Why Is Oral Phenylephrine on the Market After Compelling Evidence of Its Ineffectiveness as a Decongestant?

Ineffective over-the-counter (OTC) drugs should be removed from the US market. Despite solid research showing that oral phenylephrine is ineffective as a decongestant, the US Food and Drug Administration has failed to respond to a 2015 citizen's petition to remove it from the OTC nasal decongestant monograph. Other examples of scientifically proven ineffective OTC medications include guaifenesin as an expectorant, dextromethorphan as a cough suppressant, and chlorpheniramine for cold symptoms.

A Statewide Study of the Epidemiology of Emergency Medical Services' Management of Pediatric Asthma.

OBJECTIVES: Little is known about emergency medical services' (EMS') management of pediatric asthma. This study's objective was to describe the demographic, clinical, and geographic characteristics of current EMS' management of pediatric asthma in the state with the fourth-largest pediatric population. METHODS: This was a retrospective observational study of EMS patients ages 2 to 18 years with an asthma exacerbation from 2011 to 2016. Patients from Florida's EMS Tracking and Reporting System were included if their EMS chief complaint indicated respiratory distress, if they received at least 1 albuterol treatment, and if they were transported to a hospital. RESULTS: A total of 11,226 patients met the inclusion criteria. The median age was 9 years, and 49% were African-American. Geospatial analysis revealed 4 rural counties with disproportionate numbers of African-American patients. In addition to albuterol, 37% of patients received ipratropium bromide and 9% received systemic corticosteroids. Adjusted logistic regression revealed that the strongest predictors of receiving systemic corticosteroids from EMS were intravenous access (odds ratio, 33.4; 95% confidence interval, 24.4-45.6) and intravenous magnesium sulfate administration (odds ratio, 5.0; 95% confidence interval, 3.4-7.3), indicating a more severe presentation. CONCLUSIONS: This statewide study demonstrated low rates of EMS administration of ipratropium bromide and systemic corticosteroids, both evidence-based treatments for asthma exacerbations. Targeted EMS education should attempt to increase utilization of both those medications. In addition, the feasibility and efficacy of EMS administration of oral systemic corticosteroids for children should be explored.

Nonprescription medications for respiratory symptoms: Facts and marketing fictions.

BACKGROUND: There are many nonprescription (over-the-counter [OTC]) medications available on pharmacy shelves marketed for relief of respiratory symptoms. The number of such medications has been increasing. OBJECTIVE: This review provides an evidence-based examination of OTC products used for respiratory symptoms. METHODS: Antihistamines, decongestants, mucolytics, antitussives, and intranasal steroids were selected as the most common OTC medications taken by adults and children for various respiratory symptoms. Controlled clinical trials of efficacy were identified by searching a medical literature data base. Those trials and key publications related to the pharmacokinetics and pharmacodynamics of the products were reviewed. RESULTS: Comparisons of the various OTC antihistamines' ability to suppress the effects of histamine were related to their clinical benefit. Intranasal corticosteroids are the preferred agents for maintenance therapy of persistent nasal congestion and are highly effective for symptoms of inhalant allergy other than allergic conjunctivitis. The disconnect between marketing claims and evidence was demonstrated for antihistamines and oral alpha-1 adrenergic agonist decongestants. Data for OTC mucolytics and antitussives were insufficient to justify their use based on the evidence. CONCLUSION: There was little relationship between marketing claims and evidence regarding OTC medications used for respiratory symptoms. Analysis of data supported cetirizine, levocetirizine, and fexofenadine as the most effective of the OTC antihistamines. There were no data that supported the use of oral phenylephrine as a decongestant. Neither OTC mucolytics or antitussives provided sufficient evidence to justify their use.

Application of multicategory exposure marginal structural models to investigate the association between long-acting beta-agonists and prescribing of oral corticosteroids for asthma exacerbations in the Clinical Practice Research Datalink.

