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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ADRENALIN safely and effectively. See full prescribing information for ADRENALIN.
ADRENALIN (epinephrine injection) 1 mg/mL (1:1000) for intramuscular, subcutaneous, and intraocular use Initial U.S. Approval: 1939
---------------------------INDICATIONS AND USAGE--------------------------- Adrenalin ®^ is a non-selective alpha and beta adrenergic agonist indicated for: Emergency treatment of allergic reactions (Type 1), including anaphylaxis (1.1) Induction and maintenance of mydriasis during intraocular surgery (1.2)
-----------------------DOSAGE AND ADMINISTRATION----------------------- Anaphylaxis: o Adults and Children 30 kg (66 lbs) or more : 0.3 to 0.5 mg (0.3 to 0. mL) intramuscularly or subcutaneously into anterolateral aspect of the thigh every 5 to 10 minutes as necessary (2.1) o Children 30 kg (66 lbs) or less : 0.01 mg/kg (0.01 mL/kg), up to 0.3 mg (0.3 mL), intramuscularly or subcutaneously into anterolateral aspect of the thigh every 5 to 10 minutes as necessary (2.1) Intraocular surgery: Dilute 1 mL with 100 to 1000 mL of an ophthalmic irrigation fluid, for ophthalmic irrigation or intracameral injection (2.2)
-------------- - ------DOSAGE FORMS AND STRENGTHS ----- ----------------- Injection: 1 mg/mL (1:1000) (3)
------------------------------CONTRAINDICATIONS------------------------------- None (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------ Undiluted ophthalmic administration: associated with corneal endothelial damage (5.1) Do not inject into buttocks, digits, hands, or feet (5.2) May aggravate angina pectoris or produce ventricular arrhythmias, particularly in patients with underlying heart disease, administer with caution when used intramuscularly or subcutaneously (5.3)
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE 1.1 Anaphylaxis 1.2 Induction and Maintenance of Mydriasis during Intraocular Surgery 2 DOSAGE AND ADMINISTRATION 2.1 Anaphylaxis 2.2 Induction and Maintenance of Mydriasis during Intraocular Surgery 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Injury with Undiluted Intraocular Solution 5.2 Incorrect Locations of Injection 5.3 Disease Interactions 5.4 Allergic Reactions Associated with Sulfite 6 ADVERSE REACTIONS 6.1 Adverse Reactions Associated with Intramuscular/Subcutaneous Use (for Anaphylaxis) 6.2 Adverse Reactions Associated with Intraocular Use (for Mydriasis) 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS
Patients with hyperthyroidism, Parkinson’s disease, diabetes, and pheochromocytoma are at greater risk of having adverse reactions when used intramuscularly or subcutaneously (5.3) Presence of sulfite in this product should not deter use for anaphylaxis (5.4) -------------------------------ADVERSE REACTIONS------------------------------ Common adverse reactions to systemically administered epinephrine include anxiety, apprehensiveness, restlessness, tremor, weakness, dizziness, sweating, palpitations, pallor, nausea and vomiting, headache, and respiratory difficulties. Arrhythmias, including fatal ventricular fibrillation, rapid rises in blood pressure producing cerebral hemorrhage, and angina have occurred (6) To report SUSPECTED ADVERSE REACTIONS, contact JHP Pharmaceuticals at 1-866-923-2547 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ------------------------------DRUG INTERACTIONS------------------------------- Sympathomimetic agents: possible additive effects (7) Cardiac glycosides, halogenated hydrocarbon anesthetics, or diuretics: observe for development of cardiac arrhythmias (7) Tricyclic antidepressants, MAO inhibitors, levothyroxine sodium, and certain antihistamines: potentiate effects of epinephrine (7) Beta-adrenergic blocking drugs: antagonize the cardiostimulating and bronchodilating effects of epinephrine (7) Alpha-adrenergic blocking drugs: antagonize the vasoconstricting and hypertensive effects of epinephrine (7) Ergot alkaloids may reverse the pressor response to epinephrine (7) --------------------USE IN SPECIFIC POPULATIONS------------------- Elderly patients and pregnant women may be at greater risk of developing adverse reactions when epinephrine is administered parenterally (8.1, 8.5) See 17 for PATIENT COUNSELING INFORMATION Revised: December 2012
8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Induction and Maintenance of Mydriasis during Intraocular Surgery 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed
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FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Adrenalin®^ is indicated for use as follows:
1.1 Anaphylaxis
Emergency treatment of allergic reactions (Type I), including anaphylaxis, which may result from allergic reactions to insect stings, biting insects, foods, drugs, sera, diagnostic testing substances and other allergens, as well as idiopathic anaphylaxis or exercise- induced anaphylaxis. The signs and symptoms associated with anaphylaxis include hypotension, airway swelling, laryngospasm, bronchospasm, urticaria, pruritus, angioedema, swelling of the eyelids, lips, and tongue, vomiting, diarrhea and abdominal cramps.
