`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
`
` EPINEPHRINE INJECTION USP safely and effectively. See full
`
` prescribing information for EPINEPHRINE INJECTION USP.
`
`
`
`
`
`EPINEPHRINE INJECTION USP, 1 mg/mL (1:1000) ampule, for
`
`
`
`
`intravenous, intramuscular, subcutaneous, and intraocular use
`
`
`
`
`Initial U.S. Approval: 1939
`
`
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`
`Indications and Usage (1.2)
`02/2016
`
`
`Indications and Usage (1.3)
`10/2015
`
`
`Dosage and Administration (2.1, 2.3)
`02/2016
`
`
`Dosage and Administration (2.4)
`10/2015
`
`
`Warnings and Precautions (5.7)
`10/2015
`
`
`
`Warnings and Precautions (5.1, 5.3, 5.4, 5.6, 5.9)
`02/2016
`
`
`
`
`
`Warnings and Precautions (5.8)
`05/2016
`
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`Epinephrine is a non-selective alpha and beta adrenergic agonist indicated:
`
`
`
`
`
`• To increase mean arterial blood pressure in adult patients with
`
`
`
`
`
`
`
`hypotension associated with septic shock. (1.1)
`
`
`
`• For emergency treatment of allergic reactions (Type 1), including
`
`
`
`anaphylaxis. (1.2)
`• For induction and maintenance of mydriasis during intraocular surgery.
`
`
`
`
`(1.3)
`
`
`
`
`
`
`
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`• Monitor patient for acute severe hypertension. (5.1)
`
`
`• Avoid extravasation into tissues, which can cause local necrosis. (5.2)
`
`
`
`
`• Do not inject into buttocks, digits, hands, or feet. (5.3)
`
`
`
`
`• Potential for pulmonary edema, which may be fatal. (5.4)
`
`
`
`
`• May constrict renal blood vessels and decrease urine formation. (5.5)
`
`
`
`
`
`• May induce potentially serious cardiac arrhythmias or aggravate angina
`
`
`
`
`pectoris, particularly in patients with underlying heart disease. (5.6)
`
`
`
`• Rare cases of serious skin and soft tissue infections have been reported
`
`
`
`following epinephrine injection. Advise patients to seek medical care if
`
`
`they develop signs or symptoms of infection. (5.8)
`
`• Patients with hyperthyroidism, Parkinson's disease, diabetes, and
`
`
`
`
`
`pheochromocytoma are at greater risk of having adverse reactions when
`
`used intravenously, intramuscularly, or subcutaneously. (5.9)
`
`
`
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`
`Most common adverse reactions to systemically administered epinephrine are
`
`
`
`headache; anxiety; apprehensiveness; restlessness; tremor; weakness;
`
`
`
`dizziness; sweating; palpitations; pallor; peripheral coldness; nausea/vomiting;
`
`and/or respiratory difficulties. Arrhythmias, including fatal ventricular
`
`
`
`fibrillation, rapid rises in blood pressure producing cerebral hemorrhage, and
`
`
`
`angina have occurred. (6.1, 6.2)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Belcher
`
`Pharmaceuticals at (727) 471-0850 or FDA at 1-800-FDA-1088 or
`
`
`
`
`www.fda.gov/medwatch.
`
`
`------------------------------DRUG INTERACTIONS------------------------------­
`
`• Drugs that counter the pressor effects of epinephrine include alpha
`
`
`
`blockers, vasodilators such as nitrates, diuretics, antihypertensives, and
`
`
`
`ergot alkaloids. (7)
`
`
`• Drugs that potentiate the effects of epinephrine include
`
`
`
`
`sympathomimetics, beta blockers, tricyclic antidepressants, MAO
`
`inhibitors, COMT inhibitors, clonidine, doxapram, oxytocin,
`
`levothyroxine sodium, and certain antihistamines. (7)
`
`
`
`• Drugs that increase the arrhythmogenic potential of epinephrine include
`
`
`
`beta blockers, cyclopropane and halogenated hydrocarbon anesthetics,
`
`
`
`quinidine, antihistamines, exogenous thyroid hormones, diuretics, and
`
`
`
`
`cardiac glycosides. Observe for development of cardiac arrhythmias. (7)
`
`
`• Potassium-depleting drugs, including corticosteroids, diuretics, and
`
`
`theophylline, potentiate the hypokalemic effects of epinephrine. (7)
`
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------­
`
`• Pregnancy: Epinephrine may lead to fetal anoxia, spontaneous abortion or
`
`
`
`
`both. (8.1)
`
`
`• 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
`
`
`
`
`
`
`•
`
`
`
`
`
`
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`• Hypotension associated with septic shock:
`
`
`o Dilute epinephrine in dextrose solution prior to infusion. (2.2)
`
`
`
`
`o Infuse epinephrine into a large vein. (2.2)
`
`
`o Intravenous infusion rate of 0.05 mcg/kg/min to 2 mcg/kg/min, titrated
`
`
`
`
`
`
`
`to achieve desired mean arterial pressure (2.2)
`
`
`o Wean gradually. (2.2)
`
`
`
`• Anaphylaxis:
`
`
`o Adults and Children 30 kg (66 lbs) or more: 0.3 to 0.5 mg (0.3 to
`
`
`
`
`
`
`
`0.5 mL) intramuscularly or subcutaneously into anterolateral aspect of
`
`
`
`the thigh every 5 to 10 minutes as necessary. (2.3)
`
`
`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. (2.3)
`
`
`Intraocular surgery:
`
`o Dilute 1 mL with 100 to 1000 mL of an ophthalmic irrigation fluid, for
`
`
`
`
`ophthalmic irrigation or intracameral injection. (2.4)
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`Injection solution: 1 mg/1 mL (1:1000), 2 mL single-use ampule. (3)
`
`
`
`
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`None. (4)
`
`
`
`
`2
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`1.1 Hypotension associated with Septic Shock
`
`
`1.2 Anaphylaxis
`
`1.3
`Induction and Maintenance of Mydriasis during Intraocular
`
`
`
`
`Surgery
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1 General Considerations
`
`
`2.2 Hypotension associated with Septic Shock
`
`
`2.3 Anaphylaxis
`
`2.4
`Induction and Maintenance of Mydriasis during Intraocular
`
`
`
`
`Surgery
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Hypertension
`
`
`5.2 Extravasation and Tissue Necrosis with Intravenous Infusion
`
`
`
`5.3
`Incorrect Locations of Injection for Anaphylaxis
`
`
`
`5.4
`Pulmonary Edema
`
`
`5.5 Renal Impairment
`
`
`5.6 Cardiac Arrhythmias and Ischemia
`
`
`
`5.7
`Injury with Undiluted Intraocular Solution
`
`
`
`5.8
`Serious Infections at the Injection Site
`
`
`
`5.9 Other Disease Interactions
`
`
`Revised: 5/2016
`
`
`
`
`
`6
`
`
`7
`
`8
`
`
`ADVERSE REACTIONS
`
`
` 6.1 Adverse Reactions associated with Epinephrine Infusion (for
`
`Hypotension associated with Septic Shock)
`
`
`6.2 Adverse Reactions associated with Intramuscular or
`
`Subcutaneous Use (for Anaphylaxis)
`
`
`6.3 Adverse Reactions Associated with Intraocular Use (for
`
`Mydriasis)
`
`DRUG INTERACTIONS
`
`USE IN SPECIFIC POPULATIONS
`
`
`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
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`Reference ID: 3932746
`
`
`
`
`1
`
`

`

`
`
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Hypotension associated with Septic Shock
`
`14.2
`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.
`
`
`
`
`
`
`Reference ID: 3932746
`
`
`
`
`2
`
`

`

`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`1
`
`
`INDICATIONS AND USAGE
`
`
`1.1 Hypotension associated with Septic Shock
`
`
`
`
`Epinephrine Injection USP, 1 mg/mL (1:1000) is indicated to increase mean arterial blood
`
`
`
`
`
`
`
`pressure in adult patients with hypotension associated with septic shock.
`
`
`
`
`
`
`Anaphylaxis
`1.2
`
`
`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 flushing,
`
`apprehension, syncope, tachycardia, thready or unobtainable pulse associated with hypotension,
`convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, airway swelling,
`laryngospasm, bronchospasm, pruritus, urticaria or angioedema, swelling of the eyelids, lips, and
`tongue.
`
`
`
`
`
`
`
`Induction and Maintenance of Mydriasis during Intraocular Surgery
`1.3
`
`Induction and maintenance of mydriasis during intraocular surgery.
`
`2
`
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1 General Considerations
`
`
`Inspect visually for particulate matter and discoloration prior to administration, whenever
`
`
`
`solution and container permit. Do not use if the solution is colored or cloudy, or if it contains
`
`particulate matter. Discard any unused portion.
`
`
`
`2.2 Hypotension associated with Septic Shock
`
`
`
`
`Dilute epinephrine in 5 percent dextrose solution or 5 percent dextrose and sodium chloride
`
`solution. These dextrose containing fluids provide protection against significant loss of potency
`
`by oxidation. Administration in saline solution alone is not recommended. Whole blood or
`
`
`plasma, if indicated to increase blood volume, should be administered separately.
`
`
`Add 1 mL (1 mg) of epinephrine from its ampule to 1,000 mL of a 5 percent dextrose containing
`
`
`
`solution. Each mL of this dilution contains 1 mcg of epinephrine.
`
`
`
`Correct blood volume depletion as fully as possible before any vasopressor is administered.
`
`
`When, as an emergency measure, intraaortic pressures must be maintained to prevent cerebral or
`
`
`coronary artery ischemia, epinephrine can be administered before and concurrently with blood
`
`
`volume replacement.
`
`
`
`Reference ID: 3932746
`
`
`
`
`3
`
`

`

`
`
` Whenever possible, give infusions of epinephrine into a large vein. Avoid using a catheter tie-in
`
`
`technique, because the obstruction to blood flow around the tubing may cause stasis and
`increased local concentration of the drug. Occlusive vascular diseases (for example,
`
`
`
`
`atherosclerosis, arteriosclerosis, diabetic endarteritis, Buerger’s disease) are more likely to occur
`
`
`
`in the lower than in the upper extremity; therefore, avoid the veins of the leg in elderly patients
`
`or in those suffering from such disorders. There is potential for gangrene in a lower extremity
`
`
`when infusions of catecholamine are given in an ankle vein.
`
`
`
`
`
` To provide hemodynamic support in septic shock associated hypotension in adult patients, the
`
` suggested dosing infusion rate of intravenously administered epinephrine is 0.05 mcg/kg/min to
`
`
` 2 mcg/kg/min, and is titrated to achieve a desired mean arterial pressure (MAP). The dosage may
`
`
` be adjusted periodically, such as every 10 - 15 minutes, in increments of 0.05 mcg/kg/min to
`
`
`
`
`
`
` 0.2 mcg/kg/min, to achieve the desired blood pressure goal.
`
`
`
`
`
`
`Continuous epinephrine infusion is generally required over several hours or days until the
`
`patient’s hemodynamic status improves. The duration of perfusion or total cumulative dose
`
`cannot be predicted.
`
`
`
`
`After hemodynamic stabilization, wean incrementally over time, such as by decreasing doses of
`
`
`epinephrine every 30 minutes over a 12- to 24-hour period.
`
`
`
`
`
`Anaphylaxis
`2.3
`
`Inject epinephrine intramuscularly or subcutaneously into the anterolateral aspect of the thigh,
`through clothing if necessary. When administering to a child, to minimize the risk of injection
`
`
`related injury, hold the leg firmly in place and limit movement prior to and during an injection.
`
`
`
`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.
`
`
`Adults and Children 30 kg (66 lbs) or more: 0.3 to 0.5 mg (0.3 mL to 0.5 mL) of undiluted
`epinephrine 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 epinephrine
`
`
`administered intramuscularly or subcutaneously in the anterolateral aspect of the thigh, up to a
`
`maximum of 0.3 mg (0.3 mL) per injection, repeated every 5 to 10 minutes as necessary.
`
`
`Monitor clinically for reaction severity and cardiac effects.
`
`
`Reference ID: 3932746
`
`
`
`
`4
`
`

