Device mechanics and evaluation of inspiratory flow rate required of the beclomethasone dipropionate breath-actuated inhaler.

Background: Approximately 80% of patients with asthma and chronic obstructive pulmonary disease incorrectly use a metered-dose inhaler and, therefore, fail to obtain full benefit from their inhaler medication. Beclomethasone dipropionate (BDP) hydrofluoroalkane, an inhalation aerosol administered via a breath-actuated inhaler (BAI) has been designed to improve ease of use over press-and-breathe metered-dose inhalers by eliminating the need for hand-breath coordination. Objective: To present the mechanics of the BAI device, assess the minimum reliable inspiratory flow rate required to trigger an actuation, and evaluate if intended users can safely and effectively use the BDP BAI according to the instructions for use (IFU). Methods: Six random batches (three batches each of 40 µg and 80 µg) of 10 inhalers were evaluated for the minimum inspiratory flow rate required for actuation trigger. Each inhaler was tested for actuation at five flow rates: 12, 14, 16, 18, and 20 L/min. Simulated-use testing was conducted with 91 participants from six representative user groups in the United States to assess the use of a placebo-filled production-equivalent BDP BAI according to the IFU. Results: Across the 40-µg batches, 83% of the devices actuated at 16 L/min and 100% actuated at 18 and 20 L/min. For the 80-µg batches, 67% and 100% actuated at 18 L/min and 20 L/min, respectively. All the participants demonstrated successful use of the BDP BAI during the study session. Isolated safety-critical errors with the potential for no-dose delivery were recorded for 15 participants but were considered unrelated to the design of the IFU. Conclusion: The BDP BAI consistently triggered actuation at an airflow rate of 20 L/min and was successfully used based on guidance from the IFU only. This device provides an alternative for patients who find it difficult to use metered-dose inhaler devices correctly.

Efficacy and safety of beclomethasone dipropionate nasal aerosol in pediatric patients with seasonal allergic rhinitis.

BACKGROUND: Aerosolized intranasal corticosteroid formulations are desirable for many patients with allergic rhinitis (AR), especially children, who wish to avoid the "wet feeling" and "drip down the throat" associated with aqueous formulations. Beclomethasone dipropionate (BDP) hydrofluoroalkane nasal aerosol has been shown to be safe and effective in adolescents and adults with AR. OBJECTIVE: To evaluate the efficacy and safety of BDP nasal aerosol in pediatric patients with moderate to severe seasonal AR. METHODS: In this double-blinded, placebo-controlled study, children (6-11 years of age) with seasonal AR were randomized to once-daily treatment with BDP nasal aerosol 80 µg (n = 239) or 160 µg (n = 242) or placebo (n = 234). The primary end point was change from baseline in average morning and evening reflective total nasal symptom score over the 2-week treatment period. RESULTS: Treatment with BDP nasal aerosol showed significantly greater improvements in average morning and evening reflective total nasal symptom score vs placebo (80 µg, -0.71; 160 µg, -0.76; P < .001 for the 2 comparisons). Similarly, significantly greater improvements in average morning and evening instantaneous total nasal symptom score were seen with BDP nasal aerosol vs placebo (80 µg, -0.63; 160 µg, -0.73; P < .001 for the 2 comparisons). The incidence of adverse events from BDP nasal aerosol was comparable to that from placebo. CONCLUSION: BDP nasal aerosol (80 or 160 µg/d) provided significant and clinically meaningful nasal symptom relief and an established overall safety profile similar to that of placebo, suggesting that it is an effective and well-tolerated treatment option for pediatric patients with moderate to severe seasonal AR. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT012073190.

A valved holding chamber does not decrease the bronchodilator activity of budesonide-formoterol combination metered dose inhaler.

