Clinical Bioequivalence of Wixela Inhub and Advair Diskus in Adults With Asthma.

Background: Wixela® Inhub® is a dry powder inhaler approved as a generic equivalent to Advair® Diskus® (fluticasone propionate [FP]/salmeterol fixed-dose combination) for patients with asthma or chronic obstructive pulmonary disease (COPD). This study aimed at confirming the local (lung) therapeutic equivalence of both the FP and salmeterol components of Wixela Inhub (test [T]) to Advair Diskus (reference [R]) after inhalation. Methods: This randomized, double-blind, double-dummy, placebo-controlled, parallel-group study in patients ≥18 years with mild-to-moderate persistent asthma compared the local therapeutic equivalence (using forced expiratory volume in 1 second [FEV1]) of FP/salmeterol (100/50 µg) after inhaled delivery via T and R. Results: Randomized patients (N = 1127) received T (n = 512), R (n = 512), or placebo (n = 103). T and R significantly increased day 1 FEV1 area under the effect curve over 12 hours of the change from baseline (AUC[0-12]) and day 29 trough FEV1 over placebo, indicating that these endpoints were sufficiently sensitive for evaluation of bioequivalence. On day 1, T and R each increased FEV1 AUC(0-12) over placebo (3.134 L•h [T], 2.677 L•h [R]; each p < 0.0001). Following twice-daily dosing for 28 days, T and R also each increased trough FEV1 (measured on day 29) over placebo (235 mL [T], 215 mL [R]; each p < 0.0001). Least-squares mean T/R ratios (90% confidence intervals) for day 1 FEV1 AUC(0-12) and day 29 trough FEV1 were 1.120 (1.016-1.237) and 1.069 (0.938-1.220), respectively, indicating that T and R were bioequivalent for both co-primary endpoints. FP/salmeterol was well tolerated when administered via either T or R. Conclusions: These results demonstrate that the therapeutic effects of Wixela Inhub are bioequivalent to Advair Diskus in the lung. Wixela Inhub represents a therapeutically equivalent new FP/salmeterol treatment option for use in the treatment of asthma and COPD.

Barriers to the Administration of Epinephrine in Schools.

BACKGROUND: Anaphylaxis is a serious and growing concern in the school setting as the prevalence of food allergies and food-induced severe allergic reactions continues to increase. METHODS: A cross-sectional, web-based survey was conducted regarding anaphylactic events that occurred during the 2014-2015 school year. Eligible schools were enrolled in the EPIPEN4SCHOOLS® program (Mylan Specialty L.P., Canonsburg, PA), which provides free epinephrine auto-injectors to qualifying US schools. Participating schools completed a 29-item survey on anaphylactic event occurrence and treatment, epinephrine stock, school policies regarding anaphylaxis, school staff training, and school nursing coverage. RESULTS: Responses were provided by 12,275 schools. Epinephrine was administered on school property for 63.7% of reported anaphylactic events (1272/1998). In 38.5% (235/610) of events for which epinephrine was not used, antihistamines were cited as the reason. Only 59.4% of schools cited epinephrine as their standard first-line therapy for anaphylaxis. School nurses were most likely to be trained in anaphylaxis recognition and permitted to administer epinephrine; however, just 53.6% of schools had a full-time nurse on staff. CONCLUSIONS: Process-related barriers to the appropriate use of epinephrine go beyond access to medication. Widespread staff training and review of school policies are needed to ensure that anaphylaxis is appropriately managed in schools.

Guidance for compassionate restraint of small children to prevent injuries with epinephrine autoinjectors.

BACKGROUND: Without securing a child properly, injuries can happen with the use of pediatric epinephrine autoinjectors (EAI), and lacerations and embedded needles have been reported. Health care providers should ensure that instruction is provided to parents on how to hold a child during an injection with an EAI. OBJECTIVE: To demonstrate the compassionate restraint of small children during an allergic emergency to ensure the safe use of an EAI. METHODS: A patient was used to illustrate a compassionate restraint technique during a mock injection with an EAI. RESULTS: One possible technique was illustrated here to reinforce the need for complete, yet compassionate restraint of small children during the use of an EAI. The exact position intended to be used by parents or caregivers will need to be practiced with their children to ensure a safe injection in the event of an allergic emergency. CONCLUSION: Reinforcement of proper EAI use and visual guidance that illustrate compassionate restraint can potentially prevent EAI-related injuries.

