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)].

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)].

Nasal spray:

• 1 mg/0.1 mL of epinephrine per spray in a single-dose nasal spray
• 2 mg/0.1 mL of epinephrine per spray in a single-dose nasal spray

5.1 Potential Altered Absorption of Neffy in Patients with Underlying Structural or Anatomical Nasal Conditions

Clinical pharmacology studies with neffy included subjects with history of allergic rhinitis, but did not include subjects with underlying structural and anatomical nasal conditions (e.g., polyps, history of nasal fractures or injuries, or history of nasal surgery). Absorption of neffy may be affected by underlying structural and anatomical nasal conditions. Consider use of other epinephrine products given by other routes of administration for patients with underlying structural or anatomical nasal conditions.

5.2 Risks Associated with Use of Epinephrine in Certain Coexisting Conditions

Some patients may be at greater risk for developing adverse reactions after epinephrine administration. Despite these concerns, it should be recognized that the presence of these conditions is not a contraindication to epinephrine administration in an acute, life-threatening situation. Therefore, patients with these conditions, and/or any other person who might be in a position to administer neffy to a patient experiencing anaphylaxis should be carefully instructed in regard to the circumstances under which epinephrine should be used.

Epinephrine should be administered with caution to patients who have heart disease, including patients with cardiac arrhythmias, coronary artery disease, or hypertension. In such patients, or in patients who are on drugs that may sensitize the heart to arrhythmias, epinephrine may precipitate or aggravate angina pectoris, as well as produce ventricular arrhythmias [see Drug Interactions (7) and Adverse Reactions (6)].

Epinephrine can temporarily exacerbate the underlying condition or increase symptoms in patients with the following: hyperthyroidism, Parkinson's disease, diabetes, renal impairment. Epinephrine should be administered with caution in patients with these conditions, including elderly patients and pregnant women.

5.3 Allergic Reactions Associated with Sulfite

Epinephrine is the preferred treatment for serious allergic or other emergency situations even though neffy contains sodium metabisulfite, a sulfite that may in other products cause allergic-type reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in certain susceptible persons. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. The presence of a sulfite(s) in neffy should not deter administration of the drug for treatment of serious allergic or other emergency situations.

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.

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

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.

8.1 Pregnancy

8.2 Lactation

8.4 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 [see Adverse Reactions (6) and Clinical Pharmacology (12.2, 12.3)].

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.

8.5 Geriatric Use

Clinical pharmacology studies of neffy for the emergency treatment of type I allergic reactions, including anaphylaxis, did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger adult subjects. However, other reported clinical experience with use of epinephrine for the treatment of anaphylaxis has identified that geriatric patients may be particularly sensitive to the effects of epinephrine. Neffy should be administered with caution in elderly patients who are at greater risk for developing adverse reactions after epinephrine administration.

12.1 Mechanism of Action

Epinephrine acts on both alpha and beta-adrenergic receptors.

Through its action on alpha-adrenergic receptors, epinephrine lessens the vasodilation and increased vascular permeability that occurs during anaphylaxis, which can lead to loss of intravascular fluid volume and hypotension.

Through its action on beta-adrenergic receptors, epinephrine causes bronchial smooth muscle relaxation and helps alleviate bronchospasm, wheezing and dyspnea that may occur during anaphylaxis.

Epinephrine alleviates pruritus, urticaria, and angioedema. It may also relieve gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxer effects on the smooth muscle of the stomach, intestine, uterus, and urinary bladder.

12.2 Pharmacodynamics

Four clinical pharmacology studies of neffy in adults and one clinical pharmacology study in pediatric subjects who weigh 30 kg or greater are described below. All doses were administered by study staff unless otherwise stated.

12.3 Pharmacokinetics

Pharmacokinetics assessments were performed in the clinical pharmacology studies described in the Pharmacodynamics subsection [see Clinical Pharmacology (12.2)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies to evaluate the carcinogenic potential of epinephrine have not been conducted. Epinephrine and other catecholamines have been shown to have mutagenic potential in vitro. Epinephrine was positive in the Salmonella bacterial reverse mutation assay, positive in the mouse lymphoma assay, and negative in the in vivo micronucleus assay. Epinephrine is an oxidative mutagen based on the E. coli WP2 Mutoxitest bacterial reverse mutation assay. This should not prevent the use of epinephrine where indicated [see Indications and Usage (1)]. The potential for epinephrine to impair reproductive performance has not been evaluated, but epinephrine has been shown to decrease implantation in female rabbits dosed subcutaneously with 1.2 mg/kg/day (15-fold the highest human intramuscular or subcutaneous daily dose) during gestation days 3 to 9.

13.2 Animal Toxicology and/or Pharmacology

In a single-dose nasal toxicity study, treatment of neffy in rats induced epinephrine-related histopathological changes in the nose, such as minimal ulceration of the exposed mucosa (at ≥2.3-fold the recommended clinical dose of neffy 2 mg based on local surface area), and nasal passages, such as minimal to mild necrosis in the nasal turbinate and parietal wall in the rostral-most level (at ≥1.2-fold the recommended clinical dose of neffy 2 mg based on local surface area) on day 2. These findings were often associated with minimal to mild neutrophilic inflammation and were reversible after 14 days post-dose.

How Supplied

Neffy (epinephrine nasal spray) is available in 1 mg and 2 mg strengths as described in Table 4.

Storage and Handling

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.

Administration

• Neffy nasal spray is for single use and delivers the entire dose upon activation.
• Advise patients when to seek emergency medical assistance for close monitoring of the anaphylactic episode and in the event further treatment is required.
• Instruct patients and/or caregivers in the appropriate use of neffy. Administer neffy into one nostril pointing straight into the naris, press the plunger firmly to activate [see Dosage and Administration (2.2) and Instructions for Use]. If a second dose of neffy is needed, administer a new neffy nasal spray into the same nostril (ipsilateral side) starting 5 minutes after the first dose.
• Advise patients that improper dosing in the nose may result in some drug dripping out of the nose and not being available for absorption. If symptoms do not improve or worsen, patients and/or caregivers should administer a second dose of neffy in the same nostril starting 5 minutes after the first dose.

Risks Associated with Certain Coexisting Conditions

Advise patients with coexisting conditions (cardiac arrhythmia, coronary artery disease, hypertension, pulmonary edema, hyperthyroidism, renal impairment, Parkinson's disease, diabetes), for increased risks that may be associated with use of epinephrine [see Warnings and Precautions (5.2)].