Gertrude Noonan

Safety and Tolerability of Montelukast in Placebo-Controlled Pediatric Studies and Their Open-Label Extensions

Montelukast is a potent leukotriene‐receptor antagonist administered once daily that provides clinical benefit in the treatment of asthma and allergic rhinitis in children and adults. Because of its wide use as a pediatric controller, there is a need for a further review of the safety and tolerability of montelukast in children.

Reports of suicidality in clinical trials of montelukast.

BACKGROUND In recent years, a number of drugs and drug classes have come under scrutiny by the US Food and Drug Administration regarding suicidality (including suicidal behavior and ideation). OBJECTIVE We sought to perform 2 reviews (requested by the US Food and Drug Administration) of the number of events possibly related to suicidality reported in Merck clinical trials of montelukast. METHODS Method 1 was a descriptive review of clinical adverse experiences (AEs) from 116 studies (double-blind and open-label, adult and pediatric, and single- and multiple-dose studies) completed as of March 2008. Summaries were constructed from investigator-reported AE terms possibly related to suicidality (completed suicide, suicide attempt, and suicidal ideation) or self-injurious behavior. Method 2 used a retrospective adjudication of investigator-reported AEs and other events listed in the study database described as possibly suicidality-related adverse events (PSRAEs) in a prespecified set of 41 double-blind, placebo-controlled trials completed as of April 2008. RESULTS No completed suicides were reported in any study. For the descriptive review, 20,131 adults and children received montelukast, 9,287 received placebo, and 8,346 received active control; AEs possibly related to suicidality were rare and were similar between the montelukast and placebo or active-control groups. For the adjudicated review across 22,433 patients, there were 730 adjudicated events. In 9,929 patients taking montelukast, 1 PSRAE was identified (classified as suicidal ideation); none were identified in 7,780 and 4,724 patients taking placebo and active control, respectively. CONCLUSIONS Assessed by using 2 complementary methods, there were no reports of completed suicide, and reports of PSRAEs were rare in patients receiving montelukast and similar to those seen in control subjects.

Analysis of behavior-related adverse experiences in clinical trials of montelukast

BACKGROUND Frequencies of behavior-related adverse experiences (BRAEs) in controlled clinical studies of leukotriene modifier drugs have not been summarized. OBJECTIVE We sought to compare the frequency of BRAEs in patients receiving montelukast or placebo in a retrospective analysis of Merck clinical trial data. METHODS An adverse experience database was constructed to include all double-blind, placebo-controlled trials of montelukast meeting prespecified criteria. BRAEs (described using the Medical Dictionary for Regulatory Activities controlled vocabulary dictionary) were prespecified to include any term in the Psychiatric Disorders System Organ Class, selected terms related to general disorders, and terms related to akathisia. Frequencies of BRAEs (overall, leading to study discontinuation, and/or serious) were summarized. Analyses estimated the odds ratios (ORs) for montelukast versus placebo based on the frequency of patients with BRAEs in each study. RESULTS In total 35 adult and 11 pediatric placebo-controlled trials were included; 11,673 patients received montelukast, 8,827 received placebo, and 4,724 received active control. The frequency of patients with 1 or more BRAEs was 2.73% and 2.27% in the montelukast and placebo groups, respectively; the OR for montelukast versus placebo was 1.12 (95% CI, 0.93-1.36). The frequency of patients with a BRAE leading to study discontinuation was 0.07% and 0.11% in the montelukast and placebo groups, respectively (OR, 0.52; 95% CI, 0.17-1.51). The frequency of patients with a BRAE considered serious was 0.03% in both treatment groups. CONCLUSION Reports of BRAEs were infrequent in clinical trials of montelukast. Those leading to study discontinuation or considered serious were rare. Frequencies were similar regardless of treatment group.

Effect of montelukast or salmeterol added to inhaled fluticasone on exercise-induced bronchoconstriction in children

OBJECTIVES To evaluate the effect of montelukast, 5 mg, or inhaled salmeterol, 50 microg, added to inhaled fluticasone in reducing the maximum percentage decrease in forced expiratory volume in 1 second (FEV1) after a standardized exercise challenge and response to rescue bronchodilation with albuterol in children aged 6 to 14 years with persistent asthma and exercise-induced bronchoconstriction (EIB). METHODS Randomized, double-blind, double-dummy, multicenter, 2-period, 4-week, crossover study conducted between December 22, 2005 and November 14, 2008 at 30 centers in Europe, Asia, Mexico, and South America. Patients with asthma receiving inhaled corticosteroids demonstrated an FEV1 of 70% or higher of the predicted value and EIB (defined as a decrease in FEV1 > or = 15% compared with preexercise baseline FEV1 on 2 occasions before randomization). Standardized exercise challenges were performed at baseline (prerandomization) and at the end of each active treatment period. RESULTS Of 154 patients randomized, 145 completed the study. Montelukast, compared with salmeterol, significantly reduced the mean maximum percentage decrease in FEV1 (10.6% vs 13.8%; P = .009), mean area under the curve for the first 20 minutes after exercise (116.0% x min vs 168.8% x min; P = .006), and median time to recovery (6.0 vs 11.1 minutes; P = .04). Response to albuterol rescue after exercise challenge was significantly greater (P < .001) with montelukast. Montelukast and salmeterol were generally well tolerated. CONCLUSIONS Attenuation and response of EIB to albuterol rescue after exercise challenge were significantly better with montelukast than with salmeterol after 4 weeks of treatment.

