NEFFY

Neffy contains epinephrine, a sympathomimetic catecholamine. Chemically, epinephrine is (-)-3,4-dihydroxy-α-[(methylamino)methyl] benzyl alcohol with molecular weight of 183.21 g/mol and the following structure: Neffy (epinephrine nasal spray) is supplied as single-dose nasal sprays containing 1 mg or 2 mg of epinephrine in 0.1 mL solution for nasal administration. Inactive ingredients include benzalkonium chloride, disodium edetate, n-dodecyl beta-D-maltoside, sodium chloride, sodium metabisulfite, and hydrochloric acid or sodium hydroxide to adjust pH, in water for injection. The pH range is approximately 3 to 5.5. Chemical Structure

Neffy is indicated for emergency treatment of type I allergic reactions, including anaphylaxis, in adult and pediatric patients aged 4 years and older who weigh 15 kg or greater. Neffy is an alpha and beta-adrenergic receptor agonist indicated for emergency treatment of type I allergic reactions, including anaphylaxis, in adult and pediatric patients 4 years of age and older who weigh 15 kg or greater. ( 1 )

The recommended dosage for patients 4 years of age and older who weigh 15 kg or greater is based on weight. Neffy is for nasal administration. ( 2.1 ) Recommended Dosage Patient's Weight Dosage 30 kg or Greater One spray of neffy 2 mg 15 kg to less than 30 kg One spray of neffy 1 mg In absence of clinical improvement or if symptoms worsen after initial treatment, administer a second dose of neffy in the same nostril with a new nasal spray starting 5 minutes after the first dose. ( 2.1 ) Advise patients when to seek emergency medical assistance for close monitoring of the anaphylactic episode and in the event further treatment is required. ( 2.1 ) It is recommended that patients are prescribed and have immediate access to two neffy nasal sprays at all times. See full prescribing information for administration instructions. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage for patients aged 4 years and older who weigh 15 kg or greater is based on weight and the dosage is provided in Table 1. For nasal administration [see Dosage and Administration (2.2) ] . Table 1: Recommended Dosage of Neffy Based on Patient's Weight Patients Weight Dosage 30 kg or Greater One spray of neffy 2 mg 15 kg to less than 30 kg One spray of neffy 1 mg In the absence of clinical improvement or if symptoms worsen after the initial treatment, a second dose of neffy may be administered in the same nostril with a second nasal spray starting 5 minutes after the first dose. Advise patients when to seek emergency medical assistance for close monitoring of the anaphylactic episode and in the event further treatment is required. It is recommended that patients are prescribed and have immediate access to two neffy nasal sprays at all times. 2.2 Administration Instructions Neffy is for nasal use only. Each neffy nasal spray is for single use and delivers the entire dose upon activation. Do not prime or attempt to reuse neffy for more than one administration. Administer neffy by inserting the nozzle of the nasal spray fully into one nostril until fingers touch the nose (see Figure 1 ). Hold the nasal spray straight into the nose - do not angle the nasal spray to the inside septum or outer wall of the nose as some medication may be lost. Press the plunger firmly to activate. Avoid sniffing during and after administration. If a second dose of neffy is needed, administer a new nasal spray into the same nostril starting 5 minutes after the first dose (see Figure 1 ). More than two sequential doses of epinephrine should be administered under direct medical supervision. Refer patients and caregivers to the Instructions for Use for detailed administration instructions. Figure 1: Administration of Neffy If neffy is frozen and is needed in an emergency, do not wait to thaw, seek emergency medical care immediately [see How Supplied/Storage and Handling (16) ]. Figure 1

None. None ( 4 )