OBJECTIVE: Spacers and valved holding chambers (VHCs) were developed to facilitate using pressurized metered dose inhaler (pMDI) by patients who could not coordinate the actions required for successful pMDI use. There is little in vivo evidence about how VHC may affect the bronchodilation from combination drugs in pMDI. This study was to determine the effect, if any, of VHC on the bronchodilating actions of the pMDI budesonide/formoterol combination. METHODS: Sixteen adult asthmatic subjects with 15% or greater reversibility of forced expiratory volume in one second (FEV-1), 15 minutes after inhaling 180-360 µg of albuterol, participated. The study had a randomized crossover design with each subject using budesonide-formoterol pMDI as described in the product information one timeand on a second occasion using the pMDI with a VHC. Spirometry and impedance osscilometry were measured at baseline and repeatedly over a 12-hour period. This study was approved by IntegReview Institutional Review Board, Austin, TX, USA. The clinical trial number for this study was NCT 009-15538 (http://www.westernskymed.com). RESULTS: The area under the curve of FEV-1, the FEV-1, and the fraction FEV-1/FVC was similar over the 12-hour time frame with both methods. Resistance was not different at any time point. In both procedures, the onset of bronchodilation occurred rapidly within 3 to 5 minutes. CONCLUSIONS: In well-trained asthmatic subjects, both tested methods caused equivalent bronchodilation. This suggests a VHC itself has no deleterious effect on the bronchodilator activity in the combined drug. These results may not apply to patients who have coordination problems with the pMDI and further study is indicated.

Oral immunotherapy for peanut allergy in clinical practice is ready.

Oral immunotherapy (OIT) for peanut allergy is ready for clinical allergy practice. Some physicians, particularly at academic centers, believe that OIT is not ready for clinical practice. The shortcomings of the present general recommendations of food avoidance and provision of epinephrine autoinjectors for a select number of patients demand a different approach. In peanut-allergic patients, the rate of accidental reactions is ~10% annually. Between 1 and 2% of these reactions require epinephrine or emergency department visits. Food allergy and peanut allergy, specifically, have a large negative impact on the quality of life (QOL) for patients and their families, which can be psychosocially debilitating. These decreases in health-related QOL continue into adulthood. There is only an ~20% chance of spontaneous remission in peanut allergy. Given this climate, three private allergy practices have begun providing OIT to 150 patients with peanut anaphylaxis. One hundred eleven (74%) patients were able to tolerate eight peanuts (8 g, ~2 g of protein). During outpatient dosing, epinephrine was used at a rate of 8 per 10,000 doses. To date, there have been no long-term (>24-36 months) unexpected reactions. OIT decreases risk and in one study, conducted in a practice setting, it was shown to improve QOL. OIT is a meaningful clinical procedure that can help our patients.

Efficacy of budesonide/formoterol pressurized metered-dose inhaler versus budesonide pressurized metered-dose inhaler alone in Hispanic adults and adolescents with asthma: a randomized, controlled trial.

BACKGROUND: Few clinical trials in asthma have focused on Hispanic populations. OBJECTIVE: To compare the efficacy and safety of budesonide/formoterol (BUD/FM) with BUD in an ethnically diverse group of Hispanic participants with asthma previously treated with inhaled corticosteroids (ICS). METHODS: This 12-week, randomized, double-blind, active-controlled study (NCT00419757) was designed to enroll Hispanic participants (self-reported) (≥12 years of age) with moderate to severe asthma requiring medium- to high-dose ICS. After a 2-week run-in period (low-dose BUD pressurized metered-dose inhaler [pMDI] 80 µg × 2 inhalations [160 µg] twice daily), participants with a symptom score greater than 0 (scale: 0-3) on 3 or more of 7 run-in days and forced expiratory volume in 1 second (FEV(1)) 45%-85% predicted were randomized to BUD/FM pMDI 160/4.5 µg × 2 inhalations (320/9 µg) twice daily or BUD pMDI 160 µg × 2 inhalations (320 µg) twice daily. RESULTS: Randomized participants (n = 127 BUD/FM; n = 123 BUD) were predominately Mexican (51%) or Puerto Rican (21%). During low-dose ICS run-in, the mean symptom score was 1.0; however, mean predose FEV(1) improved (2.10-2.21 L). During randomized treatment, small, but not statistically significant, improvements favored BUD/FM vs BUD (am peak expiratory flow [PEF; primary efficacy variable] 25.4 vs 19.9 L/min; pm PEF 20.6 vs 15.8 L/min; predose FEV(1) 0.16 vs 0.11 L; rescue medication use -0.7 vs -0.6 inhalations/d). Most adverse events were mild or moderate in intensity. CONCLUSIONS: Improvement in clinically relevant control end points occurred in both BUD/FM and BUD groups; both treatments were well tolerated in this Hispanic asthma population but were not significantly differentiated.

