The Safety of Long-Acting Beta Agonist Inhalers

Pharmacology Watch

Do long-acting beta agonist inhalers increase the severity of asthma? Yes, according to the results from a large meta-analysis recently published in the Annals of Internal Medicine. Pooled data from 19 trials with nearly 34,000 participants found that the long-acting beta agonists salmeterol, formoterol, and eformoterol were associated with higher rates of asthma exacerbations, requiring hospitalization, (odds ratio 2.6 [95% CI, 1.6-4.3]) and life-threatening exacerbations (odds ratio 1.8 [CI, 1.1-2.9]), compared to placebo. In subgroup analyses, the odds ratio for hospitalizations was 1.7 for salmeterol and 3.2 for formoterol. The risk of hospitalization was especially high in children on long-acting beta agonists (odds ratio 3.5 [CI, 1.3-9.3]). The odds ratio for adults was 2.0 (CI 1.1-3.9). Although the rate of death was low, the odds ratio for asthma-related death was 3.5 (CI, 1.3-9.3).

In the largest of the studies included in the meta-analysis, the Salmeterol Multicenter Asthma Research Trial (SMART), in which 26,000 patients were followed for 6 months on salmeterol or placebo, there was a 2-fold increase in life-threatening asthma exacerbations and a 4-fold increase in asthma related deaths. The authors conclude that long-acting beta agonist use increases the risk of hospitalizations due to asthma, life-threatening asthma exacerbations, and asthma-related deaths. The authors also conclude that inhaled corticosteroids cannot adequately protect against the adverse effects of these drugs (Ann Int Med. 2006;144:904-912).

An accompanying editorial suggests that physicians should follow current guidelines which emphasize use of inhaled corticosteroids as the first-line treatment for patients with mild-to-moderate persistent asthma. Only after maximal corticosteroid doses have been reached should long-acting beta agonist be considered (Ann Int Med. 2006;144:936-937).

The FDA met one year ago to discuss long-acting beta agonist and required black box warnings on the labeling for these drugs; however, there usage has changed very little in the ensuing year.

Treating Chronic Primary Insomnia

Cognitive behavioral therapy is more effective than zopiclone for the treatment of chronic primary insomnia in older adults, according to a new study from Norway. In a randomized, double-blind, placebo-controlled trial, 46 adults (mean age, 60.8; 22 women) with chronic primary insomnia were randomized to cognitive behavioral therapy, sleep medication with zopiclone 7.5 mg each night, or placebo for 6 weeks. The cognitive behavioral therapy consisted of 6 weekly sessions lasting 50 minutes that covered sleep hygiene education, sleep restriction, stimulus control, cognitive therapy, and progressive relaxation techniques. The main outcome was polysomnographic data and sleep diaries, which were used to determine total wake time, total sleep time, sleep efficiency, and slow-wave sleep.

Cognitive behavioral therapy (CBT) resulted in improved short-term and long-term outcomes compared with zopiclone on 3 of 4 outcome measures. CBT improved sleep efficiency from 81.4% to 90.1% at 6-month follow-up compared to a decrease from 82.3% to 81.9% with zopiclone. CBT resulted in better sleep architecture and less time awake during the night. Total sleep time was similar in all 3 treatment groups but, at 6 months, patients receiving CBT had better sleep efficiency than those taking zopiclone. The authors conclude that cognitive behavioral therapy is superior to zopiclone for management of insomnia, both in the short term and long-term. For most outcomes, zopiclone did not differ from placebo (JAMA. 2006;295:2851-2858).

Zopiclone is a new generation sleep medication available in Europe. The active isomer of zopiclone has been available in the United States since April 2005 (eszopiclone - Lunesta).

New Breakthrough in Smoking Cessation?

Varenicline, Pfizer's new smoking cessation drug, is the subject of 3 articles in the July 5 issue of JAMA. The drug, which is a partial agonist of the 4 2 nicotinic receptor, blocks the action of nicotine but provides a lower level of stimulation of dopamine release to reduce craving and withdrawal symptoms. Two of the 3 articles compared varenicline to bupropion and placebo in combination with behavioral counseling over 12 weeks of treatment. In both studies, varenicline was significantly more effective than placebo or bupropion (JAMA. 2006;296:47-55, 56-63). In the third study, 12 more weeks of varenicline was found to be significantly more effective than placebo in maintaining abstinence. This study also found that after 24 weeks of treatment, the benefit of the drug was maintained up to one year (JAMA. 2006;296:64-71). An accompanying editorial points out that while the studies of varenicline are promising and the drug represents a new agent with a different mechanism of action, it is not a panacea for smoking cessation, with quit rates still under 50% in these studies (JAMA. 2006;296:94-95). These studies could not come at a better time for Pfizer, as the company plans to market the drug within the next few months under the trade name Chantix.

FDA Actions

The FDA has given Biogen-Idec approval to resume marketing natalizumab (Tysabri) for the treatment of relapsing forms of multiple sclerosis. The monoclonal antibody was initially marketed in November 2004, but was withdrawn four months later, after three patients developed progressive multifocal leukoencephalopathy (PML) in clinical trials. Subsequent trials have not shown any additional cases of PML, but the drug is limited to use in patients who have failed or have not tolerated alternative therapies for multiple sclerosis. The re-approval is a restricted distribution program which includes registration of patients, prescribers, infusion centers, and pharmacies and includes patient education materials. Patients are also required to have a brain MRI prior to initiation of therapy. More information is available at:

Duramed Pharmaceuticals have received approval to market a new 91 day birth control regimen consisting of 84 days of levonorgestrel 0.15 mg with ethinyl estradiol 0.03 mg, and seven days of ethinyl estradiol 0.01 mg (Seasonique). This product differs from the company's other 91 day birth control regimen (Seasonale) in that it incorporates estradiol rather than placebo for the last seven days in order to reduce bloating and breakthrough bleeding. Both products result in four menstrual periods per year.

The FDA has approved Genentech's ranibizumab (Lucentis) for the treatment of neovascular (wet) age-related macular degeneration (AMD). The drug, which is injected intraocularly, inhibits vascular endothelial growth factor A which is thought to contribute to proliferation, vascular leakage, and angiogenesis. Many ophthalmologists have been using Genentech's other anti-angiogenesis drug bevacizumab (Avastin) for the treatment of AMD, although it is not approved for this indication. Compounded bevacizumab injected intraocularly is approximately $17 per dose. Ranibizumab marketed as Lucentis is projected to cost approximately $2000 per dose.

Two former blockbuster drugs are making the switch to generics. Sertraline (Zoloft- Pfizer) will be available later this year in both generic pill and liquid form. In 2005, Zoloft was the most popular antidepressant in the US. The FDA has also approved a generic form of simvastatin (Zocor) Merck & Co.'s enormously popular statin for the treatment of hypercholesterolemia. Generic simvastatin is currently available 5, 10, 20, 40, and 80 mg strengths.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5416. E-mail: