Epinephrine Nasal Spray

Introduction Overview

Generic Name

epinephrine nasal spray

Brand Name

Neffy

Dosage Form

nasal spray (1 mg/0.1 mL, 2 mg/0.1 mL)

Drug Class

Adrenergic bronchodilators, Catecholamines, Vasopressors

Pharmacokinetics

Absorption:
Epinephrine delivered via Neffy nasal spray is rapidly absorbed through the highly vascularized nasal mucosa, enabling prompt systemic exposure essential for the treatment of anaphylaxis. The nasal route offers a needle-free alternative, with absorption kinetics comparable to intramuscular injection, enabling bioavailability sufficient to elicit rapid therapeutic effects. Factors influencing absorption include nasal mucosal integrity and presence of nasal conditions such as polyps or prior surgery, which may affect drug delivery. Clinical studies demonstrate epinephrine plasma concentrations peak quickly after nasal administration, supporting rapid onset of action critical for emergency use.

Distribution:
Once absorbed, epinephrine is distributed widely throughout the body with rapid penetration into vascular-rich tissues. It binds poorly to plasma proteins, resulting in a relatively high free circulating fraction that acts on adrenergic receptors throughout the cardiovascular, respiratory, and gastrointestinal systems. The volume of distribution approximates total body water due to its hydrophilic nature. Epinephrine targets alpha and beta adrenergic receptors distributed in smooth muscle, cardiac tissue, and the nervous system, mediating vasoconstriction, bronchodilation, and cardiac stimulation vital during anaphylaxis.

Metabolism:
Epinephrine undergoes rapid enzymatic metabolism primarily in the liver, adrenal medulla, and other tissues through catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) pathways. These metabolic steps convert epinephrine into inactive metabolites such as metanephrine and vanillylmandelic acid (VMA). The presence of MAO inhibitors or other interacting drugs can prolong epinephrine's activity or enhance adverse effects. The nasal route bypasses first-pass hepatic metabolism, contributing to the rapid availability of active drug in systemic circulation.

Elimination:
The metabolites of epinephrine are predominantly eliminated via renal excretion. The parent compound has a short plasma half-life, approximately 2–3 minutes, necessitating prompt dosing and sometimes repeated administration in persistent anaphylactic episodes. Renal function impacts the clearance of metabolites, and caution should be exercised in patients with renal impairment. The short half-life correlates with the cessation of clinical effects typically within minutes, emphasizing the importance of emergency medical follow-up after initial nasal administration.

Dosage Forms

Available Dosage Forms:
- Nasal spray containing epinephrine at 1 mg/0.1 mL for children weighing 33 to 66 lbs (15–30 kg).
- Nasal spray containing epinephrine at 2 mg/0.1 mL for patients weighing 66 lbs (30 kg) or greater.
Each spray delivers a single fixed dose for immediate use in anaphylaxis.

Dosages for Adults and Adolescents:
- Adults and children ≥66 lbs (≥30 kg) receive the 2 mg dose administered as one spray into either nostril.
- Children aged 4 years and older, weighing between 33 and 66 lbs (15–30 kg), receive the 1 mg dose administered similarly.
- If symptoms persist or recur, a second dose may be administered in the same nostril five minutes after the first dose.

Specific Patient Populations:
- Neffy is approved for use in children aged 4 years and older weighing at least 33 lbs (15 kg).
- Safety and efficacy have not been established in children below this weight or age.
- Patients with nasal abnormalities (polyps, history of nasal surgery or injury) should consult healthcare providers before use, as absorption may be altered.
- Due to the presence of sulfites as excipients, caution is advised in patients with sulfite sensitivity, although it is generally not a contraindication.
- Use in pregnant or breastfeeding individuals should follow a risk-benefit assessment owing to insufficient safety data.

Mechanism Of Action

Neffy works by delivering epinephrine, a potent endogenous catecholamine, via a nasal spray, providing rapid systemic absorption to manage severe allergic reactions (anaphylaxis). At the molecular level, epinephrine acts as an agonist on both alpha- and beta-adrenergic receptors spread throughout various tissues, including vascular smooth muscle, cardiac tissue, and the respiratory tract.

