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Criteria for Outpatient Use Guidelines

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Aerosolized Agents (Metered-Dose Inhalers) -
Inhaled Anti-Inflammatory Drugs:  Corticosteroids

[Developed, January 1995; Revised, February, 1997; August 1997; March 1998; February 1999; January 2000; March 2000; January 2001; January 2002; February 2003; July 2007; July 2010; August 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

Because asthma is comprised of both inflammatory and bronchoconstrictive components, asthma treatment plans include routine use of inhaled corticosteroids (ICS) to manage inflammatory processes in asthma patients requiring chronic treatment. Higher ICS doses may contribute to a decrease in linear growth velocity in children, but adult height does not appear to be significantly inhibited following ICS use in childhood.  All ICS doses may contribute to decreased bone formation in children and bone mineral density in adults.  Close monitoring of growth and bone formation markers in children and fracture risk in adults is warranted with long-term ICS use.  The lowest effective ICS dose should be utilized for the shortest required time period.   

Maximum recommended orally inhaled doses for available aerosolized corticosteroids as individual agents are summarized in Table 1.  Prescribed dosages exceeding these recommendations will be reviewed.

Table 1
Maximum Daily Recommended Adult Doses for ICS as Individual Agents in Asthma
DRUG DOSE/DAY ACTUATIONS/DAY
beclomethasone dipropionate HFA inhalation aerosol (QVAR®) 640 mcg/day 40 mcg/actuation:
16 (8 actuations twice daily)
80 mcg/actuation:
8 (4 actuations twice daily)
budesonide inhalation powder
(Pulmicort Flexhaler™)		 1440 mcg/day 90 mcg/actuation:
16 (8 actuations twice daily)
180 mcg/actuation:
8 (4 actuations twice daily)
flunisolide CFC inhalation aerosol
(AeroBid®, AeroBid-M®)		 2000 mcg/day 250 mcg/actuation:
8 (4 actuations twice daily)
fluticasone HFA inhalation aerosol
(Flovent® HFA)		 Prior therapy with: bronchodilators alone - 880 mcg/day or inhaled corticosteroids - 880 mcg/day 44 mcg/actuation:
20 (10 actuations twice daily)
110 mcg/actuation:
8 (4 actuations twice daily)
220 mcg/actuation:
4 (2 actuations twice daily)
fluticasone HFA inhalation aerosol
(Flovent® HFA)		 Prior therapy with: oral corticosteroids - 1760 mcg/day  44 mcg/actuation:
40 (20 actuations twice daily)
110 mcg/actuation:
16 (8 actuations twice daily)
220 mcg/actuation:
8 (4 actuations twice daily)
fluticasone dry powder inhaler (Flovent® Diskus) Prior therapy with:
   bronchodilators alone – 1000 mcg/day
   inhaled corticosteroids – 1000 mcg/day		 50 mcg/actuation:
20 (10 actuations twice daily)
100 mcg/actuation:
10 (5 actuations twice daily)
250 mcg/actuation:
4 (2 actuations twice daily)
fluticasone dry powder inhaler (Flovent® Diskus) Prior therapy with:
   oral corticosteroids – 2000 mcg/day		 50 mcg/actuation:
40 (20 actuations twice daily)
100 mcg/actuation:
20 (10 actuations twice daily)
250 mcg/actuation:
8 (4 actuations twice daily)
mometasone inhalation powder (Asmanex®) Prior therapy with:
   bronchodilators alone – 440 mcg/day
   inhaled corticosteroids – 440 mcg/day		 110 mcg/actuation:
4 (4 actuations once daily in evening or 2
    actuations twice daily)
220 mcg/actuation:
2 (2 actuations once daily in evening or 1
    actuation twice daily)
mometasone inhalation powder (Asmanex®) Prior therapy with:
   oral corticosteroids – 880 mcg/day		   110 mcg/actuation:
8 (4 actuations twice daily)
220 mcg/actuation:
4 (2 actuations twice daily)

 

Combined therapy with ICS and long-acting beta2-agonists is FDA-approved for use in asthma therapy   as well as the management of chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis.  Advair Diskus® 250 mcg/50 mcg is the only fluticasone/salmeterol dose approved for use in adult patients with COPD, while budesonide/formoterol (Symbicort®) 160 mcg/4.5 mcg is the recommended strength for COPD.

The maximum recommended orally inhaled doses for available aerosolized corticosteroids as combination therapy is summarized in Table 2.  Prescribed dosages exceeding these recommendations will be reviewed.

