and 8% had been hospitalized.

Over a 28-week period, each patient used a salmeterol inhaler or a placebo inhaler twice a day along with their current drug regimen.

The study, published in the January issue of Chest, found that white patients on either salmeterol or a placebo showed almost no difference in the number of life-threatening or fatal respiratory or asthma-related episodes.

The researchers noted that before the study began, blacks reported had higher hospitalization and emergency room visit rates due to asthma.
(Source: NewsTarget.com 2.21.06)

Serevent May Pose Greater Risk of Death to Blacks

Fri, 13 Jan 2006 00:00:00 -0800

Recently released information about a safety trial on the asthma drug Serevent indicates that blacks who took the drug were four times as likely to have life threatening respiratory episodes or deaths as blackks who did not take the drug. No similar dicrepancy was observed among whites, however.

The trial, conducted in 2003, was terminated early and the findings resulted in the FDA requiring the addition of a “black box” warning on the product label for both of GlaxoSmithKline’s (GSK) asthma drugs Serevent and Advair.

Of the 13,176 subjects treated with Serevent for 28 weeks, 13 died. Only three deaths were reported among the 13,179 participants who did not take the drug.

Significantly, of the 13 deaths, seven were black (53.8%) despite the fact that blacks represented only 18% of the total study population.

The results of the trial, called Salmeterol Multicenter Asthma Research Trial (SMART), appear in the January issue of the journal Chest.

These significant findings were first reported to the Food and Drug Administration in 2003. As mentioed above, thisa resulted in Serevent and Advair being required to have a black-box warnings added to their labels.

The warning states that use of the drug in the clinical study caused a "small but significant increase in asthma-related deaths." A separate advisory states: "Data from this study further suggests that the risk might be greater in African-American patients."

Dr. Harold S. Nelson, a professor of medicine at Denver's National Jewish Medical and Research Center, said that the apparent racial difference found in the study is probably not due to genetic or other physiologic differences between blacks and whites.

Dr. Nelson, who lead the research (and is also a consultant and speaker for GSK), believes that economically disadvantaged black participants may have had poorer control of their underlying disease.

According to Nelson, a disproportionate number of black patients who died or had life-threatening asthma-related events in the study were not taking an inhaled corticosteroid. "In the patients who were not on inhaled corticosteroids, [Serevent] may have relieved their symptoms but masked their worsening asthma."

Dr. Steven E. Gay, a member of the FDA advisory panel that evaluated the safety of long-acting beta-antagonists like Serevent, Advair, and Foradil (Schering-Plough), said that these drugs are excellent for providing additional relief to those patients who are also using inhaled corticosteroids to manage their asthma condition. As a result, the panel recommended that the drugs be kept on the market in the U.S.

As a long-acting beta-agonists, Serevent and Advair treat the symptoms of asthma but not the inflammation that causes it. Both Serevent and Advair contain the active ingredient salmeterol, but Advair also contains an inhaled corticosteroid.

Currently long-acting beta-agonists are recommended only as an additional treatment. for asthma patients. Patients using the durg should also be taking an inhaled corticosteroid to reduce inflammation and treat the underlying cause of their condition.

Gay says that further research is needed to determine if Serevent and other long-acting beta-agonists are truly dangeous to blacks. In the meantime it is the repsonsibility of doctors to insure they are used properly and to monitor patients carefully. He believes these “drugs clearly still have a role in the treatment of asthma. I monitor my African-American patients who are on the drugs closely for changes in their asthma, as I do all my patients who take them."

Asthma Drugs Educe FDA Worry

Fri, 18 Nov 2005 00:00:00 -0800

The Food and Drug Administration on Friday issued a public health advisory about potentially fatal side effects from two GlaxoSmithKline asthma drugs. The company vigorously disputed the FDA's analysis.

The agency is asking the maker of the drugs, Advair Diskus and Serevent Diskus, to add warnings to their labels that these medications "may increase the chance of severe asthma episodes, and death when those episodes occur."

Advair is GlaxoSmithKline's biggest product, with $4 billion in sales during the first nine months of 2005. Serevent's sales were $450 million.

The FDA made the same request of Schering-Plough and Novartis, which make and sell a similar asthma product called Foradil Aerolizer. They had no immediate comment.

Each of the drugs cited by the FDA is a long-acting beta 2-adrenergic agonist, or LABA, which provides asthma relief by relaxing muscles around the airways to the lungs. Although they can reduce the number of asthma episodes, the FDA says they "may increase the chances of a severe asthma episode when they do occur."

In one study, the agency says, "an increased number of people taking a LABA in addition to their usual asthma care died from their asthma compared to people taking a placebo in addition to their usual asthma care, although the number of asthma deaths in the study was small."

The FDA proposal is "inconsistent" with treatment guidelines established by the National Institutes of Health, as well as "the standard of care for asthma treatment, which could put many patients at risk of uncontrolled asthma," GlaxoSmithKline said.