Prevalence and triggers of anaphylactic events in schools.

BACKGROUND: Prevention and management of anaphylaxis in schools is an area of active interest as allergy and asthma rates in children continue to increase. A greater understanding of the prevalence and characteristics of anaphylaxis can help guide preventive and management strategies both within and outside of the school setting, with the goal of reducing morbidity and mortality. OBJECTIVE: This study was performed to elucidate the epidemiology of and management strategies for anaphylaxis in the school setting. METHODS: A cross-sectional, Web-based survey was administered to schools that participated in an initiative that provides stock epinephrine autoinjectors (EAIs) to qualifying U.S. schools. Representatives from participating schools completed a questionnaire regarding anaphylactic reactions that occurred during the 2014-2015 school year. Weighted analyses were performed to account for differential responses between schools that completed the survey and those that did not. RESULTS: A total of 12,275 of the 45,819 invited schools responded to the survey. The occurrence of one or more anaphylactic events was reported by 1358 schools. Most events (89.8% [1803/2008]) occurred in students. High school students accounted for the largest proportion of anaphylactic reactions among students (40.1% [723/1802]). Food was the most commonly identified anaphylaxis trigger across grade levels, seasons, and geographic regions. The trigger was unknown to the individual who experienced anaphylaxis in 21.8% of the events (436/1998). No known history of allergy or asthma was present in 24.5% (491/2001) and 51.3% (1026/2000) of affected individuals, respectively. Transportation to the hospital or clinic for further treatment and/or management was reported for 72.6% of the individuals with anaphylactic events (1450/1997). Results from the weighted analyses were similar to those of the unweighted analyses. CONCLUSION: Anaphylaxis occurred across grade levels and in individuals with or without known risk factors, which reinforced the need for school preparedness in both management of anaphylaxis and stocking of EAIs.

Training and administration of epinephrine auto-injectors for anaphylaxis treatment in US schools: results from the EpiPen4Schools(®) pilot survey.

BACKGROUND: Anaphylaxis is a serious, potentially life-threatening condition. Adequate preparation for anaphylaxis management is imperative for school personnel. This descriptive pilot study assessed preparedness of US schools to manage anaphylactic reactions. METHODS: An exploratory, cross-sectional, web-based, pilot survey assessed the occurrence and characteristics of anaphylactic events, as well as training provided to school personnel for the recognition and treatment of anaphylaxis. Eligible US schools were participants in the EpiPen4Schools(®) program during the 2013-2014 school year. EpiPen4Schools provides EpiPen(®) (epinephrine injection) Auto-Injectors and training materials to qualifying US schools. Survey data were parsed by US Census Bureau region and state and were evaluated using descriptive statistics. RESULTS: Schools from all 50 states and the District of Columbia participated in the survey (N=6,019). Among schools that provided information on anaphylactic events, 11% (607/5,683) reported the occurrence of one or more events, with significant variability in incidence across census regions and among states. A total of 5,613 schools provided information regarding which staff members were trained to recognize the signs and symptoms of anaphylaxis. Thirty-six percent of schools (2,022/5,613) indicated that only the school nurse and select staff were trained in anaphylaxis recognition. The proportion of schools in which most or all school staff received such training differed by region/state (range, 13%-100%). A total of 5,578 schools provided information on which staff were permitted to administer epinephrine. The majority of schools (54%; 3,024/5,578) permitted only the school nurse and select staff to administer epinephrine, although percentages varied by region/state (range, 4%-100%). CONCLUSION: Schools differed substantially in their preparedness to manage anaphylaxis, with significant disparities in staff training and permission to treat. Given the ramifications of delayed treatment, removing barriers to the recognition and treatment of anaphylactic events in schools is an important public health goal.

Anaphylaxis Triggers and Treatments by Grade Level and Staff Training: Findings from the EPIPEN4SCHOOLS Pilot Survey.

