Objective: To review three prospective.

Objective: To review three prospective, randomized, placebo-controlled, double-blind clinical studies of formoterol (Foradil Aerolizer; Novartis Pharmaceuticals; Basel, Switzerland) at dosages of 12 [micro]g and 24 [micro]g bid for the treatment of patients with asthma.

Data sources: Clinical studies submitted to the US subsistence and Drug Administration in support of the approval of Foradil Aerolizer for marketing in the United States.

Results: More patients treated regularly with formoterol, 24 [micro]g bid, had a serious asthma exacerbation than did patients who had been treated with placebo. In the first contemplation 4 of 135 adult patients (3%) who had been treated with formoterol, 24 [micro]g bid, had a serious asthma exacerbation compared to none of 136 placebo-treated patients. In the secondary study, 5 of 136 patients (37%) treated with formoterol, 24 [micro]g bid, had a serious asthma exacerbation compared to 2 of 141 placebo-treated patients (14%) In the third consideration 11 of 171 pediatric patients (64%) treated with formoterol, 24 [micro]g bid, had a serious asthma exacerbation compared to none of 176 placebo-treated patients.

Conclusion: Regular use of high-dose inhaled formoterol (24 [micro]g bid) may be associated with more every-day serious asthma exacerbations.

clew words: asthma; formoterol; long-acting [beta]-agonist

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Long-acting inhaled [[beta].sub.2]-agonists that are commonly marketed in the United States allow for twice-daily dosing and are indicated for patients who require long-term bridle of asthma symptoms. The following brace long-acting [[beta].sub.2]-agonists have been approved and are available in the United States for the long-term have charge of of asthma: formoterol (Foradil Aerolizer; Novartis Pharmaceuticals; Basel, Switzerland) and salmeterol (Serevent Diskus and Serevent Inhalation Aerosol; GlaxoSmithKline; Research Triangle Park, NC) Despite their benefit in maintaining bronchodilation (eg improved FE[Vsub1]) more [i]or[/i] less authors have voiced caution about the use of long-acting [[beta].sub.2]-agonists with regard to the potential unfolding of airway subsensitivity. (1) Bisgaard (2) exhibited concern about long-acting [[beta].sub.2]-agonists and the exhibition of tolerance in the pediatric population, concluding that the part of these drugs in pediatric asthma as regular add-on therapy is questionable. Novartis Pharmaceuticals submitted a recently made known drug application to the US nourishment and Drug Administration for marketing approval of Foradil Aerolizer at doses of 12 [micro]g and 24 [micro]g bid. Based upon our review of the just discovered drug application for Foradil Aerolizer, we conclud that this proceeds has been shown to be safe and effective as a 12-[micro]g bid dose (the US aliment and Drug Administration-approved dose). However, our review of the clinical data instanted showed a subtle signal for affair in those patients taking a dose of 24 [micro]g bid (3) in that a higher incidence of serious asthma exacerbations was noted. Based in succession this concern and pending any further clarifying data, the 24-[micro]g bid dose of Foradil Aerolizer is not generally approved for US marketing.

MATERIALS AND METHODS

Novartis Pharmaceuticals submitted data from clinical studies to support the use of orally inhaled formoterol (Foradil Aerolizer) twice daily for the long-term maintenance treatment of asthma. Three of the studies were placebo-controlled randomized clinical studies evaluating multiple doses of formoterol. pair of these trials have been reported in the literature. (45)

There were couple 12-week, double-blind, randomized, placebo-controlled, parallel-group studies performed in patients 12 to 75 years of age, with an FE[Vsub1] ranging from 40 to 80% of predicted values, and at least 15% [[beta].sub.2]-agonist reversibility. Patients required therapy with daily doses of short-acting [[beta].sub.2]-agonists for symptom bridle Stable regimens of orally inhaled or intranasal corticosteroids, oral theophylline, short-acting antihistamines, or allergen immunotherapy were allowed. Patients were randomized to receive in a blinded fashion the same of the following inhaled medications: placebo; albuterol, 180 [micro]g qid; formoterol, 12 [micro]g bid; or formoterol, 24 [micro]g bid. All patients were allowed to use albuterol, 180 [micro]g, for free therapy. Spirometry was performed at weeks 0 2 4 8 and 12 with measurements performed prior to close attention drug administration, and at 5 15 30 and 60 min, and hourly for 12 h following medicine administration. The primary efficacy conclusion point was FE[V.sub.1] at 12 h after contemplation drug administration at week 12 An important secondary completion point was asthma exacerbations, including those that met the criteria for being serious. An asthma exacerbation was considered to be serious if it springed in a life-threatening experience, inpatient hospitalization or prolongation of hospitalization, persistent disability/incapacity, or death.

The third subject of attention was a 12-month, randomized, placebo-controlled safety inquiry that was performed in children 5 to 12 years of age who were randomized to treatment with placebo, formoterol, 12 [micro]g bid, or formoterol, 24 [micro]g bid. Patients had an FE[Vsub1] between 50% and 85% of predicted, and at least 15% [[beta].sub.2]-agonist reversibility. At close attention entry, patients were using inhaled bronchodilators daily and were receiving a stable regimen of either inhaled corticosteroids or cromolyn sodium. Therapy with concomitant nasal corticosteroids, theophylline, and allergen immunotherapy was allowed if the regimens were stable. preserve therapy with albuterol, 180 [micro]g, was allowed. Spirometry was obtained with hourly measurements beginning just after put drugs into administration and extending through 12 h forward the first treatment day and after 3 weeks and 12 weeks of treatment. The primary efficacy finis point was the FE[V.sub.1] area in subordination to the curve after 3 month of treatment. An important secondary [i]finale[/i] point was asthma exacerbations. The definition of a serious asthma exacerbation in this pediatric close attention was identical to that used in the adult trials, and these results were recorded during the entire 12-month period of randomized treatment.

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