OBJECTIVE: To examine the comparative effectiveness of inhaled long-acting beta-agonist (LABA), inhaled corticosteroid (ICS), and ICS/LABA combinations. METHODS: We used a retrospective cohort design of patients older than 12 years with asthma diagnosis in the Clinical Practice Research Datalink to evaluate asthma-related morbidity measured by oral corticosteroid (OCS) initiation within 12 months of initiating LABAs, ICSs, or ICSs/LABAs. Asthma severity 12 months before drug initiation (use of OCSs, asthma-related hospital or emergency department visits, and number of short-acting beta-agonist prescriptions) and during follow-up (short-acting beta-agonist prescriptions and total number of asthma drug classes) was adjusted as a time-varying variable via marginal structural models. RESULTS: A total of 51,103 patients with asthma were followed for 12 months after receiving first prescription for study drugs from 1993 to 2010. About 92% initiated ICSs, 1% initiated LABAs, and 7% initiated ICSs/LABAs. Compared with ICSs, LABAs were associated with a 10% increased risk of asthma exacerbations requiring short courses of OCSs (hazard ratio [HR] 1.10; 95% confidence interval [CI] 1.07-1.18). ICS/LABA initiators were 62% less likely than ICS initiators (HR 0.38; 95% CI 0.12-0.66) and 50% less likely than LABA initiators to receive OCS prescriptions for asthma exacerbations (HR 0.50; 95% CI 0.14-0.78). CONCLUSIONS: In concordance with current asthma management guidelines, inhaled LABAs should not be prescribed as monotherapy to patients with asthma. The findings suggest the presence of time-dependent confounding by asthma severity, which was accounted for by the marginal structural model.

Omalizumab therapy for asthma patients with poor adherence to inhaled corticosteroid therapy.

BACKGROUND: Omalizumab, an anti-IgE monoclonal antibody, is administered by injection once or twice monthly in offices and clinics. It offers a potential alternative intervention for patients with allergic asthma that is not well controlled because of recalcitrant poor adherence to inhaled corticosteroid therapy. OBJECTIVE: To assess the effect of omalizumab therapy by measuring airway responsiveness to adenosine, a marker of allergic airway inflammation, and resource use. METHODS: Patients (N = 17) aged 6 to 26 years (mean age, 16.4 years) with poorly controlled persistent allergic asthma, less than 50% adherence to inhaled corticosteroid therapy, a forced expiratory volume in 1 second (FEV1) of 60% predicted or higher, and adenosine provocation concentration that caused a decrease in FEV1 of 20% (PC20) of 60 mg/mL or less were randomized to receive 4 months of omalizumab or placebo in a double-blind, crossover trial with a 3- to 4-month washout between treatments. Patients were instructed to continue taking inhaled corticosteroids throughout the study. The PC20 was measured before and after each period. RESULTS: Fifteen patients completed the study. The mean baseline PC20 was 14.1 mg/mL (95% CI, 10.8-18.4 mg/mL). The fold change PC20 was 0.9 (95% CI, 0.5-1.7) during placebo and 3.1 (95% CI, 1.6-6.2) during omalizumab treatment; the estimated ratio was 3.4 (95% CI, 1.2-9.3; P = .02). Six patients required one or more short courses of oral corticosteroids for asthma exacerbations during placebo, but none required this intervention during omalizumab. During the study, the median prescription refills for inhaled corticosteroids was 0.15 (95% CI, 0.00-0.33) canisters per month. CONCLUSION: Omalizumab therapy is an alternative for patients with more severe poorly controlled asthma in whom adherence does not improve with conventional interventions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00133042.

Determining Adherence to Inhaled Corticosteroids From the Epic Electronic Medical Record.

