How Does Levalbuterol (Xopenex®) Compare With Albuterol?

Darrell Hulisz, PharmD


March 30, 2010


When is levalbuterol (Xopenex®) preferred over albuterol?

Response from Darrell Hulisz, PharmD
Associate Professor, Department of Family Medicine, Case Western Reserve University, Cleveland, Ohio; Clinical Pharmacist, University Hospitals, Case Medical Center, Cleveland, Ohio

Albuterol is the most commonly prescribed inhaled beta-2 agonist and is considered a drug of choice for reversal of acute bronchospasm.[1,2] Albuterol is a 50:50 racemic mixture of (R)-albuterol (levalbuterol), the pharmacologically active enantiomer, and (S)-albuterol, which has little or no bronchodilating activity.[3] (R)-albuterol demonstrates 100-fold more potent binding to beta-2 receptors than (S)-albuterol.[1]

Development of levalbuterol was based on the following proposed advantages over racemic albuterol[3]: fewer episodes of transient tachycardia, better tolerability, and similar or greater efficacy. An examination of the literature reveals which patients benefit most from levalbuterol.

In adult and pediatric patients with asthma, clinical trials have demonstrated lower mean heart rates in patients using levalbuterol vs racemic albuterol.[4,5,6] The magnitude of this difference is modest, but it may be clinically significant in patients with a history of arrhythmias, structural heart disease, or cardiac conditions that could worsen with an episode of tachycardia (eg, decompensated heart failure).

Other studies show no difference in mean heart rate when the 2 drugs are compared head-to-head.[7] Because the adverse effect of increased heart rate is common to all beta-agonists, equimolar doses of levalbuterol and racemic albuterol would be expected to result in a similar degree of tachycardia. In other words, the transient tachycardia seen with both levalbuterol and racemic albuterol is most likely dose dependent.

Whether levalbuterol is better tolerated is somewhat controversial. Deleterious effects of racemic albuterol, especially with overuse, include hypokalemia, tachyphylaxis, and even increased mortality.[3,8,9] (S)-albuterol lacks bronchodilator activity and is metabolized 10-fold more slowly than levalbuterol, and some have theorized that it may also have negative effects such as worsening airway reactivity or proinflammatory effects.[8] This could result in preferential accumulation of the (S)-isomer over (R)-albuterol in the lung, potentially resulting in paradoxic bronchospasm.[8,9]

Nowak and colleagues[10] compared the effects of nebulized levalbuterol with those of racemic albuterol in 627 adults with an acute asthma exacerbation. Patients were randomly assigned to receive either levalbuterol 1.25 mg or albuterol 2.5 mg every 20 minutes upon emergency admission, then every 40 minutes for 3 additional doses, then as often as clinically necessary for 24 hours. All patients also received prednisone 40 mg. Levalbuterol increased forced expiratory volume by nearly 40% compared with racemic albuterol, corresponding to a 40% reduction in required hospitalizations compared with racemic albuterol. The benefit of levalbuterol was especially apparent in patients with severe asthma who had high levels of (S)-albuterol (> 1095 mg/mL). High circulating levels of [S]-albuterol are thought to be the result of excessive use of racemic albuterol. The number of asthma relapses that occurred 30 days after acute exacerbation did not differ between the 2 groups.

A prospective, multicenter, randomized, open-label trial studied hospitalized patients with acute asthma or chronic obstructive pulmonary disease (COPD) and compared treatment with nebulized levalbuterol 1.25 mg every 6-8 hours and treatment with racemic albuterol 2.5 mg every 1-4 hours. Significantly fewer total nebulizations were required with levalbuterol, and there was no increased need for rescue aerosols during 14 days of hospitalization. Most other outcome measures were similar between the 2 groups, including costs and pulmonary function studies.[11]

Truitt and colleagues[12] performed a retrospective chart review of hospitalized patients with asthma or COPD and reached similar conclusions. In a review of the literature, Ameredes and Calhoun[1] concluded that the benefit of levalbuterol over albuterol may be greatest in patients with moderate to severe asthma, particularly in those with albuterol overuse.

Cost is of primary interest when comparing the 2 agents. Prior to January 2009, metered-dose inhaler (MDI) generic formulations of albuterol were widely available and were much less expensive than branded versions of albuterol (eg, Proventil®, Ventolin®) and levalbuterol. However, many MDI formulations contained chlorofluorocarbons and are no longer available in this country because they were banned by the Food and Drug Administration for environmental reasons. Thus, multisource generic albuterol MDI is no longer available and the cost of brand-name albuterol is nearly identical to that of levalbuterol. Levalbuterol nebulization is still considerably more expensive than the available generic albuterol nebulization.[3,13]

Because of the higher cost of levalbuterol and study limitations, such as small sample size and inadequate power, some have concluded that the use of levalbuterol in place of albuterol is not strongly supported by the literature.[3,13] However, levalbuterol may be preferred over racemic albuterol in the following situations:

  • Patients with more severe asthma who need frequent doses of a beta-2 agonist despite appropriate use of controller therapies;

  • Patients with asthma or COPD and concurrent cardiac disease, especially if these conditions could potentially worsen with tachycardia (eg, poorly controlled cardiac arrhythmias, decompensated heart failure, and valvular heart disease); and

  • Patients who often experience bothersome tachycardia with albuterol and dislike using it, which could potentially lead to poor adherence.

The author wishes to acknowledge Amanda Weaver, PharmD student, for providing technical assistance.


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