October 2016 FAQs

What are the data on efficacy and safety of using injectable tobramycin for inhalation via nebulization?

Introduction

Tobramycin is an aminoglycoside antibiotic approved by the Food and Drug Administration (FDA) for multiple indications including the management of patients with cystic fibrosis (CF) infected with Pseudomonas aeruginosa.^1-4 Currently, there are FDA-approved formulations of tobramycin for injection, inhalation, and ophthalmic use.⁵ However, prior to the FDA-approval of tobramycin specifically designed for inhalation in 1998, institutions utilized the intravenous (IV) formulation for administration via inhalation.⁶ The purpose of this review is to discuss the available safety and efficacy data regarding the use of the IV formulation of tobramycin administered via inhalation, as well as other considerations when using an IV formulation via inhalation.

Safety and Efficacy Data

Studies evaluating the safety and efficacy of the IV formulation of tobramycin administered via inhalation from the past 18 years are listed in Table 2.^7-10 Studies conducted prior to the FDA-approval of the inhalation product in 1998 are not included in this table in order to highlight the most recent data.^11-17 While several studies found inhaled tobramycin to be effective and not associated with any significant safety concerns for patients with CF and P. aeruginosa infection,^{10,12,13,15-17} others investigated whether the IV formulation containing antioxidants and preservatives resulted in bronchoconstriction.^8,9,11 The 2002 study by Alothman et al found that while both a preservative and preservative-free preparation of tobramycin resulted in bronchoconstriction in children at high risk for bronchospasm, use of the preservative preparation resulted in a numerically higher rate of bronchospasm compared to the preservative-free preparation in low risk patients.⁸ The 2000 study by Ramagopal performed an uncontrolled study of 26 patients with CF and found that 19% of patients experienced > 10% reduction in FEV₁ after inhalation of tobramycin.⁹ The 1996 uncontrolled study by Nikolaizik et al in 12 patients with CF found that tobramycin inhalation was associated with bronchial constriction.¹¹ Another older study that evaluated whether tonicity may affect bronchoconstriction did not find tobramycin associated with significant bronchoconstriction compared to placebo.¹⁴ Although studies conducted prior to 1998 do not always specifically state in the methods that the IV formulation of tobramycin was utilized, it is assumed based on the fact that the inhalation solution was not commercially available.^11-17

Only one study was identified that compared the IV formulation delivered via inhalation to the inhaled formulation in 32 patients with CF infected with P. aeruginosa (Table 1).⁷ In this open-label, crossover trial, no differences were found between the IV formulation (administered continuously) and the inhalation formulation (delivered in cycles of 28 days on, 28 days off) in improvement in lung function. However, the authors concluded that superiority of one treatment could not be determined based on the small sample size.

A recent retrospective analysis evaluated the substitution of tobramycin inhalation solution (TOBI®) 300 mg (5 mL) administered twice daily with preservative-free IV tobramycin 300 mg (7.5 mL) twice daily administered via inhalation as a cost-savings measure.¹⁸ The authors found that substitution of the inhaled formulation with the IV formulation resulted in cost-savings and they did not identify any safety concerns with the substitution.

Aerosolized Delivery

One concern with use of the IV formulation via inhalation is whether it is optimized for aerosolized delivery. A 2002 review of pharmaceutical considerations to aerosol drug delivery reports that aerosolized drugs should be isotonic, pH buffered, sterile, and pyrogen free.¹⁹ This article discusses that the inhalation preparation of tobramycin (TOBI®) is formulated for aerosolized delivery so it contains no preservatives, is isotonic, has a balanced pH, and is chemically stable. In contrast, commercially available versions of IV tobramycin may require additional buffering to achieve a balanced pH, may not be isotonic, or may contain phenol.^14,19 The concern with phenol is that it may increase the risk of airway hypersensitivity with regular administration, which may not be acceptable with long-term use.¹⁹ Excipients found in the solution for injection may include phenol, sodium metabisulfite, edetate disodium, sulfuric acid, and/or sodium hydroxide.²⁰ According to the current prescribing information for the tobramycin 1.2 gram powder for injection, it is preservative- and sodium bisulfite-free.²¹ Additionally, unlike the inhaled formulations that are supplied in single-dose vials that do not require additional preparation, the preservative-free IV formulation of tobramycin is available as a powder which requires reconstitution.^6,19,22

The Society of Infectious Diseases Pharmacists (SIDP) also discussed that certain physical characteristics of IV formulations may obstruct medication delivery or result in adverse events when administered via inhalation.²³ These properties may include size, viscosity, surface tension, osmolality, tonicity, and pH. The SIDP also states that adverse events (eg, cough, airway irritation, and bronchoconstriction) may result from the preservatives in IV formulations, and recommends the use of preservative-free tobramycin in certain patients with CF.

Other Considerations

A guideline from the Cystic Fibrosis Foundation on pharmacologic approaches to treatment of initial P. aeruginosa infection published in 2014 states that the preferred inhaled antibiotic treatment for initial or new P. aeruginosa infection is tobramycin 300 mg twice daily for 28 days.²⁴ The guideline states that whether other tobramycin formulations (eg, dry powder) are as effective is not known.

Additionally, as of September 20, 2016 tobramycin injection is listed on the American Society of Health-System Pharmacy (ASHP) national drug shortage site, so compounding it for inhaled use when there is a commercially available product may not be a judicious use of the injectable product at this time.²⁵ The status of tobramycin IV can be accessed via this link: http://www.ashp.org/shortages.