OBJECTIVE: Often we call the patient's pharmacy to obtain a refill history to assess inhaled corticosteroid (ICS) adherence. The purpose of this project was to determine the accuracy of refill histories for ICS (with or without long-acting beta agonist) listed in Epic's Medication Dispense History. METHODS: We evaluated 61 patients and used data from 38 who met the following criteria: 1) under the care of the UF Pediatric Severe Asthma Clinic; 2) taking the same dose of the same ICS product for 6 months before the patient's last clinic visit; and 3) having data available from the pharmacy where the last ICS prescription was electronically sent. We called the pharmacies to obtain a verbal report of their refill record. Then, we compared the number of refills reported to the number listed in Epic's records using a Wilcoxon matched-pairs signed-ranks test. RESULTS: Of the 293 refill dates listed in Epic, 157 were duplicates, giving a 54% error. After deleting duplicates, the mean (SD) number of refills listed in Epic was 3.6 (2.0) compared with 3.3 (2.0) in pharmacies over a period of 6 months (p < 0.0001). After removing duplicates Epic correctly reported the total number of refills for 30 of the 38 patients (78.9%). Seven of the remaining patients had more refills listed in Epic while 1 patient had more refills dispensed. CONCLUSION: This study indicates that our version of Epic over-reports refills thus limiting assessment of adherence. In contrast, absence of refills in Epic is a clear indication of poor adherence.

Response to albuterol MDI delivered through an anti-static chamber during nocturnal bronchospasm.

BACKGROUND: Decreasing electrostatic charge on valved holding chambers increases the amount of drug delivered. However, there are no data demonstrating that this increases bronchodilatation. OBJECTIVE: To investigate the influence of reducing electrostatic charge on the bronchodilator response to albuterol inhaler during nocturnal bronchospasm. METHODS: This randomized double-blind, double-dummy crossover study included subjects, 18-40 years old, with nocturnal bronchospasm (20% overnight decrease in peak flow on 3 of 7 nights during run-in), FEV(1) 60-80% predicted during the day, and ≥ 12% increase after albuterol. Subjects slept in the clinical research center up to 3 nights for each treatment. FEV(1) and heart rate were measured upon awakening spontaneously or at 4:00 am, and 15 min after each dose of 1, 2, and 4 cumulative puffs of albuterol via metered-dose inhaler. The drug was administered through an anti-static valved holding chamber (AeroChamber Plus Z-Stat) or a conventional valved holding chamber containing a static charge (AeroChamber Plus). RESULTS: Of 88 consented subjects, 11 were randomized and 7 completed the study. Most exclusions were due to lack of objective evidence of nocturnal bronchospasm. Upon awakening, FEV(1) was 44 ± 9% of predicted before the anti-static chamber and 48 ± 7% of predicted before the static chamber. The mean ± SD percent increase in FEV(1) after 1, 2, and 4 cumulative puffs using the anti-static versus the static chamber, respectively, were 52 ± 26% versus 30 ± 19%, 73 ± 28% versus 48 ± 26%, and 90 ± 34% versus 64 ± 35%. The point estimates for the differences (and 95% CIs) between the devices (anti-static vs static) were 21% (4-38%) (P = .03), 23% (6-41%) (P = .02), and 25% (7-42%) (P = .01) for 1, 2, and 4 cumulative puffs, respectively. There was no significant difference in heart rate between treatments. CONCLUSIONS: Delivery of albuterol through an anti-static chamber provides a clinically relevant improvement in bronchodilator response during acute, reversible bronchospasm such as nocturnal bronchospasm.

Case Report: Can Inhaled Adenosine Attenuate COVID-19?

This case report demonstrates a small repetition of the case series carried out in Italy wherein inhaled adenosine was administered to patients experiencing severe and worsening coronavirus disease-2019 (COVID-19). The two cases are important not only because they were the first of their type in the United States, but also because both patients were DNR/DNI and were therefore expected to die. Study repetition is vitally important in medicine. New work in pharmacology hypothesizes that adenosine-regulator proteins may play a role in the pathogenesis of COVID-19 infection. Furthermore, adenosine, by interacting with cell receptor sites, has pluripotent effects upon inflammatory cells, is anti-inflammatory, and is important in tissue hypoxia signaling. Inhaled adenosine is potentially safe; thousands have received it for asthmatic challenge testing. The effects of adenosine in these two cases were rapid, positive, and fit the pharmacologic hypotheses (as seen in prior work in this journal) and support its role as a therapeutic nucleoside.

