Neffy Nasal Spray Prescribing Information

2.1 Recommended Dosage

The recommended dosage of neffy is one spray (2 mg of epinephrine) administered into one nostril. 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.
• Use the right hand to administer neffy to the right nostril and use the left hand to administer neffy to the left nostril.

Administer neffy by inserting the nozzle of the nasal spray fully into one nostril until your 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. 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)].

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 in Four Clinical Pharmacology Studies with Neffy for Adult Subjects

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.

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 1.

Adverse Reactions in a Clinical Pharmacology Study with Neffy for Pediatric Subjects

A single-arm PK/PD study (Study 5) in pediatric subjects 8 to 17 years of age who weigh 30 kg or greater with type I allergy without anaphylaxis was conducted to assess the PK/PD of neffy 2 mg. A total of 42 pediatric subjects who weigh 30 kg or greater (body weight range: 31 kg to 95 kg; age range: 8 to 17 years) were enrolled, including 21 subjects who received one nasal dose of neffy 2 mg [see Clinical Pharmacology (12.3)]. Common adverse reactions reported in these subjects who received one dose of neffy 2 mg include nasal discomfort (19%), intranasal paresthesia (19%), rhinorrhea (14%), sneezing (14%), paresthesia (10%), fatigue (10%), and feeling jittery (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 who weigh 30 kg or greater. Use of neffy for this indication is supported by 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 with neffy in pediatric patients who weigh 30 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 who weigh less than 30 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.

Systolic Blood Pressure and Pulse Rate in Healthy Adult Subjects (Study 1)

Study 1 was conducted in healthy adult subjects (N=42) that compared the pharmacokinetics (PK) [see Clinical Pharmacology (12.3)] and pharmacodynamics (PD) (i.e., pulse rate (PR) and systolic blood pressure (SBP)) of epinephrine following:

• One nasal dose of neffy 2 mg to one intramuscular dose of epinephrine injection 0.3 mg (using a needle-syringe product and an auto-injector product).
• Two nasal doses of neffy 2 mg, administered 10 minutes apart, into either same naris or opposite nares to two intramuscular doses of epinephrine injection 0.3 mg (using an auto-injector) administered 10 minutes apart.

In Study 1, SBP and PR responses were assessed as change from baseline over 60 minutes.

Results following one dose of all epinephrine products demonstrated an increase from baseline SBP and PR as shown in Figure 2. The median/mean increase in SBP and PR for neffy were within the range of both epinephrine injection treatments during the first 10 minutes post-dose. Thereafter, the median/mean SBP and PR responses for neffy were higher than both epinephrine injection treatments through 60 minutes post-dose.

Figure 2: Median Pulse Rate (PR) and Systolic Blood Pressure (SBP) Change from Baseline Following One Dose of Epinephrine in Healthy Subjects [Study 1]

Results following two nasal doses of neffy (in the same naris or opposite nares) in comparison to two intramuscular doses of epinephrine injection (using an auto-injector) showed a similar trend in median/mean SBP and PR responses.

The clinical meaning of SBP and PR responses observed in healthy subjects is unclear in the context of treating anaphylaxis.

Systolic Blood Pressure and Pulse Rate in Adult Patients with Nasal Allergen Challenge Induced Rhinitis (Study 3 and 4)

Study 3 and Study 4 were conducted in adult subjects with seasonal allergic rhinitis outside of allergy season (neffy is not approved for the treatment of allergic rhinitis). Subjects were required to have seasonal allergic rhinitis which was confirmed with a nasal allergen challenge (NAC) during screening and did not have any allergy symptoms prior to treatment. Allergic rhinitis symptoms were induced by spraying the known allergen into the subject's nostrils in which a minimum Total Nasal Symptom Score (TNSS) of ≥ 5 out of 12, with a congestion component of ≥ 2 out of 3 had to be reached.

Study 3 enrolled 36 subjects. In this cross-over study, subjects received epinephrine as each of the following:

• One nasal dose of neffy 2 mg without nasal allergen challenge (NAC).
• One nasal dose of neffy 2 mg after undergoing NAC to induce rhinitis/nasal congestion.
• One intramuscular dose of epinephrine injection 0.3 mg (using a needle syringe) without NAC.
• One intramuscular dose of epinephrine injection 0.5 mg (using a needle syringe) without NAC.

In Study 3, SBP and PR responses were assessed as a change from baseline over 60 minutes. Results showed the following:

• Median SBP and PR for neffy with NAC initially increased from baseline, but the median responses were lower than the use of neffy without NAC after 5 to 15 minutes post-dose.
• Median SBP response for neffy with NAC was initially higher than the median SBP response for the intramuscular epinephrine injection without NAC through 20 minutes, after which the median SBP response for neffy with NAC became comparable to the epinephrine injection without NAC through 60 minutes post-dose.
• Median PR response for neffy with NAC was initially higher than epinephrine injection without NAC during the first 5 minutes post-dose, but then was numerically lower than the median PR response for epinephrine injection without NAC through 60 minutes post-dose.

