`
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`205029Orig1s000
`LABELING
`
`
`
`

`

`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 (1:1,000) ampule for IV
`infusion
`Initial U.S. Approval: 1939
`----------------------------INDICATIONS AND USAGE---------------------------
`Epinephrine is an alpha and beta adrenergic agonist indicated to increase
`mean arterial blood pressure in adult patients with hypotension associated
`with septic shock. (1)
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`(cid:120) Dilute epinephrine in dextrose solution prior to infusion. (2)
`(cid:120) Infuse epinephrine into a large vein. (2)
`(cid:120) Intravenous infusion rate of 0.05 mcg/kg/min to 2 mcg/kg/min, titrated to
`achieve desired mean arterial pressure (2)
`(cid:120) Wean gradually. (2)
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`2 mL ampule containing 1 mg/1 mL epinephrine (1:1,000 Injection, USP). (3)
`-------------------------------CONTRAINDICATIONS------------------------------
`None. (4)
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`(cid:120) Correct blood volume depletion. (5.1)
`(cid:120) Titrate carefully while patient vital signs are continuously monitored.
`(5.2)
`(cid:120) Avoid extravasation into tissues, which can cause local necrosis. (5.3)
`(cid:120) Potential for pulmonary edema, which may be fatal (5.4)
`(cid:120) May constrict renal blood vessels and decrease urine formation. (5.5)
`(cid:120) May induce potentially serious cardiac arrhythmias in patients. (5.6)
`(cid:120) MAO inhibitors and antidepressants may prolong hypertension. (5.7)
`
`------------------------------ADVERSE REACTIONS-------------------------------
`Most common adverse reactions (incidence > 1%) are headache; anxiety;
`restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor;
`peripheral coldness; nausea/vomiting; and/or respiratory difficulties. (6)
`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-------------------------------
`(cid:120) Drugs that counter the pressor effects of epinephrine include alpha
`blockers, vasodilators such as nitrates, diuretics, and antihypertensives.
`(7.1)
`(cid:120) Drugs that potentiate the pressor effects of epinephrine include
`sympathomimetics, beta blockers, tricyclic antidepressants, MAO
`inhibitors, COMT inhibitors, clonidine, doxapram, and oxytocin. (7.2)
`(cid:120) Drugs that increase the arrhythmogenic potential of epinephrine include
`beta blockers, cyclopropane and halogenated hydrocarbon anesthetics,
`antihistamines, exogenous thyroid hormones, diuretics, and digitalis
`glycosides. (7.2)
`(cid:120) Potassium-depleting drugs, including corticosteroids, diuretics, and
`theophylline, potentiate the hypokalemic effects of epinephrine. (7.2)
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`(cid:120) Pregnancy: Epinephrine may lead to fetal anoxia, spontaneous abortion
`or both. (8.1)
`(cid:120) Avoid breast-feeding with epinephrine. (8.3)
`See 17 for PATIENT COUNSELING INFORMATION
`Revised: July 2014
`
`8
`
`6
`7
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`2.2 Recommended Administration
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Blood Volume Replacement
`5.2 Acute Hypertension
`5.3 Extravasation
`5.4
`Pulmonary Edema
`5.5 Renal Impairment
`5.6 Cardiac Arrhythmias
`5.7
`Prolonged Hypertension
`ADVERSE REACTIONS
`DRUG INTERACTIONS
`7.1 Epinephrine’s Effects on Other Drugs
`7.2 Effects of Other Drugs on Epinephrine
`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
`14 CLINICAL STUDIES
`Treating Hypotension from Septic Shock with Epinephrine
`16 HOW SUPPLIED/STORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`17
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`1
`
`

`

`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`Epinephrine Injection USP, 1 mg/mL (1:1,000) is indicated to increase mean arterial blood
`pressure in hypotension associated with septic shock.
`
`DOSAGE AND ADMINISTRATION
`2
`Parenteral drug products should be inspected visually for particulate matter and discoloration
`prior to administration, whenever solution and container permit. Discard any unused portion.
`
`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.
`
`Blood volume depletion should always be corrected 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.
`
`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.
`
`2
`
`