Continuous and Daily Oral Immunotherapy for Peanut Allergy: Results from a 2-Year Open-Label Follow-On Study.

BACKGROUND: The randomized, controlled PALISADE trial demonstrated the benefit of daily oral immunotherapy with Peanut (Arachis Hypogaea) allergen powder-dnfp (PTAH, formerly AR101) in peanut-allergic children and adolescents. OBJECTIVE: ARC004, the open-label follow-on study to PALISADE, used 5 dosing cohorts to explore PTAH treatment beyond 1 year and alternative dosing regimens in peanut-allergic individuals. METHODS: Active arm (PTAH-continuing) PALISADE participants who tolerated 300-mg peanut protein at the exit double-blind placebo-controlled food challenge and placebo arm (PTAH-naive) participants could enter ARC004. PTAH-continuing participants were assigned to receive daily (cohorts 1 and 3A) or non-daily (cohorts 2, 3B, and 3C) dosing regimens; PTAH-naive participants were built up to 300 mg/d PTAH, followed by maintenance dosing. At study completion, participants underwent an exit double-blind placebo-controlled food challenge with doses up to 2000 mg peanut protein. Data were assessed using descriptive statistics. RESULTS: Overall, 358 (87.5%) eligible participants (4-17 years) entered ARC004 (PTAH-continuing, n = 256; PTAH-naive, n = 102). Among PTAH-continuing participants, exposure-adjusted adverse event rates were 12.94 to 17.54/participant-year and 25.95 to 42.49/participant-year in daily and non-daily dosing cohorts, respectively; most participants (83%) experienced mild or moderate adverse events. Daily dosing cohorts appeared to have higher desensitization rates than non-daily dosing cohorts. Of all PTAH-continuing cohorts, cohort 3A had the longest daily dosing duration and the highest desensitization rates. Changes in immune markers with PTAH continuation demonstrated ongoing immunomodulation. Outcomes in PTAH-naive participants mirrored those of the PALISADE active arm. CONCLUSIONS: Continued daily PTAH treatment beyond 1 year showed sustained safety and efficacy. Ongoing immunomodulation was observed during the second year of treatment.

Beclomethasone HFA for the treatment of allergic rhinitis.

INTRODUCTION: Allergic rhinitis (AR) is a common chronic disorder, affecting 10 -30% of populations. AR has significant morbidity and expense. AR patients treat themselves with over-the-counter medications. However the usual H1 antihistamines are often inadequate. Intranasal corticosteroids effectively diminish AR symptoms. Beclomethasonedipropionate (BDP) was reported to effectively treat adults and children with AR. BDP was a chlorofluorocarbon (CFC) propellant pressurized metered dose inhaler (pMDI). Subsequently BDP appeared in an aqueous format. Some patients preferred the dryer sensation of pMDI to aqueous formulations. The protocol of Montréal, removed CFC devices from medical practice. The remaining intranasal steroids were in aqueous format. Many patients did not like the sensory perceptions using liquids intranasal. They were unlikely to be compliant. BDP hydrofluoroalkanepMDI (BDP HFA) was developed. AREAS COVERED: The need of active treatment of AR will be reviewed. Chemistry, pharmacokinetics and pharmacodynamics of BDP HFA will be presented. Clinical efficacy studies and safety data which led to the approval of BDP for use in adults and children will be reviewed. EXPERT OPINION: BDP HFA is an option to treat AR, demonstrating a favorable therapeutic index in large double-blind placebo-controlled studies. BDP HFA appeals to select AR patients.

Oral immunotherapy for peanut allergy: multipractice experience with epinephrine-treated reactions.