This pilot survey was designed to evaluate the characteristics of anaphylactic events and epinephrine autoinjector (EAI) use in children in U.S. schools. A cross-sectional, web-based, pilot survey of schools participating in the EPIPEN4SCHOOLS® program (Mylan Specialty L.P., Canonsburg, PA) assessed characteristics of anaphylactic events and EAI use during the 2013-2014 academic year. Respondents reported 757 anaphylactic events experienced by students; student grade level was noted for 724 events. Of these events, 32.3% (234/724) were experienced by students in grade school, 18.6% (135/724) by students in middle school, and 49.0% (355/724) by students in high school. Frequency of food-related triggers was consistently high across grade levels. However, many events experienced by students in high school (22.3%, 79/355), middle school (15.0%, 20/135), and grade school (14.1%, 33/234) had an unknown trigger. In 36.0% of schools (2008/5579), only the school nurse and select staff received training to recognize anaphylaxis; most staff or all staff received training in 28.9% (1610/5579) and 30.9% (1722/5579) of schools, respectively. In a majority of schools (54.2%, 3003/5544), only the school nurse and select staff were permitted to administer epinephrine, whereas most staff or all staff were permitted to administer epinephrine in 15.8% (876/5544) and 21.9% (1212/5544) of schools, respectively. Risk of anaphylaxis may be particularly high during adolescence, and some students encounter staff members who are untrained in anaphylaxis recognition or management, or both. These findings support the need for continued anaphylaxis training for the protection of all students, staff, and visitors.

Anaphylaxis in Schools: Results of the EPIPEN4SCHOOLS Survey Combined Analysis.

A pilot survey described the characteristics of anaphylactic events occurring in an initial set of participating U.S. schools during the 2013-2014 school year. This survey was subsequently readministered to large school districts, which were underrepresented in initial results. A cross-sectional survey was administered to the U.S. schools that were participating in the EPIPEN4SCHOOLS® program (Mylan Specialty L.P., Canonsburg, PA) to assess characteristics of anaphylactic events. Data from large school districts were added to initial findings in this comprehensive combined analysis. A total of 1,140 anaphylactic events were reported among 6,574 responding schools. Of 1,063 anaphylactic events with data on who experienced the event, it was observed that it occurred mostly in students (89.5%, 951/1,063). For students, anaphylactic events were reported across all grades, with 44.9% (400/891) occurring in high school students, 18.9% (168/891) in middle school students, and 32.5% (290/891) in elementary school students. Food was identified as the most common trigger (60.1%, 622/1,035). A majority of schools (55.0%, 3,332/6,053) permitted only the school nurse and select staff to administer epinephrine to treat anaphylaxis. The unpredictability of anaphylaxis is emphasized by its high occurrence in individuals with no known allergies (25.0%). A majority of schools permitted only the school nurse and select staff to treat anaphylaxis. Thus, individuals experiencing an anaphylactic event may frequently encounter staff members not being permitted to administer potentially life-saving epinephrine. Epinephrine auto-injectors provided by the EPIPEN4SCHOOLS program were used to treat 38.0% of events. Anaphylaxis can occur in children with no previously known allergies, illustrating the importance of public access to epinephrine.

EpiPen4Schools pilot survey: Occurrence of anaphylaxis, triggers, and epinephrine administration in a U.S. school setting.

BACKGROUND: Although epinephrine is the treatment of choice for anaphylaxis, it remains underused. OBJECTIVE: This study was designed to describe anaphylactic events and epinephrine autoinjector (EAI) use in U.S. schools enrolled in the EpiPen4Schools program. METHODS: This exploratory, cross-sectional, Web-based survey of 6019 schools that participated in the EpiPen4Schools program assessed anaphylactic events and EAI use at responding schools during the 2013-2014 school year. RESULTS: A total of 919 anaphylactic events were reported in 607 schools. Of the 852 anaphylactic events with data on those who experienced an event, most 88.8% (n = 757) occurred in students, and 21.9% of events (n = 187) occurred in individuals with no known allergies. Of the 851 events with data on EAI use, 74.7% (n = 636) were treated with EAIs and 8.5% (n = 54) received a second epinephrine injection. Of the 204 individuals not treated with an EAI, 77.0% (n = 157) received antihistamines, 12.7% (n = 26) received another treatment, and 8.3% (n = 17) received no treatment. Of the 850 events with data on hospital transport, 79.6% of individuals (n = 677) were transported to the hospital. Common triggers varied seasonally, with food listed most frequently overall (62.5%). CONCLUSION: More than one in ten schools that participated in the EpiPen4Schools survey reported an anaphylactic event. Approximately 25% of individuals with anaphylactic events were not treated with EAIs, and 20.4% of patients were not taken to the hospital after an anaphylactic event. Analysis of these data supports the value of stocking EAIs and of providing continuing education regarding the recognition and proper treatment of anaphylaxis for school personnel.