`

`DOSAGE FORMS AND STRENGTHS
`3
`2 mL clear glass ampule containing 1 mg/1 mL epinephrine as the hydrochloride in a sterile,
`preservative free/sulfite free solution, marked Epinephrine Injection USP, 1 mg/mL (1:1,000)
`[see Dosage and Administration(2.2)].
`
`CONTRAINDICATIONS
`
`4
`None.
`
`5
`
`WARNINGS AND PRECAUTIONS
`Blood Volume Replacement
`5.1
`Correct blood volume depletion before any vasopressor is administered.
`
`Acute Hypertension
`5.2
`Titrate epinephrine 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.
`
`Extravasation
`5.3
`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.
`
`Pulmonary Edema
`5.4
`There is risk of pulmonary edema because of the peripheral constriction and cardiac stimulation
`produced.
`
`Renal Impairment
`5.5
`Intravenously administered epinephrine initially may produce constriction of renal blood vessels
`and decrease urine formation.
`
`Cardiac Arrhythmias
`5.6
`Epinephrine may induce cardiac arrhythmias in patients, especially those patients suffering from
`heart disease, organic heart disease, or who are receiving drugs that sensitize the myocardium.
`
`3
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`

`

`Prolonged Hypertension
`5.7
`Patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or
`imipramine types may experience severe, prolonged hypertension when given epinephrine.
`
`ADVERSE REACTIONS
`6
`The following adverse reactions associated with the use 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 resistence, 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
`
`7
`
`DRUG INTERACTIONS
`Epinephrine’s Effects on Other Drugs
`7.1
`Antihypertensives: Epinephrine may antagonize the neuronal blockade produced by
`guanethidine resulting in decreased antihypertensive effect and requiring increased dosage of the
`latter.
`
`7.2
`
`Effects of Other Drugs on Epinephrine
`Drugs antagonizing pressor effects
`(cid:120) (cid:302)-blockers, such as phentolamine
`(cid:120) Vasodilators, such as nitrates
`(cid:120) Diuretics
`(cid:120) Antihypertensives
`
`Drugs potentiating pressor effects
`(cid:120) Sympathomimetics
`(cid:533)-blockers
`(cid:120)
`(cid:120) Tricyclic anti-depressants
`(cid:120) Monoamine oxidase (MAO) inhibitors
`(cid:120) Catechol-O-methyl transferase (COMT) inhibitors, such as entacapone
`(cid:120) Clonidine
`(cid:120) Doxapram
`(cid:120) Oxytocin
`
`4
`
`

`

`Drugs potentiating arrythmogenic effects
`(cid:533)-blockers
`(cid:120)
`(cid:120) Cyclopropane or halogenated hydrocarbon anesthetics, such as halothane
`(cid:120) Antihistamines
`(cid:120) Thyroid hormones
`(cid:120) Diuretics
`(cid:120) Digitalis glycosides
`
`Drugs potentiating hypokalemic effects
`(cid:120) Potassium depleting diuretics
`(cid:120) Corticosteroids
`(cid:120) Theophylline
`
`8
`
`USE IN SPECIFIC POPULATIONS
`Pregnancy
`8.1
`Pregnancy Category C: Epinephrine has been shown to have developmental effects in rabbits at a
`subcutaneous dose of 1.2 mg/kg (approximately 30 times the maximum recommended daily
`subcutaneous or intramuscular dose on a mg/m2 basis), in mice at a subcutaneous dose of
`1 mg/kg (approximately 7 times the maximum recommended daily subcutaneous or
`intramuscular dose on a mg/m2 basis), and in hamsters at a subcutaneous dose of 0.5 mg/kg
`(approximately 5 times the maximum recommended daily subcutaneous or intramuscular dose
`on a mg/m2 basis). These effects were not seen in mice at a subcutaneous dose of 0.5 mg/kg
`(approximately 3 times the maximum recommended daily subcutaneous or intramuscular dose
`on a mg/m2 basis). Although there are no adequate and well-controlled studies in pregnant
`women, epinephrine crosses the placenta (but not the blood-brain barrier) and could lead to fetal
`anoxia, spontaneous abortion or both. Data from animal studies have shown that epinephrine
`interferes with ovum implantation and fetus survival in rabbits and has teratogenic potential.
`
`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.
`
`Nursing Mothers
`8.3
`Epinephrine is distributed into breast milk. Avoid breast-feeding in mothers receiving infusion of
`epinephrine.
`
`Pediatric Use
`8.4
`Safety and effectiveness of epinephrine in pediatric patients with septic shock have not been
`established.
`
`5
`
`