Conclusion

Overall, there are limited safety and efficacy data regarding the use of IV tobramycin administered via inhalation. Many of the studies examining its use are older, have a small sample-size, are open-label or non-controlled and were conducted prior to the FDA-approval of tobramycin specifically designed for aerosolized delivery. There are several considerations regarding whether the IV formulation may be optimized for aerosolized delivery, including particle size, tonicity, osmolality, and pH. In addition, there may be safety concerns with the use of the IV formulation containing preservatives.

Table 1. Studies evaluating IV tobramycin administered via inhalation since 1997.

References

1. TOBI [package insert]. East Hanover, NJ: Novartis; 2015.
2. TOBI podhaler [package insert]. East Hanover, NJ: Novartis; 2015.
3. Bethkis [package insert]. Woodstock, IL: Chiesi USA, Inc; 2014.
4. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2016. http://clinicalpharmacology-ip.com/default.aspx. Accessed September 19, 2016.
5. Drugs@FDA [database on the Internet]. Rockville (MD): Food and Drug Administration (US), Center for Drug Evaluation and Research; 2016. Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.  Accessed September 19, 2016.
6. Vendrell M, Muñoz G, de Gracia J. Evidence of inhaled tobramycin in non-cystic fibrosis bronchiectasis. Open Respir Med J. 2015;9:30-36.
7. Nikolaizik WH, Vietzke D, Ratjen F. A pilot study to compare tobramycin 80 mg injectable preparation with 300 mg solution for inhalation in cystic fibrosis patients. Can Respir J. 2008;15(5):259-262.
8. Alothman GA, Alsaadi MM, Ho BL, et al. Evaluation of bronchial constriction in children with cystic fibrosis after inhaling two different preparations of tobramycin. Chest. 2002;122(3):930-934.
9. Ramagopal M, Lands LC. Inhaled tobramycin and bronchial hyperactivity in cystic fibrosis. Pediatr Pulmonol. 2000;29(5):366-370.
10. Wiesemann HG, Steinkamp G, Ratjen F, et al. Placebo-controlled, double-blind, randomized study of aerosolized tobramycin for early treatment of Pseudomonas aeruginosa colonization in cystic fibrosis. Pediatr Pulmonol. 1998;25(2):88-92.
11. Nikolaizik WH, Jenni-Galovic V, Schoni MH. Bronchial constriction after nebulized tobramycin preparations and saline in patients with cystic fibrosis. Eur J Pediatr. 1996;155(7):608-611.
12. Ramsey BW, Dorkin HL, Eisenberg JD, et al. Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J Med. 1993;328(24):1740-1746.
13. MacLusky IB, Gold R, Corey M, Levison H. Long-term effects of inhaled tobramycin in patients with cystic fibrosis colonized with Pseudomonas aeruginosa. Pediatr Pulmonol. 1989;7(1):42-48.
14. Chua HL, Collis GG, Le Souef PN. Bronchial response to nebulized antibiotics in children with cystic fibrosis. Eur Respir J. 1990;3(10):1114-1116.
15. Steinkamp G, Tümmler B, Gappa M, et al. Long-term tobramycin aerosol therapy in cystic fibrosis. Pediatr Pulmonol. 1989;6(2):91-98.
16. Gappa M, Steinkamp G, Tummler B, von der Hardt H. Long-term tobramycin aerosol therapy of chronic Pseudomonas aeruginosa infection in patients with cystic fibrosis. Scand J Gastroenterol Suppl. 1988;143:74-76.
17. Stephens D, Garey N, Isles A, Levison H, Gold R. Efficacy of inhaled tobramycin in the treatment of pulmonary exacerbations in children with cystic fibrosis. Pediatr Infect Dis. 1983;2(3):209-211.
18. Gauthier TP, Waski J, Unger NR, Abbo LM, Fernandez M, Aragon L. Cost reduction of inhaled tobramycin by use of preservative-free intravenous tobramycin given via inhalation. Antibiotics (Basel). 2016;5(1):2.
19. Kuhn RJ. Pharmaceutical considerations in aerosol drug delivery. Pharmacotherapy. 2002;22(3 Pt 2):80S-85S.
20. Tobramycin sulfate injection [package insert]. Lake Forest, IL: Akorn Inc; 2014.
21. Tobramycin sulfate injection powder for solution [package insert]. Big Flats, NY: X-Gen Pharmaceuticals, Inc; 2015.
22. Flume P, Klepser ME. The rationale for aerosolized antibiotics. Pharmacotherapy. 2002;22(3 Pt 2):71S-79S.
23. Le J, Ashley ED, Neuhauser MM, et al. Consensus summary of aerosolized antimicrobial agents: application of guideline criteria. Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2010;30(6):562-584
24. Mogayzel PJ Jr, Naureckas ET, Robinson KA, et al. Cystic Fibrosis Foundation pulmonary guideline. Pharmacologic approaches to prevention and eradication of initial Pseudomonas aeruginosa infection. Ann Am Thorac Soc. 2014;11(10):1640-1650.
25. Tobramycin injection. American Society of Health-System Pharmacists website. http://www.ashp.org/menu/DrugShortages/CurrentShortages/Bulletin.aspx?id=701 . Updated September 20, 2016. Accessed September 21, 2016.

October 2016

The information presented is current as September 19, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What are the comparative clinical data for albuterol versus levalbuterol?

