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Criteria for Outpatient Use Guidelines

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Aerosolized Agents (short-acting): Metered-Dose Inhalers - Beta2-Adrenergic Drugs

[Criteria Developed, January 1995; Revised, August 1995; March 1997; February 1998; February 1999; May 1999; March 2000; March 2001; March 2002; March 2003; January 2008; 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
Beta2-adrenergic drugs, used routinely in asthma management, can be identified as long-acting or short-acting agents.  Both short- and long-acting compounds can be used to prevent bronchospasm. However, short-acting compounds are the drugs of choice for acute bronchospasm as these agents act within minutes to cause bronchodilation.  Drugs in this category include albuterol, levalbuterol, and pirbuterol.  For acute bronchospasm, treatment is initiated with a short-acting beta2-adrenergic agent either as a metered-dose inhaler or a nebulizer solution.  Treatment of acute attacks is usually for a finite time period based on the intensity of the attack and/or the need for medical attention either through emergency department management or hospitalization.  Usage is individualized based on patient characteristics.

Although not FDA-approved, albuterol has become one of the mainstays of therapy for acute exacerbations of chronic obstructive pulmonary disease (COPD) due to rapid onset of action as well as efficacy in producing bronchodilation.    

For preventive/ maintenance therapy, albuterol is FDA-approved as preventive therapy for exercise-induced asthma.  While not FDA-approved, beta2-selective adrenergic agents such as albuterol are effective in COPD maintenance therapy to improve lung function and mucociliary clearance.

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.

Maximum recommended daily doses for available inhalational beta2-adrenergic agents are summarized in Table 1.  Prescribed dosages exceeding these criteria will be reviewed.

TABLE 1
Maximum Adult Daily Dose for Inhalational Beta2-Adrenergic Agents (short-acting)
DRUG MAXIMUM RECOMMENDED DAILY DOSE
Monotherapy: Albuterol (ProAir™ HFA, Proventil® HFA, Ventolin® HFA) aerosol (90 mcg albuterol base/actuation) 12 actuations/day
(total dose = 1080 mcg albuterol base)
Monotherapy: Levalbuterol (Xopenex HFA™) aerosol (45 mcg levalbuterol free base/actuation) 12 actuations/day
(total dose = 540 mcg levalbuterol free base)
Monotherapy: Pirbuterol (Maxair™ Autohaler™) aerosol (200 mcg/actuation) 12 actuations/day (total dose = 2.4 mg)
Combination therapy: Ipratropium/albuterol (Combivent®)
aerosol  [18 mcg ipratropium/90 mcg albuterol base) per actuation]		 12 actuations/day [total dose = 216 mcg ipratropium/1080 mcg albuterol base)]

Pediatrics
Proventil® HFA and Ventolin® HFA are FDA-approved for use in children 4 years of age and older for prevention/treatment of bronchospasm and prevention of exercise-induced bronchospasm.  Levalbuterol is FDA-approved for use in children 4 years of age and older for prevention/treatment of bronchospasm.  Pirbuterol (Maxair™ Autohaler™) is FDA-approved for use in children 12 years of age and older for prevention/treatment of bronchospasm. ProAir™ HFA is FDA-approved for use in children 12 years and older for prevention/treatment of bronchospasm and prevention of exercise-induced bronchospasm.

Combination therapy with ipratropium and albuterol is not FDA-approved for use in pediatric patients as safety and efficacy in this patient population have not been established.
TABLE 2
Maximum Recommended Pediatric Daily Dose for Inhalational Beta2-Adrenergic Agents (short-acting)
DRUG MAXIMUM RECOMMENDED DAILY DOSE
Albuterol (ProAir™ HFA, Proventil® HFA, Ventolin HFA®) aerosol (90 mcg albuterol base/actuation) > 4 years of age:  12 actuations/day (total dose = 1080 mcg albuterol base)
Levalbuterol (Xopenex HFA™) aerosol (45 mcg levalbuterol free base/actuation)  > 4 years of age:  12 actuations/day (total dose = 540 mcg levalbuterol free base)
Pirbuterol (Maxair™ Autohaler™) aerosol (200 mcg/actuation) > 12 years of age: 12 actuations/day (total dose = 2.4 mg)

2. Duration of Therapy

Metered-dose inhalers are designed to deliver a set number of inhalations based on the canister size as well as the medication prescribed.  Days supply for inhalational  beta2-adrenergic agents is summarized in Table 3, based on the maximum recommended doses listed in Tables 1 and 2, and the number of actuations per canister or number of capsules per blister card listed in Table 3.  Excessive use may be identified based on refill frequency.  Inappropriate supply of short-acting beta2-adrenergic agents will be monitored by reviewing excessive refills.

TABLE 3
Days Supply for Available Short-Acting Beta2-Adrenergic Metered-Dose Inhalers (Adult and Pediatric Patients)
DRUG CANISTER # ACTUATIONS PER CANISTER DAYS SUPPLY+
Monotherapy: Albuterol ProAir™ HFA (8.5 g canister) 200 ~ 16 days
Monotherapy: Proventil® HFA (6.7 g canister) 200 ~ 16 days
Monotherapy: Ventolin HFA® (18 g canister) 200 ~ 16 days
Monotherapy: Levalbuterol Xopenex HFA™ (8.4 g canister) 80 ~ 6 days
Monotherapy: Levalbuterol Xopenex HFA™ (15 g canister) 200 ~ 16 days
Monotherapy: Pirbuterol Maxair® Autohaler® 2.8 g canister 80 ~ 6 days
Monotherapy: Pirbuterol Maxair® Autohaler® 14 g canister 400 ~ 33 days
Combination Therapy: Ipratropium/albuterol Combivent® (14.7 g canister) ~200 ~16 days

+calculated based on canister size and maximum dose allowed per day (summarized in Tables 1and 2)

3.* Duplicative Therapy

The use of two or more short-acting beta2-adrenergic compounds concurrently for prevention and control of asthma symptoms is not justified and will be reviewed.  However, acute asthma exacerbations require treatment with short-acting beta2-adrenergic agents even though maintenance therapy with a long-acting beta2-agonist like salmeterol may be prescribed concomitantly.  Patients may receive a long- and short-acting beta2-adrenergic drug concurrently for short time periods to manage acute attacks.  Patient profiles containing excessive prescriptions for a short-acting beta2-adrenergic drug (i.e., frequent refill of short-acting beta2-adrenergic agonist within a 30 day time period) in conjunction with long-acting beta2-agonists 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 considered clinically relevant for short-acting beta2-adrenergic bronchodilators are summarized in Table 4.  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 4
Drug-Drug Interactions for Short-Acting Beta2-Adrenergic Agents
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/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.