LABA drugs shouldn't be the first line of defense vs. asthma, the FDA says. Instead, they should be "added to the asthma treatment plan only if other medicines do not control asthma, including the use of low-or-medium dose corticosteroids."

But GlaxoSmithKline says the combination of LABA and inhaled corticosteroid drugs is an effective first-line treatment. The FDA's proposal would limit an asthma sufferer's choices "until after a patient has failed on other treatment options and therefore may be at risk for severe outcomes, such as exacerbations and potentially death," said Dr. Kathy Rickard, a respiratory medicine executive for GlaxoSmithKline, in a prepared statement.

"Sufficient safety information about these medicines is already in the labels to help guide physicians about their appropriate use," Rickard said. "However, we will work with FDA to address the differences of opinion about how best to communicate the benefit-risk profile of these medicines for optimal patient care."

Serevent's safety has been questioned by well-known drug industry critics, Public Citizen and Dr. David J. Graham, a veteran FDA researcher. Graham told senators during a hearing last year on Merck's now-wthidrawn arthritis drug Vioxx that several other marketed drugs needed more scrutiny or tougher labels. Serevent was one of those drugs.

Serevent, Advair, and Foradil Linked to Risk of Severe Asthma Exacerbations, Death

Fri, 18 Nov 2005 00:00:00 -0800

The U.S. Food and Drug Administration (FDA) has warned healthcare professionals regarding the increased risk of severe asthma episodes and death associated with use of inhalation powders containing long-acting beta 2-adrenergic agonists (LABA) such as salmeterol xinafoate and formoterol fumarate.

Inhalation powders included in the warning include salmeterol (Serevent Diskus, made by GlaxoSmithKline), salmeterol combined with fluticasone propionate (Advair Diskus, made by GlaxoSmithKline), and formoterol (Foradil Aerolizer, made by Novartis Pharmaceuticals Corp.).

Patients receiving these medications should be advised to seek medical attention immediately if their asthma worsens, according to an alert sent today from MedWatch, the FDA's safety information and adverse event reporting system.

The warning was based on data from a 28-week clinical trial (Salmeterol Multi-center Asthma Research Trial [SMART]) in 26,355 patients, showing that addition of salmeterol to usual asthma therapy was associated with an increased risk of fatal asthma events compared with placebo (13 vs 3 deaths; 0.10% vs 0.02%). These results led to early discontinuation of the study.

Although post-hoc subpopulation analyses suggested that the relative risk (RR) of death was similar among whites (RR, 5.82; 95% confidence interval [CI], 0.70 - 48.27) and African Americans (RR, 7.26; 95% CI, 0.89 - 58.94), incidence rates were higher among African Americans.

The results from SMART were similar to those of the Salmeterol Nationwide Surveillance (SNS) study in 25,180 patients, showing the incidence of respiratory and asthma-related death to be numerically (though not statistically) greater with addition of salmeterol rather than albuterol to usual asthma therapy (12 vs 2 deaths).

Although no studies have been adequate to determine whether formoterol is also associated with an increased rate or relative risk of asthma-related death, smaller studies have linked its use to an increased incidence of serious asthma exacerbations compared with albuterol and placebo.

Healthcare professionals with asthma patients receiving these medications should be aware that LABAs are not intended as first-line therapy and should be reserved for use in those who have demonstrated an inadequate response to other asthma-controller medications such as inhaled corticosteroids.

Current guidelines from the National Heart, Lung, and Blood Institute and World Health Organization recommend inhaled corticosteroids as the first step in controller therapy, with LABAs as optional add-on therapy if low- to medium-dose inhaled corticosteroids provide inadequate relief.
The FDA notes that the warning applies to use of LABAs for the long-term control and prevention of asthma symptoms. Information is not available to determine the relevance of these findings in patients using LABAs for the prevention of exercise-induced bronchospasm or long-term control of bronchospasm due to chronic obstructive pulmonary disease.

Adverse events related to the use of long-acting beta 2-agonists should be reported to the FDA's MedWatch program by phone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, MD 20852-9787.

Safety Information About A Class of Asthma Drugs Known As Long-Acting Beta-2 Agonists

Tue, 04 Oct 2005 00:00:00 -0700

Health Canada is advising Canadians of the possible increased risks of asthma-related deaths associated with the use of a class of asthma drugs known as long-acting beta-2 agonists.

Further, Health Canada is reminding Canadians of the recommended uses of long-acting beta-2 agonists.

The asthma medications are salmeterol, which is sold under the brand name Serevent; formoterol, sold as Foradil and Oxeze; as well as two combination products containing salmeterol or formoterol in addition to an inhaled corticosteroid. The combination product with salmeterol is sold as Advair, while the formoterol product is sold as Symbicort.