Introduction

Albuterol is a beta₂-adrenergic agonist used for the treatment and prevention of bronchospasm in patients with asthma and chronic obstructive pulmonary disease (COPD).^1,2 Albuterol stimulates beta₂-adrenergic receptors in the bronchial smooth muscle, causing muscle relaxation and airway dilation.³

The albuterol molecule exists in mirror-image configurations known as stereoisomers or enantiomers.²  These enantiomers appear physically and chemically identical, but the dissimilarity in their spatial orientations causes them to behave very differently from one another in biological systems.⁴  The (R)-enantiomer is the active form of the drug; it has 100-fold greater binding affinity for the beta₂ receptor than its mirror image, (S)-albuterol.⁵  (S)-albuterol was previously thought to be inert: however, it is now believed to have pharmacologic properties that work against the action of (R)-albuterol.  In-vitro studies have shown that (S)-albuterol may cause smooth muscle contraction, augmentation of inflammatory stimuli, and increased hyperresponsiveness to spasmogens.  (S)-albuterol is also metabolized at 1/10^th the rate of (R)-albuterol; thus, it is theorized that the chronic administration of racemic albuterol may lead to the build-up of (S)-albuterol, which in turn may cause worsening bronchial hyperresponsiveness and lung function.

The product currently marketed as albuterol is a 50:50 racemic mixture of the 2 enantiomers, (R)-albuterol and (S)-albuterol; racemic albuterol has been approved for use in the United States since 1981.³  Levalbuterol, approved in 1999 and marketed under the brand name Xopenex®, is the single (R)-enantiomer of albuterol.⁶ Table 1 summarizes key characteristics of both these products.  In theory, using the (R)-enantiomer alone would produce more effective bronchodilation than using the racemic mixture, because the (S)-enantiomer would not be present to exert any opposing actions.⁵  Lower doses of levalbuterol could thus be used to produce equivalent bronchodilation while allowing for decreased side effects of tachycardia and tremor.⁷ The goal of this article is to review the comparative evidence for levalbuterol and albuterol and discuss any clinical differences in efficacy and safety.

Table 1. Characteristics of albuterol and levalbuterol.^1,6,8

Efficacy Comparisons

After FDA approval of levalbuterol, there was much discussion among clinicians about whether or not it offered any efficacy or safety benefits that would justify its use over that of generic albuterol.  The following will briefly describe studies examining the efficacy of levalbuterol versus albuterol.  Table 2 contains a summary of comparative studies, including their major outcomes and reported adverse events.  Refer to this table for detailed results of studies discussed below.

Clinical Efficacy Comparisons: Ambulatory Settings

Adult COPD Patients

Two studies compared the efficacy and safety of levalbuterol and albuterol in stable adult COPD patients.^9,10  In a small crossover study conducted by Datta and colleagues, no significant difference between levalbuterol and albuterol was found in terms of mean change in forced expiratory volume in 1 second (FEV₁) from baseline after a single dose.⁹  While both groups experienced an increase in heart rate of approximately 5 beats per minute (bpm) during the first hour after administration, there were no significant differences in heart rate or tremor between the 2 groups at any given time point.  A larger randomized controlled trial conducted by Donohue and colleagues found that COPD patients receiving levalbuterol 1.25 mg treatments three times daily used fewer doses of rescue medication than those receiving racemic albuterol 2.5 mg at the same scheduled frequency.¹⁰  However, there was no significant difference in the primary efficacy endpoint of time-normalized FEV₁ area under the curve (AUC_{(0-8 hrs)}).  Nervousness and tremor occurred in similar numbers of patients across treatment groups. No clinically significant change in heart rate was seen in any of the treatment groups 30 minutes after administration.

Pediatric Asthma Patients

Multiple comparative studies have been conducted in the ambulatory pediatric asthma population; however, the clinical applicability of these studies is limited, because most studies used a scheduled regimen, and regular daily use of inhaled β₂ agonists is not supported by asthma guidelines.⁴  A crossover study by Gawchik and colleagues examined the efficacy of various one-time doses of levalbuterol in patients 2 to 11 years of age; all doses of levalbuterol and albuterol improved FEV₁ more effectively than placebo, but the study was not powered to detect differences between levalbuterol and albuterol.¹¹  A study by Berger and colleagues compared levalbuterol to placebo in patients 4 to 11 years of age, and included racemic albuterol as an active control.¹²  Both treatments improved peak percent change in FEV₁ to a greater extent than placebo after any single dose.  There was no significant difference between levalbuterol and albuterol in terms of peak percent change in FEV₁; however, this study was not powered for the comparison of levalbuterol to albuterol.  Milgrom and colleagues conducted another study in a similar population and found that levalbuterol and albuterol produced comparable median peak percent changes in FEV₁.¹³ A study in patients 2 to 5 years of age was conducted by Skoner and colleagues.¹⁴ In this study, there was no significant difference in the change in Pediatric Asthma Questionnaire scores between the levalbuterol and albuterol groups.

Clinical Efficacy Comparisons: Hospital and Emergency Department Settings

Adult Patients

A study by Thompson and colleagues compared levalbuterol and albuterol in the emergency medical services (EMS) setting.¹⁵  In this study, levalbuterol and albuterol produced similar changes in peak flow.  However, the sample size in this study was small, so it was underpowered to detect a true difference between the groups.  A study by Nowak and colleagues examined the use of levalbuterol for acute severe asthma exacerbations in the emergency department (ED) setting.¹⁶  In this study, no difference was found between levalbuterol and albuterol in terms of time to patient discharge from the ED; a statistically nonsignificant decrease in hospitalizations was seen in the levalbuterol group.  This difference in hospitalization rates was statistically significant in patients who had not been on any kind of corticosteroid therapy prior to presentation.

