These Highlights Do Not Include All The Information Needed To Use Neffy ®

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.

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.

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.

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 a single-dose nasal spray containing 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.

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.

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.

None.

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)]

• 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)

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.

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

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.

Neffy is indicated for emergency treatment of type I allergic reactions, including anaphylaxis, in adult and pediatric patients who weigh 30 kg or greater.

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.

• Absorption of neffy may be affected by underlying structural and anatomical nasal conditions. ( 5.1)
• Administer with caution in patients with heart disease; may aggravate angina pectoris or produce ventricular arrhythmias. ( 5.2)
• May aggravate certain coexisting conditions. ( 5.2)
• The presence of a sulfite in this product should not deter use. ( 5.3)

Recommended Dosage: one spray of neffy (2 mg of epinephrine) administered into one nostril. 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)

• Neffy is for nasal use only. ( 2.2)
• 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)

Nasal spray: 2 mg/0.1 mL of epinephrine per spray in a single-dose nasal spray.

Elderly patients may be at greater risk of developing adverse reactions. ( 8.5)

• 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 Usefor 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)].

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

NDC 71872-7330-1

Rx Only

neffy ^®

(epinephrine nasal spray)

2 mg

For Use in the Nose Only (Single-dose)

Read the Instructions for Use for complete

information on how to use neffy.

1 x single-dose nasal spray device

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.

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.

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.

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.

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)] .

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.

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 Salmonellabacterial reverse mutation assay, positive in the mouse lymphoma assay, and negative in the in vivomicronucleus assay. Epinephrine is an oxidative mutagen based on the E. coliWP2 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.

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.

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.

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.

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.

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.

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 a single-dose nasal spray containing 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.

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.

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.

None.

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)]

• 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)

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.

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

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.

Neffy is indicated for emergency treatment of type I allergic reactions, including anaphylaxis, in adult and pediatric patients who weigh 30 kg or greater.

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.

• Absorption of neffy may be affected by underlying structural and anatomical nasal conditions. ( 5.1)
• Administer with caution in patients with heart disease; may aggravate angina pectoris or produce ventricular arrhythmias. ( 5.2)
• May aggravate certain coexisting conditions. ( 5.2)
• The presence of a sulfite in this product should not deter use. ( 5.3)

Recommended Dosage: one spray of neffy (2 mg of epinephrine) administered into one nostril. 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)

• Neffy is for nasal use only. ( 2.2)
• 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)

Nasal spray: 2 mg/0.1 mL of epinephrine per spray in a single-dose nasal spray.

Elderly patients may be at greater risk of developing adverse reactions. ( 8.5)

• 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 Usefor 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)].

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

NDC 71872-7330-1

Rx Only

neffy ^®

(epinephrine nasal spray)

2 mg

For Use in the Nose Only (Single-dose)

Read the Instructions for Use for complete

information on how to use neffy.

1 x single-dose nasal spray device

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.

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.

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.

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.

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)] .

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.

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 Salmonellabacterial reverse mutation assay, positive in the mouse lymphoma assay, and negative in the in vivomicronucleus assay. Epinephrine is an oxidative mutagen based on the E. coliWP2 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.

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.

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.