Table 2
Maximum Daily Recommended Dose for ICS as Combination Therapy
for Asthma and COPD in Adults
DRUG MAXIMUM DOSE/DAY ACTUATIONS/DAY+
Asthma: budesonide/formoterol fumarate inhalation aerosol (Symbicort®) 80 mcg/4.5 mcg per actuation:
320 mcg/18 mcg per day
160 mcg/4.5 mcg per actuation:
640 mcg/18 mcg per day		 80 mcg/4.5 mcg per actuation:
4 (2 actuations twice daily)
160 mcg/4.5 mcg per actuation:
4 (2 actuations twice daily)
Asthma: fluticasone propionate/salmeterol xinafoate inhalation aerosol (Advair HFA®) 45 mcg/21 mcg per actuation:
180 mcg/84 mcg per day
115 mcg/21 mcg per actuation:
460 mcg/84 mcg per day
230 mcg/21 mcg per actuation:
920 mcg/84 mcg per day		 45 mcg/21 mcg per actuation:
4 ( 2 actuations twice daily)
115 mcg/21 mcg per actuation:
4 ( 2 actuations twice daily)
230 mcg/21 mcg per actuation:
4 ( 2 actuations twice daily)
Asthma: fluticasone propionate/salmeterol xinafoate inhalation powder (Advair Diskus®) 100 mcg/50 mcg per actuation:
200 mcg/100 mcg per day
250 mcg/50 mcg per actuation:
500 mcg/100 mcg per day
500 mcg/50 mcg per actuation:
1000 mcg/100 mcg per day		 100 mcg/50 mcg per actuation:
2 (1 actuation twice daily)
250 mcg/50 mcg per actuation:
2 (1 actuation twice daily)
500 mcg/50 mcg per actuation:
2 (1 actuation twice daily)
Asthma:mometasone/formoterol inhalation aerosol (Dulera®) prior therapy with medium dose ICS:
400 mcg/20 mcg per day		 100 mcg/5 mcg per actuation:
4(2 actuations twice daily)
prior therapy with high-dose ICS:
800 mcg/20 mcg per day		 200 mcg/5 mcg per actuation:
4 (2 actuations twice daily)
COPD: budesonide/formoterol fumarate inhalation aerosol (Symbicort®) 640 mcg/18 mcg per day 160 mcg/4.5 mcg per actuation:
4 (2 actuations twice daily)
COPD:fluticasone propionate/salmeterol xinafoate inhalation powder (Advair Diskus®) 500 mcg/100 mcg per day 250 mcg/50 mcg per actuation:
2 (1 actuation twice daily)

+Number of maximum actuations per day based on dose of salmeterol and formoterol, and independent of inhaled corticosteroid dose.

B.   Pediatrics
ICS as individual agents are FDA-approved for use in pediatric asthma management in children as young as 4 years of age.  Pediatric therapy initiation differs by age for individual agents and is summarized in Table 3.  Prescribed dosages exceeding these recommendations will be reviewed.