A 2-week, randomized, open-label trial in hospitalized asthma and COPD patients was conducted by Donohue and colleagues.¹⁷  In this trial, patients were randomized to receive scheduled nebulizer treatments with either levalbuterol or racemic albuterol.  Patients in the levalbuterol group received fewer total nebulization treatments without an increased need for rescue nebulization; these patients also reported fewer β₂-mediated side effects.  However, the levalbuterol nebulizations were scheduled every 6 to 8 hours, while the racemic albuterol nebulizations were scheduled every 1 to 4 hours.  This difference in scheduled frequencies may have influenced the number of nebulization treatments, as well as the more frequent incidence of side effects in the racemic albuterol group.  The study also examined hospital costs between the groups and found no significant differences; however, these costs did not include the cost of study medications. 

A recent study by Brunetti and colleagues examined the clinical outcomes and treatment costs of levalbuterol versus albuterol in the hospital setting.¹⁸  This trial found no significant difference in the number of scheduled and as-needed nebulizations required during the course of treatment, and no clinically significant change in heart rate in either group.  However, the study did find that patients receiving levalbuterol had longer hospital stays and higher hospitalization costs on average.

Pediatric Patients

Carl and colleagues performed a large comparative study of levalbuterol and racemic albuterol in a pediatric ED and inpatient population.¹⁹  This study found that using levalbuterol in the ED resulted in fewer hospitalizations when compared to albuterol.  Among patients who were admitted to the hospital, there was no difference between levalbuterol and albuterol in terms of length of stay, number of aerosols required, or adverse effects.  Qureshi and colleagues also assessed the efficacy of levalbuterol versus racemic albuterol in the pediatric ED population.²⁰  This study, which included patients 2 to 14 years of age with acute moderate-to-severe asthma exacerbations, found no differences between groups in terms of clinical improvement measures (FEV₁ and clinical asthma score) or hospitalization rates.  A similar study by Hardasmalani and colleagues also failed to find a difference between levalbuterol and albuterol in terms of efficacy or hospitalization rates; however, this study was limited by a small sample size.²¹ 

Two trials examined the efficacy of levalbuterol and racemic albuterol when given as continuous nebulization in the ED.  Wilkinson and colleagues found that albuterol was superior to levalbuterol in terms of FEV₁ improvement and asthma score, with no difference in admission rates or side effect profile.²²  In this study, the patients receiving albuterol had worse asthma scores at baseline than the patients receiving levalbuterol; this may have allowed more opportunity for lung function improvement in the albuterol group.  A study by Andrews and colleagues found no difference between levalbuterol and albuterol in terms of time to discontinuation of continuous therapy or any other efficacy measure.²³

Adverse Effect Comparisons

Ambulatory Adult Patients

Two studies in adults have compared levalbuterol and albuterol in terms of their short-term and long-term adverse events.  A randomized, double-blind, single-day crossover study by Tripp and colleagues compared the effects of levalbuterol and albuterol on heart rate in patients greater than 12 years of age with stable asthma.²⁴  In this study, 49 patients were given escalating doses of albuterol or levalbuterol for a cumulative total dose of 16 inhaler actuations within a 2 hour period.  Mean heart rate changes from baseline were significantly different between treatment groups after 8 cumulative doses; the mean change in heart rate from baseline was 2.8 bpm greater in the albuterol group after the eighth cumulative dose (95% confidence interval [CI] 0.3 to 5.3) and 3.5 bpm greater in the albuterol group after the sixteenth cumulative dose (95% CI 0.6 to 6.4).  The clinical significance of this finding is limited, as the dosing scheme described in this study significantly exceeds the recommended doses for both agents.^1,6 The safety of levalbuterol and albuterol inhalers was also evaluated over a 52-week period in a randomized, open-label trial of ambulatory patients 12 years of age or older.²⁵  In this trial, 746 patients were randomized in a 2:1 ratio to receive levalbuterol or albuterol at a dose of 2 puffs four times daily.  There was no significant difference in the incidence of overall adverse effects (72.0% with levalbuterol versus 76.8% with albuterol, p=0.12).  β-mediated side effects were reported by 67 (13.5%) of patients in the levalbuterol group and 47 (18.8%) of patients in the albuterol group (p value not reported). 

Critically-Ill Adults

Two studies have compared the effects of levalbuterol and albuterol on heart rate in the critically ill adult patient population. A randomized crossover study by Lam and colleagues examined changes in heart rate after at least 2 consecutive doses of levalbuterol 1.25 mg or albuterol 2.5 mg (doses were given every 4 hours).²⁶  Twenty intensive care unit (ICU) patients were studied, including 10 with pre-existing tachycardia.  In patients with tachycardia at baseline, the mean largest increase in heart rate was 1.4 bpm with albuterol and 2.0 bpm with levalbuterol; in patients without tachycardia at baseline, the mean largest increase in heart rate was 4.4 bpm with albuterol and 3.6 bpm with levalbuterol (p values were not reported for between-group comparisons).  Khorfan and colleagues also examined the effects of levalbuterol and albuterol on heart rate in a larger, randomized, single-blind crossover study.²⁷  Seventy critically ill adult patients who were treated with a nebulized bronchodilator were randomized to 1 of 2 treatment groups. Group A received nebulized albuterol 2.5 mg alternated with levalbuterol 0.63 mg every 4 to 6 hours, and Group B received nebulized levalbuterol 1.25 mg alternated with albuterol 2.5 mg every 4 to 6 hours.  Heart rate was recorded before treatment and 15 minutes after treatment.  Among patients in Group A, heart rate increased by an average of 0.89 bpm with albuterol versus 0.85 with levalbuterol (p=0.89).  Among patients in group B, heart rate decreased by an average of 0.16 bpm with albuterol and increased by 1.4 bpm with levalbuterol (p=0.03 in favor of albuterol).  Neither treatment resulted in a clinically significant change in heart rate.