Study 4 enrolled 43 subjects. In this cross-over study, subjects received the following:

• Two nasal doses of neffy 2 mg (in the opposite nares) without NAC administered 10 minutes apart.
• Two intramuscular doses of epinephrine injections 0.3 mg (using a needle-syringe) without NAC administered 10 minutes apart.
• Two nasal doses of neffy 2 mg (either in the same naris or opposite nares) after NAC to induce allergic rhinitis/nasal congestion administered 10 minutes apart.
• Two intramuscular doses of epinephrine injections 0.3 mg (using a needle-syringe) after NAC to induce allergic rhinitis/nasal congestion administered 10 minutes apart.

In Study 4, SBP and PR responses were assessed as a change from baseline over 60 minutes. Results showed the following:

• Median SBP and PR responses for two nasal doses of neffy (in the same naris) after NAC increased from baseline and remained higher than median SBP and PR response for two intramuscular doses of epinephrine injections after NAC through 60 minutes post-first dose (Figure 3).
• Median SBP response for two nasal doses of neffy (in the opposite nares) after NAC was higher than for two intramuscular doses of epinephrine injections after NAC within 30 minutes post-first dose, but then decreased and became numerically lower afterwards. Median PR response for two nasal doses of neffy (in the opposite nares) after NAC was also initially higher than two intramuscular doses of epinephrine injection after NAC and became lower after 40 minutes post-first dose.

Figure 3: Median Change from Baseline for Pulse Rate (PR) and Systolic Blood Pressure (SBP) Following Two Doses of Epinephrine Administered 10 Minutes Apart in Subjects with and without Nasal Allergen Challenge (NAC) Induced Rhinitis [Study 4]

R/L: First dose administered in right naris followed by second dose administered in left naris 10 minutes apart. R/R: First dose administered in right naris followed by second dose administered in right naris 10 minutes apart. Epinephrine 0.3 mg was administered using needle-syringe product

12.3 Pharmacokinetics

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

Pharmacokinetics in Adult Patients with Nasal Allergen Challenge Induced Rhinitis (Studies 3 and 4)

See the Pharmacodynamics (12.2) for a description of Studies 3 and 4.

• In Study 3, the geometric mean plasma epinephrine concentrations in patients who received one nasal dose of neffy 2 mg after NAC initially increased more rapidly during the first 5 minutes compared to those that received one nasal dose of neffy 2 mg without NAC and one intramuscular dose of epinephrine injection (0.3 mg or 0.5 mg) without NAC. The geometric mean plasma epinephrine concentrations of patients who received neffy 2 mg with NAC declined after approximately 10 minutes post-dose and became numerically lower than both the neffy 2 mg without NAC and epinephrine injection (0.3 mg or 0.5 mg) after 20 minutes post-dose (Figure 5a).
• In Study 4, the geometric mean of plasma epinephrine concentrations in patients who received two nasal doses of neffy 2 mg, administered 10 minutes apart, (in the same naris) after NAC were higher than those who received two intramuscular doses of epinephrine injection 0.3 mg, administered 10 minutes apart, with or without NAC up to 40 minutes post-first dose and then became similar afterwards (Figure 5b). The geometric mean plasma epinephrine concentrations of patients who received two doses of neffy 2 mg, administered 10 minutes apart, (in the opposite nares) after NAC, were initially higher than those who received two intramuscular doses of epinephrine injection 0.3 mg, administered 10 minutes apart, with or without NAC for around 25 to 30 minutes post-first dose, but became lower afterwards.

Figure 5: Epinephrine Geometric Mean Plasma Concentration-Time Profiles Following One or Two Dose(s) of Epinephrine in Adult Subjects with and without Nasal Allergen Challenge Induced Rhinitis [Study 3 and Study 4]

a	b
a: Epinephrine geometric mean plasma concentration-time profiles following one dose of epinephrine in Study 3 b: Epinephrine geometric mean plasma concentration-time profiles following two doses of epinephrine in Study 4 R/L: First dose administered in right naris followed by second dose administered in left naris 10 minutes apart. R/R: First dose administered in right naris followed by second dose administered in right naris 10 minutes apart. Epinephrine 0.3 mg was administered using needle-syringe product

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 histopathology 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): 2 mg/0.1 mL of epinephrine is supplied in a carton containing two (2) blister packages each with a single-dose nasal spray product for 1 time use (NDC 82580-020-02).

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)].