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Worst Pills, Best Pills News Articles are derived from our monthly print newsletter. Worst Pills, Best Pills News provides monthly updates both for the drugs on which we have detailed drug profiles and other drugs. Often this includes more specific information about safety or efficacy concerns or new data that either support or resolve concerns regarding particular drugs. Worst Pills, Best Pills News also contains our assessment of data available on the safety and efficacy of drugs newly approved by the FDA. These articles are available for the past five years, and new articles are added monthly. Entire issues of the print newsletter will be available in PDF format for three months after publication. You can access all the information published in the newsletters simply by searching for a relevant drug, disease, drug-induced disease or condition, drug family, or policy issue.

Health Letter Articles come from the other monthly publication of Public Citizen’s Health Research Group. These articles deal primarily with policy issues related to prescription drugs such as prescription drug reimportation and issues related to the pharmaceutical industry. These articles are available for five years after publication.

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DO NOT USE! FDA Relegates ADVAIR and SEREVENT to Last Choice Status for Asthma Treatment

     Worst Pills Best Pills Newsletter article May, 2006
    

DO NOT STOP ANY ASTHMA MEDICATIONS WITHOUT FIRST CONSULTING THE HEALTHCARE PROVIDER WHO PRESCRIBED THE DRUG.

  FDA BLACK BOX WARNING FOR SALMETEROL WITH FLUTICASONE

Long-acting beta2-adrenergic agonists, such as salmeterol, one of the active ingredients in ADVAIR DISKUS, may increase the risk of asthma-related death. Therefore, when treating patients with asthma, physicians should only prescribe ADVAIR DISKUS for patients not adequately controlled on other asthma-controller medications (e.g., low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies. Data from a large placebo-controlled US study that compared the safety of salmeterol (SEREVENT Inhalation Aerosol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks on salmeterol versus 3 deaths out of 13,179 patients on placebo).

The Food and Drug Administration-approved professional product labels for the asthma drugs Advair and Serevent now state that these drugs should only be used when nothing else works to control asthma symptoms. Salmeterol, a component of these two widely-prescribed asthma drugs, is associated with an increased risk of asthma-related death. The change became effective on March 2, 2006.

Salmeterol was approved by the FDA in 1994 to treat asthma, and later approval was extended for the treatment of chronic obstructive pulmonary disease (COPD). The drug belongs to a family of asthma medications known as long acting beta2-receptor agonists. Drugs such as albuterol (PROVENTIL, VENTOLIN), metaproterenol (ALUPENT) and pirbuterol (MAXAIR) are short-acting beta agonists. This new safety labeling change does not apply to these drugs.

Salmeterol is produced by GlaxoSmithKline of Research Triangle, NC. In 2005, there were almost 20 million prescriptions dispensed in U.S. pharmacies for salmeterol (SEREVENT) and salmeterol with fluticasone (ADVAIR). Combined sales approached $3.0 billion.

We listed salmeterol as a DO NOT USE drug in the March 2003 Worst Pills, Best Pills News after a study know as the Salmeterol Multi-center Asthma Research Trial, or SMART for short, was prematurely terminated study because of an excess of asthma related deaths in patients receiving salmeterol. This study was initiated by GlaxoSmithKline in 1996. It was designed to assess the safety of salmeterol because of concerns regarding the safety of regular use of short- and long-acting beta agonists in the management of asthma. We also designated ADVAIR as a DO NOT USE drug after we learned more details concerning the SMART study.

The labeling change will appear under the “Approved Uses” section of the professional product label. The new section in the label of ADVAIR will read:

Long-acting beta2-adrenergic agonists, such as salmeterol, one of the active ingredients in ADVAIR DISKUS, may increase the risk of asthma-related death. Therefore, when treating patients with asthma, physicians should only prescribe ADVAIR DISKUS for patients not adequately controlled on other asthma-controller medications (e.g., low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies. ADVAIR DISKUS is not indicated in patients whose asthma can be successfully managed by inhaled corticosteroids along with occasional use of inhaled, short-acting beta2-agonists.

The new section in the label of salmeterol contains similar warnings.