Hospitalized Pediatric Patients

A retrospective study by Bio and colleagues examined the effects of levalbuterol and albuterol on heart rate in a population of 50 hospitalized patients aged 1 month to 12 years.²⁸  All patients in the albuterol group received 2.5 mg per dose, and most patients (76%) in the levalbuterol group received 0.63 mg per dose.  The median largest percent change in heart rate from baseline was 4.1% with levalbuterol and 5.0% with racemic albuterol (p value not significant).  However, this study excluded patients with pre-existing cardiac conditions.  A subsequent retrospective study by Kelly and colleagues examined levalbuterol and albuterol in terms of their effects on heart rate in a population of pediatric patients with cardiac diseases.²⁹  In this study, the majority of patients receiving albuterol (75%) received 1.25 mg per dose, and the majority of patients receiving levalbuterol (55%) received 0.63 mg per dose.  The overall mean increase in heart rate was 6.8 bpm in the albuterol group and 6.2 bpm in the levalbuterol group (p=0.01 for equivalence).  These findings suggest that even among pediatric patients with pre-existing heart conditions, levalbuterol does not offer benefit over albuterol in terms of effect on heart rate.

Meta-analysis and Conclusion

In 2013, Jat and colleagues conducted a meta-analysis of randomized controlled trials comparing the efficacy and safety of levalbuterol and albuterol in patients with acute asthma.³⁰  The analysis included 7 trials, 6 of which were conducted in the pediatric population.  In this meta-analysis, levalbuterol did not appear to offer any advantages over albuterol in terms of respiratory rate, oxygen saturation, percent change in FEV₁, percent change in clinical asthma score, side effects, or duration of ED care.  Patients receiving levalbuterol were less likely to be hospitalized (odds ratio 0.76, 95% CI 0.58 to 0.98); however, the authors note that this finding was heavily influenced by a single trial.  The benefit of levalbuterol on hospitalization rate was not evident when this trial was excluded from the meta-analysis.

Overall, clinical evidence supporting the use of levalbuterol is not convincing.  Comparative studies have failed to find any consistent, clinically important advantage to using levalbuterol over the racemic product.⁴  One large study by Carl and colleagues found that pediatric asthma patients who received levalbuterol in the ED were less likely to be hospitalized than those who received albuterol; however, this finding was not replicated in subsequent studies.^19-21  Current asthma guidelines offer either drug as an option for quick relief of acute asthma symptoms.³¹  The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines state that for single-dose, as-needed use, there appears to be no advantage in using levalbuterol over conventional bronchodilators.³²

Table 2. Key comparative studies of levalbuterol versus albuterol that report efficacy and safety as part of outcomes.^9-23

References

1.         Ventolin HFA [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014.

2.         Op't Holt TB. Inhaled beta agonists. Respir Care. 2007;52(7):820-832.

3.         Ameredes BT, Calhoun WJ. Levalbuterol versus albuterol. Curr Allergy Asthma Rep. 2009;9(5):401-409.

4.         Blake K, Raissy H. Chiral switch drugs for asthma and allergies: true benefit or marketing hype. Pediatr Allergy Immunol Pulmonol. 2013;26(3):157-160.

5.         Kelly HW. Levalbuterol for asthma: a better treatment? Curr Allergy Asthma Rep. 2007;7(4):310-314.

6.         Xopenex [package insert]. Lake Forest, IL: Akorn; 2015.

7.         Dalonzo GE, Jr. Levalbuterol in the treatment of patients with asthma and chronic obstructive lung disease. J Am Osteopath Assoc. 2004;104(7):288-293.

8.         Albuterol sulfate [package insert]. Columbia, SC: The Ritedose Corporation; 2014.

9.         Datta D, Vitale A, Lahiri B, ZuWallack R. An evaluation of nebulized levalbuterol in stable COPD. Chest. 2003;124(3):844-849.

10.       Donohue JF, Parsey MV, Andrews C, et al. Evaluation of the efficacy and safety of levalbuterol in subjects with COPD. COPD: Journal of Chronic Obstructive Pulmonary Disease. 2009;3(3):125-132.

11.       Gawchik SM, Saccar CL, Noonan M, Reasner DS, DeGraw SS. The safety and efficacy of nebulized levalbuterol compared with racemic albuterol and placebo in the treatment of asthma in pediatric patients. J Allergy Clin Immunol. 1999;103(4):615-621.

12.       Berger WE, Milgrom H, Skoner DP, Tripp K, Parsey MV, Baumgartner RA. Evaluation of levalbuterol metered dose inhaler in pediatric patients with asthma: a double-blind, randomized, placebo- and active-controlled trial. Curr Med Res Opin. 2006;22(6):1217-1226.