Escalating doses of C1 esterase inhibitor (CINRYZE) for prophylaxis in patients with hereditary angioedema.

BACKGROUND: Nanofiltered C1 inhibitor (human) is approved in the United States for routine prophylaxis of angioedema attacks in patients with hereditary angioedema, a rare disease caused by a deficiency of functional C1 inhibitor. OBJECTIVE: To assess the safety of escalating doses of nanofiltered C1 inhibitor (human) in patients who were not adequately controlled on the indicated dose (1000 U every 3 or 4 days). METHODS: Eligible patients had >1 attack/month over the 3 months before the trial. Doses were escalated to 1500 U every 3 or 4 days for 12 weeks, at which point, the patients were evaluated. If treatment was successful (≤1 attack/mo) or at the investigator's discretion, the patients entered a 3-month follow-up period. The patients with an average of >1 attack/month were eligible for further escalation to 2000 U and then 2500 U. RESULTS: Twenty patients started at 1500 U; 13 were escalated to 2000 U, and 12 were escalated to 2500 U. Eighteen patients reported adverse events. Two patients reported 4 serious adverse events (cerebral cystic hygroma, laryngeal angioedema attack, anemia, and bile duct stone) that were considered by investigators to be unrelated to treatment. Notably, there were no systemic thrombotic events or discontinuations due to adverse events. Fourteen patients were treated successfully (70%), continued to the follow-up period at the investigator's discretion, or experienced a reduction in attacks of >1.0/month. CONCLUSIONS: Dose escalation of nanofiltered C1 inhibitor (human) up to 2500 U was well tolerated and reduced attack frequency in the majority of patients.

Recognition and treatment of anaphylaxis in the school setting: the essential role of the school nurse.

Since anaphylaxis is unpredictable, rapid in onset, and potentially life threatening, it is critical for school staff to recognize and respond to its symptoms quickly. The symptoms of anaphylaxis can be challenging to differentiate, particularly in school-age children who may have trouble explaining what they are experiencing. School staff must understand the distinctive ways in which children describe and manifest anaphylactic symptoms, and the school nurse has a key leadership role in providing this training. The school nurse should create and coordinate individualized emergency care/action plans for students with known allergies, as well as a comprehensive care plan for all students, to ensure a safe environment and a rapid response to any life-threatening allergic reaction. This should include having epinephrine stocked and readily accessible so that it can be given promptly in the case of an anaphylactic emergency.

Preprocedural administration of nanofiltered C1 esterase inhibitor to prevent hereditary angioedema attacks.

Patients with hereditary angioedema (HAE) may have attacks triggered by dental, medical, or surgical procedures. This analysis evaluated the efficacy and safety of preprocedural administration of nanofiltered C1 esterase inhibitor (C1 INH-nf; human) for the prevention of HAE attacks during and after dental, medical, or surgical procedures. Data were reviewed retrospectively from two acute treatment trials in which at least 1000 U of C1 INH-nf was administered i.v. within 24 hours before an emergency or noncosmetic medical, surgical, or dental procedure. Dosing data, HAE attacks reported within 72 hours, and adverse events (AEs) reported within 7 days after a preprocedural dose of C1 INH-nf were analyzed to assess efficacy and safety. Forty-one unique subjects (8 children and 33 adults) received C1 INH-nf for 91 procedures (40 in children and 51 in adults). The majority of procedures (56%) involved dental work and 44% involved a variety of surgical or medical procedures. A single 1000-U dose of C1 INH-nf was administered for 96% of procedures. An HAE attack did not occur within 72 hours after C1 INH-nf dosing for 98% (89/91) of procedures. Two HAE attacks were reported after the procedure, and both were treated with C1 INH-nf and achieved relief. None of the reported AEs were judged to be related to C1 INH-nf or were associated with an HAE attack. This analysis supports the efficacy and safety of preprocedural administration of C1 INH-nf for the prevention of HAE attacks.