In addition to the new labeling changes, the FDA now requires that a Medication Guide be distributed with each and refill prescription for salmeterol-containing products. Since 1998, the FDA has had the regulatory authority to require Medication Guides for drugs that present significant public health concerns. The purpose of Medication Guides is to give patients enough information to decide if they wish to use, or continue use, a particular drug. At this time there are about 80 drugs that require Medication Guides.

The full text of the Advair Medication Guide can be found online at the FDA's web site. Anyone receiving a prescription for either of these drugs should receive a copy of the FDA-approved Medication Guide.

A black box warning was added to the professional product labeling for salmeterol-containing products on Aug. 14, 2003 and was subsequently strengthened (see Worst Pills, Best Pills News November 2003 and September 2005). A black box warning is the strongest type of warning that the FDA can request from a manufacturer and the usual standard used by the FDA for requesting such a warning is death in patients.

The most up-to-date black box warning for salmeterol with fluticasone appears at the beginning of this article.

What You Can Do

Do not stop these asthma medications without first consulting the healthcare provider who prescribed the drugs.

You should not use salmeterol (SEREVENT) or the combination of salmeterol with the steroid fluticasone (ADVAIR) as your only treatment of your asthma.

You should read the FDA-approved Medication Guide before filling a new prescription for a salmeterol containing product or a refill prescription for a salmeterol containing product. If you do not have access to the Internet, ask your pharmacist for a copy of the Medication Guide.

You should report any increased need for a short-acting beta agonist to your healthcare provider. This is a sign of deteriorating asthma control.

 

Asthma Drugs Salmeterol (SEREVENT), Salmeterol with Fluticasone (ADVAIR), and Formoterol (FORADIL)

     Worst Pills Best Pills Newsletter article March, 2006
    

DO NOT STOP ANY ASTHMA MEDICATION WITHOUT FIRST CONSULTING YOUR PHYSICIAN. ABRUPTLY STOPPING A MEDICATION MAY RESULT IN ACUTELY DETERIORATING ASTHMA CONTROL.

FDA BLACK BOX WARNING FOR SEREVENT

Data from a large placebo-controlled US study that compared the safety of salmeterol (SEREVENT Inhalation Aerosol) or placebo added to usual asthma therapy showed a small but significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks) versus those on placebo (3 of 13,179)

On Nov. 18, 2005, the Food and Drug Administration requested that additional new safety warnings be added to the professional product labels for the popular asthma drugs salmeterol (SEREVENT), salmeterol with fluticasone (ADVAIR), and formoterol (FORADIL). The new warnings concern the possibility that these drugs may increase the chance of severe asthma attacks and asthma-related death.

The FDA will also require that a Medication Guide be distributed with each new and refill prescription for these drugs. A Medication Guide is FDA-approved, scientifically accurate drug information that is written specifically for patients. The FDA has the regulatory authority to require that pharmacists distribute Medication Guides for drugs that present a significant public health risk.

Salmeterol and formoterol belong to the family of asthma drugs known as long-acting beta-agonist bronchodilators. Note that this is a different family than asthma drugs such as albuterol (PROVENTIL, VENTOLIN) and metaproterenol (ALUPENT), which are short-acting beta-agonist bronchodilators. The new warnings do not apply to the short-acting beta-agonist bronchodilators. Fluticasone is an anti-inflammatory corticosteroid, or steroid, and in combination with salmeterol is sold as Advair. The warning also does not apply to fluticasone when it is used by itself.

The FDA made the following recommendations about the use of salmeterol, formoterol, and Advair:

  • These drugs should not be the first ones prescribed to treatment for asthma.
  • These drugs should not be used by themselves to treat asthma.
  • These drugs should always be used with another asthma treatment drug and only after the other asthma treatment, such as a low-to-medium dose inhaled corticosteroid, has not controlled the asthma.

GlaxoSmithKline of Research Triangle Park, N.C., sells both of the salmeterol-containing products. Salmeterol by itself was dispensed over 2.1 million times in U.S. pharmacies in 2004 with sales exceeding $200 million. The combination product, Advair, is what Wall Street calls a “blockbuster.” More than 16.1 million Advair prescriptions were sold in the U.S. in 2004; sales topped $2.1 billion for the year.

Formoterol is produced by the Schering Corp. of Kenilworth, N.J. It is not a top seller and sales figures for 2004 are not available.

