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Zpack successfully removes Xopenex off the formulary
Short-Acting ß2 Agonist
Class Review
November 2006
Introduction
The short-acting bronchodilators are to be used primarily for rescue in the treatment of asthma, COPD, and reactive airway disease in both the home and hospital settings. These drugs may be scheduled treatment if the disease is severe enough to warrant it. Albuterol is available in many forms including metered dose inhaler, solution for nebulization, oral solution, and tablets. Levalbuterol is available as a solution for nebulization and MDI.
Albuterol was approved in 1981 and is a racemic mixture of both the R- and S-isomers of albuterol.1,2 Levalbuterol was approved in 1999 and is the R-enantiomer of albuterol.3 It was found that this is the active component in the racemic mixture of albuterol.
Pharmacology/Pharmacokinetics
The short-acting ß2 agonists work to bronchodilate the lungs in exacerbations of chronic obstructive disease. There are two kinds of ß receptors: ß1 are found primarily in the heart and ß2 receptors are found in the smooth muscle surrounding the bronchioles primarily, but also in the epithelium, eosinophils, and macrophages of the bronchi, and in the heart. The ß receptors in the heart are 14-25% ß2 receptors by weight.1
The activated ß2 adrenergic receptor activates adenylate cyclase and converts 5'-triphosphate to 3', 5'-monophosphate which allows the smooth muscle in the bronchioles to dilate.1 Activation of this receptor also has such actions as inhibiting the degranulation and release of inflammatory materials from mast cells, decreasing the diastolic blood pressure via vasodilation, accumulating intracellular serum potassium, leading to moderate hypokalemia.2
Albuterol2,4 Levalbuterol3,5
Metabolism Liver to inactive cmpds
Elimination 80-100% urine, up to 10% feces
Half-life 3.8 hours 3.3 – 4 hrs
Onset of bronchodilation 5 – 15 min 10 – 17 min
Mean time to peak effect 0.5 – 2 hrs 1.5 hrs
Mean duration of activity 2 – 6 hrs 5 – 6 hrs (up to 8 hrs)
Both drugs are absorbed over several hours from the respiratory tract. Additionally, they both have low systemic availability. However, most of an inhaled dose is swallowed and absorbed through the GI tract.2
FDA Approved Indications
Albuterol4 Levalbuterol5
Treatment of bronchospasm in patients 6 and over with reversible obstructive airway disease X X
Prevention of bronchospasm in patients 6 and over with reversible obstructive airway disease X X
Prevention of exercise induced bronchospasm in patients 4 and older X
Dosage and Administration for Adults
Albuterol4 Levalbuterol5
Treatment and prevention of bronchospams 2.5 mg q 6 – 8 hrs prn given over 5 – 15 min 0.63 mg tid q 8 hr
Acute treatment of severe bronchospams 2.5 – 5 mg initially q 20 min x 3 doses, then 2.5 – 10 mg q 1 – 4 hrs prn or 10 – 15 mg/hour by continuous nebulization 1.25 mg Q8h
Max dose 32 mg/day po 3.75 mg/day
No dosage adjustment needed for patient with either renal or hepatic impairment.
Dosage recommendations for the elderly: start at the low end of the dosage range and titrate upwards as needed.
Dosage recommendations for children: use one strength lower than those recommended for adults, but keep the same dosing schedule. It is not recommended to dose levalbuterol more than 3 times a day.
