Healthcare Professionals

MILGROM et al: Low-dose levalbuterol in children with asthma: safety and efficacy in comparison with placebo and racemic albuterol

Objective:

To determine whether XOPENEX Inhalation Solution results in improved safety and efficacy in children
with asthma*

Study Design:

• A multicenter, randomized, double-blinded, parallel-group, 3-week study comparing XOPENEX Inhalation Solution with placebo and racemic albuterol included as an active control
• After a 1-week run-in period, 338 children ages 4 to 11 years with asthma (baseline FEV1 within 40% to 85% of predicted) were randomized to receive 21 days of tid doses of the following: XOPENEX Inhalation Solution 0.31 mg (n=70) or 0.63 mg (n=70); placebo (n=65); racemic albuterol 1.25 mg (n=67) or 2.5 mg (n=66)

Primary Endpoint:

Peak FEV percent change from baseline (Day 0) on Day 21

Indication: XOPENEX Inhalation Solution is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease.

*The primary objective was to determine the comparative efficacy of XOPENEX Inhalation Solution and racemic albuterol vs placebo.

Efficacy:

XOPENEX Inhalation Solution was effective in children at low doses

XOPENEX Inhalation Solution delivered first-dose efficacy in children

Indication: XOPENEX Inhalation Solution is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease.

Important Safety Information: Due to the cardiovascular side effects associated with β-agonists, caution is generally recommended for patients with cardiovascular disorders (especially coronary insufficiency, cardiac arrhythmias, and hypertension), diabetes, hyperthyroidism, or convulsive disorders.

Safety:

XOPENEX Inhalation Solution was well tolerated in children

Important Safety Information: The most common adverse events in patients aged 6 to 11 years (occurring in ≥2% of patients receiving XOPENEX Inhalation Solution at either 0.31 mg or 0.63 mg and more frequently than patients receiving placebo) were headache, rhinitis, pharyngitis, asthma, fever, viral infection, rash, accidental injury, diarrhea, asthenia, lymphadenopathy, and urticaria.

Summary:

XOPENEX Inhalation Solution was effective in children at low doses

• XOPENEX Inhalation Solution 0.31 mg was comparable in efficacy to racemic albuterol 2.5 mg as measured by FEV1 at Day 0

XOPENEX Inhalation Solution delivered first-dose efficacy in children

• Immediately postdose, significantly more patients responded to the lowest dose of XOPENEX Inhalation Solution (0.31 mg) than to racemic albuterol 1.25 mg (P=.012)
  - Both doses of XOPENEX Inhalation Solution showed significant responses following nebulization vs placebo
  - The onset of effect (time to a 15% increase in FEV1 over test-day baseline) and duration of effect (maintenance of a >15% increase in FEV1 over test-day baseline) of levalbuterol were clinically comparable to those of racemic albuterol

XOPENEX Inhalation Solution was well tolerated in children

• XOPENEX Inhalation Solution 0.31 mg produced changes in ventricular heart rate (HR) comparable to placebo
• XOPENEX Inhalation Solution 0.31 mg and 0.63 mg had smaller increases in serum glucose than racemic albuterol 2.5 mg throughout the study (P≤.043)*
  - XOPENEX Inhalation Solution 0.31 mg did not produce a significant change in serum glucose compared with placebo throughout the study
  - All active treatment groups showed a significant decrease in potassium levels vs placebo at Day 0 (P<.002)

Due to the cardiovascular side effects associated with β-agonists, caution is generally recommended for patients with cardiovascular disorders (especially coronary insufficiency, cardiac arrhythmias, and hypertension), diabetes, hyperthyroidism, or convulsive disorders.

Systemic Β-adrenergic adverse effects were observed with all active doses and were generally dose related for (R)-albuterol.

*The clinical significance of these small differences is unknown.

• Download the Milgrom Publication  

Dosage and Administration: Children 6 to11 years old: The recommended dosage of XOPENEX Inhalation Solution for patients 6 to11 years old is 0.31 mg administered 3 times a day, by nebulization. Routine dosing should not exceed 0.63 mg, 3 times a day.

Indication: XOPENEX Inhalation Solution is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease.

Important Safety Information: Patients receiving the highest dose of XOPENEX Inhalation Solution should be monitored closely for adverse effects, and the risk of such effects should be balanced against the potential for improved efficacy.

XOPENEX brand of levalbuterol and other β-agonists can cause paradoxical bronchospasm, which may be life threatening. If additional adrenergic drugs, including other short-acting sympathomimetic bronchodilators or epinephrine, are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.