This advisory is based on a Health Canada analysis of findings from an asthma research trial conducted by GlaxoSmithKline, known as the Salmeterol Multi-center Asthma Research Trial, or SMART. The SMART study began in 1996 at the request of the U.S. Food and Drug Administration (FDA), due to increasing safety concerns about regular long-term use of salmeterol in the treatment of asthma. The study of approximately 30,000 patients was prematurely halted in January 2003 after an interim analysis suggested an increased risk of asthma-related death in patients who use Serevent (as compared to a placebo) in addition to their usual asthma therapy. The SMART study data was reviewed by an FDA advisory committee in July 2005 that looked at the safety of these asthma medications. The committee voted unanimously to keep this class of drugs on the market.

Although not conclusive, the SMART study suggests that risks may be higher in African-American patients and in those patients who were not being treated with inhaled corticosteroids at the start of the study. Corticosteroids are a family of drugs with anti-inflammatory effects that are used in asthma treatment, and they are most commonly used in the form of a powder inhaled directly or can be given orally in more severe cases.

Health Canada monitored the FDA advisory committee in July, which noted that increased risks with salmeterol may also apply to other long-acting beta-2 agonist medications such as formoterol, although data to confirm this is not yet available.

Health Canada recommends that:

Salmeterol and formoterol can only be used with an appropriate dose of inhaled corticosteroid as determined by a physician.

Long-acting beta-2 agonists are not a substitute for inhaled or oral corticosteroids.
Serevent, Foradil or Advair should never be used to treat acute or sudden onset of asthma symptoms and attacks.
Symbicort is not indicated for the treatment of sudden asthma symptoms and attacks.

Oxeze may be used to treat acute, or the sudden onset of asthma symptoms, in patients 12 years and older.
Medical attention should be sought if a patient's use of asthma medications becomes less effective, or if more inhalations than usual are required.

Patients must not stop or reduce their asthma therapy without first consulting their prescribing physician. Abruptly stopping medications may result in deteriorating asthma control, which can be life-threatening.
Patients with asthma who have any questions about their current prescription or treatment should contact their physician or pharmacist directly.

The prescribing information for Serevent and Advair has been updated. Health Canada is engaged in an ongoing review of these products, and is in the process of reviewing the safety data for the other long-acting beta-2 agonists. Further action may be taken if necessary.

Health Canada has requested that manufacturers of these medications inform physicians of the SMART study findings and of the outcome of the FDA advisory committee meeting. The FDA panel only reviewed data relating to Serevent (salmeterol) and Foradil (formoterol).

Long-acting beta-2 agonists are prescribed as regular treatment to prevent asthma symptoms such as wheezing, shortness of breath and cough. Serevent and Advair are manufactured by GlaxoSmithKline. Foradil is manufactured by Novartis, and Oxeze and Symbicort are manufactured by AstraZeneca.

Serevent, To Be Examined By Experts Due To Deaths Associated With Its Use

Sun, 17 Jul 2005 00:00:00 -0700

Serevent, a powdered medication inhaled by asthma patients to keep their airways open, will be a focus of an FDA Pulmonary-Allergy Drugs Advisory Committee meeting today as it has been linked to 13 deaths related to asthmatic symptoms in patients who took the drug to avoid asthma attacks.

FDA documents released yesterday indicate that about a year ago, the agency asked Glaxo to strengthen Serevent's existing so-called black box warning, the most serious a drug label can carry. The FDA wanted the label to say that a study found a "a small but significant" risk for asthma-related deaths in all Serevent users and not just African-Americans, as previously indicated.

Although Glaxo halted its study of Serevent in 2003 after finding that it couldn't enroll enough people and that there was a slight increase in asthma-related deaths in Serevent patients compared to those taking a placebo, pulmonologist and vice president of Glaxo's respiratory medicine development center, defended Serevent, saying that the drug had actually proven to be very effective. However she suggested that Serevent patients should take it with corticosteroids and those who do not could be at increased risk for asthma attacks.

FDA Orders "Black Box" Warning for Asthma Drugs

Thu, 14 Jul 2005 00:00:00 -0700

The US Food and Drug Administration has cleared asthma drugs Advair and Serevent, allowing them to stay on the market as long as warning labels clearly alert patients to potential risks.

Made by GlaxoSmithKline, the medications contain salmeterol, a bronchodilator known as a beta2-agonist. It works by relaxing the bronchial muscles, thereby improving air flow for many of the 15 million asthma sufferers in the U.S.

Regulators became alarmed when Glaxo reported that it had to stop tests of the drug when about 50 out of 26,000 patients being studied suffered more severe asthma attacks. A few died.

After a review by its panel of experts, the FDA voted 12-0 to keep the drugs on the market while adding a "black box" warning, the most extreme warning that can be put on drugs.

The tests were launched in 1996 at the behest of the FDA to address specific questions about Serevent and Advair. In 2003, the trials were stopped after 50 people experienced serious, life-threatening episodes or died, compared with 36 episodes in patients who had been given a placebo.

One statistic that initially raised concerns was that African-Americans in the study appeared to have a higher rate of death. Twenty black people who had receive the drug died, compared with five who were taking the placebo.

But doctors involved in the study and other researchers agreed that the statistic was misleading and did not indicate that blacks were at higher risk of dying from taking the drugs. FDA panelists stressed that the higher death rate in the test was a fluke and that it would be irresponsible to mislead blacks into turning from medication that could prolong their lives.

