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.

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.

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.].

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.

Chapter 14: Nonallergic rhinitis.

Rhinitis is characterized by one or more of the following nasal symptoms: congestion, rhinorrhea (anterior and posterior), sneezing, and itching. It is classified as allergic or nonallergic, the latter being a diverse syndrome that is characterized by symptoms of rhinitis that are not the result of IgE-mediated events. Excluding infectious rhinitis and underlying systemic diseases, clinical entities that can be classified among the disorders that make up the nonallergic rhinitis syndromes include gustatory rhinitis, nonallergic rhinitis with eosinophilia syndrome (NARES), atrophic, drug-induced (rhinitis medicamentosa), hormone induced, senile rhinitis (of the elderly), rhinitis associated with chronic rhinosinusitis with or without nasal polyps, and the idiopathic variant formerly known as vasomotor rhinitis but more accurately denoted as nonallergic rhinopathy (NAR). The prevalence of nonallergic rhinitis has been observed to be one-third that of allergic rhinitis, affecting ~7% of the U.S. population or ~22 million people. NAR is the most common of the nonallergic rhinitis subtypes, comprising at least two-thirds of all nonallergic rhinitis sufferers. Although certain precipitants such as perfume, strong odors, changes in temperature or humidity, and exposure to tobacco smoke are frequently identified as symptom triggers, NAR may occur in the absence of defined triggers. The diagnosis of nonallergic rhinitis is purely clinical and relies on a detailed history and physical exam. Skin testing or in vitro testing to seasonal and perennial aeroallergens is required to make the diagnosis of nonallergic rhinitis. Because of the heterogeneous nature of this group of disorders, treatment should be individualized to the patient's underlying pathophysiology and/or symptoms and is often empiric.

Chapter 14: Nonallergic rhinitis.

Rhinitis is characterized by one or more of the following nasal symptoms: congestion, rhinorrhea (anterior and posterior), sneezing, and itching. It is classified as allergic or nonallergic, the latter being a diverse syndrome that is characterized by symptoms of rhinitis that are not the result of IgE-mediated events. Excluding infectious rhinitis and underlying systemic diseases, clinical entities that can be classified among the disorders that make up the nonallergic rhinitis syndromes include gustatory rhinitis, nonallergic rhinitis with eosinophilia syndrome (NARES), atrophic, drug-induced (rhinitis medicamentosa), hormone induced, senile rhinitis (of the elderly), rhinitis associated with chronic rhinosinusitis with or without nasal polyps, and the idiopathic variant formerly known as vasomotor rhinitis but more accurately denoted as nonallergic rhinopathy (NAR). The prevalence of nonallergic rhinitis has been observed to be one-third that of allergic rhinitis, affecting ∼7% of the U.S. population or ∼22 million people. NAR is the most common of the nonallergic rhinitis subtypes, comprising at least two-thirds of all nonallergic rhinitis sufferers. Although certain precipitants such as perfume, strong odors, changes in temperature or humidity, and exposure to tobacco smoke are frequently identified as symptom triggers, NAR may occur in the absence of defined triggers. The diagnosis of nonallergic rhinitis is purely clinical and relies on a detailed history and physical exam. Skin testing or in vitro testing to seasonal and perennial aeroallergens is required to make the diagnosis of nonallergic rhinitis. Because of the heterogeneous nature of this group of disorders, treatment should be individualized to the patient's underlying pathophysiology and/or symptoms and is often empiric.

Nonallergic rhinopathy (formerly known as vasomotor rhinitis).

This review focuses on the poorly understood condition of nonallergic rhinopathy (NAR) at a clinical level, with an eye on current optimal treatment. NAR is the new designation for the conditions formerly referred to as vasomotor rhinitis or nonallergic idiopathic rhinitis. The clinical characteristics and differential diagnosis are provided in detail in this review, and the disease should now be characterized sufficiently for clinical studies.

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.