Psychometric validation of two patient-reported outcome measures to assess symptom severity and changes in symptoms in hereditary angioedema.

PURPOSE: Hereditary angioedema (HAE) is a rare disorder characterized by highly variable, acute attacks of swelling at various anatomical locations. Clinical measures do not adequately assess the diversity of symptoms characteristic of an attack. Two disease-specific, patient-reported outcome measures were developed to comprehensively capture symptom severity and change: the Treatment Outcome Score (TOS) and the Mean Symptom Complex Severity (MSCS) score. METHODS: This study comprised a secondary analysis of pooled data from a randomized controlled trial to evaluate the psychometric properties, including reliability and validity, and minimally important difference (MID) of the TOS and MSCS score. RESULTS: HAE patients (n = 73) had a mean age of 33 years, and 60% were female. Test-retest evaluation demonstrated moderate to substantial agreement (ICCs = 0.53 for TOS; 0.62 for MSCS score). The TOS and change in MSCS score were moderately to highly correlated with a Global Improvement Measure at 4 h (TOS: r = 0.90; MSCS: r = -0.59). Anchor- and distribution-based analyses suggested that conservative estimates for MID are 30 points for TOS and -0.30 points for 4-h change in MSCS score. CONCLUSIONS: The psychometric tests performed here provide evidence of the reliability and validity of the TOS and MSCS for evaluating symptom severity and change in HAE patients. The TOS and MSCS score provide an example of measurement methodology that may be used to precisely capture symptom severity and change in a disease characterized by acute attacks.

Rhinitis and rhinologic headaches.

Rhinologic headache, a headache of nasal origin, generally has been attributed to past facial trauma causing nasal mucosa-septal contact points. Patients who have not knowingly experienced nasal trauma may have contact points caused by mucosal inflammation or anatomic abnormalities (septal spurs, septal deviation, and enlarged turbinates) and can develop rhinologic headaches. A population of 66 such patients was studied to classify the type of patient susceptible to such headaches and to examine the type of underlying inflammation or anatomic abnormality responsible for creating their mucosal contact points. Most patients were women with a mean age at the time of initial presentation of 40 years. VMR was the most frequent cause of nasal inflammation, either alone or in combination with allergic rhinitis. Generally, headache symptoms improved with treatment of the underlying nasal inflammation in the majority of patients.

Efficacy of azelastine nasal spray in patients with an unsatisfactory response to loratadine.

OBJECTIVE: To evaluate the effectiveness and safety of azelastine nasal spray, desloratadine, and the combination of azelastine nasal spray plus loratadine compared with placebo in patients with seasonal allergic rhinitis who had an unsatisfactory response to loratadine. METHODS: This was a 2-week, multicenter, placebo-controlled, randomized, double-blind study in patients with moderate-to-severe symptoms of seasonal allergic rhinitis. Following a 1-week, open-label lead-in period, during which the patients received loratadine 10 mg daily, those patients who met the symptom qualification criteria (<25% to 33% improvement taking loratadine) were randomized to treatment with azelastine nasal spray 2 sprays per nostril, twice daily, azelastine nasal spray 2 sprays per nostril, twice daily, plus loratadine 10 mg daily, desloratadine 5 mg daily plus placebo (saline) nasal spray, or placebo (saline) nasal spray/placebo capsules. The primary efficacy variable was the change from baseline to day 14 in the total nasal symptom score, consisting of runny nose, sneezing, itchy nose, and nasal congestion symptom scores recorded twice daily (AM and PM) in patient diary cards. RESULTS: A total of 428 patients with an unsatisfactory response to loratadine completed the double-blind treatment period. After 2 weeks of treatment, azelastine nasal spray (P < 0.001), azelastine nasal spray plus loratadine (P < 0.001), and desloratadine (P = 0.039) significantly improved the total nasal symptom score compared with placebo. CONCLUSIONS: Azelastine nasal spray is an effective treatment for patients with seasonal allergic rhinitis who do not respond to loratadine and is an alternative to switching to another oral antihistamine or to using multiple antihistamines.