Adverse Effects (Safety Data, taken from Package Inserts)
Despite the fact that these two agents are selective for the ß2 receptor, they still cause tachycardia to some degree. None of the ß2 agonists are completely selective, and furthermore, with increasing doses of any agent, the selectivity for the ß2 receptor decreases.1
Adults
levalbuterol1.25 mg racemic albuterol2.5 mg
Tachycardia 2.7 2.7
Dizziness 2.7 0
Nervousness 9.6 8.1
Anxiety 2.7 0
Tremor 6.8 2.7
Dyspepsia 2.7 1.4
Rhinitis 2.7 6.8
Increased cough 4.1 2.7
Children
levalbuterol0.63 mg racemic albuterol1.25 mg
Asthma 9.0 6.3
Headache 11.9 9.4
Myalgia 1.5 1.6
Pharyngitis 10.4 0
Rhinitis 10.4 3.1
Drug Mean Changes from Baseline2
Heart Rate (bpm) Glucose (mg/dL)
Adults
Levalbuterol 1.25 mg 6.9 10.3
Albuterol (racemic) 2.5 mg 5.7 8.2
Significant No no
Children
Levalbuterol 0.63 mg 6.7 5.2
Albuterol (racemic) 1.25 mg 6.4 8.0
Significant No no
Precautions/Contraindications
Warning for both agents for paradoxical bronchospasm, deterioration of asthma, immediate hypersensitivity reactions, and cardiovascular effects. Use of anti-inflammatory agents may be necessary to help control the disease process in addition to these agents alone.4,5
High doses of albuterol may inhibit uterine contractions during labor in some reports.4
Drug Interactions
Non-selective beta blockers antagonize the effects of beta agonists. Therefore, a selective beta agonist should be used in asthmatic patients. Use with caution in patients receiving non-potassium sparing diuretics, as the combination may decrease serum levels of potassium. Elevated digoxin levels were seen in patients taking albuterol. Additionally, a patient should not take a monoamine oxidase inhibitor or a tricyclic antidepressant within two weeks of albuterol therapy due to the risk of serious adverse cardiac events.4,5
Clinical Trials
Trial Regimens Methods Results Comments
Carl, et al Levalbuterol Nebs 1.25mg q20min or albuterol 2.5mg q20min in the ER 547 enrollments from 478 children (85% black, 67% male) with acute asthmaExcluded: first episode, no current treatment, pregnant, hypersensitive to alb, CF, cyanosis, uncorrected congenital heart disease, chronic obstructive lung diseaseLev n=278Alb n=269Pts <6 y/o face mask nebPts >=6y/o mouthpiece nebReceive nebs q20 min until met discharge criteria or max of 6 tx in 2 hrs (admit the pt at that point)Given oral prednisone after 1st treatment if not meet DC criteriaSupplemental O2 given prnOption for intensification of therapy if requiredPrimary outcome measure: hospital admission rate 547 episodes in 477 patients. 1º EndPt: 36% admin rate for levalbuterol vs. 45% for albuterol. There was no difference in other endpoints. Outcome Alb Leva P Value
Hosp Admin 45 36 0.02
LOS Hrs 2.2 2.3 0.25
Tx/patient 4.1 3.7 0.08
Resp Rate 35.6 37.0 0.26
NNT for primary endpoint: 10.6Pts who used >=2 aerosols in previous 2 hours had 40% higher hospital admission rate (RR=1.39, 95% CI=1.13-1.72, p=0.02)Pts who used >3 aerosols in previous 2 hours had more admissions (RR=1.34, 95% CI=1.09-1.51, p=0.004) More patients in the levalbuterol group were treated with chromylin.The Admission criteria was not well defined and based on the ER MD who was not part of the study. Because data on pulmonary function wasn't noted, reasons for the difference in admission rate are unclear.
Debapriya et al Levalb 1.25mg Alb 2.5mg Alb 2.5mg + Ipr 0.5mg or placebo. Randomized DB, Placebo CCT, comparing albuterol, levalbuterol, ipratropium and placebo in patients with COPD. N=30PEP : FEV1 FVC, pulse, O2 sat. Positive Bronchodilator Response
Time (hr) 0.5 1
Alb 43% 47%
Alb/Ipr 43% 53%
Levalb 40% 40%
Placebo 13% 13%
None of the bronchodilators increase FEV1 past 4 hrs. None of the other 1º EndPt show significant differences. The duration of action of albuterol and levalbuterol was shorter than described in other studies.