Activation of alpha-1 adrenergic receptors results in vasoconstriction of small blood vessels, which counters the widespread vasodilation and increased vascular permeability characteristic of anaphylaxis. This vasoconstriction helps restore blood pressure and redirects blood flow to vital organs such as the heart and brain, preventing shock.

Beta-1 adrenergic receptor stimulation in cardiac tissue increases heart rate and contractility, enhancing cardiac output during hypotensive states. Concurrently, beta-2 adrenergic receptor activation relaxes bronchial smooth muscle, alleviating bronchospasm, improving airway patency, and facilitating easier breathing.

Additionally, epinephrine’s action on beta-2 receptors in the gastrointestinal tract leads to relaxation of stomach and intestinal smooth muscles, which may reduce nausea and abdominal cramping symptoms commonly associated with anaphylaxis. Compared with injectable epinephrine formulations, nasal delivery through Neffy offers needle-free administration while maintaining similar receptor interactions and physiological responses.

Clinical studies confirm that the nasal route provides fast onset and effective reversal of life-threatening allergic reactions by harnessing these mechanisms. Research into alternative delivery routes underscores the importance of rapid adrenergic receptor activation to counteract systemic hypersensitivity responses and prevent fatal outcomes.

Pharmacological Actions

Acts as a non-selective adrenergic agonist stimulating alpha-1, beta-1, and beta-2 receptors.
Induces vasoconstriction via alpha-1 receptor activation to raise blood pressure and reduce mucosal edema.
Stimulates beta-1 receptors to increase heart rate and myocardial contractility, improving cardiac output during shock.
Activates beta-2 receptors causing bronchodilation to relieve airway constriction and wheezing.
Relaxes smooth muscles of the gastrointestinal tract, potentially reducing symptoms like nausea associated with anaphylaxis.
Rapid systemic absorption via nasal mucosa for immediate onset of action in emergency situations.
Provides needle-free administration, improving accessibility and ease of use during acute allergic episodes.
Counters the pathophysiologic mechanisms of anaphylaxis including hypotension, bronchospasm, and angioedema.
Prevents progression of anaphylactic shock by restoring vascular tone and improving oxygenation.
Modulates neurotransmitter release in sympathetic nervous system enhancing overall vital organ perfusion.

Therapeutic Or Clinical Uses

Emergency treatment of severe allergic reactions (anaphylaxis) in adults and children aged 4 years and older weighing at least 33 lbs (15 kg).
Management of anaphylactic episodes caused by insect stings, food allergies, medications, exercise, or idiopathic reasons.
Immediate intervention to reverse symptoms such as airway constriction, hypotension, and angioedema.
Needle-free alternative to injectable epinephrine for patients requiring rapid self-administration.
Treatment option for patients with needle phobias or difficulty with intramuscular injections.
Use in both pre-hospital and hospital settings to facilitate timely management of anaphylaxis.
Provision of a portable, patient-friendly device to ensure prompt epinephrine delivery when allergic reaction occurs.
Supplementary dosing with additional nasal sprays when symptoms persist or worsen after first administration.
Utility in schools, workplaces, and other locations where patients at risk of anaphylaxis may require immediate treatment.
Potential use in patients with contraindications or reluctance to receive injectable formulations.

Side Or Adverse Effects

Throat irritation and nasal discomfort at the site of administration.
Tingling sensation in the nose and mouth following nasal spray use.
Headache, possibly due to vasoconstrictive effects of epinephrine.
Feelings of nervousness, over-excitement, anxiety, or restlessness after dosing.
Fatigue and shakiness resulting from systemic adrenergic stimulation.
Runny nose, sneezing, itchy nose, and nasal congestion related to local irritation.
Gum pain and numbness in the mouth potentially linked to local mucosal effects.
Dizziness and nausea, which may accompany systemic epinephrine absorption.
Vomiting as part of the gastrointestinal side effect profile.
Potential aggravation of angina or arrhythmias in patients with underlying heart disease.
Rare risk of prolonged tachycardia or palpitations following administration.
Local irritation or injury if sprayed inappropriately into eyes or mouth.
Exacerbation of preexisting hypertension due to vasopressor effects.
Possible allergic reaction to sulfite preservatives present in the formulation.
Transient increase in blood pressure that requires monitoring in susceptible individuals.