1.2 Induction and Maintenance of Mydriasis during Intraocular Surgery
Induction and maintenance of mydriasis during intraocular surgery.
2 DOSAGE AND ADMINISTRATION
2.1 Anaphylaxis
Inject Adrenalin intramuscularly or subcutaneously into the anterolateral aspect of the thigh. The injection may be repeated every 5 to 10 minutes as necessary. For intramuscular administration, use a needle long enough (at least 1/2 inch to 5/8 inch) to ensure the injection is administered into the muscle. Monitor the patient clinically for the severity of the allergic reaction and potential cardiac effects of the drug, with repeat doses titrated to effect. Do not administer repeated injections at the same site, as the resulting vasoconstriction may cause tissue necrosis.
Inspect visually for particulate matter and discoloration prior to administration. Do not use if the solution is colored or cloudy, or if it contains particulate matter.
Adults and Children 30 kg (66 lbs) or more: 0.3 to 0.5 mg (0.3 to 0.5 mL) of undiluted Adrenalin administered intramuscularly or subcutaneously in the anterolateral aspect of the thigh, up to a maximum of 0.5 mg (0.5 mL) per injection, repeated every 5 to 10 minutes as necessary. Monitor clinically for reaction severity and cardiac effects.
Children less than 30 kg (66 lbs): 0.01 mg/kg (0.01 mL/kg) of undiluted Adrenalin administered intramuscularly or subcutaneously in the anterolateral aspect of the thigh, up to a maximum of 0.3 mg (0.3 mL), repeated every 5 to 10 minutes as necessary. Monitor clinically for reaction severity and cardiac effects.
2.2 Induction and Maintenance of Mydriasis during Intraocular Surgery
Adrenalin®^ must be diluted prior to intraocular use. Dilute 1 mL of Adrenalin®^ 1 mg/mL (1:1000) in 100 to 1000 mL of an ophthalmic irrigation fluid to create an epinephrine concentration of 1:100,000 to 1:1,000,000 (10 mcg/mL to 1 mcg/mL). Use the irrigating solution as needed for the surgical procedure.
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Epinephrine should be administered with caution in patients who have heart disease, including patients with cardiac arrhythmias, coronary artery or organic heart disease, cerebrovascular 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) ]
Other Patients and Diseases
Epinephrine should be administered with caution to patients with hyperthyroidism, Parkinson’s disease, diabetes mellitus, pheochromocytoma, elderly individuals, and pregnant women. Patients with Parkinson’s disease may experience psychomotor agitation or notice a temporary worsening of symptoms. Diabetic patients may experience transient increases in blood sugar.
5.4 Allergic Reactions Associated with Sulfite
Adrenalin®^ contains sodium bisulfite which may cause mild to severe allergic reactions including anaphylaxis or asthmatic episodes in susceptible individuals. However, the presence of bisulfite in this product should not preclude its use for the treatment of serious allergic or other emergency situations even if the patient is sulfite-sensitive, as the alternatives to using epinephrine in a life-threatening situation may not be satisfactory.