BACKGROUND: Peanut allergy creates the risk of life-threatening anaphylaxis that can disrupt psychosocial development and family life. The avoidance management strategy often fails to prevent anaphylaxis and may contribute to social dysfunction. Peanut oral immunotherapy may address these problems, but there are safety concerns regarding implementation in clinical practice. OBJECTIVE: The purpose of this report is to communicate observations about the frequency of epinephrine-treated reactions during peanut oral immunotherapy in 5 different allergy/immunology practices. METHODS: Retrospective chart review of peanut oral immunotherapy performed in 5 clinical allergy practices. RESULTS: A total of 352 treated patients received 240,351 doses of peanut, peanut butter, or peanut flour, and experienced 95 reactions that were treated with epinephrine. Only 3 patients received 2 doses of epinephrine, and no patient required more intensive treatment. A total of 298 patients achieved the target maintenance dose for a success rate of 85%. CONCLUSION: Peanut oral immunotherapy carries a risk of systemic reactions. In the context of oral immunotherapy, those reactions were recognized and treated promptly. Peanut oral immunotherapy may be a suitable therapy for patients managed by qualified allergists/immunologists.

Efficacy and safety of fluticasone/formoterol combination therapy in patients with moderate-to-severe asthma.

BACKGROUND: The inhaled corticosteroid, fluticasone propionate, and the long-acting ß(2)-adrenergic agonist, formoterol fumarate, are both highly effective treatments for bronchial asthma. This study (NCT00393952/EudraCT number: 2006-005989-39) compared the efficacy and safety of fluticasone/formoterol combination therapy (flutiform(®); 250/10 µg) administered twice daily (b.i.d.) via a single aerosol inhaler, with the individual components (fluticasone 250 µg b.i.d.; formoterol 10 µg b.i.d.), in adult and adolescent patients with moderate-to-severe asthma. METHODS: This was a 12-week, double-blind, randomised, parallel-group, multicentre, placebocontrolled phase 3 study. The co-primary efficacy endpoints were: i) the mean change in the forced expiratory volume in the first second (FEV(1)) from morning pre-dose at baseline to pre-dose at week 12 (fluticasone/formoterol 250/10 µg vs. formoterol), ii) the mean change in FEV(1) from morning pre-dose at baseline to 2 h post-dose at week 12 (fluticasone/formoterol 250/10 µg vs. fluticasone), and iii) the number of patients who discontinued prematurely due to lack of treatment efficacy (fluticasone/formoterol 250/10 µg vs. placebo). The secondary endpoints included measures of lung function, disease control, and asthma symptoms. Safety was assessed based on adverse events, vital signs, and clinical laboratory evaluations. RESULTS: Overall, 395 (70.9%) patients completed the study. Fluticasone/formoterol 250/10 µg b.i.d. was superior to the individual components and placebo for all three co-primary endpoints and demonstrated numerically greater improvements for multiple secondary efficacy analyses. Fluticasone/formoterol combination therapy had a good safety profile over the 12 weeks. CONCLUSION: Fluticasone/formoterol combination therapy will provide clinicians with an efficacious alternative treatment option for patients with moderate-to-severe asthma.

Study of levocetirizine in seasonal allergic rhinitis.

OBJECTIVE: To evaluate the efficacy of levocetirizine 5 mg once daily in reducing seasonal allergic rhinitis (SAR) symptoms in US adults. RESEARCH DESIGN AND METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolled adults aged 18 to 65 years with SAR symptoms in the spring in the US. After a single-blind placebo run-in period, subjects received levocetirizine 5 mg or placebo once daily over 14 days. ClinicalTrials.gov registry no.: NCT00621959. MAIN OUTCOME MEASURES: Primary efficacy variable was the Total 5-Symptom Score (T5SS). Secondary variables included Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), Work Productivity and Activity Impairment-Allergy Specific (WPAI-AS) questionnaire, and Epworth Sleepiness Scale (ESS). Safety assessments were based on adverse events (AEs). RESULTS: The intent-to-treat population comprised 596 subjects (levocetirizine, n = 301; placebo, n = 295). Comparison of mean T5SS over the total treatment period showed a nonsignificant between-group difference (levocetirizine, 8.90 +/- 0.19; placebo, 9.04 +/- 0.19; adjusted mean difference, -0.14; p = 0.546). Levocetirizine showed numerical (mean RQLQ, WPAI-AS, ESS) and statistically superior differences (two domains within WPAI-AS) compared with placebo upon analysis of secondary efficacy variables. The incidence of treatment-emergent AEs was similar (levocetirizine, 23.9%; placebo, 24.4%). As the lack of efficacy was inconsistent with all previous levocetirizine studies, post hoc analyses were performed to assess the influence of pollen counts, geography, and other factors; however, no conclusive explanation could be identified. CONCLUSIONS: In this study, levocetirizine 5 mg QD was well tolerated but failed to show significant efficacy compared with placebo in a US adult population with SAR. This finding is inconsistent with all previous studies with levocetirizine and in contrast to a concurrently run, similarly designed US study. It reflects the importance of conducting duplicate studies as there is always a small but real risk of false negative results in clinical studies, irrespective of the methodologic quality.