`

`
`
`
`
` Induction and Maintenance of Mydriasis during Intraocular Surgery
` 2.4
`
`
`
`
`
` Epinephrine must be diluted prior to intraocular use. Dilute 1 mL of epinephrine 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.
`
`
`
`After dilution in an ophthalmic irrigating fluid, epinephrine may also be injected intracamerally
`
`
`as a bolus dose of 0.1 mL at a dilution of 1:100,000 to 1:400,000 (10 mcg/mL to 2.5 mcg/mL).
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`Injection solution: 1 mg/1 mL (1:1000) epinephrine as a sterile solution in a 2 mL single-use
`
`
`
`
`
`clear glass ampule, marked Epinephrine Injection USP, 1 mg/mL (1:1000).
`
`
`
`
`
`CONTRAINDICATIONS
`
`
`4
`
`None.
`
`
`5
`
`
`WARNINGS AND PRECAUTIONS
`
`
`5.1 Hypertension
`
`
`When Epinephrine Injection is administered intravenously, titrate the infusion while monitoring
`
`
`
`
`
`vital signs. Invasive arterial blood pressure monitoring and central venous pressure monitoring
`
`
`
`
`are recommended. Because of varying response to epinephrine, dangerously high blood pressure
`
`
`
`
`may occur.
`
`
`Patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or
`
`
`
`
`imipramine types may experience severe, prolonged hypertension when given epinephrine.
`
`Extravasation and Tissue Necrosis with Intravenous Infusion
`5.2
`
`
`
`
`When Epinephrine Injection is administered intravenously, the infusion site should be checked
`
`frequently for free flow. Avoid extravasation of epinephrine into the tissues, to prevent local
`
`
`
`
`
`necrosis. Blanching along the course of the infused vein, sometimes without obvious
`
`
`extravasation, may be attributed to vasa vasorum constriction with increased permeability of the
`
`
`vein wall, permitting some leakage. This also may progress on rare occasions to superficial
`
`
`slough. Hence, if blanching occurs, consider changing the infusion site at intervals to allow the
`
`effects of local vasoconstriction to subside.
`
`
`Antidote for Extravasation Ischemia: To prevent sloughing and necrosis in areas in which
`
`
`extravasation has taken place, infiltrate the area with 10 mL to 15 mL of saline solution
`
`
`
`containing from 5 mg to 10 mg of phentolamine, an adrenergic blocking agent. Use a syringe
`
`
`
`with a fine hypodermic needle, with the solution being infiltrated liberally throughout the area,
`
`which is easily identified by its cold, hard, and pallid appearance. Sympathetic blockade with
`
`phentolamine causes immediate and conspicuous local hyperemic changes if the area is
`
`infiltrated within 12 hours.
`
`
`Reference ID: 3932746
`
`
`
`
`5
`
`

