Home - forum - List of practitionners TWO LONG-ACTING BRONCHODILATORS COULD INCREASE THE RISK OF SERIOUS AGGRAVATION OF ASTHMA.
Publish on [www.destinationsante.com] [3 October 2005]
A potentially fatal risk.
The FDA is stepping up its warnings, while the Public Citizen association is urging people to stop using them.
What are we to think? Do Serevent and Advair, available in France under the names Serevent and Seretide, really represent a serious risk?
It all started on 23 January 2003 when after only 28 weeks the manufacturer of these products stopped a study which was designed to evaluate their long-term safety. SMART (Salmeterol Multi-center Asthma Research Trial) was halted because of the number of deaths: 13 deaths and 37 cases of life-threatening events for 13 176 patients treated, compared with 3 deaths and 23 serious incidents in the control group.
The consumer organisation, Public Citizen, founded by activist Ralph Nader, has already blacklisted these medical products and recommended to people that they avoid them.
However it was not until July 2005 that the Food and Drug Administration (FDA) posted its evaluation of this study online. Must these products continue to be made available? The Advisory Committee of the FDA met on 13 July last to take a decision. Its twelve members decided unanimously to continue making these medical products available, with considerable emphasis on warnings.
For its part, Public Citizen is asking for more. It is calling on patients "not to use salmeterol (Serevent), the combination of salmeterol with the corticosteroid fluticasone (Advair) or formoterol (Foradil) to treat asthma". It urges them "to report to their doctors any increased need for short-acting bronchodilators (Ventoline or an equivalent, editor) as this is a sign that the asthma is deteriorating".
Above all, according to the association, "do not stop any asthma medication without first consulting your physician. Abruptly stopping a medication may result in acutely deteriorating asthma control".
Pr Jean Bousquet, Director of the Montpellier (France) Asthma Centre and WHO Collaborating Centre, says that he "quite agrees with points 2 and 3 of this argument. However, a patient whose condition is properly balanced by his treatment (bronchodilator) must continue it. Only in the case of a problem must he consult his doctor, who will then decide whether to increase the doses of inhaled corticoids, combine other treatments or start a treatment using antileukotrienes".
Medication and asthma
Treating asthma is a constant battle. A battle against the inflammation of the bronchial tubes, which is responsible for the symptoms:
The choice weapon is the inhalation of corticoids. They have considerably lowered the mortality rate. When they have reached their limit, doctors have two choices;
Long-acting bronchodilators used to dilate the bronchial tubes in the medium to long term. However they have no anti-inflammatory effect. Therefore they do not act on the cause of the disease. That is why they must always be combined with a corticoid;
Or antileukotrienes. These medical products taken in association with corticoids in the form of tablets act on a different path of the bronchial inflammation;
In the event of an attack or temporary problem, short-acting bronchodilators can also be used. Ventoline is the best known one.
Sources:
1. FDA: Evaluation of the SMART study, 13 July 2005, minutes of the ’Pulmonary-Allergy Drugs Advisory Committee’, 16 August 2005;
2. Public Citizen, Worst Pills, Best Pills, March 2003 and September 2005, interview with Dr Peter Lurie, 23 September 2005;
3. Interview with Pr Jean Bousquet, 25 September 2005.
[www.destinationsante.com]
ANTI-ASTHMA DRUGS: THE FDA CONFIRMS THE VERDICT, WHILE EUROPE WAITS
Publish on [www.destinationsante.com] [2 December 2005]
Three anti-asthma drugs have just had their indications strictly limited by the Food and Drug Administration (FDA). The risk of the drugs causing a serious or even fatal exacerbation of the disease was in fact confirmed by the American authority.
The safety of these drugs has been the subject of debate for months on the other side of the Atlantic. Destination Santé had already raised this issue. An ad hoc Advisory Committee which met on 13 and 14 July had played for time, but the FDA has made up its mind. The use of three products is to be revised.
Because of “the risk of death for some patients from an asthma attack”, these drugs must not be used as a first resort. They must be used to complement an inhaled corticoid, and a first treatment involving a corticoid and a short-term bronchodilator (such as ventoline for instance) must be tried first. The patient information leaflets for each product – Serevent Diskus (salmeterol), Advair Diskus (salmeterol + fluticasone) and Foradil Aerolizer have been revised by the FDA.
The issue is being monitored, according to the AFSSaPS The European Agency for the Evaluation of Medicinal Products (EMEA) stated that “none of these products has been the subject of authorisation in Europe. (…) The Agency cannot take up the matter of its own accord, but must wait for a Member State to refer the issue to it”. When we contacted the French Agency for the Safety of Health Products (AFSSaPS), it emphasised the fact that the Americans were going along with practices recommended in France. In its version updated on 19 May 2005, the Summary of Product Characteristics (SPC) for Seretide stated, for instance, that this drug “is recommended (…) for patients whose asthma cannot be properly controlled by an inhaled corticoid treatment and a short-term bronchodilator (…)”. And for patients whose asthma has been brought under control by “the administration of an inhaled corticoid treatment (and) continued treatment involving an inhaled long-term (…) bronchodilator”.
The issue has not yet been settled. The AFSSaPS has said that the EMEA’s Pharmacovigilance Group is producing an inventory and that individual communications may take place in various EU countries, depending on the practices observed.
What are patients to think? Prof. Jean Bousquet, Director of the Asthma centre in Montpellier which cooperates with the WHO, explained to us recently that “a patient whose treatment is well-balanced (with a bronchodilator) must be continued. Only in the case of a problem must he speak to his doctor, who will then decide whether to increase the doses of inhaled corticoids and of treatment combinations, or to start a treatment using antileucotrienes”. Under no circumstances should patients take the initiative of modifying or stopping a treatment in progress.
CORTICOIDS MUST ALWAYS BE USED TO COMBAT ASTHMA. THREE OPTIONS ARE POSSIBLE:
• Inhaled corticoids are in fact the best weapon. However, they are not always enough;
• In the event of a crisis or a temporary problem, doctors prescribe short-term bronchodilators;
• If necessary, other anti-inflammatory drugs, antileukotrienes, can be used to supplement the treatment. They are taken in the form of tablets, together with corticoids.
• And long-term bronchodilators, which do not have an anti-inflammatory function. They are the subject of the restrictions applied by the FDA.
Sources: FDA, 23 November 2005, EMEA, and AFSSaPS, 24 November 2005
DO NOT USE! FDA RELEGATES ADVAIR AND SEREVENT TO LAST CHOICE STATUS FOR ASTHMA TREATMENT
Publish on [www.worstpills.org] 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)
Publish on [www.worstpills.org] 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
Publish on [www.worstpills.org] 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
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.