The most common adverse events in patients aged 6 to 11 years (occurring in =2% of patients receiving XOPENEX Inhalation Solution at either 0.31 mg or 0.63 mg and more frequently than patients receiving placebo) were headache, rhinitis, pharyngitis, asthma, fever, viral infection, rash, accidental injury, diarrhea, asthenia, lymphadenopathy, and urticaria.

BERGER et al: Evaluation of levalbuterol metered dose inhaler in pediatric patients with asthma: a double-blind, randomized, placebo and active-controlled trial

Objective:

To evaluate the efficacy and safety of XOPENEX HFA Inhalation Aerosol in pediatric patients aged 4 to 11 years with asthma

Study Design:

• A multicenter, randomized, double-blind, parallel-group, 4-week clinical trial of pediatric patients comparing XOPENEX HFA with placebo, with Proventil® HFA as an active control
• After a 1-week placebo run-in period, 150 pediatric patients were randomized to receive 4 weeks of qid doses of the following: XOPENEX HFA 90 mcg (n=76), Proventil HFA 180 mcg (n=39), or placebo HFA (n=35)

Primary Endpoint:

• Peak percent change in FEV1 from visit predose averaged over the double-blind treatment period

Indication: XOPENEX HFA Inhalation Aerosol is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 4 years of age and older with reversible obstructive airway disease.

Proventil HFA is a registered trademark of Schering Corporation.

Efficacy:

Efficacy started with a strong response

Safety:

XOPENEX HFA significantly improved airway function vs placebo in pediatric patients, with a low incidence of adverse events

Indication: XOPENEX HFA Inhalation Aerosol is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 4 years of age and older with reversible obstructive airway disease.

Summary:

Efficacy started with a strong response

More pediatric patients achieved peak increases in FEV1 of the double-blind period ₁ of ≥15% from visit predose averaged over the double-blind period

• XOPENEX HFA produced significant improvement in the primary endpoint, peak percent change in FEV₁ from visit predose averaged over the double-blind treatment period, compared with placebo (least squares [LS] mean: 25.6% with XOPENEX HFA vs 16.8% with placebo; P<.001)
• 89% of pediatric patients treated with XOPENEX HFA achieved an average peak increase in FEV₁ of ≥15% (71% with Proventil HFA; 39% with placebo)*2
• 34% of pediatric patients treated with XOPENEX HFA achieved an average peak increase in FEV₁ of ≥30% (24% with Proventil HFA; 15% with placebo)
• Significant decrease with XOPENEX HFA vs placebo in rescue medication use in both number of days per week (P<.01) and number of doses per day (P<.01)

* Based on data averaged over 4 weeks.

XOPENEX HFA was well tolerated in pediatric patients

• Low incidence of β-mediated adverse events with XOPENEX HFA

• Download the Berger Publication  

Important Safety Information: XOPENEX HFA Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to levalbuterol tartrate, racemic albuterol, or any component of the drug product.

XOPENEX brand of levalbuterol and other β-agonists can cause paradoxical bronchospasm, which may be life threatening. Potential drug interactions include: β-blockers, which can block the pulmonary effect of β-agonists and can cause severe bronchospasm in asthmatic patients; diuretics (non-potassium-sparing), whose ECG changes and/or hypokalemia side effects can worsen with administration of β-agonists; digoxin, where serum levels can decrease 16% to 22% with administration of β-agonists; monoamine oxidase inhibitors and tricyclic antidepressants, which can potentiate the action of albuterol on the vascular system.

If additional adrenergic drugs, including other short-acting sympathomimetic bronchodilators or epinephrine, are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.

Due to the cardiovascular side effects associated with β-agonists, caution is generally recommended for patients with cardiovascular disorders (especially coronary insufficiency, cardiac arrhythmias, and hypertension), diabetes, hyperthyroidism, or convulsive disorders.

References:
1. Berger WE, Milgrom H, Skoner DP, Tripp K, Parsey MV, Baumgartner RA; for the XOPENEX Pediatric Asthma Group. 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. 2. Data on file, CSR 051-354, Table 14.2.4.3.1. Sunovion Pharmaceuticals Inc, Marlborough, MA.