We listed salmeterol as a DO NOT USE drug in January 2003. We did so because the FDA announced that a large safety study had been terminated early due to the fact that data from the trial suggested an increased risk of life-threatening asthma episodes or asthma-related deaths with the use of the drug (see Worst Pills, Best Pills News March 2003).

The terminated safety study was called the Salmeterol Multi-center Asthma Research Trial, or SMART for short. This study was initiated by GlaxoSmithKline in 1996. It was designed to assess the safety of salmeterol because concerns existed regarding the safety of the regular use of both short- and long-acting beta agonists in the management of asthma.  

A black box warning was added to the professional product labeling for salmeterol-containing products on Aug.14, 2003 and was subsequently strengthened (see Worst Pills, Best Pills News November 2003 and September 2005). A black box warning is the strongest type of warning that the FDA can request from a manufacturer and the usual standard used by the FDA for requesting such a warning is death in patients.

What You Can Do

Do not stop any asthma medication without first consulting your physician. Abruptly stopping a medication may result in acutely deteriorating asthma control.

You should not use salmeterol (SEREVENT), the combination of salmeterol with the steroid fluticasone (ADVAIR), or formoterol (FORADIL) as the only treatment of your asthma.

You should report to your physician any increased need for a short-acting beta agonist. This is a sign of deteriorating asthma.

 

Asthma Medicines That Can Cause Asthma Attacks: Do Not Use SEREVENT, ADVAIR or FORADIL

     Worst Pills Best Pills Newsletter article September, 2005
    

DO NOT STOP ANY ASTHMA MEDICATION WITHOUT FIRST CONSULTING YOUR PHYSICIAN. ABRUPTLY STOPPING A MEDICATION MAY RESULT IN ACUTELY DETERIORATING ASTHMA CONTROL.

The Food and Drug Administration advisory committee has voted in favor of putting stronger warnings on three widely used asthma inhalers — salmeterol (SEREVENT), salmeterol with the steroid fluticasone (ADVAIR) and formoterol (FORADIL). These medicines are long-acting asthma inhalers, used to keep asthma under control over time, rather than helping to stop an acute asthma attack.

The FDA convened a meeting of its Pulmonary-Allergy Drugs Advisory Committee on July 13, 2005 to discuss the safety of these drugs. The advisory committee voted to keep these drugs on the market but recommend stronger safety warnings on the professional product labels for all three drugs.

These inhalers are in the family of asthma drugs known as long-acting beta-agonist bronchodilators. Note that this is a different family of medicines than the asthma drugs albuterol (PROVENTIL, VENTOLIN), metaproterenol (ALUPENT) and pirbuterol (MAXAIR). Those are short-acting beta-agonist bronchodilators, and are used to improve breathing during an asthma attack.

GlaxoSmithKline of Research Triangle Park, N.C., sells both of the salmeterol-containing products. Salmeterol by itself was dispensed over 2.1 million times in U.S. pharmacies in 2004 with sales exceeding $200 million. The combination product, Advair, is what Wall Street terms a “blockbuster.” More than 16.1 million Advair prescriptions were sold in the U.S. in 2004; sales topped $2.1 billion for the year.

Formoterol is produced by the Schering Corp. of Kenilworth, N.J. Formoterol is not a top seller and sales figures for 2004 are not available.

We listed salmeterol as a DO NOT USE drug in the March 2003 issue of Worst Pills, Best Pills News after the FDA announced on January 23, 2003 that a large safety study involving salmeterol had been halted prematurely. The study was halted because an interim analysis of outcomes suggested that the drug may be associated with an increased risk of life-threatening asthma episodes or asthma-related deaths.

The prematurely terminated study went by the name of the Salmeterol Multi-center Asthma Research Trial, or SMART for short. GlaxoSmithKline initiated the study in 1996. It was designed to assess the safety of salmeterol because of concerns regarding the safety of regular use of short- and long-acting beta agonists in the management of asthma. There were 25,858 patients recruited before the study was stopped.

At that time, Public Citizen’s attempts to obtain detailed information about the SMART study from the FDA were fruitless. Because the SMART study was conducted after salmeterol was approved and did not fulfill any regulatory requirement on the part of GlaxoSmithKline, details of the study could not be released under the FDA’s interpretation of the Freedom of Information Act. The agency considered this important safety information to be protected confidential commercial information that could not be released to the public.