Segmental Bioimpedance for Measuring Amlodipine-Induced Pedal Edema: A Placebo-Controlled Study

BACKGROUND The development of antihypertensives requires efficient and accurate tools for identifying pedal edema. Methodologies used to gauge the potential of an agent to induce pedal edema in short-term (<4-week) clinical trials have not been reported in the literature. OBJECTIVE The purpose of this study was to identify a robust and practical method for measuring drug-induced pedal edema for use in the clinical development of antihypertensives. The efficacy of segmental bioimpedance in the detection of increased pedal edema was compared with that of clinical pitting assessment, ankle circumference, and water displacement volumetry. METHODS The study population consisted of male and female healthy subjects and patients with stage 1 or 2 hypertension who were otherwise healthy. Participants were randomly assigned to receive amlodipine 10 mg or placebo once daily in this 6-week, double-blind, parallel-group study. Amlodipine was used as a means of inducing ankle edema, and not for the treatment of hypertension. Patients with hypertension were required to undergo a washout of antihypertensive therapies. Edema was evaluated using segmental bioimpedance at 10 kHz, clinical pitting assessment, ankle circumference, and water displacement at weeks 2, 4, and 6. The ANOVA model used included treatment and baseline values as covariates, with treatment pairs compared via t tests derived from the model. RESULTS A total of 47 individuals were randomized (49% male; 29 [62%] with hypertension; mean [SD] age, 59 [5.9] years; baseline body mass index, 28.6 kg/m(2) [2.8]; blood pressure 146.6 [10.7]/93.5 [6.5] and 139.3 [8.3]/89.5 [4.5] in individuals with and without hypertension, respectively; amlodipine 10 mg, n = 24; placebo, n = 23). At weeks 2, 4, and 6, statistically significant treatment differences in changes from baseline were detected using water displacement (mean [90% CI] treatment differences, +39.0 g [+17.9 to +60.1], +61.9 g [+36.1 to +87.6], and +72.2 g [+42.3 to +102.1], respectively; all, P ≤ 0.001), ankle circumference (+4.74 mm [+2.38 to +7.11; P < 0.001], +2.92 mm [+0.33 to +5.49; P = 0.032], and +5.16 mm [+2.21 to +8.11; P = 0.002]), and bioimpedance (-11.7 Ω [-18.1 to -5.4], -18.3 Ω [-26.2 to -10.4], and -20.9 Ω [-29.7 to -12.0]; all, P≤0.001), but no significant differences were detected using clinical assessment of pitting. CONCLUSION In this population of healthy subjects and patients with hypertension, segmental bioimpedance was comparable to water displacement and ankle circumference and outperformed clinical assessment of pitting for the detection of ankle edema, supporting the use of segmental bioimpedance as a drug-development tool to objectively quantify amlodipine-induced pedal edema.

Effect of montelukast, a once-daily leukotriene receptor antagonist, on peak expiratory flow variability

BACKGROUND Peak expiratory flow (PEF) is an important measure of airway functin in asthma. PEF variability (PEFvar) assessment is described in asthma treatment guidelines as another means of evaluating patient status and response to therapy. OBJECTIVE The goal of this study was to determine the clinical effect of oral montelukast, a leukotriene receptor antagonist, on PEFvar in asthmatic patients and to assess the relationship of PEFvar with other clinical measures. METHODS This was a retrospective analysis of data from a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, details of which have been published previously. Eligible patients had chronic stable asthma, had a forced expiratory volume in 1 second (FEV1) that was 50% to 85% of the predicted value, used inhaled beta-agonists, had at least 15% improvement in absolute FEV1 after inhaled beta-agonist administration, and showed a minimal predefined level of daytime asthma symptoms. Treatment consisted of a 2-week, single-blind, placebo run-in period followed by a 12-week, double-blind treatment period (montelukast 10 mg or matching placebo once daily at bedtime). RESULTS Six hundred eighty-one patients (age range, 15-79 years) were randomized to treatment at 50 centers. Baseline PEFvar was 11.44% +/- 6.55% and 10.62% +/- 6.48% in the montelukast and placebo groups, respectively. PEFvar decreased 20.1% and 7.5% from baseline in the montelukast and placebo groups, respectively. The between-group difference was significant (P < 0.001). PEFvar had low correlation with other clinical measures. CONCLUSIONS Over 12 weeks of treatment, montelukast significantly reduced PEFvar compared with placebo, indicating improved asthma control. The relative reduction in PEFvar was similar in patients with different degrees of variability at baseline. PEFvar did not correlate highly with other outcome variables and may measure different aspects of the disease.