Table 3
Maximum Recommended Pediatric Doses for ICS as Individual Agents in Asthma
DRUG DOSE/DAY ACTUATIONS PER DAY
beclomethasone dipropionate HFA inhalation aerosol children 5-11 years:  160 mcg/day 40 mcg/actuation:
4 actuations (2 actuations twice daily)
80 mcg/actuation:
2 actuations (1 actuation twice daily)
beclomethasone dipropionate HFA inhalation aerosol adolescents 12-18 years:  640 mcg/day 40 mcg/actuation:
16 actuations (8 actuations twice daily)
80 mcg/actuation:
8 actuations (4 actuations twice daily)
budesonide inhalation powder children, adolescents 6-18 years: 720 mcg/day 90 mcg/actuation:
8 actuations (4 actuations twice daily)
180 mcg/actuation:
4 actuations (2 actuations twice daily)
flunisolide CFC inhalation aerosol children 6-15 years:  1000 mcg/day 250 mcg/actuation:
4 (2 actuations twice daily)
flunisolide CFC inhalation aerosol adolescents 16-18 years:  2000 mcg/day 250 mcg/actuation:
8 (4 actuations twice daily)
fluticasone HFA inhalation aerosol children 4-11 years (regardless of prior therapy):  176 mcg/day   44 mcg/actuation:
4 (2 actuations twice daily)
fluticasone HFA inhalation aerosol adolescents 12-18 years:
prior therapy with: 
     bronchodilators alone – 880 mcg/day
     inhaled corticosteroids – 880 mcg/day		 44 mcg/actuation:
20 (10 actuations twice daily)
110 mcg/actuation:
8 (4 actuations twice daily)
220 mcg/actuation:
4 (2 actuations twice daily)
fluticasone HFA inhalation aerosol adolescents 12-18 years: 
prior therapy with:
oral corticosteroids – 1760 mcg/day		 44 mcg/actuation:
40 (20 actuations twice daily)
110 mcg/actuation:
16 (8 actuations twice daily)
220 mcg/actuation:
8 (4 actuations twice daily)
fluticasone dry powder inhaler children 4-11 years (regardless of prior therapy):  200 mcg/day   50 mcg/actuation:
4 (2 actuations twice daily)
100 mcg/actuation:
2 (1 actuation twice daily)
fluticasone dry powder inhaler adolescents 12-18 years:
prior therapy with: 
     bronchodilators alone – 1000 mcg/day
     inhaled corticosteroids – 1000 mcg/day		 50 mcg/actuation:
20 (10 actuations twice daily)
100 mcg/actuation:
10(5 actuations twice daily)
250 mcg/actuation:
4 (2 actuations twice daily)
fluticasone dry powder inhaler adolescents 12-18 years: 
prior therapy with:
oral corticosteroids – 2000 mcg/day		 50 mcg/actuation:
40 (20 actuations twice daily)
100 mcg/actuation:
20 (10 actuations twice daily)
250 mcg/actuation:
8 (4 actuations twice daily)
mometasone inhalation powder children 4-11 years (regardless of prior therapy):  110 mcg/day  110 mcg/actuation:
1(1 actuation once daily in evening)
mometasone inhalation powder adolescents 12-18 years:
prior therapy with: 
     bronchodilators alone – 440 mcg/day
     inhaled corticosteroids – 440 mcg/day		 110 mcg/actuation:
4 (4 actuations once daily in evening or 2
actuations twice daily)
220 mcg/actuation:
2 (2 actuations once daily in evening or 1
actuation twice daily)
mometasone inhalation powder adolescents 12-18 years: 
prior therapy with:
oral corticosteroids – 880 mcg/day		   110 mcg/actuation:
8 (4 actuations twice daily)
220 mcg/actuation:
4 (2 actuations twice daily)

Combination therapy with ICS and long-acting beta2-agonists in aerosol form is only FDA-approved for use in asthma management in children 12 years of age and older; combined ICS/ long-acting beta2-agonist therapy as inhalation powder is FDA-approved for use in asthma management in children 4 years of age and older.  Maximum recommended orally inhaled doses for available aerosolized corticosteroids as combination therapy are summarized in Table 4.  Prescribed dosages exceeding these recommendations will be reviewed.

Table 4
Maximum Recommended Doses for ICS as Combination Therapy
for Asthma in Pediatric Patients
DRUG MAXIMUM DOSE/DAY ACTUATIONS/DAY+
budesonide/formoterol fumarate inhalation aerosol# adolescents 12-18 years:
80 mcg/4.5 mcg per actuation:
320 mcg/18 mcg per day
160 mcg/4.5 mcg per actuation:
640 mcg/18 mcg per day		   80 mcg/4.5 mcg per actuation:
4 (2 actuations twice daily)
160 mcg/4.5 mcg per actuation:
4 (2 actuations twice daily)
fluticasone propionate/salmeterol HFA inhalation aerosol* adolescents 12-18 years:
45 mcg/21 mcg per actuation:
180 mcg/84 mcg per day
115 mcg/21 mcg per actuation:
460 mcg/84 mcg per day
230 mcg/21 mcg per actuation:
920 mcg/84 mcg per day		   45 mcg/21 mcg per actuation:
4 ( 2 actuations twice daily)
115 mcg/21 mcg per actuation:
4 ( 2 actuations twice daily)
230 mcg/21 mcg per actuation:
4 ( 2 actuations twice daily)
fluticasone propionate/salmeterol inhalation powder^ children 4-11 years:  200 mcg/100 mcg per day 100 mcg/50 mcg per actuation:
2 (1 actuation twice daily)
fluticasone propionate/salmeterol inhalation powder^ adolescents 12-18 years:
100 mcg/50 mcg per actuation:
200 mcg/100 mcg per day
250 mcg/50 mcg per actuation:
500 mcg/100 mcg per day
500 mcg/50 mcg per actuation:
1000 mcg/100 mg per day		   100 mcg/50 mcg per actuation:
2 (1 actuation twice daily)
250 mcg/50 mcg per actuation:
2 (1 actuation twice daily)
500 mcg/50 mcg per actuation:
2 (1 actuation twice daily)
mometasone/formoterol inhalation aerosol † adolescents 12-18 years:
    prior therapy with medium dose ICS:
400 mcg/20 mcg per day		   100 mcg/5 mcg per actuation:
4(2 actuations twice daily)
mometasone/formoterol inhalation aerosol † adolescents 12-18 years:
   prior therapy with high-dose ICS:
800 mcg/20 mcg per day		   200 mcg/5 mcg per actuation:
4 (2 actuations twice daily)