Asthma is a dangerous disease, especially when it is untreated or under-treated. No one now taking prescribed medications should stop taking them without consulting their physician. It can be dangerous to suddenly stop taking prescribed medications.

Sales of Servent and Advair, marketed as Seretide in Europe, topped $4 billion last year. Novartis' asthma remedy, Foradil, which was also reviewed, brought in only $320 million.

Five Brands of Risk

Tue, 07 Dec 2004 00:00:00 -0800

It's been a tough couple of weeks for the U.S. Food and Drug Administration (FDA) and pharmaceutical companies. But it's also been difficult for the millions of people who are taking any of five medications cited as potentially dangerous at a Nov. 18 Senate hearing.

That hearing was held to explore the FDA's record on warning people about drug risks. During his testimony, David J. Graham, associate director of the FDA's office of drug safety, said underpublicized safety risks of five drugs weight loss medication Meridia; acne drug Accutane; asthma medication Serevent; cholesterol drug Crestor; and painkiller Bextra could lead to restrictions or withdrawal of the drugs from the market.

More than 15 million prescriptions were filled for the five drugs during the first nine months of this year, according to IMS Health, a pharmaceutical information and health care consulting company. While the makers rigorously defend the drugs' safety when taken as directed, some people who take them are scared.

Michael Miller, director of the Center for Preventive Cardiology at the University of Maryland Medical Center in Baltimore, said at least 10 patients have called asking what to do. While some research suggests that Crestor carries greater risk of serious side effects than other statins, Miller said current knowledge does not warrant taking most patients off the drug. He will continue to monitor patients carefully and won't prescribe Crestor to those at high risk for the most serious side effects.

If you are taking one of these drugs and want to consider another treatment, experts recommend consulting with your doctor before stopping or changing any regimen. Some drugs interact with others, so you should tell your doctor about any drugs -- prescription or over-the-counter -- you're taking on a regular basis.

For those taking any of the five drugs, risks and options are discussed below.

Meridia Used for weight loss, works by "acting on the appetite control centers in the brain," according to its maker, Abbott Laboratories. The drug works best when combined with a low-calorie diet, the company says.

Risks Elevated risk of cardiovascular side effects, including heart attack and stroke.

Drugmaker Response Illinois-based Abbott says it stands behind the safety of the drug.

Alternatives The best way to drop pounds: Eat less, move more, doctors said. "I very much believe in behavior modification and lifestyle changes," said Tania Heller, medical director of Suburban Hospital's Center for Eating Disorders and Adolescent Obesity. For patients at high risk for complications of obesity -- such as those with type 2 diabetes -- drugs may help speed weight loss, Heller said. "But the key point to get across is not to rely only on medication" to lose weight, she said.

For patients who need medication, obesity drug Xenical, made by Roche Pharmaceuticals, is another option. The drug works by preventing about a third of the fat in the food you eat from being digested. Studies show that patients taking the drug lost twice as much weight as those on the same diet without medication. Side effects -- increased frequency and urgent need to empty the bowels, and gas with an oily discharge do not enhance its popularity.

Accutane A synthetic form of Vitamin A, used to treat severe acne.

Risks Can cause severe birth defects when taken by pregnant women.

Drugmaker Response The risk for birth defects when the drug is taken by pregnant women has been known since its 1982 approval, said Carolyn Glynn, spokeswoman for Roche Pharmaceuticals. Roche and the companies that distribute the three generic forms of Accutane require doctors to test women for pregnancy before prescribing the drug, and to sign forms stating they've educated patients about known risks.

Alternatives Oral antibiotics and topical medications should be tried before taking Accutane. But neither type of drug is considered as effective as Accutane in treating the most severe cases of acne, said Paula Bourelly, assistant professor of dermatology at Georgetown University Hospital. Since Accutane is the only medication considered effective for the most severe forms of acne, patients with the very worst cases have limited options. Bourelly said she has had new patients report taking antibiotics for months in an effort to clear up their acne.

Serevent A long-acting inhaled bronchodilator (a drug that widens the airways in the lungs) used for long-term management of asthma and chronic obstructive pulmonary disease.

Risks "Rare but serious asthma episodes and asthma-related fatalities occurred in a study with Serevent," GlaxoSmithKline reports on its Web site. "These risks may be greater in African Americans." Researchers think risks are higher for people with certain types of beta receptors (which exist on cells that line the surface of organs, including the lungs); this type of receptor seems more common in black patients. Some people of other races may have this type of beta receptor, too, doctors said.

Drugmaker Response GlaxoSmithKline says it addressed this concern by adding a "black box" to Serevent's label in August 2003, warning patients and doctors of this risk, according to a written statement the company issued on the day of Graham's testimony. Patients should not stop taking Serevent without their doctor's approval, the statement says.

