Therapeutic Substitution of Albuterol - Implemented 1/15/2013 After years of evaluation, comparative studies have not consistently demonstrated clinical or safety advantages of levalbuterol over racemic albuterol. Both drugs have similar effects on heart rate when comparable doses are used (similar increases among both tachycardic and non-tachycardic patient groups). No difference in the length of inpatient hospital stay has been identified. No differences in the Emergency Department treatment requirements have been seen, nor have differences been demonstrated in the length of ER visits. The cost of levalbuterol is prohibitive compared to albuterol. Medical City spent over $200,000 on levalbuterol in 2012. The same number of treatments could have been performed using albuterol at a cost of $15,000. After consideration of efficacy, safety, and cost, the Pharmacy & Therapeutics Committee has approved the therapeutic substitution of albuterol for levalbuterol orders in adults. Pediatric physicians are encouraged to utilize albuterol and it will be promoted by pediatric hospital staff members. The adult therapeutic substitution protocol follows: Drug Prescribed Xopenex 0.63mg Q8h Xopenex 1.25mg Q8h Xopenex 0.63mg Q2, Q4, or Q6h Xopenex 1.25mg Q2, Q4, or Q6h Drug Dispensed/Administered Albuterol 1.25mg Q6h Albuterol 2.5mg Q6h Albuterol 1.25mg at same frequency Albuterol 2.5mg at same frequency For an adult patient who has been found to be intolerant to albuterol, the physician may obtain levalbuterol by indicating Do not substitute as part of the order. Page 1
Medical City Hospital Therapeutic Interchange proposal: Levalbuterol (Xopenex) to Racemic Albuterol Background: Levalbuterol (Xopenex) is a β-2 agonist indicated for treatment and prevention of bronchospasm. Levalbuterol is the R-enantiomer of albuterol (e.g., Proventil), a 50:50 mixture of R-albuterol and S-albuterol. Levalbuterol (R-albuterol) causes bronchodilation, while in vitro S-albuterol increases airway hyperreactivity and is pro-inflammatory. Early evidence implied that levalbuterol, at a dose one-fourth that of racemic albuterol, could produce equivalent bronchodilation with fewer side effects. Thus, a product containing only the R-enantiomer alone (i.e., Xopenex) should be more effective and cause fewer side effects. However, both levalbuterol and racemic albuterol present similar dose-related adverse effect profiles. Common adverse reactions include deterioration of asthma, β-adrenergic side effects (tachycardia, tremor, nervousness), hypokalemia and hyperglycemia. The incidence of asthma and increase/change in glucose and potassium levels is comparable in levalbuterol and racemic albuterol. Numerous studies have compared levalbuterol to albuterol for asthma in various settings: adults, pediatrics, ICU, emergency room, etc. Clinical Trials: In the study by Nelson, the change in peak FEV1 response to the first dose in the combined levalbuterol group was significantly greater compared with the combined racemic albuterol group (0.92 and 0.82 L, respectively; P =.03), with similar but non-significant results after 4 weeks (0.84 and 0.74 L, respectively). The greatest increase in FEV1 was seen after levalbuterol 1.25 mg, especially in subjects with severe asthma. Author concluded that levalbuterol appears to provide a better therapeutic index than the standard dose of racemic albuterol. In a study by Kelly using a double-blind, parallel-group design in 328 asthma patients, patients were randomly assigned to levalbuterol 0.63mg or 1.25mg, R,S-albuterol 1.25mg or 2.5mg, or placebo. The drug was administered by nebulization three times a day for four weeks. Improvement in peak FEV1 after four weeks was similar in the combined levalbuterol vs combined albuterol groups (p=0.13). Heart rate increased 3.6 beats/min with levalbuterol 1.25mg and 4.9 beats/min with albuterol 2.5mg. The percentage of patients reporting tremor or nervousness did not differ between the levalbuterol 0.63 mg and albuterol 2.5 mg groups (p=0.098). Other comparative studies in chronic asthma have not shown differences between levalbuterol and albuterol in regard to FEV1. In a study in the emergency department setting published by Nowak, 627 adults with severe asthma were randomized to levalbuterol 1.25mg or albuterol 2.5mg. Medications were given by nebulization every 20 minutes times three, then every 40 minutes times three, then as needed for 24 hours. All patients also received prednisone. The primary outcome measure was time to discharge. Secondary outcomes were FEV1 improvement and need for admission. Levalbuterol improved FEV1 slightly more than albuterol (p=0.02). However, improvement Page 2