`

`
`
` 5.3
` Incorrect Locations of Injection for Anaphylaxis
`
`
`
`
` When Epinephrine Injection is used for the treatment of anaphylaxis, the most appropriate
`location for administration is into the anterolateral aspect of the thigh (vastus lateralis muscle)
`
`
`
`
`because of its location, size, and available blood flow. Injection into (or near) smaller muscles,
`such as in the deltoid, is not recommended due to possible differences in absorption associated
`with this use.
`
`
`Do not administer repeated injections of epinephrine at the same site, as the resulting
`
`
`
`vasoconstriction may cause tissue necrosis.
`
`
`Do not inject into buttock. Injection into the buttock may not provide effective treatment of
`
`
`anaphylaxis and has been associated with the development of Clostridial infections (gas
`
`
`
`gangrene). Cleansing with alcohol does not kill bacterial spores, and therefore, does not lower
`
`this risk.
`
`
`Do not inject into digits, hands, or feet. Epinephrine is a strong vasoconstrictor. Accidental
`
`
`
`injection into the digits, hands or feet may result in loss of blood flow to the affected area and
`has been associated with tissue necrosis.
`
`
`
`Pulmonary Edema
`5.4
`
`
`When Epinephrine Injection is administered intravenously, there is risk of pulmonary edema
`
`
`because of the peripheral constriction and cardiac stimulation produced. Treatment of pulmonary
`
`
`
`
`edema consists of a rapidly acting alpha-adrenergic blocking drug (such as phentolamine
`
`
`
`
`mesylate) and respiratory support.
`
`
`
`Renal Impairment
`5.5
`
`
`Intravenously administered epinephrine initially may produce constriction of renal blood vessels
`
`
`
`and decrease urine formation.
`
`
`Cardiac Arrhythmias and Ischemia
`5.6
`
`
`
`Epinephrine may induce cardiac arrhythmias and angina pectoris in patients, especially patients
`
`
`
`
`
`suffering from coronary artery disease, organic heart disease, cerebrovascular disease,
`
`
`
`
`hypertension, or patients who are receiving drugs that sensitize the myocardium [see Adverse
`
`
`
`Reactions (6) and Drug Interactions (7)]. Treatment of arrhythmias consists of administration of
`
`
`
`
`a beta-adrenergic blocking drug (such as propranolol).
`
`
`
`Injury with Undiluted Intraocular Solution
`5.7
`
`
`Epinephrine must be diluted before intraocular use. Other epinephrine products that contain
`
`
`
`
`
`
`sodium bisulfite have been associated with corneal endothelial damage when used in the eye at
`
`
`
`
`undiluted concentrations (1 mg/mL). Although this Epinephrine product contains no sulfites or
`
`
`
`
`preservatives, warning is still advised [see Dosage and Administration (2.4)].
`
`
`
`Reference ID: 3932746
`
`
`
`
`6
`
`

`

`
`
` Serious Infections at the Injection Site
` 5.8
`
`
` Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and
`
`myonecrosis caused by Clostridia (gas gangrene), have been reported at the injection site
`
`
`
`
`
`following epinephrine injection for anaphylaxis. Clostridium spores can be present on the skin
`
`
`
`
`and introduced into the deep tissue with subcutaneous or intramuscular injection. While
`
`
`cleansing with alcohol may reduce presence of bacteria on the skin, alcohol cleansing does not
`
`
`
`kill Clostridium spores. To decrease the risk of Clostridium infection, do not inject Epinephrine
`
`
`
`
`
`Injection into the buttock [see Warnings and Precautions (5.3)]. Advise patients to seek medical
`
`
`care if they develop signs or symptoms of infection, such as persistent redness, warmth, swelling,
`
`or tenderness, at the epinephrine injection site.
`
`
`
`5.9 Other Disease Interactions
`
`
`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.
`
`Despite these concerns, the presence of these conditions is not a contraindication to epinephrine
`
`administration in an acute, life-threatening situation.
`
`
`6
`
`
`ADVERSE REACTIONS
`
`
`Adverse Reactions associated with Epinephrine Infusion (for Hypotension
`6.1
`
`
`
`
`
`
`associated with Septic Shock)
`
`
`
`The following adverse reactions associated with the infusion of epinephrine were identified in
`
`
`
`the literature. Because these reactions are reported voluntarily from a population of uncertain
`
`
`size, it is not always possible to estimate their frequency reliably or to establish a causal
`
`
`relationship to drug exposure.
`
`
`
`Cardiovascular disorders: tachycardia, supraventricular tachycardia, ventricular arrhythmias,
`
`
`
`
`
`myocardial ischemia, myocardial infarction, limb ischemia, pulmonary edema
`
`Gastrointestinal disorders: Nausea, vomiting
`General disorders and administrative site conditions: Chest pain, extravasation,
`
`
`Metabolic: hypoglycemia, hyperglycemia, insulin resistance, hypokalemia, lactic acidosis
`
`
`
`Nervous system disorders: Headache, nervousness, paresthesia, tremor, stroke, central nervous
`
`
`system bleeding
`
`Psychiatric disorders: Excitability
`
`Renal disorders: Renal insufficiency
`
`Respiratory: Pulmonary edema, rales
`
`
`Skin and subcutaneous tissue disorders: Diaphoresis, pallor, piloerection, skin blanching, skin
`
`necrosis with extravasation
`
`
`Reference ID: 3932746
`
`
`
`
`7
`
`

