Pharmacokinetics/pharmacodynamics of epinephrine after single and repeat administration of neffy, EpiPen, and manual intramuscular injection.

BACKGROUND: Epinephrine is the first-line treatment for severe allergic reactions, and rapid treatment is associated with lower rates of hospitalization and death. Current treatment options (epinephrine auto-injectors and manual intramuscular injection) are considered cumbersome, and most patients/caregivers fail to use them, even during severe reactions. An intranasal epinephrine delivery device, neffy, has been designed to provide an additional option for patients/caregivers. OBJECTIVE: We sought to assess the comparative pharmacokinetics and pharmacodynamics of neffy 2.0 mg, EpiPen 0.3 mg, and manual intramuscular injection 0.3 mg. METHODS: This was a phase 1, randomized, 6-treatment, 6-period, 2-part crossover study in 59 healthy subjects. Pharmacokinetic and pharmacodynamic parameters following single and repeat doses of epinephrine were assessed before dosing and at various postdose intervals. RESULTS: The pharmacokinetic profile of neffy was bracketed by approved injection products, with a mean peak plasma level of 481 pg/mL, which fell between EpiPen (753 pg/mL) and epinephrine manual intramuscular injection (339 pg/mL). When dosed both once and twice, neffy resulted in more pronounced increases in pharmacodynamic parameters relative to EpiPen or manual injection. CONCLUSIONS: neffy's pharmacokinetic profile was bracketed by approved injection products, with pharmacodynamic responses that were comparable to or better than approved injection products. neffy is expected to be a safe and effective option, particularly for patients/caregivers who are reluctant to carry and use injection devices.

Pharmacokinetic and pharmacodynamic comparison of epinephrine, administered intranasally and intramuscularly: An integrated analysis.

BACKGROUND: Manual intramuscular epinephrine injection is the standard of care for treating severe allergic reactions and anaphylaxis. Epinephrine autoinjectors were approved on the basis of the assumption that their pharmacokinetic and pharmacodynamic profiles are equivalent to manual intramuscular injection; however, although there is emerging evidence for product-related differences in pharmacokinetic profiles, very little is known about the comparative pharmacodynamic profiles. OBJECTIVE: To compare pharmacokinetic and pharmacodynamic profiles of epinephrine delivered through manual intramuscular injection, autoinjectors, and intranasal spray. METHODS: This integrated analysis was based on data from 4 randomized cross-over phase 1 trials that compared the pharmacokinetics and pharmacodynamics of epinephrine using manual intramuscular epinephrine 0.3 mg injection, epinephrine 0.3 mg autoinjectors (Symjepi and EpiPen), and epinephrine 1 mg intranasal spray (neffy). RESULTS: Data from 175 participants showed that although neffy (1.0 mg intranasal spray) resulted in a maximum concentration (258 pg/mL) that was lower than or comparable with manual epinephrine intramuscular injection (254 pg/mL), Symjepi (438 pg/mL) and EpiPen (503 pg/mL), it led to comparable increases in systolic blood pressure (maximum effect [Emax], 16.9, 10.9, 14.9, and 18.1 mm Hg, respectively). The effect of neffy on diastolic blood pressure was also markedly more pronounced than that of other products (Emax, 9.32, 5.51, 5.78, and 5.93 mm Hg, respectively). CONCLUSION: Intranasal delivery of epinephrine using neffy increases systolic blood pressure more efficiently than do manual intramuscular injection and epinephrine autoinjectors, despite lower maximum plasma concentrations.

Development of neffy, an Epinephrine Nasal Spray, for Severe Allergic Reactions.

Epinephrine autoinjectors (EAIs) are used for the treatment of severe allergic reactions in a community setting; however, their utility is limited by low prescription fulfillment rates, failure to carry, and failure to use due to fear of needles. Given that delayed administration of epinephrine is associated with increased morbidity/mortality, there has been a growing interest in developing needle-free, easy-to-use delivery devices. neffy (epinephrine nasal spray) consists of three Food and Drug Administration (FDA)-approved components: epinephrine, Intravail A3 (absorption enhancer), and a Unit Dose Spray (UDS). neffy's development pathway was established in conjunction with the FDA and the European Medicines Agency and included multiple clinical trials to evaluate pharmacokinetic and pharmacodynamic responses under a variety of conditions, such as self-administration and allergic and infectious rhinitis, as well as an animal anaphylaxis model of severe hypotension, where neffy demonstrated a pharmacokinetic profile that is within the range of approved injection products and a pharmacodynamic response that is as good or better than injections. The increased pulse rate (PR) and blood pressure (BP) observed even one minute following the administration of neffy confirm the activation of α and ß adrenergic receptors, which are the key components of epinephrine's mechanism of action. The results suggest that neffy will provide a safe and effective needle-free option for the treatment of severe allergic reactions, including anaphylaxis.