was not sustained and did not shorten ED length of stay. There was no difference in time to discharge or need for hospitalization. However, hospitalization rate was lower with levalbuterol in a subset of patients not using inhaled corticosteroids at home (3.8% vs 9.3%, p=0.03). In the ICU setting, the effects of 2.5 mg albuterol and levalbuterol 1.25 mg on heart rate were compared in the study by Lam. The mean increase in heart rate was about 2 beats per minute in the patients with tachycardia. Heart rate increased by a mean of about 4 beats per minute in patients without baseline tachycardia. There was no significant difference between albuterol and levalbuterol. Study by Quereshi in the emergency department setting enrolled 129 children ages 2-14 with moderate to severe asthma. Patients were randomized to levalbuterol 2.5mg or albuterol 5mg. Medications were given by nebulization every 20 minutes times three, then every 30 to 60 minutes as needed. All children received prednisone. Primary outcome measures were changes from baseline in asthma score and FEV1 after the first, third, and fifth treatments. Secondary outcomes included need for hospitalization, heart rate, length of emergency department stay, number of treatments, and oxygen saturation. There were no significant differences between groups in primary or secondary outcomes or adverse effects. The study was underpowered to detect a difference in FEV1. Another study by Carl JC for pediatric asthma patients presenting to an emergency department for acute asthma were randomized to levalbuterol 1.25 mg or albuterol 2.5 mg. The primary outcome measures were need for hospitalization and speed of improvement. Fewer patients in the levalbuterol group required hospitalization (36% vs 45%; p=0.02). Although the study reported a lower hospital admission rate compared to albuterol, their baseline admission rate was higher than other reports. Use of two or more albuterol treatments before presentation was associated with increased risk of admission (RR 1.39, p=0.002) although length of hospital stay was similar in both groups. Mean heart rate and mean maximal heart rate were similar between the levalbuterol and albuterol groups. The investigators did not see a difference in tremor between groups. Recently in 2011, Khorfan et al compared albuterol to levalbuterol using a randomized, singleblind, crossover, prospective study in 70 critically ill adult patients. Patients were randomized to alternating nebulized combination of albuterol or levalbuterol with ipratropium every 4 to 6 hours. Group A received albuterol 2.5mg alternating with levalbuterol 0.63 mg. Group B received albuterol 2.5 mg alternating with levalbuterol 1.25 mg. Heart rate was recorded before and after each treatment. In group A, change in heart rate after albuterol was 0.89 ± 4.5 beats/min (n= 303) compared with 0.85 ± 5.3 beats/min after levalbuterol (n= 301, P=.89). In group B, heart rate decreased 0.16 _ 5.1 beats/min after albuterol 2.5 mg (n= 114) compared to an increase of 1.4 ± 5.4 beats/min after levalbuterol 1.25 mg (n= 118, P=.03). Authors concluded that nebulized albuterol and ipratropium does not cause significant tachycardia or tachyarrhythmias. Substitution of levalbuterol for albuterol to avoid tachycardia and tachyarrhythmias is unwarranted. Page 3