Precautions

Always carry two Neffy nasal sprays in case a second dose is required for persistent or recurrent symptoms.
Consult healthcare providers before use if you have nasal polyps, history of nasal surgery, or other nasal abnormalities.
Inform your provider if you have heart conditions such as angina, arrhythmias, or hypertension as epinephrine may aggravate these.
Use caution if you have kidney disease, Parkinson’s disease, thyroid disorders, or low potassium levels.
Pregnant or breastfeeding women should discuss risks and benefits with their healthcare providers due to limited safety data.
Do not spray into eyes or mouth; intended strictly for intranasal administration.
Do not test or prime the device before use to avoid loss of dose.
Be aware that some symptoms may persist even after administration; emergency medical evaluation is essential post-use.
Inform your healthcare provider about all concurrent medications to avoid drug interactions.
Patients with sulfite allergy should inform their healthcare provider but do not withhold use unless advised otherwise.
Children under 4 years of age or weighing less than 33 lbs (15 kg) should not use Neffy due to lack of safety data.
Avoid sniffing immediately after administration to reduce loss of the drug from the nasal cavity.
Store at room temperature, protected from freezing as freezing can render the spray ineffective.
Replace before expiration date to ensure potency and efficacy.

Warnings

Neffy is intended for emergency treatment of anaphylaxis; always seek immediate emergency medical care after use.
Failure to promptly use Neffy during an anaphylactic episode could result in severe morbidity or death.
Using Neffy improperly or delayed administration may reduce effectiveness in reversing anaphylaxis.
May cause adverse cardiovascular effects including arrhythmias, palpitations, or worsening angina in susceptible patients.
Carrying only one dose is insufficient; having two devices is critical in case symptoms persist or recur.
Patients might be unable to self-administer if experiencing severe symptoms; caregivers should be trained on use.
Do not inject or use by routes other than intranasal as safety and efficacy have not been established for other routes.
Potential for increased nervous system effects such as tremors, anxiety, or headache especially if overdosed.
Neffy contains sulfites, which can rarely cause hypersensitivity reactions in susceptible individuals.
Improper storage such as freezing or exposure to extreme temperatures can compromise drug efficacy.
Risk of incomplete dosing if the spray leaks or drips out of the nose during administration.
Not established as safe or effective for use in patients younger than 4 years or under 33 lbs (15 kg).
Repeat dosing should not be done more frequently than recommended due to the risk of serious side effects.
Emergency medical services must be contacted immediately after initial dosing regardless of symptom improvement.
Patients should be educated on anaphylaxis signs and the importance of timely delivery of epinephrine.

Contraindication

Known hypersensitivity to epinephrine or any component of the Neffy nasal spray formulation.
Patients with narrow-angle glaucoma due to potential increase in intraocular pressure following adrenergic stimulation.
Use caution in patients with known sulfite allergy; although not absolute, consider alternative treatment if severe sensitivity exists.
Not indicated for patients younger than 4 years of age or weighing less than 33 pounds (15 kg) due to insufficient safety data.
Contraindicated for non-anaphylactic indications where epinephrine use is not clinically warranted.
Avoid extranasal administration routes due to lack of safety and efficacy data.
Do not use if the nasal spray device is damaged or if liquid appears discolored or contains particulate matter.
Contraindicated in situations where untreated tachyarrhythmias or severe hypertension would worsen with sympathomimetic agents.
Not recommended in patients with preexisting severe cardiovascular disorders without physician consultation.
Patients with acute narrow-angle glaucoma should avoid use unless benefits outweigh risk.
Contraindicated in patients with pheochromocytoma except with close medical supervision.
Do not administer if patient experiences hypersensitivity reaction to a prior dose.
Avoid use as a prophylactic agent; indicated only for emergency treatment of anaphylaxis.
Contraindicated if patient has received a monoamine oxidase inhibitor (MAOIs) within the past 14 days due to risk of hypertensive crisis.
Avoid concurrent use with beta-blockers without careful medical oversight due to risk of antagonistic interactions.