NELSON et al: Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma

Objective:

To evaluate the benefits and risks associated with the use of XOPENEX Inhalation Solution (optically pure (R)-albuterol [levalbuterol]) and racemic albuterol in the treatment of asthma in comparison with placebo in patients aged ≥12 years with moderate-to-severe asthma

Study Design:

• A 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-arm clinical trial
  - After a 1-week placebo run-in period, 362 patients were randomized to receive XOPENEX Inhalation Solution 0.63 mg (n=72), XOPENEX Inhalation Solution 1.25 mg (n=73), racemic albuterol 1.25 mg (n=68), racemic albuterol 2.5 mg (n=74), or placebo (n=75) tid via nebulizer
  - Approximately 50% of patients had baseline FEV₁ <60% of predicted and were further analyzed as a subset of the total population

Primary Endpoint:

Peak change in FEV₁ after 4 weeks

Indication: XOPENEX Inhalation Solution is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease.

Efficacy:

XOPENEX Inhalation Solution delivered significant improvement in moderate-to-severe asthma patients

XOPENEX Inhalation Solution 1.25 mg demonstrated improvements at first dose in severe patients

Indication: XOPENEX Inhalation Solution is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease.

Important Safety Information: Due to the cardiovascular side effects associated with β-agonists, caution is generally recommended for patients with cardiovascular disorders (especially coronary insufficiency, cardiac arrhythmias, and hypertension), diabetes, hyperthyroidism, or convulsive disorders.

Safety:

XOPENEX Inhalation Solution was well tolerated

XOPENEX Inhalation Solution 0.63 mg produced similar efficacy to racemic albuterol 2.5 mg with fewer β-adrenergic side effects

• XOPENEX Inhalation Solution 0.63 mg demonstrated lower increases in heart rate vs racemic albuterol 2.5 mg
• XOPENEX Inhalation Solution 0.63 mg also demonstrated a lower incidence of nervousness and tremor
• XOPENEX Inhalation Solution 1.25 mg demonstrated a slightly higher rate of systemic β-adrenergic events vs albuterol 2.5 mg (nervousness: 9.6% vs 8.1%; tremor: 6.8% vs 2.7%)¹
  - Patients receiving the highest dose of XOPENEX Inhalation Solution should be monitored closely for adverse effects, and the risk of such effects should be balanced against the potential for improved efficacy

Summary:

XOPENEX Inhalation Solution delivered significant improvement in moderate-to-severe asthma patients

• Significantly higher FEV₁ improvements at Week 4 vs placebo

XOPENEX Inhalation Solution 1.25 mg demonstrated improvements at first dose in severe patients

• 44% FEV₁ improvement within minutes (Day 0, Week 0) in a subset of severe patients with FEV₁ ≤60% predicted (a clinically significant improvement continued up to 8 hours in some patients)²

XOPENEX Inhalation Solution was well tolerated

• XOPENEX Inhalation Solution 0.63 mg demonstrated fewer Β-adrenergic side effects vs racemic albuterol 2.5 mg
• Patients receiving the highest dose of XOPENEX Inhalation Solution should be monitored closely for adverse effects, and the risk of such effects should be balanced against the potential for improved efficacy

• Download the Nelson Publication  

Indication: XOPENEX Inhalation Solution is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease.

Important Safety Information: XOPENEX brand of levalbuterol and other β-agonists can cause paradoxical bronchospasm, which may be life threatening. Potential drug interactions include: ß-blockers, which can block the pulmonary effect of β-agonists and can cause severe bronchospasm in asthmatic patients; diuretics (non-potassium-sparing), whose ECG changes and/or hypokalemia side effects can worsen with administration of β-agonists; digoxin, where serum levels can decrease 16% to 22% with administration of β-agonists; monoamine oxidase inhibitors and tricyclic antidepressants, which can potentiate the action of albuterol on the vascular system. If additional adrenergic drugs, including other short-acting sympathomimetic bronchodilators or epinephrine, are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects. Due to the cardiovascular side effects associated with β-agonists, caution is generally recommended for patients with cardiovascular
disorders (especially coronary insufficiency, cardiac arrhythmias, and hypertension), diabetes, hyperthyroidism, or convulsive disorders.

The most common adverse events in patients aged 12 years and older (occurring in ≥2% of patients receiving XOPENEX Inhalation Solution at either 0.63 mg or 1.25 mg and more frequently than patients receiving placebo) were viral infection, rhinitis, nervousness, tremor, flu syndrome, sinusitis, accidental injury, anxiety, cough increased, pain, tachycardia, turbinate edema, migraine, dizziness, dyspepsia, and leg cramps.

References:
^1. XOPENEX Inhalation Solution [prescribing information]. Marlborough, MA: Sunovion Pharmaceuticals Inc; August 2007.
^2. Data on file, CSR 051-024, Table 5.4.5. Sunovion Pharmaceuticals Inc, Marlborough, MA.