Criteria for Outpatient Use Guidelines

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[Developed, February 2008; Revised, October 2010]

Information on indications for use or diagnosis is assumed to be unavailable.  All criteria may be applied retrospectively; prospective application is indicated with [*].

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1.* Dosage

Adults
Short-acting, nebulized beta2-adrenergic bronchodilators are FDA-approved for use in the relief of acute, potentially recurrent bronchospasm in patients with reversible obstructive airway disease. Long-acting, nebulized beta2-adrenergic agents are FDA-approved for us as maintenance therapy in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.  The anticholinergic, ipratropium, is FDA-approved to manage bronchospasm associated with exacerbations of COPD. While not FDA-approved, the Expert Panel 3 guidelines from the National Heart Lung and Blood Institute document benefit when multiple ipratropium doses are administered adjunctively with beta2-agonists in the emergency department to manage more severe acute asthma exacerbations, and the Global Initiative for Asthma (GINA) guidelines state that ipratropium may be considered an alternative bronchodilator in patients who experience adverse effects to short-acting beta2-agonists (e.g., tachycardia, arrhythmia, tremor).   Ipratropium/albuterol combination therapy is FDA-approved for use as second-line therapy in adult COPD patients who continue to experience bronchospasm with an aerosol bronchodilator and require a second bronchodilator. Recommended adult dosages are summarized in Table 1.  Patient profiles with dosages exceeding these recommendations will be reviewed.

Table 1
Maximum Recommended Dose for Nebulized Bronchodilators in Adults

DRUG	MAXIMUM RECOMMENDED DOSE
Short-Acting Agents: Sympathomimetics Albuterol (AccuNeb®, various generics) [0.63 mg/3 ml (0.021%); 1.25 mg/3 ml (0.042%); 2.5 mg/3 ml (0.083%); 5 mg/ml (0.5%)]	2.5 mg four times daily by nebulization*+
Short-Acting Agents: Sympathomimetics Levalbuterol (Xopenex®) [0.31 mg/3 ml; 0.63 mg/3 ml; 1.25 mg/3 ml; 1.25 mg/0.5 ml]	1.25 mg three times daily by nebulization^
Short-Acting Agents: Sympathomimetics Ipratropium (various generics) [500 mcg/2.5 ml (0.02%)]	500 mcg four times daily, with doses 6 hours apart
Long-acting Agents: Sympathomimetics Arformoterol (Brovana®) [15 mcg/2 ml]	15 mcg twice daily by nebulization
Long-acting Agents: Sympathomimetics Formoterol (Perforomist®) [20 mcg/2 ml]	20 mcg twice daily by nebulization
Combination Therapy Ipratropium/albuterol (DuoNeb®, generic) [0.5 mg/3 mg# per 3 ml]	3 ml 6 times per day

*Accuneb® not evaluated for use in acute bronchospasm attacks; higher nebulized albuterol doses may be necessary to manage patients with acute asthma exacerbations
+Manufacturers of albuterol state that more frequent administration or higher doses not recommended; however, in severe asthma exacerbations, the National Asthma Education and Prevention Program Expert Panel (NAEPPEP) recommends albuterol doses of 2.5-5 mg every 20 minutes for 3 doses, then 2.5-10 mg every 1-4 hours as needed, or 10-15 mg/hour by continuous nebulization
^For acute asthma exacerbations, NAEPPEP recommends levalbuterol doses of 1.25-2.5 mg every 20 minutes for 3 doses, then 1.25-5 mg every 1-4 hours as needed
#2.5 mg albuterol base

Pediatrics
Short-acting beta2-adrenergic bronchodilators are FDA-approved to manage bronchospasm episodes in pediatric patients with reversible obstructive airway disease.  Albuterol nebulized solution is FDA-approved to provide bronchospasm relief in children 2 years of age and older with reversible obstructive airway disease.  Levalbuterol nebulized solutions are FDA-approved for use in the management and prevention of acute asthma exacerbations in children 6 years of age and older.  Ipratropium is FDA-approved for use in children 12 years of age and older for management of bronchospasm associated with COPD.  Recommended dosages are summarized in Table 2.  Patient profiles with dosages exceeding these recommendations will be reviewed.

Table 2
Maximum Recommended Dose for Nebulized Bronchodilators in Pediatric Patients

DRUG	MAXIMUM RECOMMENDED DOSE
Short-acting Agents: Sympathomimetics Albuterol (AccuNeb®, various generics) [0.63 mg/3 ml (0.021%); 1.25 mg/3 ml (0.042%); 2.5 mg/3 ml (0.083%); 5 mg/ml (0.5%)]	Accuneb®:* 2-12 years of age:  0.63 mg-1.25 mg 4 times daily Albuterol nebulized solution (0.083%):+ 2-12 years of age: > 15 kg:  2.5 mg 4 times daily Albuterol nebulized solution (0.5%):+ 2-12 years of age: < 15 kg: 1.25 mg 4 times daily > 15 kg:  2.5 mg four times daily 12 years of age and older:  2.5 mg four times daily
Short-acting Agents: Sympathomimetics Levalbuterol (Xopenex®) [0.31 mg/3 ml; 0.63 mg/3 ml; 1.25 mg/3 ml; 1.25 mg/0.5 ml]	6 years to 11 years of age:#  0.63 mg three times daily 12 years of age and older:^ 1.25 mg three times daily
Short-acting Agents:  Anticholinergics Ipratropium [500 mcg/2.5 ml (0.02%)]	> 12 years of age: 500 mcg 4 times daily, every 6 hours apart