Rapid increases in epinephrine concentration following presumed intra-blood vessel administration via epinephrine autoinjector.

While epinephrine autoinjectors have been the standard of care for the out-of-hospital treatment of anaphylaxis, their use has been associated with potential cardiovascular risks including intravascular injection, resulting in rapid increases in blood pressure and pulse rate. ARS Pharmaceuticals, Inc conducted a clinical trial designed to assess the pharmacokinetics and pharmacodynamics of ARS-1, an intranasal epinephrine spray in development, compared to EpiPen in subjects with a documented history of seasonal allergies. During the conduct of this study, a presumed intrablood vessel injection following EpiPen administration by a medical professional was observed in a female subject. The subject reported palpitations within 1 minute of receiving EpiPen injection; at 4 minutes postinjection, blood pressure was 221/128 mmHg (baseline 118/79), and pulse rate was 71 (baseline 56). In contrast, across all subjects (N = 36) the mean maximum increases in systolic blood pressure, diastolic blood pressure, and pulse rate were 12.0 mmHg, 2.8 mmHg, and 16.3 bpm, respectively. When this subject was removed from the pharmacokinetic analysis, the mean epinephrine Cmax of the remaining subjects was 801.1 pg/mL after administration of EpiPen; however, at 4 minutes postinjection this subject had a plasma epinephrine level of 4390 pg/mL, a >6.3-fold increase, illustrating the risks that may be associated with out-of-hospital epinephrine injections that are included as warnings in the product labeling. Despite the potential risks associated with accidental intravessel injection, it is important to note that intramuscular administration of epinephrine is currently the best currently available out-of-hospital treatment for severe allergic reactions and anaphylaxis.

The efficacy of intranasal antihistamines in the treatment of allergic rhinitis.

OBJECTIVES: To discuss the new use of intranasal antihistamines as first-line therapies, compare and contrast this class of medication with the traditionally available medications, and discuss the potential for intranasal antihistamines to provide relief superior to second-generation oral antihistamines. DATA SOURCES: Review articles and original research articles were retrieved from MEDLINE, OVID, PubMed (1950 to November 2009), personal files of articles, and bibliographies of located articles that addressed the topic of interest. STUDY SELECTION: Articles were selected for their relevance to intranasal antihistamines and their role in allergic rhinitis. Publications included reviews, treatment guidelines, and clinical studies (primarily randomized controlled trials) of both children and adults. RESULTS: This panel was charged with reviewing the place of intranasal antihistamines in the spectrum of treatment for allergic rhinitis. Intranasal antihistamines have been shown in numerous randomized, placebo-controlled trials to be more efficacious than the oral antihistamines. Although intranasal corticosteroids are considered by some to be superior to intranasal antihistamines, multiple studies have shown an equal effect of the 2 classes of medication. Both intranasal corticosteroids and intranasal antihistamines have been shown to reduce all symptoms of allergic rhinitis. In addition, some intranasal antihistamines have a more rapid onset of action than intranasal corticosteroids. CONCLUSIONS: The future of allergy treatment will likely involve a combination of both intranasal corticosteroids and intranasal antihistamines because of the benefits of local administration and their additive effect on efficacy.

Comprehensive review of olopatadine: the molecule and its clinical entities.

Olopatadine is a tricyclic compound with antihistaminic, mast cell-stabilizing, and anti-inflammatory properties. In the United States olopatadine is approved as a b.i.d. ophthalmic solution, Patanol (Alcon Laboratories, Inc., Fort Worth, TX) to treat all signs and symptoms of allergic conjunctivitis and as a q.d. formulation, Pataday (Alcon Laboratories, Inc.), to treat itching associated with allergic conjunctivitis. A nasal spray, Patanase (Alcon Laboratories, Inc.), was approved in 2008 for treatment of the symptoms of seasonal allergic rhinitis. The available data on olopatadine was assessed with regard to future uses through a comprehensive literature review and a Roundtable Discussion held at the 2009 meeting of the American Academy of Allergy Asthma and Immunology. The unique mechanisms of action of olopatadine still under study include mast cell stabilization, potent H(1)-anthistaminic activity, and anti-inflammatory effects. Data support consideration of nasal olopatadine for as-needed use for episodic symptoms of allergic rhinitis, for treatment of nonallergic rhinitis, and for use in combination with topical steroids for patients with moderate-to-severe allergy symptoms.