Truitt T, et al.9Retrospective chart reviewSupported by Sepracor Albuterol 2.5 mg q 4h (Alb) vsLevalbuterol 1.25 mg q 8h (Lev) 231 charts reviewedTwo six-month periods with these two drugs on formulary Charts were searched for ICD codes for asthma, COPDExcluded: concomitant cognitive disturbances, cancerAlb n=125 (90 pts COPD, 35 pts asthma)Lev n=106 (87 pts COPD, 19 pts asthma)PEP: total number of neb treatments requiredSEP: Primary endpoint reached30.8 treatments alb vs 19.0 treatments lev p<0.001 Additional outcome measures: changes in PFTs, duration of hospitalization, disposition following hospitalization, pharmacy utilization costs, resource utilization costsBy design (treatment protocol) the pts treated with alb automatically had twice as many nebs scheduled than the pts on levUsed inflated basis of AWP to calculate cost of drug
Acquisition Cost
Albuterol Levalbuterol
How supplied 0.83 mg/mL (3 ml vial) 0.417 mg/mL
Typical dose 2.5 mg 1.25 mg
Cost per dose $0.10 $2.41
Cost per day $0.40 q 6h$0.60 q 4h $7.23 q 8h$9.64 q6h$14.46 q4h
Conclusions
Albuterol and levalbuterol share many of the same characteristics and actions. There has been discrepancy in the literature surrounding levalbuterol's superiority to albuterol. Many claims have been made which indicate that S-albuterol, the inactive enantiomer in albuterol may not be inactive, but have some detrimental properties. Some of these are that S-albuterol works in opposition to R-albuterol, that S-albuterol leads to the tolerance effect seen with the bronchodilator, that it increases airway hyperresponsiveness, and that it causes the systemic effects of racemic albuterol.6
To date, there has been no study demonstrating a significant difference between levalbuterol and albuterol. Because of the lack of data to support superiority of levalbuterol it is difficult to justify the additional expense of levalbuterol.
Cockcroft et al7 found that tolerance developed after six days to groups treated with R-albuterol or racemic albuterol. However patients did not develop tolerance after being treated with S-albuterol or to placebo treatment. Doing this, they proved that S-albuterol was not responsible for the development of tolerance.
Randomized trials have not demonstrated that S-albuterol causes hyperresponsiveness in the lung tissue of asthmatic patients.
Three studies show that the systemic effects of racemic albuterol are due to the R- enantiomer, and not the S-enantiomer.
Two studies8,9 both sponsored by Sepracor, the manufacturer of Xopenex®, claim that levalbuterol led to fewer hospitalizations and decreased cost to the hospital. However, the Carl study did not predefine hospital admission criteria and the two groups of patients that were admitted had no difference in clinical presentation at admission, end of ED stay, and duration of hospitalization.
References
1. Pleasants RA. Focus on inhaled ß2 – agonists: efficacy, safety, and patient preference. Pharmacotherapy. 2004; 24 (5 pt 2):44S-54S.
2. Proventil®. Clinical Pharmacology. Accessed 10/18/04.
3. Xopenex®. Clinical Pharmacology. Accessed 10/18/04.
4. Armstrong. Albuterol inhalation aerosol. Package insert, West Roxbury, MA; 2003.
5. Sepracor. Xopenex®. Package insert, Marlborough, MA; 2002.
6. Ahrens R, Weinberger M. Levalbuterol and racemic albuterol: are there therapeutic differences? [Editorial]. J Allergy Clin Immunol. 2001;108:681-84.
7. Cockcroft DW, Davis BE, Swystun VA, et al. Tolerance to the bronchoprotective effect of ß2 agonists: comparison of the enantiomers of salbutamol with racemic salbutamol and placebo. J Allergy Clin Immunol. 1999;103:1049-53.
8. Carl JC, Myers TR, Kirchner HL, et al. Comparison of racemic albuterol and levalbuterol for treatment of acute asthma. J Pediatr. 2003;143:731-36.
9. Truitt T, Witko, Halpern M. Levalbuterol compared to racemic albuterol. Chest. 2003;123:128-135.
10. McEvoy GK, et al, Ed. AHFS Drug Information 2004. 2004. American Society of Health-System Pharmacists. Bethseda, MD. P. 1233.
