Drugs Log

The risks of two widely used asthma drugs outweigh their benefits for both children and adults, a U.S. Food and Drug Administration advisory panel said Thursday.

The health panel targeted GlaxoSmithKline’s Serevent and Foradil, made jointly by Novartis AG and Schering-Plough, for restrictions, but it excluded Advair, Glaxo’s biggest-selling drug in the class of medications known as long-acting beta-agonists. It also left alone a fourth such drug, AstraZeneca’s Symbicort.

The health experts did not say that the use of Serevent and Foradil should be abandoned altogether. Instead, they said the medications’ labeling should be reworded to urge doctors to use the drugs along with an inhaled corticosteroid — as guidelines already recommend.

That may help explain why Advair and Symbicort were spared. Serevent contains just one active ingredient, salmeterol, while Foradil contains only formoterol. Advair is a combination of both salmeterol and fluticasone (an inhaled cortocosteroid), while Symbicort contains formoterol and another steroid (budesonide). All of these drugs relax airway muscles, letting asthma patients breathe more easily.

The controversy over these drugs has been going on for several years, with two FDA officials recently calling for banning the use of these drugs for anyone under 17. The results of studies noting a rise in asthma-related deaths by people using the medications have already resulted in a black-box warning that use could “increase the risk of asthma-related death.”

The advisory panel voted 10 to 17 on whether the benefits of Serevent outweighed its risk as maintenance therapy for adults, and voted 6 to 21 on the same question for adolescents ages 12 to 17, Dow Jones reported. Foradil received similar votes on the same questions: 9 to 18 for adults and 6 to 21 for adults.

The panelists were unanimous in voting that the benefits of the two drugs did not outweigh risks when used for children ages 11 and younger.

The announcement followed a two-day meeting on the issue by the expert advisory panel. The FDA is not obligated to follow the advice of its advisory panels but usually does so.

Speaking before Thursday’s decision, one expert said the problem is not with the drugs, but with their misuse.

“This is an over-interpretation of the risk without adequate consideration of benefit,” said Dr. Miles Weinberger, a professor of pediatrics at the University of Iowa. “However, there has been irresponsible marketing of the products, salmeterol and formoterol, and irresponsible prescribing by many physicians.”

“Since most patients with chronic asthma can be controlled with inhaled steroids alone, using these more expensive combination formulations as first line is inappropriate but strongly encouraged by marketing practices” of drug makers, Weinberger said.

In the panel’s first day of hearings on Wednesday, FDA officials themselves were split over the risks of the drugs.

One official told the panel members that more than 14,000 people may have died since 1994 after taking the drugs, while another suggested that an even greater number might have died without them, according to The New York Times.

Last week, two FDA officials, who work in the agency’s safety division, posted an assessment on the agency Web site, saying asthma sufferers of all ages should not take the medicines. But a third FDA official concluded that Advair and Symbicort are safe for adults, but that all four drugs should no longer be used by children 17 and younger, the Times said.

The panel was reviewing an FDA study of 110 trials that included 60,954 people and found an increase in asthma-related hospitalization, asthma-related intubation, and asthma-related death in asthmatic patients with the use of these drugs. The risk varied, however, depending on the particular drug studied.

For example, there were 20 asthma-related deaths, 16 among people taking long-acting beta agonists compared with four patients not taking these drugs. All the deaths were in patients taking Serevent, the FDA notes.

The increased risk wasn’t seen when a long-acting beta agonist was used along with an inhaled corticosteroid, the agency found.

The greatest risk appears to be among children aged 4 to 11; women also appeared to be at greater risk than men.

Weinberger thinks that long-acting beta agonists should be used only in combination with inhaled steroids.

“All trials of the combination of long-acting beta agonists and an inhaled steroid demonstrate substantial additive effect for patients not fully controlled on the inhaled steroid alone,” Weinberger said. “The sensible approach is to use the combination products only after inadequate control is observed with an inhaled steroid alone.”

For their part, the drugs’ manufacturers said they believe there is adequate evidence that their products are safe and effective when used properly.