`

`8.5 Geriatric Use
`Clinical studies of epinephrine 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.
`
`OVERDOSAGE
`10
`Myocardial ischemia and infarction, cardiomyopathy, pulmonary edema, and renal insufficiency
`were observed in literature reports of accidental overdoses.
`
`Toxic effects of overdosage can be counteracted by injection of an alpha-adrenergic blocker
`(such as phentolamine mesylate) and a beta-adrenergic blocker (such as propranolol). Rapid-
`acting vasodilators such as nitrites, or alpha-adrenergic blocking agents can be given to
`counteract the marked pressor effect of large doses of epinephrine causing a sharp rise in the
`blood pressure. Treatment of acute toxicity is mainly supportive since epinephrine is rapidly
`inactivated in the body.
`
`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.
`
`DESCRIPTION
`11
`Epinephrine Injection USP, 1 mg/mL (1:1,000) is supplied as a sterile aqueous solution that is
`colorless and nonpyrogenic. Each milliliter contains 1 mg Epinephrine base (as the
`hydrochloride), Sodium Chloride 9 mg (for isotonicity), and Water for Injection, USP, qs.
`Contains no sulfites. May contain Hydrochloric Acid for pH adjustment.
`
`This sterile solution is to be administered after dilution by the intravenous route. The solution
`contains no preservatives such as sulfites.
`
`Epinephrine, USP is a sympathomimetic (adrenergic) agent designated chemically as 4-[1-
`hydroxy-2 (methylamino) ethyl]-1,2 benzenediol, a white, microcrystalline powder. It has the
`following structural formula:
`
`6
`
`