Short-Acting ß2 Agonist
Class Review
November 2006
Introduction
The short-acting bronchodilators are to be used primarily for rescue in the treatment of asthma, COPD, and reactive airway disease in both the home and hospital settings. These drugs may be scheduled treatment if the disease is severe enough to warrant it. Albuterol is available in many forms including metered dose inhaler, solution for nebulization, oral solution, and tablets. Levalbuterol is available as a solution for nebulization and MDI.
Albuterol was approved in 1981 and is a racemic mixture of both the R- and S-isomers of albuterol.1,2 Levalbuterol was approved in 1999 and is the R-enantiomer of albuterol.3 It was found that this is the active component in the racemic mixture of albuterol.
Pharmacology/Pharmacokinetics
The short-acting ß2 agonists work to bronchodilate the lungs in exacerbations of chronic obstructive disease. There are two kinds of ß receptors: ß1 are found primarily in the heart and ß2 receptors are found in the smooth muscle surrounding the bronchioles primarily, but also in the epithelium, eosinophils, and macrophages of the bronchi, and in the heart. The ß receptors in the heart are 14-25% ß2 receptors by weight.1
The activated ß2 adrenergic receptor activates adenylate cyclase and converts 5'-triphosphate to 3', 5'-monophosphate which allows the smooth muscle in the bronchioles to dilate.1 Activation of this receptor also has such actions as inhibiting the degranulation and release of inflammatory materials from mast cells, decreasing the diastolic blood pressure via vasodilation, accumulating intracellular serum potassium, leading to moderate hypokalemia.2
Albuterol2,4 Levalbuterol3,5
Metabolism Liver to inactive cmpds
Elimination 80-100% urine, up to 10% feces
Half-life 3.8 hours 3.3 – 4 hrs
Onset of bronchodilation 5 – 15 min 10 – 17 min
Mean time to peak effect 0.5 – 2 hrs 1.5 hrs
Mean duration of activity 2 – 6 hrs 5 – 6 hrs (up to 8 hrs)
Both drugs are absorbed over several hours from the respiratory tract. Additionally, they both have low systemic availability. However, most of an inhaled dose is swallowed and absorbed through the GI tract.2
FDA Approved Indications
Albuterol4 Levalbuterol5
Treatment of bronchospasm in patients 6 and over with reversible obstructive airway disease X X
Prevention of bronchospasm in patients 6 and over with reversible obstructive airway disease X X
Prevention of exercise induced bronchospasm in patients 4 and older X
Dosage and Administration for Adults
Albuterol4 Levalbuterol5
Treatment and prevention of bronchospams 2.5 mg q 6 – 8 hrs prn given over 5 – 15 min 0.63 mg tid q 8 hr
Acute treatment of severe bronchospams 2.5 – 5 mg initially q 20 min x 3 doses, then 2.5 – 10 mg q 1 – 4 hrs prn or 10 – 15 mg/hour by continuous nebulization 1.25 mg Q8h
Max dose 32 mg/day po 3.75 mg/day
No dosage adjustment needed for patient with either renal or hepatic impairment.
Dosage recommendations for the elderly: start at the low end of the dosage range and titrate upwards as needed.
Dosage recommendations for children: use one strength lower than those recommended for adults, but keep the same dosing schedule. It is not recommended to dose levalbuterol more than 3 times a day.
