Neffy Drug Information

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.

The following clinically significant adverse reactions are described elsewhere in the labeling: Risks Associated with Use of Epinephrine in Certain Coexisting Conditions Allergic Reactions Associated with Sulfite 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. 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.

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 . 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 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 . 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

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.

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 .

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.

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.

Pregnancy Risk Summary Prolonged experience with epinephrine use in pregnant women over several decades, based on published literature, have not identified a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with anaphylaxis, and treatment with epinephrine should not be delayed (see Clinical Considerations ). In animal reproduction studies, epinephrine administered by the subcutaneous route to pregnant rabbits, mice, and hamsters, during the period of organogenesis, resulted in adverse developmental effects (including gastroschisis, and embryonic lethality, and delayed skeletal ossification) at doses approximately 2 times the maximum recommended daily intramuscular, subcutaneous, or intravenous dose (see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and Embryo/Fetal Risk During pregnancy, anaphylaxis can be catastrophic and can lead to hypoxic-ischemic encephalopathy and permanent central nervous system damage or death in the mother and, more commonly, in the fetus or neonate. Treatment of anaphylaxis during pregnancy should not be delayed.

Data Animal Data In an embryofetal development study with pregnant rabbits dosed during the period of organogenesis (on days 3 to 5, 6 to 7 or 7 to 9 of gestation), epinephrine caused teratogenic effects (including gastroschisis) at doses approximately 15 times the maximum recommended intramuscular, subcutaneous, or intravenous dose (on a mg/m 2 basis at a maternal subcutaneous dose of 1.2 mg/kg/day for two to three days). Animals treated on days 6 to 7 had decreased number of implantations. In an embryofetal development study, pregnant mice were administered epinephrine (0.1 to 10 mg/kg/day) on Gestation Days 6 to 15. Teratogenic effects, embryonic lethality, and delays in skeletal ossification were observed at approximately 3 times the maximum recommended intramuscular, subcutaneous, or intravenous dose (on a mg/m 2 basis at maternal subcutaneous dose of 1 mg/kg/day for 10 days). These effects were not seen in mice at approximately 2 times the maximum recommended daily intramuscular or subcutaneous dose (on a mg/m 2 basis at a subcutaneous maternal dose of 0.5 mg/kg/day for 10 days). In an embryofetal development study with pregnant hamsters dosed during the period of organogenesis from gestation days 7 to 10, epinephrine produced reductions in litter size and delayed skeletal ossification at doses approximately 2 times the maximum recommended intramuscular, subcutaneous, or intravenous dose (on a mg/m 2 basis at a maternal subcutaneous dose of 0.5 mg/kg/day).

Pediatric Use The safety and effectiveness of neffy for emergency treatment of type I allergic reactions, including anaphylaxis, have been established in pediatric patients aged 4 years and older who weigh 15 kg or greater. Use of neffy for this indication is supported by extrapolation from the clinical pharmacology studies in adults that compared the PK/PD profile of neffy to epinephrine injection products with established safety and effectiveness for this indication and clinical pharmacology data (Study 5) in pediatric patients aged 4 years and older who weigh 15 kg or greater. The safety and effectiveness of neffy have not been established in pediatric patients less than 4 years of age and who weigh less than 15 kg.

Overdosage of epinephrine has been reported to produce extremely elevated arterial pressure, which may result in cerebrovascular hemorrhage, particularly in elderly patients. Overdosage may also result in pulmonary edema because of peripheral vascular constriction together with cardiac stimulation. Epinephrine overdosage can also cause transient bradycardia followed by tachycardia which may be accompanied by fatal cardiac arrhythmias; premature ventricular contractions followed by multifocal ventricular tachycardia; atrial tachycardia and occasionally by atrioventricular block; extreme pallor and coldness of the skin; metabolic acidosis; kidney failure.

Epinephrine is rapidly inactivated in the body and treatment following overdosage with epinephrine is primarily supportive. Treatment of epinephrine associated pulmonary edema consists of a rapidly acting alpha-adrenergic blocking drug (such as phentolamine mesylate) and respiratory support. Treatment of epinephrine associated arrhythmias consists of administration of a beta-adrenergic blocking drug (such as propranolol). If necessary, pressor effects may be counteracted by rapidly acting vasodilators or α-adrenergic blocking drugs.

If prolonged hypotension follows such measures, it may be necessary to administer another pressor drug. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.