13.       Milgrom H, Skoner DP, Bensch G, Kim KT, Claus R, Baumgartner RA. Low-dose levalbuterol in children with asthma: safety and efficacy in comparison with placebo and racemic albuterol. J Allergy Clin Immunol. 2001;108(6):938-945.

14.       Skoner DP, Greos LS, Kim KT, Roach JM, Parsey M, Baumgartner RA. Evaluation of the safety and efficacy of levalbuterol in 2-5-year-old patients with asthma. Pediatr Pulmonol. 2005;40(6):477-486.

15.       Thompson M, Wise S, Rodenberg H. A preliminary comparison of levalbuterol and albuterol in prehospital care. J Emerg Med. 2004;26(3):271-277.

16.       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(3):259-267.

17.       Donohue JF, Hanania NA, Ciubotaru RL, et al. Comparison of levalbuterol and racemic albuterol in hospitalized patients with acute asthma or COPD: a 2-week, multicenter, randomized, open-label study. Clin Ther. 2008;30 Spec No:989-1002.

18.       Brunetti L, Poiani G, Dhanaliwala F, Poppiti K, Kang H, Suh DC. Clinical outcomes and treatment cost comparison of levalbuterol versus albuterol in hospitalized adults with chronic obstructive pulmonary disease or asthma. Am J Health Syst Pharm. 2015;72(12):1026-1035.

19.       Carl JC, Myers TR, Kirchner HL, Kercsmar CM. Comparison of racemic albuterol and levalbuterol for treatment of acute asthma. J Pediatr. 2003;143(6):731-736.

20.       Qureshi F, Zaritsky A, Welch C, Meadows T, Burke BL. Clinical efficacy of racemic albuterol versus levalbuterol for the treatment of acute pediatric asthma. Ann Emerg Med. 2005;46(1):29-36.

21.       Hardasmalani MD, DeBari V, Bithoney WG, Gold N. Levalbuterol versus racemic albuterol in the treatment of acute exacerbation of asthma in children. Pediatr Emerg Care. 2005;21(7):415-419.

22.       Wilkinson M, Bulloch B, Garcia-Filion P, Keahey L. Efficacy of racemic albuterol versus levalbuterol used as a continuous nebulization for the treatment of acute asthma exacerbations: a randomized, double-blind, clinical trial. J Asthma. 2011;48(2):188-193.

23.       Andrews T, McGintee E, Mittal MK, et al. High-dose continuous nebulized levalbuterol for pediatric status asthmaticus: a randomized trial. J Pediatr. 2009;155(2):205-210 e201.

24.       Tripp K, McVicar WK, Nair P, et al. A cumulative dose study of levalbuterol and racemic albuterol administered by hydrofluoroalkane-134a metered-dose inhaler in asthmatic subjects. J Allergy Clin Immunol. 2008;122(3):544-549.

25.       Hamilos DL, D'Urzo A, Levy RJ, et al. Long-term safety study of levalbuterol administered via metered-dose inhaler in patients with asthma. Ann Allergy Asthma Immunol. 2007;99(6):540-548.

26.       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(19):1971-1975.

27.       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(6):1466-1472.

28.       Bio LL, Willey VJ, Poon CY. Comparison of levalbuterol and racemic albuterol based on cardiac adverse effects in children. J Pediatr Pharmacol Ther. 2011;16(3):191-198.

29.       Kelly A, Kennedy A, John BM, Duane B, Lemanowicz J, Little J. A comparison of heart rate changes associated with levalbuterol and racemic albuterol in pediatric cardiology patients. Ann Pharmacother. 2013;47(5):644-650.

30.       Jat KR, Khairwa A. Levalbuterol versus albuterol for acute asthma: a systematic review and meta-analysis. Pulm Pharmacol Ther. 2013;26(2):239-248.

31.       Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma–Summary Report 2007. J Allergy Clin Immunol. 2007;120(5):S94-S138.

32.       Global Strategy for the Diagnosis, Management and Prevention of COPD – 2016. Global Initiative for Chronic Obstructive Lung Disease website. http://goldcopd.org/. Updated 2016. Accessed July 21, 2016.

October 2016

Prepared by:
Laura Koppen, PharmD
PGY2 Drug Information Resident
University of Illinois at Chicago
College of Pharmacy

The information presented is current as of July 20, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What evidence supports the efficacy of ranolazine (Ranexa®) for the treatment of atrial fibrillation?

Introduction

Atrial fibrillation (AF), a supraventricular tachyarrhythmia which causes an “irregularly irregular” rhythm, is caused by either a structural or electrophysiological abnormality that changes the atrial tissue to produce abnormal conduction.¹ It is the most common type of arrhythmia affecting up to 6.1 million adults in the United States with trends indicating a future increase in incidence.^1,2 About 35% of patients with AF are ≥80 years old.¹ Atrial fibrillation is associated with an increased risk of stroke, heart failure (HF), dementia, and mortality.¹ Symptoms of AF range from no symptoms to palpitations, dyspnea, hypotension, syncope, and/or fatigue, which is the most common.¹ Atrial fibrillation can be classified as paroxysmal, persistent, long-standing persistent, or permanent.