Nationwide Shortage of Albuterol Inhalers and Off-Label Use in COVID-19 Patients.

The surge in COVID-19 cases during the 2020 Spring led to a nationwide shortage of albuterol inhalers. As a new surge has begun, shortages may make it difficult for patients with obstructive lung disease, including children with asthma, to obtain refills. Since there is no evidence that albuterol relieves symptoms in COVID-19 patients with respiratory symptoms not caused by bronchospasm, it is reasonable for clinicians to not prescribe it for COVID-19 patients unless they also have asthma or chronic obstructive pulmonary disease.

Continuous Albuterol With Benzalkonium in Children Hospitalized With Severe Asthma.

BACKGROUND AND OBJECTIVES: The albuterol dropper bottle used to prepare solutions for continuous nebulization contains the preservative benzalkonium chloride (BAC). BAC, by itself, has been shown to cause bronchospasm. We hypothesized that BAC would decrease the therapeutic efficacy of albuterol in patients with acute asthma exacerbations. METHODS: We performed a retrospective cohort study comparing the clinical outcomes of patients <18 years of age receiving continuous nebulized albuterol with and without BAC. For the primary end point (duration of continuous albuterol nebulization), we compared the 2 groups with Kaplan-Meier estimate of survival curves, conducted a log-rank test of difference, and adjusted for baseline characteristics using multivariable Cox regression. A P value <.05 was considered significant. RESULTS: A total of 477 patients were included in the analysis (236 exposed to BAC and 241 controls). The duration of continuous nebulization was significantly longer in the BAC group than in the control group (median of 9 vs 6 hours; 15.7% required continuous nebulization compared to 5.8% of controls at 24 hours). The control group was 79% more likely to stop continuous nebulization at any particular point in time (hazard ratio 1.79; 95% confidence interval: 1.45 to 2.22; P < .001) and 43% more likely to stop additional respiratory support (hazard ratio 1.43; 95% confidence interval: 1.16 to 1.75; P < .001). CONCLUSIONS: BAC is a functional albuterol antagonist associated with a longer duration of continuous albuterol nebulization treatment and additional respiratory support, suggesting that preservative-free albuterol formulations are safer for use in continuous nebulization.

Early administration of steroids in the ambulance setting: Protocol for a type I hybrid effectiveness-implementation trial with a stepped wedge design.

BACKGROUND: Pediatric asthma exacerbations are a frequent reason for emergency care. Early administration of oral systemic corticosteroids (OCS) in the emergency department (ED) decreases hospitalization rates and ED length-of-stay (LOS). However, it is unknown whether even earlier OCS administration by emergency medical services (EMS) in the prehospital setting further improves outcomes. PURPOSE: To describe the background and methods of a type 1 hybrid effectiveness-implementation trial of EMS-administered OCS for pediatric asthma patients incorporating a stepped wedge design and the RE-AIM framework. METHODS: The study employs a non-randomized stepped wedge design where multiple EMS agencies adopt OCS as a treatment for pediatric asthma exacerbations at varying times. This design accommodates ethical considerations of studying pediatric subjects in the prehospital setting where informed consent is not feasible. We will compare hospitalization rates, ED LOS, and short-term healthcare costs between pediatric asthma patients who do and do not receive OCS from EMS. Using geographic information systems (GIS), we will measure how differences in outcomes scale with increasing EMS transport time. We will use the RE-AIM framework to guide a mixed methods analysis of barriers and enablers to EMS administration of OCS for pediatric asthma patients, including quantitative measures of adoption and uptake and qualitative EMS provider focus group data. CONCLUSION: This trial will determine if earlier EMS administration of OCS to pediatric asthma patients decreases hospitalizations, ED LOS, and short-term healthcare costs, and if those outcomes scale with longer EMS transport times. We will identify barriers and enablers to implementing EMS-administered OCS for pediatric asthma patients.

Randomized, Double-Blind, Crossover, Clinical-End-Point Pilot Study to Examine the Use of Exhaled Nitric Oxide as a Bioassay for Dose Separation of Inhaled Fluticasone Propionate.