#Budesonide/formoterol inhalation aerosol only indicated for children > 12 years of age
*Fluticasone/salmeterol inhalation aerosol is only indicated for children > 12 years of age
^Fluticasone/salmeterol inhalation powder may be used in children > 4 years of age for maintenance treatment in asthma
+Number of maximum actuations per day based on dose of salmeterol and formoterol, and independent of inhaled corticosteroid dose
†Mometasone/formoterol inhalation aerosol only indicated for children > 12 years of age

 

2.   Duration of Therapy

ICS, both as individual agents and as combination therapy, are FDA-approved for managing chronic asthma and COPD and may be continued indefinitely, as both COPD and asthma are chronic, lifelong processes.  However, days supply per canister is limited based on the number of actuations per canister combined with the maximum recommended dose per day.   Recommended days supply for available ICS as individual agents or combined with long-acting beta2-agonists are summarized in Tables 5 and 6. Fluticasone propionate is available as two different formulations in three dosage strengths per formulation. Each dosage strength is associated with a maximum recommended dose (cited in Tables 1 and 3) which is used in combination with the number of actuations per drug canister to calculate days supply.  Excessive use of ICS may be identified based on refill frequency.  Inappropriate supply of ICS will be reviewed by monitoring refill requests.

TABLE 5
Days Supply+ for Available Oral Inhalational Corticosteroids as Individual Agents When Maximum Doses are Utilized (Adults and Children)
DRUG # OF ACTUATIONS OR DOSES PER CANISTER/PACKAGE DAYS SUPPLY+
beclomethasone dipropionate HFA aerosol
40 mcg/actuation (7.3 g canister) 		100 ~ 6.25 days (adult)
25 days (child)
beclomethasone dipropionate HFA aerosol
80 mcg/actuation (7.3g canister)		 100 ~12.5 days (adult)
50 days (child)
budesonide inhalation powder 90 mcg/actuation 60 ~ 3.75 days (adult)
~ 7.5 days (child)
budesonide inhalation powder 180 mcg/actuation
 120 15 days (adult)
30 days (child)
flunisolide CFC aerosol (7 g canister) 100 ~12.5 days (adults, adolescents)
25 days (child)
fluticasone propionate aerosol 44 mcg/actuation (10.6 g canister) 120 30 days (child)
BD alone, ICS:  6 days (adult, adolescents)
OCS:   3 days (adults, adolescents)
fluticasone propionate aerosol 110 mcg/actuation (12 g canister) 120 BD alone, ICS:  15 days (adults, adolescents)
OCS:  7.5 days (adults, adolescents)
fluticasone propionate aerosol 220 mcg/actuation (12 g canister) 120 BD alone, ICS:  30 days (adults, adolescents)
OCS:  15 days (adults, adolescents)
fluticasone dry powder inhaler 50 mcg/actuation (60 blisters)  60                                                        15 days (child)
BD alone, ICS:  3 days (adult, adolescents)
OCS:   1.5 days (adults, adolescents)
fluticasone dry powder inhaler 100 mcg/actuation (60 blisters)  60                                                     30 days (child)
BD alone, ICS:  6 days (adults, adolescents)
OCS:  3 days (adults, adolescents)
fluticasone dry powder inhaler 250 mcg/actuation (60 blisters) 60                                                      BD alone, ICS:  15 days (adults, adolescents)
OCS:  7.5 days (adults, adolescents)
mometasone inhalation powder 110 mcg/actuation  30 30 (child)
BD alone, ICS:  7.5 days (adults, adolescents)
OCS:  3.75 days (adults, adolescents)
mometasone inhalation powder 220 mcg/actuation 30  BD alone, ICS:  15 days (adult, adolescents)
OCS:   7.5 days (adults, adolescents)
mometasone inhalation powder 220 mcg/actuation 60  BD alone, ICS:  30 days (adults, adolescents)
OCS:  15 days (adults, adolescents)
mometasone inhalation powder 220 mcg/actuation 120* BD alone, ICS:  60 days (adults, adolescents)
OCS:  30 days (adults, adolescents)