Adverse Effects (Safety Data, taken from Package Inserts)
Despite the fact that these two agents are selective for the ß2 receptor, they still cause tachycardia to some degree. None of the ß2 agonists are completely selective, and furthermore, with increasing doses of any agent, the selectivity for the ß2 receptor decreases.1
Adults
levalbuterol1.25 mg racemic albuterol2.5 mg
Tachycardia 2.7 2.7
Dizziness 2.7 0
Nervousness 9.6 8.1
Anxiety 2.7 0
Tremor 6.8 2.7
Dyspepsia 2.7 1.4
Rhinitis 2.7 6.8
Increased cough 4.1 2.7
Children
levalbuterol0.63 mg racemic albuterol1.25 mg
Asthma 9.0 6.3
Headache 11.9 9.4
Myalgia 1.5 1.6
Pharyngitis 10.4 0
Rhinitis 10.4 3.1
Drug Mean Changes from Baseline2
Heart Rate (bpm) Glucose (mg/dL)
Adults
Levalbuterol 1.25 mg 6.9 10.3
Albuterol (racemic) 2.5 mg 5.7 8.2
Significant No no
Children
Levalbuterol 0.63 mg 6.7 5.2
Albuterol (racemic) 1.25 mg 6.4 8.0
Significant No no
Precautions/Contraindications
Warning for both agents for paradoxical bronchospasm, deterioration of asthma, immediate hypersensitivity reactions, and cardiovascular effects. Use of anti-inflammatory agents may be necessary to help control the disease process in addition to these agents alone.4,5
High doses of albuterol may inhibit uterine contractions during labor in some reports.4
Drug Interactions
Non-selective beta blockers antagonize the effects of beta agonists. Therefore, a selective beta agonist should be used in asthmatic patients. Use with caution in patients receiving non-potassium sparing diuretics, as the combination may decrease serum levels of potassium. Elevated digoxin levels were seen in patients taking albuterol. Additionally, a patient should not take a monoamine oxidase inhibitor or a tricyclic antidepressant within two weeks of albuterol therapy due to the risk of serious adverse cardiac events.4,5
Clinical Trials
Trial Regimens Methods Results Comments
Carl, et al Levalbuterol Nebs 1.25mg q20min or albuterol 2.5mg q20min in the ER 547 enrollments from 478 children (85% black, 67% male) with acute asthmaExcluded: first episode, no current treatment, pregnant, hypersensitive to alb, CF, cyanosis, uncorrected congenital heart disease, chronic obstructive lung diseaseLev n=278Alb n=269Pts <6 y/o face mask nebPts >=6y/o mouthpiece nebReceive nebs q20 min until met discharge criteria or max of 6 tx in 2 hrs (admit the pt at that point)Given oral prednisone after 1st treatment if not meet DC criteriaSupplemental O2 given prnOption for intensification of therapy if requiredPrimary outcome measure: hospital admission rate 547 episodes in 477 patients. 1º EndPt: 36% admin rate for levalbuterol vs. 45% for albuterol. There was no difference in other endpoints. Outcome Alb Leva P Value
Hosp Admin 45 36 0.02
LOS Hrs 2.2 2.3 0.25
Tx/patient 4.1 3.7 0.08
Resp Rate 35.6 37.0 0.26
NNT for primary endpoint: 10.6Pts who used >=2 aerosols in previous 2 hours had 40% higher hospital admission rate (RR=1.39, 95% CI=1.13-1.72, p=0.02)Pts who used >3 aerosols in previous 2 hours had more admissions (RR=1.34, 95% CI=1.09-1.51, p=0.004) More patients in the levalbuterol group were treated with chromylin.The Admission criteria was not well defined and based on the ER MD who was not part of the study. Because data on pulmonary function wasn't noted, reasons for the difference in admission rate are unclear.
Debapriya et al Levalb 1.25mg Alb 2.5mg Alb 2.5mg + Ipr 0.5mg or placebo. Randomized DB, Placebo CCT, comparing albuterol, levalbuterol, ipratropium and placebo in patients with COPD. N=30PEP : FEV1 FVC, pulse, O2 sat. Positive Bronchodilator Response
Time (hr) 0.5 1
Alb 43% 47%
Alb/Ipr 43% 53%
Levalb 40% 40%
Placebo 13% 13%
None of the bronchodilators increase FEV1 past 4 hrs. None of the other 1º EndPt show significant differences. The duration of action of albuterol and levalbuterol was shorter than described in other studies.