`

`
`
`
`
`
`
`
`
`
`
` Adverse Reactions associated with Intramuscular or Subcutaneous Use (for
` 6.2
`
`
` 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 (5.9)].
`
`
`
`
` 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 (5.6)]. 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 (5.6)]. Rapid rises in blood pressure associated with epinephrine use have produced
`
`
`
`cerebral hemorrhage, particularly in elderly patients with cardiovascular disease [see Warnings
`
`
`
`and Precautions (5.6)].
`
`
`
`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.
`
`Skin: sweating.
`
`
`Other:
`
`
`Patients with Parkinson’s disease may experience psychomotor agitation or a temporary
`
`
`
`worsening of symptoms [see Warnings and Precautions (5.9]. Diabetic patients may experience
`
`
`transient increases in blood sugar [see Warnings and Precautions (5.9)].
`
`
`
`
`
`Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected
`
`
`area [see Warnings and Precautions (5.3)]. 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
`
`
`
`(5.3)].
`
`
`Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and
`
`myonecrosis caused by Clostridia (gas gangrene), have been reported following epinephrine
`
`
`
`
`injection in the thigh [see Warnings and Precautions (5.8)].
`
`
`
`
`
`
`
`Reference ID: 3932746
`
`
`
`
`8
`
`

`

`
`
` 6.3
` Adverse Reactions Associated with Intraocular Use (for Mydriasis)
`
`
`
`
`
`
`
`
` Epinephrine products containing sodium bisulfite have been associated with corneal endothelial
`
` damage when used in the eye at undiluted concentrations (1 mg/mL). Although this Epinephrine
`
` product contains no sulfites or preservatives, warning is still advised [see Warnings and
`
` Precautions (5.7)].
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Belcher Pharmaceuticals at
`
`
`
`
`(727) 471-0850 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`DRUG INTERACTIONS
`7
`
`
`Drugs antagonizing pressor effects of epinephrine
`
`
`• α-blockers, such as phentolamine
`
`
`• Vasodilators, such as nitrates
`
`
`• Diuretics
`
`
`
`• Antihypertensives
`
`• Ergot alkaloids
`
`
`Drugs potentiating pressor effects of epinephrine
`
`
`
`• Sympathomimetics
`
`
`• β-blockers, such as propranolol
`
`
`• Tricyclic anti-depressants
`
`
`• Monoamine oxidase (MAO) inhibitors
`
`
`
`• Catechol-O-methyl transferase (COMT) inhibitors, such as entacapone
`
`
`• Clonidine
`
`
`• Doxapram
`
`
`• Oxytocin
`
`
`Drugs potentiating arrhythmogenic effects of epinephrine. Patients who are concomitantly
`
`
`
`
`receiving any of the following drugs should be observed carefully for the development of cardiac
`
`
`
`arrhythmias [see Warnings and Precautions (5.6) and Adverse Reactions (6)].
`
`
`
`
`
`• β-blockers, such as propranolol
`
`
`
`• Cyclopropane or halogenated hydrocarbon anesthetics, such as halothane
`
`
`• Antihistamines
`
`
`• Thyroid hormones
`
`
`• Diuretics
`
`
`• Cardiac glycosides, such as digitalis glycosides
`
`
`
`
`• Quinidine
`
`
`Drugs potentiating hypokalemic effects of epinephrine
`
`
`• Potassium depleting diuretics
`
`
`• Corticosteroids
`
`
`
`• Theophylline
`
`
`
`
`Reference ID: 3932746
`
`
`
`
`9
`
`