Fexofenadine in pediatrics: oral tablet and suspension formulations.

Allergic rhinitis is a common chronic condition in children. Oral antihistamines are a first-line treatment option in allergic rhinitis and different formulations are available to aid administration to children. The tablet formulation of the second-generation antihistamine fexofenadine has established efficacy and safety in both adults and children. To aid administration in young children, a new oral suspension formulation of fexofenadine has been developed, indicated for the relief of seasonal allergic rhinitis symptoms in children aged 2-11 years and for uncomplicated skin manifestations of chronic idiopathic urticaria in children aged 6 months-11 years. Clinical studies have shown the oral suspension to have both bioequivalence with the 30 mg tablet formulation and a favorable safety and tolerability profile.

The future of the long-acting beta-adrenergic bronchodilators in the treatment of asthma.

The combination of long-acting beta-agonist (LABA) bronchodilators with inhaled corticosteroids (ICSs) has been shown to be an extremely effective treatment for asthma. Use of LABA as monotherapy for asthma is associated with increased adverse events including exacerbations and asthma deaths. However, intensive evaluation of the combined LABA-ICS therapy provided no signals of increased risk. LABA appears to potentiate the effects of ICS. This provides the opportunity for use a of lower ICS dose for asthma control with less risk of steroid side effects. The combination of formoterol and budesonide used as both maintenance and relief medications may offer superior asthma control with less medication use. The recent introduction of 24-hour LABA, which are in clinical trials, makes possible the concept of very effective once-daily combinations of LABA and ICS, which would be expected to increase patient adherence and improve asthma outcomes. The 24-hour LABA will likely be combined with a 24-hour anticholinergic to treat chronic obstructive pulmonary disease. Whether this dual combination with ICS will enhance our treatment of more severe asthma remains an exciting hypothesis to be tested.

Daytime sleepiness and cognitive performance improve in seasonal allergic rhinitis treated with intranasal fluticasone propionate.

Patients with symptomatic allergic rhinitis often complain of daytime drowsiness and impairment in their speed of thinking responses. In this study, we compared subjects with allergic rhinitis treated with intranasal fluticasone propionate or placebo. We measured nasal symptoms, daytime sleepiness, and cognitive performance. Total nasal symptoms (p = 0.002) and nasal congestion (p = 0.003) improved in the intranasal fluticasone propionate group. Concomitantly, daytime sleepiness decreased (p = 0.001) and cognitive performance improved (p = 0.02). The placebo-treated subjects did not show any significant changes. Effective therapy of allergic rhinitis ameliorates the symptoms of daytime sleepiness and decreased cognitive performance.

Once-daily immediate-release fexofenadine and sustained-release pseudoephedrine combination: a new treatment option for allergic rhinitis.

Allergic rhinitis symptoms, in particular nasal congestion, can have a significant impact on patient quality of life, resulting in reduced productivity and daytime sleepiness. Newer-generation antihistamines are commonly used to treat allergic rhinitis; however, in patients with severe congestion, a combination of a newer-generation antihistamine and a decongestant is particularly beneficial. A new once-daily fexofenadine/pseudoephedrine combination has been developed and recently approved in the US. The combination provides an effective, well-tolerated antihistamine and a reliable, sustained-release pseudoephedrine system. In addition, small tablet size and once-daily dosing may provide patients with increased convenience and improve adherence. In summary, the combination of immediate-release fexofenadine/sustained-release pseudoephedrine offers an important additional option for the treatment of allergic rhinitis.

Medium and long-term growth in children receiving intranasal beclomethasone dipropionate: a clinical experience.

