Asthma - Safety Issues

There has been concern recently regarding the safety of such long-acting beta-agonists as salmeterol and formoterol. SMART examined the safety of salmeterol compared with placebo in over 26,000 patients. Patients who stated they had a diagnosis of asthma and were on at least one medication used for asthma (even a short-acting beta-agonist) could be entered into the trial.

Patients who had never been on a long-acting beta-agonist were excluded. Patients were given medication for the study duration and were followed up only by telephone interview every 4 weeks over the 28 weeks of the study.

This study raised concerns because there were increased respiratory deaths or life-threatening experiences noted in the African American male population using salmeterol compared with placebo (relative risk 4.1; 95% CI, 1.54–10.9).

The study found that this group also tended to use oral steroids more frequently, to have more frequent and longer hospitalizations, to have higher rates of incubation, and to use less inhaled corticosteroids as maintenance therapy compared with the other groups studied.

There are legitimate concerns about the overuse of beta-agonist medications causing adverse effects and perhaps even attenuating the beta-receptor’s response to beta-agonists for a subset of asthma patients who have certain polymorphisms of the beta-receptor ARG-ARG.

However, the findings of SMART likely reflect suboptimal compliance with inhaled corticosteroids. The consequent ‘‘black box’’ warning imposed by the Food and Drug Administration in the United States emphasizes that patients should be optimized on inhaled corticosteroids before the use of long-acting beta-agonists is considered.

Hence, while further studies are needed to clarify the safety of long-acting beta-agonists in asthma patients that have certain beta-receptor polymorphisms, the vast majority of asthma patients are likely to benefit from the use of these medications when inhaled corticosteroids alone are unable to achieve total control or when there are intolerable side effects from higher dose inhaled corticosteroids.

Omalizumab, a highly humanized monoclonal antibody against IgE, has been shown to reduce exacerbations and steroid requirements for patients with allergic asthma. Omalizumab has been recommended for use in patients who are not optimally controlled on standard therapies or have significant side effects from inhaled corticosteroids.

Because omalizumab is systemically delivered, this agent may be effective in patients who have significant smaller airway disease. Earlier in 2007, there were concerns raised regarding potentially significant anaphylactic events despite the molecule being approximately 95% humanized with a 5% complimentary determining region that is mouse derived.

Xolair, a brand of omalizumab, received a ‘‘black box’’ warning that states it should be administered in a monitored medical setting with personnel trained and able to manage anaphylaxis, but there is no specific time requirement as to how long patients should be monitored.