+calculated based on canister size and maximum dose allowed per day (summarized in Tables 1and 3)
*for more than 2 inhalations daily
BD = bronchodilator; ICS = inhaled corticosteroids; OCS = oral corticosteroids

Table 6
Days Supply+ for Available Oral Inhalational Corticosteroids as Combination Therapy
When Maximum Doses are Utilized
DRUG # OF ACTUATIONS OR
DOSES PER CANISTER		 DAYS SUPPLY+
budesonide/formoterol inhalation aerosol 80 mcg/4.5 mcg/actuation  120 30
budesonide/formoterol inhalation aerosol 160 mcg/4.5 mcg/actuation 120 30
fluticasone propionate/salmeterol inhalation aerosol - 45 mcg fluticasone/21 mcg salmeterol/actuation  120 30
fluticasone propionate/salmeterol inhalation aerosol - 115 mcg fluticasone/21 mcg salmeterol/actuation  120 30
fluticasone propionate/salmeterol inhalation aerosol - 230 mcg fluticasone/21 mcg salmeterol/actuation 120 30
fluticasone propionate/salmeterol inhalation powder  100 mcg fluticasone/50 mcg salmeterol/actuation 60 blisters 60 30
fluticasone propionate/salmeterol inhalation powder  250 mcg fluticasone/50 mcg salmeterol/actuation 60 blisters 60 30
fluticasone propionate/salmeterol inhalation powder  500 mcg fluticasone/50 mcg salmeterol/actuation 60 blisters 60 30
mometasone/formoterol inhalation aerosol
100 mcg mometasone/5 mcg formoterol/actuation		 120 30
mometasone/formoterol inhalation aerosol
200 mcg mometasone/5 mcg formoterol/actuation		 120 30

+calculated based on canister size and maximum allowed dose per day (summarized in Tables 2 and 4)

3.* Duplicative Therapy

Concurrent use of inhaled corticosteroids with systemic corticosteroids may result in augmented adverse effects, especially when high doses of inhaled corticosteroids are utilized. The concomitant use of two or more inhaled corticosteroids for the treatment of asthma 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 interactions considered clinically relevant for inhaled corticosteroids with or without beta agonists are summarized in Table 7.  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 7
Drug-Drug Interactions for Inhaled Corticosteroids
TARGET DRUG INTERACTING DRUG INTERACTION RECOMMENDATIONS CLINICAL SIGNIFICANCE
budesonide, budesonide/salmeterol, fluticasone, fluticasone/salmeterol, mometasone, mometasone/formoterol CYP3A4 inhibitors (e.g., azole antifungals, erythromycin, clarithromycin, protease inhibitors) potential for increased steroid concentrations with risk for excessive adrenal suppression and Cushing syndrome development concurrent administration not recommended by manufacturers of Advair HFA®/Advair Diskus®, Flovent® Diskus; Flovent® HFA not recommended with ritonavir; for all others, adjunctively administer combination cautiously; monitor patients for signs/symptoms of corticosteroid excess budesonide: 3-moderate; fluticasone: 2-major (Clinical Pharmacology)
budesonide: moderate; fluticasone: major (DrugReax)
steroids quinolones increased potential for serious tendonitis, tendon rupture with concurrent therapy closely monitor patients requiring combination therapy; discontinue quinolone if tendon pain develops 3-moderate (Clinical Pharmacology)
systemic steroids bupropion potential increased seizure risk due to systemic steroid-induced lowering of seizure threshold utilize only recommended bupropion dosages; initiate bupropion therapy with low doses and titrate slowly when combination therapy warranted; closely monitor patients for seizure development major (DrugReax)
2-major (Clinical Pharmacology)
budesonide/formoterol, fluticasone/salmeterol, mometasone/formoterol MAOIs (including linezolid) concurrent administration of MAOIs with beta agonists may increase risk of  development 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)
budesonide/formoterol, fluticasone/salmeterol, mometasone/formoterol TCAs concurrent administration of  TCAs with beta agonists may potentiate effects on cardiovascular system and increase risk of adverse events Cautiously administer TCAs and beta 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)
budesonide/formoterol, fluticasone/salmeterol, mometasone/formoterol beta blockers concurrent administration may decrease effectiveness of beta-adrenergic blocker or beta-2 agonists like formoterol, salmeterol 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)
budesonide/formoterol, fluticasone/salmeterol, mometasone/formoterol diuretics potential for worsening of diuretic associated  hypokalemia and/or ECG changes with beta-agonist concurrent administration, especially with high beta-agonist doses administer combination cautiously ; monitoring potassium levels may be necessary 3-moderate (Clinical Pharmacology)

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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.