`

`
`
`Epinephrine should not be used to counteract circulatory collapse or hypotension caused by
`
`
`phenothiazines, as a reversal of the pressor effects of epinephrine may result in further lowering
`
`of blood pressure.
`
`
`Epinephrine may antagonize the neuronal blockade produced by guanethidine resulting in
`
`
`decreased antihypertensive effect and requiring increased dosage of the latter.
`
`
`
`
`8
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`
`
`
`Pregnancy
`8.1
`
`
`Teratogenic Effects: Pregnancy Category C:
`
`
`
`
` There are no adequate and well-controlled studies in pregnant women. Epinephrine crosses the
`
`
`
` placenta. Epinephrine should be used during pregnancy only if the potential benefit justifies the
`
` potential risk to the fetus (fetal anoxia, spontaneous abortion, or both). Epinephrine is teratogenic
`
`
` in rabbits, mice, and hamsters dosed during organogenesis.
`
` Epinephrine has been shown to have teratogenic effects (including gastroschisis and embryonic
`
`
`lethality) when administered subcutaneous in rabbits at approximately 15 times the maximum
`recommended intramuscular or subcutaneous dose (on a mg/m2 basis at a maternal subcutaneous
`
`
`
`
`dose of 1.2 mg/kg/day for two to three days).
`
`In mice, teratogenic effects (including embryonic lethality) were observed at approximately 3
`times the maximum recommended intramuscular or subcutaneous dose (on a mg/m2 basis at
`
`
`
`
`
`
`
`maternal subcutaneous dose of 1 mg/kg/day for 10 days). These effects were not seen in mice at
`
`approximately 2 times the maximum recommended daily intramuscular or subcutaneous dose
`(on a mg/m2 basis at a subcutaneous maternal dose of 0.5 mg/kg/day for 10 days).
`
`
`
`
`
`In hamsters, teratogenic effects were observed at approximately 2 times the maximum
`recommended intramuscular or subcutaneous dose (on a mg/m2 basis at a maternal subcutaneous
`
`
`
`
`dose of 0.5 mg/kg/day for 4 days).
`
`
`
`
`
`Labor and Delivery
`8.2
`Epinephrine usually inhibits spontaneous or oxytocin induced contractions of the pregnant
`
`
`human uterus and may delay the second stage of labor. Avoid epinephrine during the second
`
`
`
`
`
`stage of labor. In dosage sufficient to reduce uterine contractions, the drug may cause a
`
`prolonged period of uterine atony with hemorrhage. Avoid epinephrine in obstetrics when
`
`
`
`maternal blood pressure exceeds 130/80 mmHg.
`
`
`Use with caution during labor and delivery. Although epinephrine improves maternal
`hypotension associated with anaphylaxis, it may result in uterine vasoconstriction, decreased
`
`
`uterine blood flow, and fetal anoxia.
`
`Reference ID: 3932746
`
`
`
`
`10
`
`

`

`
`
`Nursing Mothers
`8.3
`
`
`It is not known whether epinephrine is excreted in human milk. Because many drugs are excreted
`
`
`in human milk, caution should be exercised when epinephrine is administered to a nursing
`
`woman.
`
`
`Pediatric Use
`8.4
`
`
`Safety and effectiveness of epinephrine in pediatric patients with septic shock have not been
`
`
`established.
`
`
`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 epinephrine 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 of epinephrine for the treatment of hypotension associated with septic shock did
`
`not include sufficient numbers of subjects aged 65 and over to determine whether they respond
`
`
`differently from younger subjects. Other reported clinical experience has not identified
`
`
`differences in responses between the elderly and younger patients. In general, dose selection for
`
`
`
`an elderly patient should be cautious, usually starting at the low end of the dosing range,
`
`reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of
`
`
`concomitant disease or other drug therapy.
`
`
`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.
`
`
`
`Reference ID: 3932746
`
`
`
`
`11
`
`

`

`
`
`OVERDOSAGE
`10
`
`
`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.
`
`
`
`Epinephrine overdosage may 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
`
`
`
`tachyca