12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Epinephrine acts on both alpha- and beta-adrenergic receptors.

12.2 Pharmacodynamics

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 also alleviates pruritus, urticaria, and angioedema and may 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.

When given subcutaneously or intramuscularly, epinephrine has a rapid onset and short duration of action.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage According to Patient Body Weight

• Patients greater than or equal to 30 kg (approximately 66 pounds or more): Epinephrine injection, 0.3 mg
• Patients 15 kg to 30 kg (33 pounds to 66 pounds): Epinephrine injection, 0.15 mg

2.2 Administration Instructions

• Inject the single-dose epinephrine injection, 0.3 mg or epinephrine injection, 0.15 mg intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. Do not inject intravenously, and do not inject into buttocks, into digits, hands or feet [see Warnings and Precautions (5.2)].
• Instruct caregivers of young children who are prescribed an epinephrine injection, 0.3 mg or epinephrine injection, 0.15 mg and who may be uncooperative and kick or move during an injection to hold the leg firmly in place and limit movement prior to and during an injection [see Warnings and Precautions (5.2)].
• Each epinephrine injection, 0.3 mg or epinephrine injection, 0.15 mg is a single-dose epinephrine injection for single use. Since the doses of epinephrine delivered from epinephrine injection, 0.3 mg or epinephrine injection, 0.15 mg are fixed, consider using other forms of injectable epinephrine if doses lower than 0.15 mg are deemed necessary.
• With severe persistent anaphylaxis, repeat injections with an additional epinephrine injection, 0.3 mg or epinephrine injection, 0.15 mg may be necessary. More than two sequential doses of epinephrine should only be administered under direct medical supervision [see Warnings and Precautions (5.1)].
• The epinephrine solution in the clear window of the Epinephrine Injection 0.3 mg (Auto-Injector) or Epinephrine Injection 0.15 mg (Auto-Injector) should be inspected visually for particulate matter and discoloration.

Discarding After Use:

The epinephrine injection 0.3 mg and epinephrine injection 0.15 mg each contain 1 mL epinephrine solution. Approximately 0.7 mL remains in the auto- injector after activation, but is not available for future use, and should be discarded.

13 NONCLINICAL TOXICOLOGY

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 (40-fold the highest human intramuscular or subcutaneous daily dose) during gestation days 3 to 9.