Alternatives For those who don't want to take Serevent, there are several options, depending on the severity of the patient's asthma. Those with mild asthma may use a rescue medication like albuterol, which is taken only when the patient feels short of breath or has other asthmatic symptoms, said Martha White, an allergist at the Institute for Asthma and Allergy in Wheaton and Chevy Chase.

People with asthma who have symptoms at least twice a week need more treatment, White said. Options include another long-acting bronchodilator called Foradil, inhaled corticosteroids and Singulair, a leukotriene inhibitor (which is thought to work by blocking a substance that is released by cells in the lungs during asthma attacks).

Inhaled corticosteroids are considered the most effective at managing asthma symptoms, but they carry a heightened risk particularly at higher dosages of oral thrush (mouth infection), skin thinning and bruising with long-term use. The side effects for Foradil, usually used in combination with inhaled corticosteroids, include tremors, fast or irregular heartbeat, headache, muscle cramps or pain and, in rare cases, bronchospasms (narrowing of the airways). The side effects for Singulair which is not as effective as inhaled corticosteroids at controlling asthma symptoms include fatigue, fever, stomach pain and upset stomach.

Bextra A COX-2 painkiller often used to treat osteoarthritis.

Risks Bextra may have the same cardiovascular risks as those that caused Merck & Co. to pull Vioxx from the market in September. Some experts say that COX-2 drugs in general may be unsafe for long-term use. Existing research both confirms and refutes this risk, so more studies are needed.

Drugmaker Response Pfizer considers the drug to be "safe and effective," said spokeswoman Mariann Caprino. The drug company looks forward to the FDA's February 2005 meeting on the safety of Bextra and Celebrex, the only other COX-2 drug left on the market, Caprino said.

Alternatives Other choices include NSAIDs (nonsteroidal anti-inflammatory drugs), available by prescription (including Mobic and Daypro) and over-the-counter (including Motrin, Aleve and Advil).

Weight loss, if needed, and regular exercise may also ease pain. To relieve pain temporarily, heat and ice may help. Topical medications such as corticosteroids, Bengay and capsaicin may also ease soreness. Some patients may find relief through corticosteroid or hyaluronic acid injections into sore joints. Injection complications include infection, and repeated corticosteroid shots can increase risks of cataracts and bone weakening. In rare cases, skin whitens and thins at the injection site.

Crestor A statin drug used to treat high cholesterol.

Risks Kidney failure and rhabdomyolysis, a rare but potentially fatal muscle disease. Complications are more likely at higher doses (the highest approved dose in the United States is 20 milligrams; highest dosages elsewhere extend to 40 milligrams).

Drugmaker Response In a written statement issued Nov. 19, AstraZeneca said senior FDA officials reassured the firm that "there is no concern in relation to Crestor's safety and that they [the FDA] have issued a statement explaining that Dr. Graham's testimony does not reflect the views of the agency." The company has also run newspaper advertisements to reassure patients taking Crestor of the drug's safety.

Alternative treatments Other statin drugs include Lipitor, Zocor, Pravachol and Lescol. The decision on which to take should be made in consultation with your doctor, since dose and duration of treatment may vary depending on how high your cholesterol is, how low the target is and other factors. All statin drugs carry some risk for rhabdomyolysis, as well as risk of increasing liver enzymes. Liver function should be monitored regularly.

Diet and exercise are also powerful tools to help keep cholesterol and blood pressure in check, though doctors caution patients not to forego medication for levels deemed dangerously high by their doctors.

But don't stop taking your medication even if your cholesterol levels dip into safer territory. Former president Bill Clinton, who underwent emergency heart bypass surgery in September, had stopped taking his statin medication after losing weight and becoming more fit. His LDL or "bad" cholesterol level had decreased since his last presidential physical, from 177 to 114 when measured the week before his heart surgery. The recommended LDL level is less than 70.

Concern About Drug Safety Doesn't Stop With Vioxx

Mon, 22 Nov 2004 00:00:00 -0800

Doctors have been taking calls from anxious patients ever since a Senate hearing on Vioxx last week at which an FDA scientist expressed concerns about the safety of five other drugs on the market.

That David Graham of the Food and Drug Administration's Office of Drug Safety named names was surprising. But to anyone who has kept up with the scientific literature and the drugs' evolving labels, the names themselves were not.

Steven Galson, an FDA administrator, attempted to temper Graham's testimony by saying the agency must consider benefits as well as risks, "so that safe and effective drugs remain available to patients who need them."

Some of what is known about the five drugs so far:

Accutane. Accutane can cause major fetal defects, and Roche, its maker, has warned against use during pregnancy since it came on the market in 1982. Yet, according to the March of Dimes, thousands of pregnant women have taken it.

In 2001, the FDA approved a voluntary system developed by Roche to prevent pregnant women from taking Accutane. But an FDA review found the proportion of Accutane users who were pregnant might actually have gone up in the year since the system went into effect.

In February, an FDA advisory panel recommended a more-restrictive program that would set up a registry of all Accutane prescribers, all pharmacists who dispense it and all users. It has not yet been implemented.