Drug Interactions

Concurrent use with monoamine oxidase inhibitors (MAOIs) may potentiate hypertensive effects of epinephrine, increasing risk of hypertensive crisis.
Beta-adrenergic blockers (e.g., propranolol) may reduce the effectiveness of epinephrine by antagonizing beta receptors.
Tricyclic antidepressants can enhance adrenergic response to epinephrine, increasing risk of cardiovascular side effects.
Cardiac glycosides (e.g., digoxin) may increase the risk of arrhythmias when used with epinephrine.
Alpha-blockers like phentolamine can antagonize the vasoconstrictive effects mediated via alpha receptors.
Catechol-O-methyltransferase (COMT) inhibitors and ergot alkaloids used in Parkinson’s disease may interact with epinephrine, affecting efficacy and safety.
Diuretics may exacerbate hypokalemia caused by epinephrine-induced intracellular potassium shift, increasing risk of arrhythmias.
Antihistamines like diphenhydramine, tripelennamine, or chlorpheniramine may alter vascular responses when administered concomitantly.
Concurrent nasal spray medications can affect nasal mucosa integrity and absorption kinetics of Neffy.
Thyroid medications like levothyroxine may have additive cardiovascular effects when combined with epinephrine.
Labor-inducing agents may interact with epinephrine, affecting uterine contractility and maternal hemodynamics.
Use caution with other sympathomimetic drugs to avoid additive hypertensive and cardiac stimulation effects.
Monitor patients closely when switching or combining with different formulations of epinephrine (injectable vs nasal).
Herbal supplements such as St. John's Wort may alter metabolism of epinephrine through cytochrome P450 interactions.
Patient-specific drug interaction risk assessment is essential prior to initiation due to multiple potential pharmacodynamic and pharmacokinetic interactions.

Preparations Of The Drug

Neffy nasal spray is formulated as a sterile aqueous solution containing epinephrine at concentrations of 1 mg/0.1 mL or 2 mg/0.1 mL.
Inactive ingredients include benzalkonium chloride (preservative), disodium edetate (chelator), n-dodecyl beta-D-maltoside (surfactant), sodium chloride (tonicity agent), sodium metabisulfite (antioxidant preservative), and pH adjusters (hydrochloric acid or sodium hydroxide).
The formulation is designed for intranasal administration with single-dose, pre-measured nasal spray devices ensuring accurate dosing without priming or testing prior to use.
Device packaging includes two nasal sprays per carton to facilitate immediate access to a second dose if needed in a severe allergic emergency.
Formulated to maintain stability at room temperature; do not freeze as this compromises delivery mechanism and efficacy.
Contains sulfite preservatives, important for stability but may require caution in patients with known sulfite sensitivity.
The nasal spray device allows needle-free administration, easing use in non-clinical settings such as schools or homes.
Manufactured under stringent pharmaceutical quality controls by ARS Pharmaceuticals, specializing in emergency drug delivery systems.
Packaging includes detailed instructions for use, warning labels, and expiration date to ensure safety and effectiveness.
The solution is isotonic and buffered to be compatible with the nasal mucosa and minimize irritation.
Designed for rapid systemic uptake to replicate effects of injectable epinephrine for anaphylaxis management.
The nasal spray utilizes a metered-dose mechanism to ensure the correct amount is delivered with each actuation.
The product is intended for single-use only and should be discarded after administration or once expired.
Patient support programs such as neffy Connect are available to assist with medication access and affordability.
Storage recommendations include maintaining the product between 68°F and 77°F (20°C to 25°C), and protecting from light and moisture.