Conclusions from clinical trials: Older trials suggested an advantage for levalbuterol over racemic albuterol. However, most data suggesting such benefit were retrospective and non-randomized trials. The newer trials have failed to confirm these advantages. Comparative studies have not shown the clinical advantages of levalbuterol over racemic albuterol. For most patients, there was no difference in hospital length of stay or need for hospitalization. Both drugs have similar effects on heart rate when comparable doses are used, and there's no proof that albuterol causes more inflammation and agitation. It is possible that certain subsets of patients might achieve greater bronchodilation from levalbuterol than albuterol. This includes patients requiring high doses of albuterol. Also, hospitalization rate was lower with levalbuterol in a subset of patients not using inhaled corticosteroids at home. Prospective study in such subsets is needed. There may be a greater increase in FEV1 after first dose of levalbuterol vs albuterol. However, initial improvement in FEV1 has not lead to decreased length of stay or treatment requirements in the ED. Current data do not support routine use of levalbuterol over albuterol. For most patients, albuterol is just as effective, safe and well-tolerated as levalbuterol. The National Asthma Education and Prevention Program (NAEPP) guidelines state that levalbuterol, at half the dose of albuterol, produces similar bronchodilation and side effects as albuterol [Evidence level A; High-quality randomized controlled trial (RCT)]. Dose Equivalency: Based on a study by Lotvall and colleagues, as well as the AUC and C max data provided in the Xopenex product labeling, the bronchoprotective effects and plasma concentrations of 1.25mg of Xopenex is closest to a dose of 2.5mg of racemic albuterol. Dose Equivalency Chart Xopenex (levalbuterol) 1.25mg 0.63mg Albuterol (racemic) 2.5mg 1.25mg Page 4
Proposal for therapeutic interchange of levalbuterol (Xopenex) to racemic albuterol: Prescribed* Xopenex 0.63mg Q8h Xopenex 1.25mg Q8h Xopenex 0.63mg Q2, Q4, or Q6h Xopenex 1.25mg Q2, Q4, or Q6h Profiled & Dispensed Albuterol 1.25mg Q6h Albuterol 2.5mg Q6h Albuterol 1.25mg at same frequency Albuterol 2.5mg at same frequency *The presence or absence of PRN status will not affect the interchange. Physicians may override the interchange by indicating Do not substitute or similar phrases in the chart. Comparative usage at MCD over last 12 months Albuterol usage at MCD (1.25mg/0.5ml) 853 units $4,068.81 Albuterol usage at MCD (2.5mg/3ml) 444 units $4,357.56 Total Albuterol (last 12 months) 1297 units $8,426.37 Xopenex usage at MCD (1.25mg/0.5ml): 2669 units $208,448.97 Drug Cost: Albuterol 1.25 mg / 3 ml - $4.77, $0.16/unit Levalbuterol (Xopenex) 1.25 mg / 0.5ml - $78.10, $2.60/unit References: 1. Kelly HW. Levalbuterol for asthma: a better treatment? Curr Allergy Asthma Rep 2007;7:310-4. 2. National Asthma Education and Prevention Program, U.S. Department of Health and Human Services, National Institutes of Health, Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma: Full Report 2007. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. 3. Nowak R, Emerman C, Hanrahan JP, et al. A comparison of levalbuterol with racemic albuterol in the treatment of acute severe asthma exacerbations in adults. Am J Emerg Med 2006;24:259-67. 4. Lam S, Chen J. Changes in heart rate associated with nebulized racemic albuterol and levalbuterol in intensive care patients. Am J Health Syst Pharm 2003;60:1971-5. 5. Berger WE, Milgrom H, Skoner DP, et al. Evaluation of levalbuterol metered dose inhaler in pediatric patients with asthma: a doubleblind, randomized, placebo- and active-controlled trial. Curr Med Res Opin 2006;22:1217-26. 6. Carl JC, Myers TR, Kirchner HL, Kercsmar CM. Comparison of racemic albuterol and levalbuterol for treatment of acute asthma. J Pediatr 2003;143:731-6. 7. Qureshi F, Zaritsky A, Welch C, et al. Clinical efficacy of racemic albuterol versus levalbuterol for the treatment of acute pediatric asthma. Ann Emerg Med 2005;46:29-36. 8. Nelson HS, Bensch G, Pleskow WW, DiSantostefano R, DeGraw S, Reasner DS, Rollins TE, Rubin PD. Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. J Allergy Clin Immunol. 1998 Dec;102(6 Pt 1):943-52. Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. 9. Lotvall J, Palmquist M, Arvidsson P, Maloney A, Ventresca GP, Ward J. The therapeutic ratio of R-albuterol is comparable with that of RS-albuterol in asthmatic patients. J Allergy Clin Immunol 2001;108:726-31. 10. Khorfan FM, Smith P, Watt S, Barber KR. Effects of nebulized bronchodilator therapy on heart rate and arrhythmias in critically ill adult patients. Chest 2011; 140;1466-72. Page 5