Bextra. As with Accutane, Graham did not call for Bextra in the same class of drugs as Vioxx to come off the market. But, he said, too little is known about Bextra's effect on heart attack or stroke risk. Last month, Pfizer sent a letter to health-care professionals mentioning results of two Bextra trials in heart-bypass-surgery patients. In both, the Bextra groups had more heart attacks and strokes than the placebo groups.

Crestor. This cholesterol drug has drawn regulators' attention in Europe and Canada.

At the Senate hearing, Graham said Crestor is the only statin drug that causes kidney failure. And, he said, it carries a higher risk of rhabdomyolysis than any other statin. Rhabdomyolysis is a potentially fatal muscle complication that benched another statin, Baycol, in 2001.

In June, Crestor maker AstraZeneca released a revised package insert for use in the European Union. It highlighted the rhabdomyolysis issue. Later that month, the Canadian government issued an advisory warning of a possible link between Crestor and rhabdomyolysis, especially at higher doses

Two months after the FDA approved Crestor in August 2003, consumer watchdog Public Citizen warned consumers not to use it because of kidney toxicity. The group has asked the FDA to ban Crestor.

Meridia. Graham said that few patients stay on the weight-loss drug very long because extended use can lead to increased blood pressure and stroke. Before Meridia was approved in 1997, an FDA advisory panel voted 5-4 that the drug's benefits did not outweigh its risks. Public Citizen has twice petitioned the FDA to pull it off the market.

Serevent. The Glaxo asthma drug, approved in 1994, dilates breathing passages. In 2003, its label began carrying a "black box" warning, the strongest type of warning, about the results of a large U.S. study that showed a small but significant increase in asthma-related deaths in patients who took Serevent. Advair, another Glaxo asthma treatment, which contains Serevent and a steroid, carries the same warning.

Richard Honsinger, a Los Alamos, N.M., asthma and allergy specialist, says he fielded some calls from worried patients after Graham's pronouncement. He says Serevent only relieves symptoms and should be taken along with a steroid to prevent permanent scarring in the lungs from inflammation.

Salmeterol Warning Cites Risk of Asthma Deaths

Wed, 01 Oct 2003 00:00:00 -0700

The labels of three GlaxoSmithKline asthma products containing salmeterol now have boxed warnings citing a "small but significant increase in asthma-related deaths," based on recommendations from the Food and Drug Administration.

The interim results of a study of approximately 29,000 asthma patients in the Salmeterol Multi-Center Asthma Research Trial (SMART) showed more asthma-related deaths and life-threatening asthmatic episodes among African American patients taking salmeterol than among those taking a placebo.

The products with label changes are Serevent Inhalation Aerosol (salmeterol xinafoate), Serevent Diskus (salmeterol xinafoate inhalation powder), and Advair Diskus (fluticasone propionate and salmeterol inhalation powder). Serevent Diskus is approved for treatment of asthma in patients aged 4 years and older, while both Serevent Inhalation Aerosol and Advair Diskus are approved for patients aged 12 years and older.

The "Dear Healthcare Professional" letter included with the products states that patients currently taking these medications should not stop suddenly this may lead to life-threatening asthmatic episodes due to uncontrolled asthma. In addition, the letter reminds physicians that patients taking salmeterol as their only asthma therapy should add an inhaled corticosteroid to their treatment regimens.

However, the warning implies a much broader problem than exists, Dr. Harold Nelson, professor of medicine at the National Jewish Medical and Research Center, Denver, told this newspaper. The adverse outcomes occurred in patients who were not only African American, but who were not taking inhaled corticosteroids. Those taking inhaled corticosteroids concurrently with salmeterol had no adverse effects, regardless of ethnicity.

In a 28-week safety study, asthma patients aged 12 years and older were given either 42 [micro]g of salmeterol or a placebo twice daily. Although the study was meant to include approximately 60,000 patients, it was stopped at the halfway point due to evidence of increased risk of asthma-related deaths among patients who received salmeterol: 13 deaths among 13,174 patients, compared with 4 asthma-related deaths among 13,179 patients who received placebo. Approximately 17% of the study subjects were African American.

The SMART study did not include outcome analyses based on demographic traits, but a later subgroup analysis showed a statistically significant increase in the number of asthma-related deaths among African American patients who received salmeterol compared with those who received placebo (eight vs. one). In addition, a weakness of the SMART study is that the only information about concomitant medication is the form that patients filled out at the beginning of the study, Dr. Nelson noted.

However, the FDA maintains that the benefits of salmeterol outweigh the risks when patients with asthma and chronic obstructive pulmonary disease use the medication properly and that includes taking inhaled corticosteroids concomitantly.

Labeling Changes for Drug Products that Contain Salmeterol

Mon, 18 Aug 2003 00:00:00 -0700

The Food and Drug Administration is announcing the addition of new safety information and warnings to the labeling for drug products that contain salmeterol, a long-acting bronchodilator used to treat asthma and chronic obstructive pulmonary disease (COPD). The products affected by these changes are Serevent Inhalation Aerosol, Serevent Diskus, and Advair Diskus. The new labeling for these products will contain a boxed warning about a small, but significant, increased risk of life-threatening asthma episodes or asthma-related deaths observed in patients taking salmeterol in a recently completed large U.S. safety study.