Truitt T, et al.9Retrospective chart reviewSupported by Sepracor Albuterol 2.5 mg q 4h (Alb) vsLevalbuterol 1.25 mg q 8h (Lev) 231 charts reviewedTwo six-month periods with these two drugs on formulary Charts were searched for ICD codes for asthma, COPDExcluded: concomitant cognitive disturbances, cancerAlb n=125 (90 pts COPD, 35 pts asthma)Lev n=106 (87 pts COPD, 19 pts asthma)PEP: total number of neb treatments requiredSEP: Primary endpoint reached30.8 treatments alb vs 19.0 treatments lev p<0.001 Additional outcome measures: changes in PFTs, duration of hospitalization, disposition following hospitalization, pharmacy utilization costs, resource utilization costsBy design (treatment protocol) the pts treated with alb automatically had twice as many nebs scheduled than the pts on levUsed inflated basis of AWP to calculate cost of drug
Acquisition Cost
Albuterol Levalbuterol
How supplied 0.83 mg/mL (3 ml vial) 0.417 mg/mL
Typical dose 2.5 mg 1.25 mg
Cost per dose $0.10 $2.41
Cost per day $0.40 q 6h$0.60 q 4h $7.23 q 8h$9.64 q6h$14.46 q4h
Conclusions
Albuterol and levalbuterol share many of the same characteristics and actions. There has been discrepancy in the literature surrounding levalbuterol's superiority to albuterol. Many claims have been made which indicate that S-albuterol, the inactive enantiomer in albuterol may not be inactive, but have some detrimental properties. Some of these are that S-albuterol works in opposition to R-albuterol, that S-albuterol leads to the tolerance effect seen with the bronchodilator, that it increases airway hyperresponsiveness, and that it causes the systemic effects of racemic albuterol.6
To date, there has been no study demonstrating a significant difference between levalbuterol and albuterol. Because of the lack of data to support superiority of levalbuterol it is difficult to justify the additional expense of levalbuterol.
Cockcroft et al7 found that tolerance developed after six days to groups treated with R-albuterol or racemic albuterol. However patients did not develop tolerance after being treated with S-albuterol or to placebo treatment. Doing this, they proved that S-albuterol was not responsible for the development of tolerance.
Randomized trials have not demonstrated that S-albuterol causes hyperresponsiveness in the lung tissue of asthmatic patients.
Three studies show that the systemic effects of racemic albuterol are due to the R- enantiomer, and not the S-enantiomer.
Two studies8,9 both sponsored by Sepracor, the manufacturer of Xopenex®, claim that levalbuterol led to fewer hospitalizations and decreased cost to the hospital. However, the Carl study did not predefine hospital admission criteria and the two groups of patients that were admitted had no difference in clinical presentation at admission, end of ED stay, and duration of hospitalization.
References
1. Pleasants RA. Focus on inhaled ß2 – agonists: efficacy, safety, and patient preference. Pharmacotherapy. 2004; 24 (5 pt 2):44S-54S.
2. Proventil®. Clinical Pharmacology. Accessed 10/18/04.
3. Xopenex®. Clinical Pharmacology. Accessed 10/18/04.
4. Armstrong. Albuterol inhalation aerosol. Package insert, West Roxbury, MA; 2003.
5. Sepracor. Xopenex®. Package insert, Marlborough, MA; 2002.
6. Ahrens R, Weinberger M. Levalbuterol and racemic albuterol: are there therapeutic differences? [Editorial]. J Allergy Clin Immunol. 2001;108:681-84.
7. Cockcroft DW, Davis BE, Swystun VA, et al. Tolerance to the bronchoprotective effect of ß2 agonists: comparison of the enantiomers of salbutamol with racemic salbutamol and placebo. J Allergy Clin Immunol. 1999;103:1049-53.
8. Carl JC, Myers TR, Kirchner HL, et al. Comparison of racemic albuterol and levalbuterol for treatment of acute asthma. J Pediatr. 2003;143:731-36.
9. Truitt T, Witko, Halpern M. Levalbuterol compared to racemic albuterol. Chest. 2003;123:128-135.
10. McEvoy GK, et al, Ed. AHFS Drug Information 2004. 2004. American Society of Health-System Pharmacists. Bethseda, MD. P. 1233.