This was a randomized, double-blind, crossover, clinical-end-point pilot study examining the hypothesis that inhaled fluticasone propionate decreases exhaled nitric oxide (eNO) concentrations within a week of beginning treatment and shows evidence of dose separation across the marketed dose range. Subjects had a ≥6-month history of asthma and screening eNO ≥60 parts per billion. At the start of each treatment period, eNO was ≥55 parts per billion, and forced expiratory volume in 1 second was ≥50% predicted. Subjects attended a clinic visit daily on consecutive mornings during each of 3 1-week treatment periods to measure eNO and receive once-daily doses of 100/50, 250/50, or 500/50 fluticasone propionate/salmeterol combination product (Advair® Diskus). Daily eNO value recorded was the highest of 3 measurements; 1 inhalation of treatment was then administered. Procedures were repeated for 3 treatment cycles, separated by 14-day minimum washouts. A total of 105 subjects were screened; 22 were randomized; and 17 completed all treatments. Mean percentage eNO decrease (standard deviation) from day 1 baseline for each treatment period was 36.6 (±18.7), 45.3 (±16.5), and 54.6 (±12.5) with Advair® 100/50, 250/50, and 500/50, respectively. Mean percentage decrease in eNO across each treatment (dose) was modeled using a mixed-model ANOVA. Although the overall treatment was significant (P = .0015), because of the relatively small sample size and within-subject variability, only the 100/50 vs 500/50 (P = .0003) and 250/50 vs 500/50 (P = .047) treatments were significantly different.

Direct Observed Therapy of Inhaled Corticosteroids for Asthma at School or Daycare.

Background: Poor adherence with inhaled corticosteroid (ICS) medication is common in the pediatric population and can result in poor asthma control with increased frequency of asthma-related complications. The purpose of this study was to determine whether or not the initiation of ICS administration twice per day at school/daycare in patients with poor medication adherence at home improves asthma health care outcomes. Methods: We retrospectively selected patients followed by our Pediatric Pulmonology Clinic who had poorly controlled asthma and had been assigned to receive ICS twice daily at school/daycare due to poor adherence with ICS therapy. We analyzed the number of short courses of oral corticosteroids, hospital admissions, emergency department visits, and intramuscular methylprednisolone administrations for asthma exacerbations for the year before and after the intervention. The Wilcoxon signed rank test with continuity correction was used in the primary analysis. Results: Forty-nine patients who met the inclusion criteria were identified, but only 40 actually started the intervention. The number of oral corticosteroid courses per year decreased from 1.35 ± 1.1 before the intervention to 0.68 ± 1.2 (P = 0.008) postintervention, hospital admissions per year decreased from 0.45 ± 0.7 to 0.10 ± 0.3 (P = 0.006), emergency department visits per year decreased from 0.55 ± 0.8 to 0.28 ± 0.6 (P = 0.084), and intramuscular repository methylprednisolone injections per year for asthma exacerbations decreased from 0.20 ± 0.4 to 0.10 ± 0.3 (P = 0.23). Conclusion: These results indicate that school/daycare administration of ICS may be an effective option to improve indicators of asthma exacerbations in children with poor adherence to ICS at home.

Anti-immunoglobulin E therapy with omalizumab for asthma.