On January 23, 2003, FDA released a talk paper announcing the preliminary results of an interim analysis of the Salmeterol Multi-center Asthma Research Trial (SMART), which compared the effects of salmeterol (Serevent Inhalation Aerosol, 42mcg twice-daily) to placebo in patients with asthma for a period of 28 weeks. Since that time, FDA has worked closely with GlaxoSmithKline, the sponsor of the study and the manufacturer of Serevent and Advair, to carefully review the study results and to develop appropriate labeling to reflect the new information provided by this study.

The primary endpoint for the SMART study was the occurrence of either respiratory-related death or a respiratory-related life-threatening experience (e.g., requirement for mechanical ventilation). Secondary endpoints included all-cause death, asthma-related death, and asthma-related death or life-threatening experience.

Although the study was intended to enroll 60,000 patients, the study was stopped by the sponsor after review of the results of a planned interim analysis, which was performed after approximately half of the intended number of patients was enrolled. The analysis includes 13,174 patients treated with Serevent, and 13,179 patients treated with placebo. The analysis showed no significant difference between treatment groups for the primary endpoint, however, a higher number of asthma-related deaths (13 vs. 4), and a higher number of asthma-related deaths or life-threatening experiences (36 vs. 23) were observed in the Serevent group compared to placebo.

The SMART study was not prospectively designed to analyze differences in outcome based on demographic characteristics; however post-hoc subgroup analyses based on race and ethnicity were conducted. These analyses showed no increase in respiratory- or asthma-related events among Caucasian patients; however, among African-American patients there was a statistically significant increase in primary events (respiratory-related death of life-threatening experience) in the Serevent group (20 vs. 7). In addition, the occurrence of asthma-related death (8 vs. 1) and asthma-related death or life-threatening experience (19 vs. 4) was statistically significantly greater in African-American patients treated with Serevent compared to placebo.

FDA emphasizes that based on available data, the benefits of treatment with salmeterol in patients with asthma and COPD continue to outweigh the potential risks when used according to the instructions contained in the product labeling. FDA strongly advises patients that they should NOT stop taking products that contain salmeterol, or any other medication, for asthma or COPD without first talking to their physicians. Abruptly stopping drugs for the treatment of asthma and COPD can result in serious worsenings of these diseases that could be life-threatening. FDA further emphasizes that all asthma drugs, including salmeterol, should be prescribed as part of a comprehensive plan that takes into account the patient's asthma severity and fully educates the patient in the disease and its proper treatment.

Serevent Inhalation Aerosol, Serevent Diskus, and Advair Diskus, which all contain salmeterol as an active ingredient, are manufactured by GlaxoSmithKline of Research Triangle Park, N.C.

Misuse of Inhalers May Worsen Asthma

Fri, 15 Aug 2003 00:00:00 -0700

After years of mystery, scientists say they finally understand why asthma patients who use the most common types of inhalers often suffer from a rebound effect that makes their condition worse.

Airway-opening inhalers including albuterol, ventolin and salbutamol appear to cause a biochemical reaction that exacerbates swelling in the body's airway. The swelling, in turn, can block air flow and make breathing more difficult.

"Everyone knew that effect that was there, but no one knew why. Now we know," says Dr. Tom Stibolt, a pulmonologist with the Kaiser Permanente health plan in Portland, Ore.

Over the past two decades, a new generation of medications known as beta2-agonists, commonly found in inhalers, has let asthmatics breathe more easily by opening up their airways. But doctors have long known those patients can relapse if they don't use another kind of inhaler that reduces inflammation in the airway, which causes constriction in the first place.

On the one hand, the bronchodilating inhalers known as "relievers" are a good temporary measure "because they save lives while you do the things you need to do to reduce the inflammation," Stibolt says. But patients often are so impressed by the rapid response of the inhalers that they don't use the anti-inflammation inhalers known as "controllers" that provide a recurrence.

"They say this medication isn't doing anything," Stibolt says. "But it's preventing a problem, not relieving it. The mediations they desperately need to be on don't do anything they notice."

As the inflammation on the walls of the airway gets worse, the reliever inhalers fail to work properly as they become overwhelmed, he explains. "It actually worsens the problem in the long term."

The airway constriction can even last for weeks after a patient stops using the reliever inhalers, says Stephanie Shore, a senior physiology lecturer at the Harvard School of Public Health.

However, she adds, the number of affected patients appears to be small. Some may have inherited a propensity to develop the problem.

In the new study, researchers at the University of Cincinnati examined genetically altered mice that were designed to have different levels of a receptor that works to keep the airway open and unblocked by swelling. The results of the study appear in the Aug. 15 issue of the Journal of Clinical Investigation.