6 ADVERSE REACTIONS
6.1 Adverse Reactions Associated with Intramuscular/Subcutaneous Use (for Anaphylaxis)
Common adverse reactions to systemically administered epinephrine include anxiety, apprehensiveness, restlessness, tremor, weakness, dizziness, sweating, palpitations, pallor, nausea and vomiting, headache, and respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with heart disease, hypertension, or hyperthyroidism [ see Warnings and Precautions (5.3) ].
Due to the lack of randomized, controlled clinical trials of epinephrine for the treatment of anaphylaxis, the true incidence of adverse reactions associated with the systemic use of epinephrine is difficult to determine. Adverse reactions reported in observational trials, case reports, and studies are listed below by body system:
Cardiovascular: angina, arrhythmias, hypertension, pallor, palpitations, tachyarrhythmia, tachycardia, vasoconstriction, and ventricular ectopy.
Angina may occur in patients with coronary artery disease [see Warnings and Precautions (5.3) ].
Arrhythmias, including fatal ventricular fibrillation, have occurred, particularly in patients with underlying organic heart disease or patients receiving drugs that sensitize the heart to arrhythmias [see Warnings and Precautions (5.3) ].
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Rapid rises in blood pressure associated with epinephrine use have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease [ see Warnings and Precautions (5.3) ].
Respiratory: respiratory difficulties.
Neurological: dizziness , disorientation , excitability , headache , impaired memory , lightheadedness , nervousness , panic, psychomotor agitation, sleepiness , tingling , tremor, and weakness.
Psychiatric: anxiety, apprehensiveness, restlessness.
Gastrointestinal: nausea, vomiting.
Other:
Patients with Parkinson’s disease may experience psychomotor agitation or a temporary worsening of symptoms [see Warnings and Precautions (5.3) ].
Diabetic patients may experience transient increases in blood sugar [see Warnings and Precautions (5.3) ].
Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area [ see Warnings and Precautions (5.2) ]. Adverse events experienced as a result of an injection into these areas include increased heart rate, local reactions including injection site pallor, coldness, hypoesthesia, and tissue loss, or injury at the injection site resulting in bruising, bleeding, discoloration, erythema, and skeletal injury.
Injection into the buttock has resulted in cases of gas gangrene [ see Warnings and Precautions (5.2) ].
Skin: sweating.
6.2 Adverse Reactions Associated with Intraocular Use (for Mydriasis)
Epinephrine containing sodium bisulfite has been associated with corneal endothelial damage when used in the eye at undiluted concentrations (1 mg/mL).
7 DRUG INTERACTIONS
Epinephrine should be administered cautiously to patients taking other sympathomimetic agents because of the possibility of additive effects.
Patients who are concomitantly receiving cardiac glycosides, digitalis, diuretics, quinidine, and other antiarrhythmics should be observed carefully for the development of cardiac arrhythmias [ see Warnings and Precautions (5.3) and Adverse Reactions (6.1) ].
Administer epinephrine cautiously to patients receiving halogenated hydrocarbon general anesthetics, such as halothane, as coadministration may result in arrhythmias.
The effects of epinephrine may be potentiated by tricyclic antidepressants such as imipramine, monoamine oxidase inhibitors (MAOI), levothyroxine sodium, and certain antihistamines, notably diphenhydramine, tripelannamine, and dexchlorpheniramine.
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Clinical use data support weight-based dosing for treatment of anaphylaxis in pediatric patients, and other reported clinical experience with the use of epinephrine suggests that the adverse reactions seen in children are similar in nature and extent to those both expected and reported in adults.
The safety and effectiveness of epinephrine (at a dilution of 1:100,000 to 1:400,000) for induction and maintenance of mydriasis during intraocular surgery have been established in pediatric patients. Use of Adrenalin for induction and maintenance of mydriasis during intraocular surgery in pediatric patients is supported by adequate and well controlled studies in adults and uncontrolled studies in pediatric patients.