Cost and resource utilization comparisons of second-generation antihistamines vs. montelukast for allergic rhinitis treatment.

This study evaluates the costs and utilization burden associated with oral, branded second-generation antihistamines (BSGAs) compared with montelukast (MTLK) as first-choice treatment in newly diagnosed allergic rhinitis (AR) patients without asthma. We compared annual medical costs of illness and utilization changes from 1 year before index AR diagnosis to 1 year after for continuously enrolled AR patients initiating therapy with BSGA or MTLK. Multivariate regressions for each outcome variable adjusted for confounders including age, sex, geographic region, Charlson Comorbidity Index, RxRisk Score, 18 comorbidity groups, and payer type. Treatment selection bias was evaluated by propensity score with all covariates plus instrumental variables including physician type and likelihood of prescribing MTLK versus BSGA. Insurance claims data for the years 2003-2007 included AR patients in all regions of the United States. The final sample included 13,703 AR patients taking BSGAs (84%) or MTLK (16%). After confounder adjustment, MTLK patients experienced higher total medical costs ($1,542 versus $989), drug costs ($714 versus $477), AR drug costs ($474 versus $298), and outpatient visit costs ($480 versus $277) than BSGA patients (all values of p < 0.025). MTLK patients experienced higher total visits (0.96), AR outpatient visits (0.71), and comorbidity visits (0.12) than BSGA patients (all values of p < 0.01). MTLK patients were more likely to add additional AR therapy medications (MTLK, 43.2%; BSGA, 31.6%; p < 0.01). New AR patients prescribed MTLK as first-line medication therapy have higher medical costs and resource utilization than those prescribed first-line oral BSGAs. These differences persisted after adjustment for patient fixed effects, available confounders, and treatment propensity scores.

Erratum to: Risk and safety requirements for diagnostic and therapeutic procedures in allergology: World Allergy Organization Statement.

[This corrects the article DOI: 10.1186/s40413-016-0122-3.].

Pharmacologic characteristics and adrenal suppression with newer inhaled corticosteroids: A comparison of ciclesonide and fluticasone propionate.

BACKGROUND: Inhaled corticosteroids (ICSs) are the most potent anti-inflammatory choice for patients with asthma. Selecting the most appropriate ICS for a patient requires a thorough understanding of the pharmacologic properties of each drug. OBJECTIVE: This review details the pharmacologic properties of ciclesonide (CIC) and fluticasone propionate (FP) and reviews the available data on suppression of the hypothalamic-pituitary-adrenal axis as a measure of systemic exposure and safety profile. METHODS: Clinical studies and case reports were identified through a MEDLINE and EMBASE search of English-language articles. The databases were searched for the years 1990 to April 2005 using the terms ciclesonide, fluticasone, ICS, and adrenal suppression. All studies were clinical trials of pharmacologic properties of the ICSs in humans. RESULTS: A total of 1082 articles were identified. CIC and FP are 2 of the most potent ICSs. Both have high receptor-binding affinities (12 times and 18 times that of dexamethasone, respectively), and both may provide enhanced respiratory effects through a prolonged pulmonary residence time. The CIC metered dose inhaler dispenses smaller and more highly respirable particles than FP (1.1-2.1 pm vs 2.8-3.2 microm, respectively). Therefore, a greater percentage of administered CIC is topically deposited in the lungs (52% vs 12% to 13% for FP). CIC is delivered as an inactive parent compound, which is converted to its active metabolite, desisobutyryl-CIC (des-CIC), by esterases in the airways. More than 50% of a dose of CIC is deposited and distributed evenly throughout the lungs of healthy adults; lipid conjugation in the lung also may increase lung residence time. On entering the systemic circulation, both corticosteroids are rapidly cleared by the liver (elimination half-life of 3.5 hours for CIC vs 7.8 hours for FP). However, plasma protein binding is greater with CIC/des-CIC (99%/ approximately 99%) than FP (90%), resulting in reduced amounts of des-CIC (660 pg/d) may result in adrenal suppression. CIC has not been reported to produce any significant adrenal suppression throughout its studied dose range (up to 1280 micro/d). CONCLUSIONS: A review of the literature suggests that CIC, as compared with FP, achieves greater pulmonary deposition, causes fewer adverse oropharyngeal effects, deposits less biologically active drug in the systemic circulation, and has less potential for adrenal suppression.

