New Inhaled Formulations for the Treatment of Asthma in Children and Adolescents

Kelly Jane Lunsford, PharmD


Pediatr Pharm. 2015;21(12) 

In This Article

Variations of Existing Formulations

Albuterol Sulfate

On April 1, 2015, the FDA approved albuterol sulfate inhalation powder (ProAir® RespiClick), a breath-actuated, multi-dose, dry-powder, shortacting beta-agonist (SABA) inhaler. It is approved for the treatment or prevention of bronchospasm in patients 12 years of age and older with reversible obstructive airway disease. The rationale for this product is based on references revealing nearly two-thirds of patients cannot correctly coordinate inhalation and actuation of a metered-dose inhaler.[11] Children aged 6 to 11 years were not included in this approval, but could benefit greatly from this formulation.

The recommended dose of ProAir® Respiclick is two inhalations every four to six hours. Each actuation delivers 108 mcg of albuterol sulfate (equivalent to 90 mcg albuterol base). Each inhaler supplies 200 doses. In order to deliver the mediation, patients only need to breathe in deeply through the mouthpiece. ProAir® Respiclick should not be used with a spacer or volume holding chamber.[12]

ProAir® Respiclick was studied in two identical 12-week placebo-controlled trials in 316 total subjects 12 years of age and older with asthma.[12] Subjects were randomized to either ProAir® Respiclick 180 mcg four times daily or placebo. All patients were maintained on ICS treatment. In Study 1, 44 of 78 patients treated with ProAir® Respiclick achieved a 15% increase in FEV1 within 30 minutes post-dose on Day 1. The median time to onset was 5.7 minutes and median duration of effect, as measured by a 15% increase, was approximately 2 hours. Study 2 showed similar results.

A double-blind, randomized, placebo-controlled, single-dose crossover study evaluated ProAir® Respiclick and ProAir® HFA in 337 subjects 12 years of age and older with persistent asthma.[12] ProAir® Respiclick had greater efficacy than placebo at administered doses of 90 and 180 mcg. Adverse effects experienced in ≥ 5% of patients treated with ProAir Respiclick for 52 weeks include upper respiratory tract infection, nasopharyngitis, sinusitis, bronchitis, cough, oropharyngeal pain, headache, and pyrexia.

Tiotropium Bromide

Tiotropium bromide (Spiriva® Respimat®) inhalation spray was approved by the FDA for maintenance treatment of asthma in patients 12 years of age and older on September 16, 2015.[13] The recommended starting dose for tiotropium bromide in children 12 years of age for maintenance treatment of asthma is two inhalations of the 1.25 mcg dose once-daily. The Respimat device differs from the previous Handihaler formulation in that it delivers a dose as a soft mist that has been shown to more effectively disperse small particles to the lower respiratory tract than a dry powder inhaler. The Respimat device, however, requires similar cartridge insertion, priming, and breath coordination as traditional hydrofluoroalkane (HFA) inhalers. To deliver a dose of the medication, patients must turn the base of the inhaler until it clicks, flip open the cap of the mouthpiece, and then simultaneously press the dose release button while inhaling deeply.[14] While this formulation does have the advantage of improved delivery to the site of action, the number of steps involved in the administration of each dose could prove to be problematic for children and/or their caregivers.

Two identical, randomized, controlled trials were conducted in 912 subjects with asthma (mean age 53 years) who were receiving therapy with a LABA and ICS.[15] Subjects were randomly assigned to receive either two puffs of tiotropium 2.5 mcg or matching placebo delivered each morning using a soft-mist inhaler (Respimat) as add-on therapy. The co-primary endpoints for each trial were peak FEV1 response (within 3 hours after administration of the maintenance and study drugs) and the trough FEV1 response at week 24. The mean change in peak FEV1 from baseline at 24 weeks was greater with tiotropium than with placebo in both trials with a difference of 86 ± 34 mL (p = 0.01) in trial 1 and 154 ± 32 mL in trial 2 (p < 0.001). Trough FEV1 also improved with a difference of 88 ± 31 ml (p = 0.01) and 111 ± 30 mL (p < 0.001) respectively.

A randomized, double-blind, placebo-controlled, incomplete crossover study was conducted in adolescents age 12 to 17 years to evaluate the safety and efficacy of three doses of tiotropium as add-on treatment.[16] One hundred and five subjects were randomized 1:1:1:1 to receive tiotropium 5 mcg, 2.5 mcg, 1.25 mcg, or placebo once-daily in the evening for three four-week periods. Patients also received medium-dose ICS therapy. The primary end point was peak FEV1, measured three hours post-dose. Peak FEV1 response for tiotropium 5 mcg was significantly greater than placebo (treatment difference 489 mL; p = 0.0043). Adverse events were consistent between groups.

While current approval is only for adolescents aged 12 to 17 years, studies have been conducted in younger children. In a phase II, double-blind, placebo-controlled, incomplete-crossover study, 101 subjects age 6 to 11 years were randomized to receive three out four of the following treatments: tiotropium 5 mcg, 2.5 mcg, 1.25 mcg, or placebo once-daily in the evening for three four-week periods.[17] Subjects also received medium-dose ICS therapy, with or without a leukotriene modifier. The primary end point was peak FEV1, measured three hours post-dose. The adjusted mean responses with tiotropium 5 mcg (272 mL; p < 0.001) 2.5 mcg (290 mL; p < 0.001) and 1.25 mcg (261 mL; p = 0.0011) were significantly greater than with placebo (185 mL). The safety and tolerability of all doses of tiotropium were comparable with those of placebo.