`

`CLINICAL PHARMACOLOGY
`12
`Mechanism of Action
`12.1
`(cid:40)(cid:83)(cid:76)(cid:81)(cid:72)(cid:83)(cid:75)(cid:85)(cid:76)(cid:81)(cid:72) (cid:68)(cid:70)(cid:87)(cid:86) (cid:82)(cid:81) (cid:69)(cid:82)(cid:87)(cid:75) (cid:68)(cid:79)(cid:83)(cid:75)(cid:68) (cid:11)(cid:302)(cid:12)- (cid:68)(cid:81)(cid:71) (cid:69)(cid:72)(cid:87)(cid:68) (cid:11)(cid:533)(cid:12)-adrenergic receptors. The mechanism of the rise
`in blood pressure is 3-fold: a direct myocardial stimulation that increases the strength of
`ventricular contraction (positive inotropic action), an increased heart rate (positive chronotropic
`action), and peripheral vasoconstriction.
`
`Pharmacodynamics
`12.2
`Following intravenous administration of epinephrine, increases in systolic blood pressure and
`heart rate are observed. Decreases in systemic vascular resistance and diastolic blood pressure
`are observed at low doses of epinephrine because of (cid:533)2-mediated vasodilation, but are overtaken
`(cid:69)(cid:92) (cid:302)1-mediated peripheral vasoconstriction at higher doses leading to increase in diastolic blood
`pressure. The onset of blood pressure increase following an intravenous dose of epinephrine is
`< 5 minutes and the time to offset blood pressure response occurs within 20 min. Most vascular
`beds are constricted including renal, splanchnic, mucosal and skin.
`
`Pharmacokinetics
`12.3
`Following intravenous injection, epinephrine is rapidly cleared from the plasma with an effective
`half-life of < 5 min. A pharmacokinetic steady state following continuous intravenous infusion is
`achieved within 10-15 min. In patients with septic shock, epinephrine displays dose-proportional
`pharmacokinetics in the infusion dose range of 0.03 to 1.7 mcg/kg/min.
`
`Epinephrine is extensively metabolized with only a small amount excreted unchanged.
`Epinephrine is rapidly degraded to vanillylmandelic acid, an inactive metabolite, by monoamine
`oxidase and catechol-O-methyltransferase that are abundantly expressed in the liver, kidneys and
`other extraneuronal tissues. The tissues with the highest contribution to removal of circulating
`exogenous epinephrine are the liver (32%), kidneys (25%), skeletal muscle (20%), and
`mesenteric organs (12%).
`
`Special Populations
`Elderly
`In a pharmacokinetic study of 45-minute epinephrine infusions given to healthy men aged 20 to
`25 years and healthy men aged 60 to 65 years, the mean plasma metabolic clearance rate of
`epinephrine at steady state was greater among the older men (144.8 versus 78 mL/kg/min for a
`14.3 ng/kg/min infusion).
`
`Body Weight
`Body weight has been found to influence epinephrine pharmacokinetics. Higher body weight
`was associated with a higher plasma epinephrine clearance and a lower concentration plateau.
`
`NONCLINICAL TOXICOLOGY
`13
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`Adequate carcinogenesis studies have not been reported. An equivocal response of epinephrine
`was found when tested in Salmonella typhimurium strain TA 100 in the absence of metabolic
`activation system (S9) and negative in the presence of activation system (S9).
`
`7
`
`

`

`There are no data from either animal or human studies regarding potential for the impairment of
`fertility.
`
`Animal Toxicology and/or Pharmacology
`13.2
`Epinephrine was associated with metabolic effects, decreased mesenteric, coronary and renal
`conductance in a sheep model of septic shock. Data from hemolysis study have shown that
`epinephrine at 1:1,000 dilution is non-hemolytic. Epinephrine infusion significantly increased the
`MAP (69 vs. 86 mmHg) and cardiac output (6.4 vs. 7.1 L/min) and decreased renal blood flow
`(330 vs. 247 mL/min).
`
`CLINICAL STUDIES
`14
`Treating Hypotension from Septic Shock with Epinephrine
`Fourteen clinical studies from the literature documented that epinephrine increases the mean
`arterial pressure (MAP) in patients with hypotension associated with septic shock.
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`Epinephrine Injection USP, 1 mg/mL (1:1,000) is a sterile solution containing 1 mg/1 mL
`epinephrine as the hydrochloride in each 2 mL clear glass ampule. Epinephrine contains no
`preservatives, such as sulfites. Supplied in a box of 10 ampules (NDC 62250-103-10).
`
`Protect from light until ready to use.
`Do not refrigerate. Protect from freezing.
`Store at room temperature, between 20 - 25°C (68 - 77°F).
`Protect from alkalis and oxidizing agents.
`Solutions for intravenous use should be inspected visually for particulate matter and
`discoloration, whenever solution and container permit.
`Do not use after the expiration date.
`
`PATIENT COUNSELING INFORMATION
`17
`If possible, interrogate patients regarding any pre-existing conditions, such as heart disease or
`diabetes, medications that they are taking, or any known hypersensitivity to sympathomimetic
`drugs.
`
`Revised: July 2014
`
`Manufactured for:
`
`Belcher Pharmaceuticals, LLC, Largo, FL 33777 USA
`
`Manufactured by:
`
`Sintetica SA
`Via Penate 5
`6850 Mendrisio, Switzerland
`
`8
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`