Atrial Fibrillation

According to the American College of Cardiology/American Heart Association guidelines on AF, rhythm control may be suitable in patients with persistent symptoms associated with AF, difficulty in achieving rate control, young age, tachycardia-mediated cardiomyopathy, first episode of AF, AF precipitated by an acute illness, or due to patient preference.¹ Currently, the recommended agents for the rhythm-control strategy to maintain a normal sinus rhythm include: amiodarone, dofetilide, dronedarone, flecainide, propafenone, and sotalol.^1,3 Factors that should be considered when choosing the appropriate therapy include: presence of coronary artery disease (CAD), significant left ventricular (LV) hypertrophy, HF, risk or presence of QT prolongation and torsades de pointes (TdP), as well as age, renal and hepatic function.^1,4 The aforementioned agents are associated with severe adverse effects and toxicities, which make the selection of antiarrhythmic agents dependent on the safety of the drug rather than efficacy.¹ (Table 1) One of the major concerns is the proarrhythmic effect which severely restricts the use of these drugs in patients with HF with reduced ejection fraction limiting the treatment option to amiodarone.⁴ Presently, amiodarone is considered the most effective antiarrhythmic for rhythm control, however, since it is associated with serious adverse events it is not recommended as first-line treatment.¹ There is a general consensus that safer and more effective antiarrhythmic drugs that have atrial selectivity are clinically needed for the treatment of AF, especially in the setting of HF.^1,5

Table 1. Major safety concerns with agents used in rhythm-control for AF¹

Ranolazine (Ranexa^®)

In 2006, ranolazine (Ranexa^®) received Food and Drug Administration (FDA) approval for the treatment of chronic angina.⁶ Ranolazine reduces calcium overload responsible for lowering the action potential threshold and increasing the risk of atrial fibrillation by inhibiting the late sodium current (I_Na,late) dose-dependent manner.^2,6-8 Ranolazine is under investigation for various indications either alone or in combination with other anti-arrhythmic agents. Although not currently approved by the FDA as an antiarrhythmic agent, ranolazine is unique because it has atrial selective properties and less proarrhythmic effects than the currently available antiarrhythmic drugs.^3,9 This review will focus on the evidence from major trials to evaluate the role of ranolazine in AF and postoperative AF.

Summary of Literature

The beneficial antiarrhythmic effect was first observed in the MERLIN-TIMI 36 trial, a Phase III double-blind, multicenter, placebo-controlled, randomized controlled trial. A total of 6560 patients hospitalized for non-ST-elevation acute coronary syndrome (ACS) on standard therapy received ranolazine 200 mg intravenously over 1 hour, followed by 80 mg/h infusion for up to 96 hours then oral ranolazine ER 1000 mg twice daily or placebo. Although there was no significant difference between ranolazine and placebo for the composite endpoint cardiovascular (CV) death, myocardial infarction (MI), or recurrent ischemia (hazard ratio [HR], 0.92; 95% CI, 0.83 to 1.02; P=0.11), an analysis of the high-risk patients showed a reduced incidence of recurrent AF, including in patients with HF and low ejection fraction. When all supraventricular arrhythmias were considered, a significant reduction was seen in the ranolazine group compared to placebo (44.7% vs. 55%, p<0.001). While the study was not designed to look at AF endpoints, it was speculated that further investigations for the use of ranolazine in AF would be required due to the positive effects identified.^9-11 The findings of this study are limited because it was not intended to test for antiarrhythmic effects of ranolazine.

Another randomized, parallel, placebo-controlled Phase II study, the HARMONY trial, compared ranolazine and dronedarone, alone and in combination in 134 patients with paroxysmal AF.¹² The study found that ranolazine 750 mg twice daily in combination with dronedarone 225 mg or 150 twice daily significantly reduced AF burden by 59% and 43% compared to placebo, respectively.^9,12 This benefit was not observed with either agent alone.

Ranolazine was also investigated outside of the US in a pivotal dose ranging trial (RAFFAELO) in patients with persistent AF after successful electrical cardioversion. In this Phase II, randomized, double-blind, multicenter, placebo-controlled trial, 241 patients were randomized to receive ranolazine 375 mg, 500 mg, 750 mg twice daily or placebo.¹³ None of the doses significantly reduced the recurrence of AF except when the 500 mg and 750 mg groups were combined and compared to the 375 mg group (p=0.035). Since this was a Phase II study, sample size was a limitation; however, this study does suggest that there could be a role of ranolazine in the prevention of post-cardioversion recurrent AF.¹⁴ Overall, all three doses of ranolazine were determined to be safe, and no proarrhythmic effect or QT prolongation was observed.^9,13

Ranolazine has also been studied in patients with new-onset AF or postoperative AF.^14-20 These studies produced mixed results with an overall trend showing benefit, and mostly consisted of small patient populations.¹⁴ In one single-center, double-blind, randomized trial,  there was no difference between ranolazine and placebo in the incidence of postoperative AF possibly because of spontaneous conversion after surgery.⁹  Studies looking specifically at patients undergoing coronary artery bypass surgery showed that the incidence of postoperative AF was significantly lower in patients receiving ranolazine compared to usual care, or amiodarone.^18-20 In patients with non-postoperative new onset AF, conversion rates to normal sinus rhythm were observed with single-dose ranolazine in combination with amiodarone resulting in higher rates and shorter time to conversion.^14-17

Strengths and Limitations

Overall, only relatively small studies with the exception of the MERLIN-TIMI 36 trial are available evaluating the use of ranolazine in AF. These studies show a trend towards a modest beneficial effect of ranolazine.²¹ Despite being a large trial, the findings from the MERLIN-TIMI 36 trial are limited because the study was not designed to assess the outcome of ranolazine in AF. Although there are numerous studies available assessing the use of ranolazine for different clinical presentations of AF, another limitation is that not enough studies are available for each distinctive presentation of AF. There is a clinical need for alternative treatment strategies in patients with HF and AF, however, studies in this subpopulation are lacking even though experimental models have shown benefit.¹⁸