The researchers report they discovered an interaction between chemicals that contributes to the growth of inflammation.

Shore, who wrote a commentary accompanying the study, says researchers will need to turn to tests in humans to see if the findings translate to people.

For now, Stibolt says, asthma patients need to understand the importance of using both the reliever and controller inhalers. "If you're using enough controller medication, you hardly use any reliever medication," he says, adding most people should just have to use the reliever inhalers a couple of times a week.

Some patients, however, wrongly accept their poor breathing. "The problem is they don't come in and say, 'I'm using a lot of reliever mediation, help me.' They just figure that's the way it is," he says.

In a separate development, the U.S. Food and Drug Administration (FDA) on Thursday warned users of three asthma drugs that those medications carry a small risk of a life-threatening asthma attack.

The FDA found that patients taking drugs with salmeterol, a long-acting bronchodilator, were likelier -- but still not likely -- to have a dangerous asthma episode. The affected drugs are sold under the names Serevent Inhalation Aerosol, Serevent Diskus and Advair Diskus, all of which are made by GlaxoSmithKline.

The agency said the benefits of these drugs "continue to outweigh the risks when used according to the instructions," and warned of the dangers of stopping the drugs without first consulting a doctor.

FDA Issues Warning On Asthma Drug

Fri, 15 Aug 2003 00:00:00 -0700

Some patients using a popular asthma medication called salmeterol may face a small increased risk of severe, and occasionally fatal, asthma attacks, the Food and Drug Administration warned yesterday.

The side effects are rare, and the FDA said the drug's benefits still appear to outweigh the potential risks when patients follow medication instructions.

It is dangerous to abruptly stop taking the drug, so concerned patients should talk with a doctor, the FDA cautioned.

The FDA first alerted patients and doctors to the problem in January, and now has formally added the warning to the labels of three salmeterol-containing brands Serevent Inhalation Aerosol, Serevent Diskus, and Advair Diskus.

Salmeterol is a long-acting drug used to prevent asthma attacks by relaxing airways. Salmeterol users are urged to always have a fast-acting medicine an inhaled corticosteroid on hand in case the prevention fails and they have problems breathing.

GlaxoSmithKline, which makes all three salmeterol products, launched a large study to compare how well people using inhaled Serevent fared compared with those given a dummy drug.

The study was supposed to enroll 60,000 subjects but was stopped early when researchers counted more asthma-related deaths among Serevent users particularly black patients. The study counted 13 asthma-related deaths among 13,174 Serevent users, compared with four deaths among 13,179 placebo recipients. Among black participants, there were eight Serevent users who died as opposed to one placebo recipient.

Asthma Drug Warning

Wed, 29 Jan 2003 00:00:00 -0800

Health authorities in the U.S. have issued a warning about asthma drug Serevent.

The Food and Drug Administration says some patients using the medication could face life-threatening complications. The person could have trouble breathing and may require intubation the insertion of a tube into the throat forcing open the airways.

Officials say the problems are rare and that the drug's benefits outweigh the risks.

Serevent is also used in Canada but Health Canada hasn't issued a warning. It was approved for use in 1994.

Patients are encouraged to talk to their doctors if they are using Serevent.

Serevent is an aerosol spray made by GlaxoSmithKline. Patients use it twice a day to prevent asthma attacks.

Glaxo started a study looking at the number of asthma-related deaths in patients taking the drug. The 28-week study involved 26,000 patients.

Researchers found a greater risk of problems and death among black patients.

They said deaths were less common among those who use a companion drug, corticosterioids, which controls inflammation. Black patients were less likely to be using the companion drug and were at risk of having lung problems and more likely to die than white patients.

Glaxo would not reveal the number of people who had died.

Serevent Asthma Death Advair, Foradil Side Effects Lawyer

Wed, 29 Jan 2003 00:00:00 -0800

DOWNLOAD OUR SEREVENT INFORMATION PACKAGE

Injured by Serevent?

David Graham, the FDA researcher who questioned Vioxx's safety before it was recalled has recently raised safety concerns about Serevent. Recently a warning was added to Serevent concerning asthma-related fatalities in studies. Data from a large placebo-controlled US study that compared the safety of Serevent (Generic: Salmeterol) and a placebo showed an increase in asthma-related deaths in patients receiving Serevent. In patients taking Serevent there were 13 deaths out of 13,176. In patients taking the placebo there were only 3 of 13,179.

An older study showed 36 patients taking Serevent died from asthma or had life-threatening attacks. Some patients taking Serevent have had trouble breathing and required intubations, the insertion of a tube into the throat forcing open the airways. Serevent is an aerosol spray. Patients usually use it twice a day to prevent asthma attacks.

Serevent Label Update
The label for Serevent has been updated with a warning stating that the drug can increase the chance of severe asthma attacks that can result in death. The Food & Drug Administration (FDA) made this announcement on May 16, 2006.

If you or a loved one took Serevent and suffered side effects, please fill out the form at the right for a free case evaluation by a qualified drug side effects attorney.