The following clinically significant adverse reactions are described elsewhere in the labeling: Risks Associated with Use of Epinephrine in Certain Coexisting Conditions [see Warnings and Precautions (5.2) ] Allergic Reactions Associated with Sulfite [see Warnings and Precautions (5.3) ] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Most common adverse reactions are: Adults (incidence ≥ 2%): nasal discomfort, headache, rhinorrhea, dizziness, nausea, vomiting, and throat irritation. ( 6 ) Pediatric patients 4 years of age and older who weigh 15 kg or greater (incidence ≥10%): nasal discomfort, nasal congestion, paresthesia, rhinorrhea, sneezing, upper respiratory tract congestion, epistaxis, rhinalgia, nasal dryness, dry throat, fatigue, and feeling jittery. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact ARS Pharmaceuticals Operations, Inc. at 1-877-MY-NEFFY (877-696-3339) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Adverse Reactions with Neffy in Adult Subjects The safety of neffy 2 mg is based on four clinical pharmacology studies in 175 healthy adults and adults with type I allergy without anaphylaxis, who did not have structural or anatomical nasal conditions [see Clinical Pharmacology (12.2 , 12.3) ] . The four clinical pharmacology studies were designed to compare the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of one dose of neffy 2 mg sprayed into one nostril or two doses of neffy 2 mg sprayed into either the same or opposite nostril, administered 10 minutes apart, with PK and PD profiles of one or two dose(s) of epinephrine injection administered intramuscularly. The common adverse reactions that occurred with neffy 2 mg after one and two dose(s) are listed in Table 2. Table 2: Adverse Reactions with One or Two Dose(s) of Neffy with Incidence Greater than or Equal to 2% in Adults [Studies 1, 2, 3, and 4] Adverse Reaction Data include subjects with nasal allergen challenge induced rhinitis Neffy 2 mg One Dose Neffy 2 mg Two Doses Two nasal doses of neffy 2 mg were administered 10 minutes apart N = 134 The trials used a crossover design and therefore the total number of subjects do not match the number of unique subjects (n = 175) N = 85 Nasal discomfort 13 (10%) 11 (13%) Headache 8 (6%) 15 (18%) Rhinorrhea 4 (3%) 6 (7%) Dizziness 4 (3%) 2 (2%) Nausea 4 (3%) 2 (2%) Vomiting 3 (2%) 2 (2%) Throat irritation 2 (2%) 16 (19%) Feeling jittery 1 (1%) 9 (11%) Abdominal pain 1 (1%) 3 (4%) Tremor 0 (0%) 7 (8%) Nasal pruritus 0 (0%) 3 (4%) Sneezing 0 (0%) 3 (4%) Gingival pain 0 (0%) 3 (4%) Hypoesthesia oral 0 (0%) 3 (4%) Nasal Congestion 0 (0%) 2 (2%) Adverse Reactions with Neffy in Pediatric Subjects 4 Years of Age and Older Weighing 15 kg or Greater A single-arm clinical pharmacology study (Study 5) in pediatric subjects 4 to 17 years of age who weigh 15 kg or greater with type I allergy without anaphylaxis was conducted to assess the pharmacokinetic/pharmacodynamic (PK/PD) of neffy 1 mg and 2 mg [see Clinical Pharmacology (12.2 , 12.3) ] . Pediatric subjects (n=21) who weigh 30 kg or greater received one nasal dose of neffy 2 mg and common adverse reactions reported in these subjects include nasal discomfort (19%), intranasal paresthesia (19%), rhinorrhea (19%), sneezing (14%), epistaxis (10%), rhinalgia (10%), paresthesia (10%), fatigue (10%), and feeling jittery (10%). Pediatric subjects (n=21) who weigh 15 to less than 30 kg received one nasal dose of neffy 1 mg and common adverse reactions reported in these subjects include nasal congestion (19%), upper respiratory tract congestion (14%), dry throat (10%), nasal dryness (10%), and paresthesia (10%). Adverse Reactions from Postapproval Use of Epinephrine Products The following adverse reactions have been identified during postapproval use of epinephrine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular : angina, arrhythmias (including fatal ventricular fibrillation), cerebral hemorrhage, hypertension, pallor, palpitations, tachyarrhythmia, tachycardia, vasoconstriction, ventricular ectopy, and stress cardiomyopathy Metabolism and Nutrition Disorders : transient hyperglycemia, sweating Neurological : disorientation, impaired memory, panic, psychomotor agitation, sleepiness, tingling, weakness Psychiatric : anxiety, apprehensiveness, restlessness Respiratory : respiratory difficulties

Neffy may alter nasal mucosa for up to 2 weeks after administration and increase systemic absorption of nasal products, including neffy. ( 7.1 ) Cardiac glycosides, diuretics or anti-arrhythmics: observe for development of cardiac arrhythmias. ( 7.2 ) Tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, certain antihistamines, and catechol-O-methyl transferase inhibitors may potentiate effects of epinephrine. ( 7.3 ) Beta-adrenergic blocking drugs antagonize cardiostimulating and bronchodilating effects of epinephrine. ( 7.4 ) Alpha-adrenergic blocking drugs antagonize vasoconstricting and hypertensive effects of epinephrine. ( 7.4 ) Ergot alkaloids may reverse the pressor effects of epinephrine. ( 7.4 ) 7.1 Potential Increased Exposure of Nasal Spray Drugs Neffy may alter nasal mucosa for up to 2 weeks after administration, and thus may increase systemic absorption of nasal products, including neffy, potentially increasing the risk of adverse reactions associated with these products. 7.2 Drugs Increasing Risk of Cardiac Arrhythmias Patients who receive epinephrine while concomitantly taking cardiac glycosides, diuretics, or anti-arrhythmics should be observed carefully for the development of cardiac arrhythmias [see Warnings and Precautions (5.2) and Adverse Reactions (6) ] . 7.3 Drugs Potentiating Effects of Epinephrine The effects of epinephrine may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, certain antihistamines, notably chlorpheniramine, tripelennamine, and diphenhydramine, and catechol-O-methyl transferase (COMT) inhibitors such as entacapone. 7.4 Drugs Antagonizing Effects of Epinephrine The cardiostimulating and bronchodilating effects of epinephrine are antagonized by beta- adrenergic blocking drugs, such as propranolol. The vasoconstricting and hypertensive effects of epinephrine are antagonized by alpha- adrenergic blocking drugs, such as phentolamine. Ergot alkaloids may also reverse the pressor effects of epinephrine.

Storage and Handling Store neffy nasal spray in the blister pack until ready to use. Store at 68°F to 77°F (20°C to 25°C). Excursions permitted up to 122°F (50°C). Do not freeze. Neffy freezes below 5°F (-15°C). If neffy freezes, it will not deliver epinephrine.