*Accuneb® not evaluated for use in acute bronchospasm attacks; higher nebulized albuterol doses may be necessary to manage patients with acute asthma exacerbations
+Manufacturers state that more frequent administration or higher doses not recommended; however, in severe asthma exacerbations, the National Asthma Education and Prevention Program Expert Panel(NAEPPEP) recommends albuterol doses of 2.5-5 mg every 20 minutes for 3 doses, then 2.5-10 mg every 1-4 hours as needed, or 10-15 mg/hour by continuous nebulization
#For acute asthma exacerbations in children 6-11 years of age, NAEPPEP recommends levalbuterol doses of 0.075 mg/kg (1.25 mg minimum) every 20 minutes x 3 doses, then 0.075—0.15 mg/kg (5 mg max) every 1—4 hours as needed
^ For acute asthma exacerbations in children 12 years and older, NAEPPEP recommends levalbuterol doses of 1.25-2.5 mg every 20 minutes for 3 doses, then 1.25-5 mg every 1-4 hours as needed

Nebulized long-acting beta2-adrenergic bronchodilators as well as combination therapy with ipratropium and albuterol are not indicated for use in pediatric patients as safety and efficacy of these agents in this patient population have not been established.

2. Duration of Therapy

Administration of short-acting, nebulized beta2-adrenergic bronchodilators may be repeated indefinitely for acute asthma exacerbations, as asthma is a chronic, lifelong disease.  However, administering short-acting, nebulized beta2-adrenergic agents for longer than 48 hours with each exacerbation is indicative of worsening asthma control and is not recommended.  Utilization of large quantities of short-acting beta2-adrenergic nebulizer solutions within a 90-day time period is not recommended and will be reviewed.

Ipratropium, long-acting, nebulized beta2-adrenergic bronchodilators, and combination therapy with ipratropium/albuterol are indicated for the management of COPD, a chronic, lifelong disease, and may be continued indefinitely under accepted guidelines.

3.* Duplicative Therapy

Adjunctive administration of multiple short-acting or long-acting, nebulized beta2-adrenergic bronchodilators does not provide additional clinical benefit and may result in additive adverse effects.  Combined administration of multiple nebulized short-acting or long-acting beta2-adrenergic bronchodilators is not recommended and will be reviewed.

Acute asthma exacerbations require treatment with short-acting, beta2-adrenergic agents even though maintenance therapy with a long-acting, beta2-adrenergic agent may be prescribed concomitantly.  Patients may receive a long- and short-acting beta2-adrenergic drug concurrently for short time periods to manage acute attacks.  Nebulized formoterol or arformoterol used in conjunction with excessive administration of a short-acting beta2-adrenergic drug (i.e., frequent refill of short-acting beta2-adrenergic agonist within a 30 day time period) is not recommended and will be reviewed.

Concurrent administration of ipratropium nebulized solution monotherapy with ipratropium/albuterol combination therapy does not provide additional clinical benefit and may result in additive adverse effects.  Combined administration of ipratropium and ipratropium combination therapy is not recommended and will be reviewed.

4.* Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions.
Drug-drug interactions are considered clinically relevant for nebulized bronchodilators are summarized in Table 3.  Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed:

Table 3
Drug-Drug Interactions for Nebulized Bronchodilators

TARGET DRUG	INTERACTING DRUG	INTERACTION	RECOMMENDATIONS	CLINICAL SIGNIFICANCE
beta2-agonists	MAOIs (including linezolid)	concurrent administration of MAOIs with beta2-agonists may increase risk of  tachycardia, hypomania, or agitation due to potentiation of effects on vascular system	administer combination cautiously or within 2 weeks of MAOI discontinuation; observe patients for adverse effects	major (DrugReax) 1-severe (Clinical Pharmacology)
beta2-agonists	TCAs	concurrent administration of  TCAs with beta2-agonists may potentiate effects on cardiovascular system and increase risk of adverse events	Cautiously administer TCAs and beta2-agonists together, including within 2 weeks of TCA discontinuation;  monitor patients and  observe for changes in blood pressure, heart rate and ECG	moderate (DrugReax) moderate (Clinical Pharmacology)
beta2-agonists	beta blockers	concurrent administration may decrease effectiveness of beta-adrenergic blocker or beta-2 agonists	combination not recommended in asthma/COPD patients; if adjunctive therapy necessary, utilize cardioselective beta blocker (e.g., atenolol, bisoprolol)	major (DrugReax) 2-major (Clinical Pharmacology)
beta2-agonists	diuretics	potential for worsening of diuretic- associated  hypokalemia and/or ECG changes with beta2-agonist concurrent administration, especially with high beta2-agonist doses	administer combination cautiously; monitor potassium levels as necessary	3-moderate (Clinical Pharmacology)
beta2-agonists	atomoxetine	concurrent administration may increase risk of cardiovascular adverse effects (e.g., tachycardia, hypertension); interaction may be less likely with inhaled beta2-agonists	monitor patients for increased cardiovascular adverse effects	major (DrugReax) 3-moderate (Clinical Pharmacology)
beta2-agonists	QTc interval-prolonging medications (e.g., class I, III anti-arrhythmics, tricyclic antidepressants, dolasetron)	concurrent administration may increase risk of cardiotoxicity (e.g., life-threatening arrhythmias, cardiac arrest) as arformoterol and formoterol may cause QTc interval prolongation and, rarely, torsades de pointes	administer combination cautiously	2-major, 3-moderate (Clinical Pharmacology)
ipratropium, ipratropium/albuterol	antimuscarinics	concurrent administration may produce additive anticholinergic effects and potential for increased adverse effects	cautiously administer ipratropium with other antimuscarinics; monitor for increased adverse effects	minor (DrugReax) 3-moderate (Clinical Pharmacology)

References

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Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and the College of Pharmacy, The University of Texas at Austin.