OBJECTIVE: To evaluate data on anti-immunoglobulin E (anti-IgE) therapy for asthma. DATA SOURCES: Information was selected from PubMed from 1989 to May 2007 using the search term omalizumab and included randomized, controlled trials. These studies evaluated asthma treatment with omalizumab and focused on its efficacy, tolerability, and cost-effectiveness in this population. STUDY SELECTION AND DATA EXTRACTION: All randomized clinical trials were reviewed (23 were identified and 19 were included; 3 were not relevant and 1 contained duplicative data). Other articles using the search words anti-IgE therapy and cost-effectiveness were evaluated; relevant information was extracted. DATA SYNTHESIS: IgE-dependent mechanisms play an important role in the development and maintenance of airway inflammation in asthma. Omalizumab is a subcutaneously administered monoclonal anti-IgE antibody that reduces unbound IgE concentrations and promotes down-regulation of IgE receptors. Results from clinical trials in adults, adolescents, and children with poorly controlled IgE-mediated asthma have shown that omalizumab improves symptom control and allows patients to be managed with lower doses of inhaled corticosteroids (ICS). It has been well tolerated in clinical trials lasting as long as 52 weeks, but injection-site reactions are common (45% in omalizumab group vs 43% in placebo group) and anaphylaxis has occurred in 0.2% of patients. A consensus expert panel has recommended that omalizumab should be considered for patients 12 years of age or older with allergic asthma who are inadequately controlled on guideline-based therapy and require maintenance therapy with systemic corticosteroids or high-dose ICSs, or who have poor adherence to ICS therapy. CONCLUSIONS: Anti-IgE therapy provides an effective and generally safe approach to the treatment of patients with IgE-mediated asthma who are not adequately controlled by conventional guideline-based medications. However, the potential benefit must be weighed against the cost and inconvenience of this new therapy.

Efficacy and safety of oral phenylephrine: systematic review and meta-analysis.

BACKGROUND: Oral phenylephrine is used as a decongestant, yet there has been no previously published systematic review supporting its efficacy and safety. OBJECTIVE: To assess the efficacy and safety of oral phenylephrine as a nonprescription decongestant. METHODS: MEDLINE, the Cochrane Central Registry of Controlled Trials, EMBASE, International Pharmaceutical Abstracts, and the Federal Register were searched for English and non-English-language studies published through January 2007 that measured the effects of oral phenylephrine on nasal airway resistance (NAR) in patients with nasal congestion. The retrieved studies were supplemented with information from our personal files and by hand searches of the references in any of the studies. Additionally, a Web of Science Search was conducted using the Cited Reference function for all published clinical trials identified. Studies included in the analysis were randomized, placebo-controlled trials; studies of combination products were excluded. Two investigators independently extracted data on NAR, self-reported decongestant effects, and cardiovascular effects (ie, heart rate, blood pressure) from each of the included studies. Meta-analyses were performed for NAR and cardiovascular effects using a random effects model. Subjective decongestant effects were summarized. RESULTS: Based on 8 unpublished studies that included 138 patients, phenylephrine 10 mg did not affect NAR more than placebo; the mean maximal difference in relative change from baseline between phenylephrine and placebo was 10.1% (95% CI -3.8% to 23.9%). Eight unpublished studies on phenylephrine 25 mg showed a significant reduction of maximal NAR compared with placebo of 27.6% (95% CI 17.5% to 37.7%). There was significant heterogeneity among the studies included in this analysis, which was partially attributable to different laboratories and methods used. Patient-reported decongestion was not consistently better for any phenylephrine dose compared with placebo, and NAR was a more sensitive measurement of efficacy. Phenylephrine showed no consistent effect on heart rate or blood pressure for doses of 25 mg or less. CONCLUSIONS: There is insufficient evidence that oral phenylephrine is effective for nonprescription use as a decongestant. The Food and Drug Administration should require additional studies to show the safety and efficacy of phenylephrine.

Benzalkonium Chloride: A Bronchoconstricting Preservative in Continuous Albuterol Nebulizer Solutions.

For convenience, many pediatric hospitals are preparing solutions for continuous nebulized albuterol using the 0.5% 20-ml multidose albuterol dropper bottle. This product contains benzalkonium chloride (BAC) that, by itself, produces bronchospasm that is dose dependent and cumulative. The bronchoconstrictive effects of BAC are greater in patients with more severe airway obstruction and increased airway responsiveness. Use of BAC-containing albuterol during severe acute asthma exacerbations may antagonize the bronchodilator response to albuterol, prolong treatment, and increase the risk of albuterol-related systemic adverse effects. Such a deleterious effect of BAC is difficult to detect because some patients improve slowly or may even worsen during treatment. We recommend that only preservative-free albuterol products be used.