Conclusions

The results seen with the studies do seem to suggest a role for ranolazine in AF; however, larger prospective studies are required to draw clinically relevant conclusions regarding the place in therapy for ranolazine.^8,21 Based on currently available studies, a recommendation for an optimal dose for the use of ranolazine in AF cannot be made since various regimens and routes of administration were used in the studies. Ranolazine would provide a beneficial alternative to the currently available options for AF due to its lack of adverse effects relative to the presently available antiarrhythmics. The benefits observed with ranolazine include a lack of proarrhythmic effect, a negligible effect on hemodynamics, and possible atrial selectivity.^21,22

References:

1.         January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 2014;130(23):e199-267.

2.         Mason FE, Sossalla S. The significance of the late Na+ current for arrhythmia induction and the therapeutic antiarrhythmic potential of ranolazine [published online April 28 2016]. J Cardiovasc Pharmacol Ther. 2016.

3.         Burashnikov A, Antzelevitch C. How do atrial-selective drugs differ from antiarrhythmic drugs currently used in the treatment of atrial fibrillation? J Atr Fibrillation. 2008;1(2):98-107.

4.         Gupta T, Khera S, Kolte D et al. Antiarrhythmic properties of ranolazine: a review of the current evidence. Int J Cardiol. 2015;187:66-74.

5.         Burashnikov A, Di Diego JM, Barajas-Martinez H, et al. Ranolazine effectively suppresses atrial fibrillation in the setting of heart failure. Circ Heart Fail. 2014;7(4):627-633.

6.         Ranexa [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2016.

7.         Saad M, Mahmoud A, Elgendy I, et al. Ranolazine in cardiac arrhythmia. Clin Cardiol. 2016;39(3):170-178.

8.         Pulford BR, Kluger J. Ranolazine therapy in cardiac arrhythmias. Pacing Clin Electrophysiol. 2016;39(9):1006-1015.

9.         Shenasa M, Assadi H, Heidary S, et al. Ranolazine: electrophysiologic effect, efficacy, and safety in patients with cardiac arrhythmias. Card Electrophysiol Clin. 2016;8(2):467-479.

10.       Morrow DA, Scirica B, Karwatowska-Prokopczuk E, et al. Effects of ranolazine on recurrent cardiovascular events in patients with non–ST-elevation acute coronary syndromes – The MERLIN-TIMI 36 Randomized Trial. JAMA. 2007;297(16):1775-1783.

11.       Scirica BM, Morrow DA, Hod H, et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation. 2007;116(15):1647-1652.

12.       Reiffel JA, Camm AJ, Belardinelli L, et al. The HARMONY Trial: combined ranolazine and dronedarone in the management of paroxysmal atrial fibrillation: mechanistic and therapeutic synergism. Circ Arrhythm Electrophysiol. 2015;8(5):1048-1056.

13.       De Ferrari GM, Maier LS, Mont L, et al. Ranolazine in the treatment of atrial fibrillation: results of the dose-ranging RAFFAELLO (Ranolazine in Atrial Fibrillation Following An ELectricaL CardiOversion) study. Heart Rhythm. 2015;12(5):872-878.

14.       Mihos CG, Krishna RK, Kherada N, et al. The use of ranolazine in non-anginal cardiovascular disorders: a review of current data and ongoing randomized clinical trials. Pharmacol Res. 2016; doi: 10.1016/j.phrs.2015.10.018.

15.       Murdock DK, Kersten M, Kaliebe J, et al. The use of oral ranolazine to convert new or paroxysmal atrial fibrillation: a review of experience with implications for possible pill in the pocket approach to atrial fibrillation.  Indian Pacing Electrophysiol J. 2009;9(5):260-267.

16.       Koskinas KC, Fragakis N, Katritsis D, et al. Ranolazine enhances the efficacy of amiodarone for conversion of recent-onset atrial fibrillation. Europace. 2014;16(7):973-979.

17.       Fragakis N, Koskinas KC, Katritsis DG, et al. Comparison of effectiveness of ranolazine plus amiodarone versus amiodarone alone for conversion of recent-onset atrial fibrillation. Am J Cardiol. 2012;110(5):673-677.

18.       Tagarakis GI, Aldonidis I, Daskalopoulou SS, et al. . Effect of ranolazine in preventing postoperative atrial fibrillation in patients undergoing coronary revascularization surgery. Curr Vasc Pharmacol. 2013;11(6):988-991.

19.       Miles RH, Passman R, Murdock DK. Comparison of effectiveness and safety of ranolazine versus amiodarone for preventing atrial fibrillation after coronary artery bypass grafting. Am J Cardiol. 2011;108(5):673-676.

20.       Hammond DA, Smotherman C, Jankowski CA, et al. Short-course of ranolazine prevents postoperative atrial fibrillation following coronary artery bypass grafting and valve surgeries. Clin Res Cardiol. 2015;104(5):410-417.

21.       Dagres N, Iliodromitis EK, Lekakis JP, et al. Ranolazine for the prevention or treatment of atrial fibrillation: a systematic review. J Cardiovasc Med. 2014;15(3):254-259.

22.       Ehrlich JR, Nattel S. Atrial-selective pharmacological therapy for atrial fibrillation: hype or hope? Curr Opin Cardiol. 2009;24(1):50-55.

October 2016

The information presented is current as September 16, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.