8.5 Geriatric Use
Clinical studies for the treatment of anaphylaxis have not been performed in subjects aged 65 and over to determine whether they respond differently from younger 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. Therefore, for the treatment of anaphylaxis, consider starting with a lower dose to take into account potential concomitant disease or other drug therapy.
For induction and maintenance of mydriasis during intraocular surgery, no overall differences have been observed between elderly and other patients.
10 OVERDOSAGE
Overdosage of epinephrine may 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. Treatment consists of a rapidly acting α-adrenergic blocking drug and respiratory support.
Epinephrine is rapidly inactivated in the body and treatment following overdose with epinephrine is primarily supportive. 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.
Epinephrine overdosage can also cause transient bradycardia followed by tachycardia and these may be accompanied by potentially fatal cardiac arrhythmias. Premature ventricular contractions may appear within one minute after injection and may be followed by multifocal ventricular tachycardia (prefibrillation rhythm). Subsidence of the ventricular effects may be followed by atrial tachycardia and occasionally by atrioventricular block. Treatment of arrhythmias consists of administration of a beta- adrenergic blocking drug such as propranolol.
Overdosage sometimes results in extreme pallor and coldness of the skin, metabolic acidosis due to elevated blood lactic acid levels, and kidney failure. Suitable corrective measures must be taken in such situations.
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11 DESCRIPTION
Adrenalin®^ (epinephrine injection, USP) is a clear, colorless, sterile solution containing 1 mg/mL (1:1000) epinephrine in a 3 mL clear glass vial. Each 1 mL of Adrenalin® solution contains 1 mg epinephrine, 9.0 mg sodium chloride, 1.0 mg sodium metabisulfite, hydrochloric acid to adjust pH, and water for injection. The pH range is 2.2-5.0.
Epinephrine is a sympathomimetic catecholamine. The chemical name of epinephrine is: 1,2-Benzenediol, 4-[(1R)-1-hydroxy-2-(methylamino)ethyl]-, or (-)-3,4-Dihydroxy-α-[2- (methylamino)ethyl]benzyl alcohol.
The chemical structure of epinephrine is:
The molecular weight of epinephrine is 183.2.
Epinephrine solution deteriorates rapidly on exposure to air or light, turning pink from oxidation to adrenochrome and brown from the formation of melanin.
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.
Epinephrine increases glycogenolysis, reduces glucose up take by tissues, and inhibits insulin release in the pancreas, resulting in hyperglycemia and increased blood lactic acid [ see Warnings and Precautions (5.3) ].
Epinephrine causes mydriasis when administered intraocularly or parenterally.
12.3 Pharmacokinetics
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Store between 20°C to 25°C (68°F to 77°F). (See USP Controlled Room Temperature.) Epinephrine is light sensitive. Protect from light and freezing.
Inspect visually for particulate matter and discoloration prior to administration. Do not use the solution if it is colored or cloudy, or if it contains particulate matter.
17 PATIENT COUNSELING INFORMATION
Advise patients or their caregivers about common adverse reactions associated with the use of epinephrine including an increase in heart rate, the sensation of a more forceful heartbeat, palpitations, sweating, nausea and vomiting, difficulty breathing, pallor, dizziness, weakness or shakiness, headache, apprehension, nervousness, or anxiety. These symptoms and signs usually subside rapidly, especially with rest, quiet and recumbent positioning.
Warn patients with a good response to initial treatment about the possibility of recurrence of symptoms and instruct patients to obtain proper medical attention if symptoms return.
Warn patients with diabetes that they may develop increased blood glucose levels following epinephrine administration.
Manufactured and Distributed by: JHP Pharmaceuticals, LLC Rochester, MI 48307
Adrenalin®^ is a registered trademark of JHP Pharmaceuticals LLC (Parsippany, NJ). US Patent No 53,