In a joint statement issued after the panel voted, Novartis and Schering-Plough said both companies “remain confident in the safety and efficacy of Foradil.” The statement added, “Novartis and Schering-Plough strongly disagree with the Joint Advisory Committees view that the benefits of Foradil do not outweigh its risks in patients using it according to current product labeling for the maintenance treatment of asthma. We believe this opinion is inconsistent with clinical evidence supporting the benefit/risk profile of Foradil in patients not adequately controlled on other asthma-controller treatments.”

In its statement before the vote, AstraZeneca said the company “believes that Symbicort exhibits a favorable benefit-risk profile in patients 6 years of age and older. Symbicort offers an important therapeutic option for asthma patients who cannot be adequately controlled on other asthma controller medications [low- to medium-dose inhaled corticosteroids] or whose disease severity clearly warrants initiation of treatment with two maintenance therapies.”

And GlaxoSmithKline said in its statement before the vote: “The combination of salmeterol with an inhaled corticosteroid provides unsurpassed asthma control to patients by improving lung function, preventing daytime and night-time symptoms and decreasing the use of rescue medications. For Advair, there was no evidence of increased risk for asthma-related death, asthma-related hospitalization, asthma-related intubation and all-cause death in any database. Therefore, no regulatory action is necessary for this product.”

Foradil
Generic Name: formoterol

Foradil is a long-acting bronchodilator that relaxes muscles in the airways to improve breathing.

Foradil is used to prevent bronchospasm in people with reversible obstructive airways disease, including symptoms of night-time asthma. It is also used in people with chronic obstructive pulmonary disease (COPD) such as emphysema and chronic bronchitis.

Foradil may also be used for other purpose not listed in this medication guide.
Important information about Foradil
Foradil capsules are for use only in the Foradil Aerolizer device. Use only one capsule at a time. Do not take the capsules by mouth. Never place a capsule in the mouthpiece of the inhaler. Do not use Foradil to treat an asthma attack that has already begun. It will not work fast enough to reverse your symptoms. Use another, short-acting inhalation medication to treat an asthma attack.

Asthma is usually treated with a combination of different drugs. To best treat your condition, use all of your medications as directed by your doctor. Do not change your doses or medication schedule without advice from your doctor.
Seek medical attention if you think any of your asthma medications are not working as well as usual. An increased need for medication could be an early sign of a serious asthma attack. Foradil may increase the risk of asthma-related death. It is critical that you use only the prescribed dose of this medicine and follow all patient instructions for safe use. Talk with your doctor about your individual risks and benefits in using Foradil.

Serevent
Generic Name: salmeterol (inhalation)
Brand Names: Serevent Diskus

Serevent is used to prevent asthma attacks. Salmeterol is a bronchodilator. It works by relaxing muscles in the airways to improve breathing. It will not treat an asthma attack that has already begun.

Serevent is also used to treat chronic obstructive pulmonary disease (COPD) including emphysema and chronic bronchitis.

Serevent may also be used for other purposes not listed in this medication guide.
Important information about Serevent
Do not use Serevent to treat an asthma attack that has already begun. It will not work fast enough to reverse your symptoms. Use another, faster-acting inhalation medication to treat an asthma attack. Serevent is has been shown to increase the risk of asthma-related death. It is critical that you use only the prescribed dose of this medicine and follow all patient instructions for safe use of the medication. Talk with your doctor about your individual risks and benefits in using Serevent.

Asthma is usually treated with a combination of different drugs. To best treat your condition, use all of your medications as directed by your doctor. Do not change your doses or medication schedule without advice from your doctor.

Do not use a second form of salmeterol (such as Advair) or use a similar inhaled bronchodilator such as formoterol or arformoterol(Foradil, Perforomist, Symbicort, or Brovana) unless your doctor has told you to.
Seek medical attention if you think any of your asthma medications are not working as well as usual. An increased need for medication could be an early sign of a serious asthma attack.

It is important to use Serevent regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Do not stop using Serevent without first talking to your doctor. Your asthma symptoms may get worse after you stop using the medication.