On August 14, 2003, the FDA announced that a black box warning was added to the professional product labeling for drug products containing salmeterol. This warning applied to both salmeterol by itself and Advair. The FDA can ask for black box warnings for drugs that have been associated with the deaths of patients and may also require them if there is strong evidence from animal experiments. A black box warning is the strongest type of safety warning that the FDA can seek for a drug’s professional product labeling (see Worst Pills, Best Pills News November 2003).

In the first serious congressional hearings examining drug safety held in almost 14 years, Dr. David Graham, an FDA medical epidemiologist, testified before Senator Charles Grassley’s Senate Finance Committee in October 2004 that the safety of salmeterol was of concern to the FDA.

It was not until the day before the July 13, 2005 Pulmonary-Allergy Drugs Advisory Committee meeting, when the FDA posted its review on the Internet, that the public was able for the first time to view the details of the SMART study. This was an unacceptable 31 months after the SMART study was stopped prematurely. The FDA’s review of the SMART study is available at http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4148B1_03_00-FDA-TOC.htm.

The main purpose of the SMART study was to measure the combined number of respiratory-related deaths or respiratory-related life-threatening experiences such as the need for intubation and mechanical ventilation in patients taking salmeterol. This is called the  primary endpoint. The study consisted of a single clinic visit for each participant during which the person’s eligibility status was evaluated.  To be eligible to participate, patients had to have a clinical diagnosis of asthma and currently take prescription asthma medications. During the single clinic visit, patients were randomly assigned to receive either two puffs daily of salmeterol or a placebo.

At the end of the 28-week study, 50 patients out of 13,176 given salmeterol either died or suffered a life-threatening event compared to 36 receiving the placebo. The difference in life-threatening respiratory events and asthma-related deaths between the groups was significant in the FDA analysis.

The following is the proposed revised black box warning for salmeterol.

FDA RECOMMENDED BLACK BOX WARNING:

WARNING: Data from a large placebo-controlled US study that compared the safety of salmeterol (SEREVENT Inhalation Aerosol) or placebo added to usual asthma therapy showed a small but significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks) versus those on placebo (3 of 13,179).

The black box warning added to salmeterol’s labeling on August 14, 2003 suggested that the risk may be greater in African-American patients compared to Caucasians. The FDA has proposed deleting this information from the black box warning because the risk for asthma-related deaths in Caucasians and African Americans treated with salmeterol relative to being treated with placebo were quite similar.

Warnings for Formoterol

The advisory committee also voted that formoterol should carry stronger warnings. At this time, formoterol does not have a black box warning in its professional product labeling as do salmeterol and Advair. The evidence for problems with formoterol is not as strong as it is with salmeterol.

In the three studies submitted by formoterol’s manufacturer to the FDA before the drug was approved, two dosages were evaluated: 12 micrograms and 24 micrograms, each given twice daily. The drug’s approval was restricted to the lower dosage because serious worsening of asthma occurred with more frequency in both adult and pediatric patients who received the higher dose. This result was serious enough to warrant a commitment from the manufacturer to conduct a post-marketing safety study, known as a phase IV study, to further examine the relative safety of the different doses of formoterol. No deaths occurred in this study.

The FDA concluded that the formoterol phase IV study was too small to provide a strong answer similar to the SMART study for salmeterol, but the results were generally compatible with the decision not to approve the higher 24-microgram-twice-daily dose of the drug.

The long-acting beta agonist asthma drugs should not be used as a replacement for inhaled steroids. These drugs should not be started in patients whose asthma is significantly worsening or acutely deteriorating. This may be life threatening. The long-acting beta agonists should not be used to treat acute asthma symptoms.

The weight of the available scientific evidence points to the long-acting beta agonists as being less safe than their short-acting counterparts. There is no evidence that patient outcomes are better with the long-acting agents compared to the older short-acting drugs.

What You Can Do

Do not stop any asthma medication without first consulting your physician. Abruptly stopping a medication may result in acutely deteriorating asthma control.

You should not use salmeterol (SEREVENT), the combination of salmeterol with the steroid fluticasone (ADVAIR), or formoterol (FORADIL) for the treatment of your asthma.

You should report to your physician any increased need for a short-acting beta agonist. This is a sign of deteriorating asthma.


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