BACKGROUND: A 12-month controlled pediatric study of intranasal beclomethasone dipropionate (BDP) reported a 0.9 cm decrease in annual height growth velocity. Since children with allergic rhinitis may be treated for years, this report evaluates long-term height growth effects. METHODS: We reviewed the clinical charts of children with allergic rhinitis who were treated for the first time with intranasal BDP and were less than 10 years of age at initiation. Height was determined by stadiometry before intranasal corticosteroid therapy and compared with height at a final visit. RESULTS: Sixty children aged 24 to 117 months (mean age, 70 months) were treated for an average of 36 months. The pretherapy height percentile was 44.6, which increased to the 52.2 percentile at the final visit. CONCLUSIONS: Long-term clinical use of intranasal BDP in children was not associated with decreased height growth. This outcome may reflect decreased long-term compliance compared with a short-term study. However, the treatment remained effective. Some children may be at special risk. Careful height measurements are recommended every 6 months.

Safety and efficacy of desloratadine 5 mg in asthma patients with seasonal allergic rhinitis and nasal congestion.

BACKGROUND: Antihistamines relieve most seasonal allergic rhinitis (SAR) symptoms, with the exception of nasal congestion, which is often the most troublesome symptom for patients. A nonsedating antihistamine that significantly decreases nasal congestion and improves symptoms of seasonal allergic asthma would be a significant advance in therapy. OBJECTIVES: To evaluate the safety and efficacy of desloratadine 5 mg in patients experiencing moderate SAR, nasal congestion, and symptoms of seasonal allergic asthma. METHODS: This 4-week, multicenter, parallel-group, double-blind study evaluated desloratadine treatment (5 mg once daily) versus placebo in 331 subjects with SAR and mild seasonal allergic asthma. Subjects evaluated SAR and asthma symptoms twice daily, recording 12-hour reflective and instantaneous severity evaluation scores. The primary efficacy parameter was the difference from baseline in AM/PM reflective total symptom scores. Changes in individual SAR and asthma symptoms were also analyzed. RESULTS: Compared with placebo, desloratadine significantly reduced mean AM/PM reflective total symptom scores for SAR, beginning with the first dose (P < 0.001) and continuing throughout days 1 to 15 (-4.90 vs -2.98; P < 0.001) and days 1 to 29 (-5.47 vs -3.73; P < 0.001). Desloratadine significantly decreased AM/PM reflective total asthma symptom scores for days 1 to 15 (P = 0.023) and AM/PM reflective nasal congestion scores over days 1 to 15 and days 1 to 29 (P = 0.006 and P = 0.014, respectively). Desloratadine was safe and well tolerated; adverse events were similar to placebo overall. CONCLUSIONS: Desloratadine provided significant relief from the signs and symptoms of SAR, including nasal congestion. In this patient population, symptoms of seasonal allergic asthma also improved.

Sleep disordered breathing and daytime quality of life in children with allergic rhinitis during treatment with intranasal budesonide.

BACKGROUND: Nasal obstruction is recognized as an important cause of sleep disordered breathing. Congestion of the nasal mucosa and obstruction are common symptoms of allergic rhinitis. Daytime sleepiness is a common finding in symptomatic allergic rhinitis. Effective therapy of the nasal congestion of allergic rhinitis should alter sleep patterns in patients with symptomatic allergic rhinitis. OBJECTIVE: To measure objective changes in polysomnograms (sleep studies) of children with allergic rhinitis before and after therapy with intranasal budesonide and to measure changes in the quality of life of these patients during treatment. METHODS: Open clinical trial with objective measurements (polysomnography) and subjective data (Rhinitis Quality of Life Questionnaire [RQLQ]). Evaluations were performed before, during, and at completion of therapeutic intervention. RESULTS: The 14 studied children tolerated the procedures and treatment without problems. The mean number of sleep arousals per hour (all apneas and hypopneas) decreased from a baseline of 8.4 to 1.2 (P = .005) after treatment. The change was mainly in hypopneic episodes (7.5-0.9, P = .003). Objective responses on the RQLQ showed improvements consistent with improved sleep and lessened rhinitis symptoms. CONCLUSIONS: Decreasing the nasal congestion associated with allergic rhinitis can improve sleep measured by objective sleep studies and lead to improvement in daytime quality of life.