Relative potency of fexofenadine HCl 180 mg, loratadine 10 mg, and placebo using a skin test model of wheal-and-flare suppression.

BACKGROUND: H1-receptor antagonists differ in their ability to produce peripheral H1-blockade. Suppression of histamine-induced flares and wheals is a useful objective test for measuring these differences. OBJECTIVE: To evaluate the relative potency of fexofenadine HCI 180 mg, loratadine 10 mg, and placebo (PBO) in suppressing histamine-induced flares and wheals and compare the onset, duration, and maximum suppression of histamine achieved with each agent. METHODS: Thirty healthy volunteers were enrolled in this randomized, double-blind, single-dose, crossover study. Flares and wheals induced by skin-prick testing with histamine 1.8 mg/mL were measured before treatment, every 20 minutes during the first hour after dosing, and thereafter hourly between 2 and 12 hours and between 23 and 25 hours postdose. RESULTS: Fexofenadine was significantly more effective than loratadine in suppressing the histamine-induced flare response at hours 2 through 7 and 10 through 12 and produced greater flare suppression than did PBO at hours 2 through 25. Onset of flare suppression occurred 2 hours after dosing with fexofenadine and 4 hours after dosing with loratadine. Likewise, fexofenadine was superior to loratadine in suppressing the wheal response from hours 1 through 12 and was more effective than PBO at hours 1 through 12, 24, and 25. Throughout the 25-hour measurement interval, the magnitude of difference in both wheal and flare suppression consistently favored fexofenadine over loratadine. CONCLUSIONS: In a skin test model of wheal-and-flare suppression, fexofenadine showed rapid distribution into the skin compartment with faster onset of action and greater potency vs loratadine.

Fluticasone propionate/salmeterol combination compared with montelukast for the treatment of persistent asthma.

BACKGROUND: Asthma is a chronic disease characterized by inflammation and bronchoconstriction. Medications that are able to effectively treat both components are advantageous. OBJECTIVE: To compare the efficacy of an inhaled corticosteroid and a long-acting beta2-agonist combination product with a leukotriene antagonist for initial maintenance therapy in patients who were symptomatic while receiving short-acting beta2-agonists alone. METHODS: A 12-week, randomized, double-blind, double-dummy, multicenter study was conducted in 432 patients 15 years of age and older with persistent asthma who were symptomatic on short-acting beta2-agonists alone. Fluticasone propionate 100 microg and salmeterol 50 microg combination product (FSC) twice daily or montelukast 10 mg once daily was administered. RESULTS: At endpoint, compared with montelukast, FSC significantly increased morning predose forced expiratory volume in 1 second (0.61 +/- 0.03 L vs 0.32 +/- 0.03 L), morning peak expiratory flow rate (peak expiratory flow rate; 81.4 +/- 5.9 L/minute vs 41.9 +/- 4.8 L/minute), evening peak expiratory flow rate (64.6 +/- 5.3 L/minute vs 38.8 +/- 4.7 L/minute), the percentage of symptom-free days (40.3 +/- 2.9% vs 27.0 +/- 2.7%), the percentage of rescue-free days (53.4 +/- 2.8% vs 26.7 +/- 2.5%), and the percentage of nights with no awakenings (29.8 +/- 2.5% vs 19.6 +/- 2.1%) (P < or = 0.011, all comparisons). At endpoint, FSC significantly reduced asthma symptom scores (-1.0 +/- 0.1 vs -0.7 +/- 0.1) and rescue albuterol use (-3.6 +/- 0.2 puffs/day vs -2.2 +/- 0.2 puffs/day) compared with montelukast (P < 0.001). At endpoint, patients treated with FSC also had a significantly greater improvement in quality of life scores and were more satisfied with their treatment compared with montelukast-treated patients (P < or = 0.001). Both treatments were well tolerated. CONCLUSIONS: Initial maintenance therapy with FSC provides greater improvement in asthma control and patient satisfaction than montelukast.