Risk and safety requirements for diagnostic and therapeutic procedures in allergology: World Allergy Organization Statement.

One of the major concerns in the practice of allergy is related to the safety of procedures for the diagnosis and treatment of allergic disease. Management (diagnosis and treatment) of hypersensitivity disorders involves often intentional exposure to potentially allergenic substances (during skin testing), deliberate induction in the office of allergic symptoms to offending compounds (provocation tests) or intentional application of potentially dangerous substances (allergy vaccine) to sensitized patients. These situations may be associated with a significant risk of unwanted, excessive or even dangerous reactions, which in many instances cannot be completely avoided. However, adverse reactions can be minimized or even avoided if a physician is fully aware of potential risk and is prepared to appropriately handle the situation. Information on the risk of diagnostic and therapeutic procedures in allergic diseases has been accumulated in the medical literature for decades; however, except for allergen specific immunotherapy, it has never been presented in a systematic fashion. Up to now no single document addressed the risk of the most commonly used medical procedures in the allergy office nor attempted to present general requirements necessary to assure the safety of these procedures. Following review of available literature a group of allergy experts within the World Allergy Organization (WAO), representing various continents and areas of allergy expertise, presents this report on risk associated with diagnostic and therapeutic procedures in allergology and proposes a consensus on safety requirements for performing procedures in allergy offices. Optimal safety measures including appropriate location, type and required time of supervision, availability of safety equipment, access to specialized emergency services, etc. for various procedures have been recommended. This document should be useful for allergists with already established practices and experience as well as to other specialists taking care of patients with allergies.

Open-label evaluation of azelastine nasal spray in patients with seasonal allergic rhinitis and nonallergic vasomotor rhinitis.

OBJECTIVE: The objective of the study was to evaluate the effectiveness of azelastine (Astelin) nasal spray, a topical second-generation antihistamine, in the treatment of symptoms of seasonal allergic rhinitis, seasonal allergic rhinitis with nonallergic triggers (mixed rhinitis), and nonallergic vasomotor rhinitis. RESEARCH DESIGN AND METHODS: A total of 2343 primary care physicians, allergists, ENT specialists, and other health professionals participated in this 2-week, open-label evaluation of azelastine nasal spray. Data were collected through a physician questionnaire that included patient demographics, rhinitis diagnosis, medication history, and inclusion/exclusion criteria; and two patient questionnaires that included symptom history, response to previous rhinitis medications, symptom control, and level of satisfaction with azelastine nasal spray. A completed physician questionnaire and two completed patient questionnaires were required for each patient to be included in the analysis. Patients who qualified for enrollment were given open-label azelastine nasal spray and instructed to administer 2 sprays per nostril twice daily for 2 weeks. RESULTS: A total of 1225 health professionals enrolled 7864 patients into the study. Completed physician and patient questionnaires were returned by 1081 health professionals and 5073 patients, 4364 of whom used azelastine nasal spray as their only rhinitis medication during the 2-week study period. The patients were predominantly caucasian (82.6%) and female (61.1%), with a mean age of 50 years. The majority had a diagnosis of mixed rhinitis (51.5%), followed by seasonal allergic rhinitis (32.3%), and nonallergic (vasomotor) rhinitis (16.2%). After 2 weeks of treatment, the percentage of patients reporting some control or complete control of individual symptoms ranged from 78% for postnasal drip in patients with nonallergic vasomotor rhinitis to 90% for sneezing in patients with seasonal allergic rhinitis. More than 85% of patients who reported difficulty sleeping or impairment of daytime activities due to rhinitis symptoms had improvement in these parameters. Azelastine nasal spray was well tolerated, the discontinuation rate due to adverse events was 2.3%. CONCLUSIONS: Azelastine nasal spray was reported to control all rhinitis symptoms, including nasal congestion, regardless of rhinitis diagnosis during the 2-week study period. Patients with seasonal allergic rhinitis and patients with seasonal allergic rhinitis plus nonallergic triggers were identified as patient types most likely to respond to azelastine nasal spray.