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` NDA 205029/S-001
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` Page 4
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` HIGHLIGHTS OF PRESCRIBING INFORMATION
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` These highlights do not include all the information needed to use
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` EPINEPHRINE INJECTION USP safely and effectively. See full
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` prescribing information for EPINEPHRINE INJECTION USP.
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` EPINEPHRINE INJECTION USP, 1 mg/mL (1:1,000) ampule for IV
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` infusion and intraocular use
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` Initial U.S. Approval: 1939
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` ----------------------------INDICATIONS AND USAGE---------------------------
` Epinephrine is an alpha and beta adrenergic agonist indicated:
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` To increase mean arterial blood pressure in adult patients with
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` hypotension associated with septic shock. (1.1)
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` For induction and maintenance of mydriasis during intraocular surgery.
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`(1.2)
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` ----------------------DOSAGE AND ADMINISTRATION-----------------------
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` Hypotension associated with septic shock:
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`o Dilute epinephrine in dextrose solution prior to infusion. (2.1)
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`o Infuse epinephrine into a large vein. (2.1)
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`o Intravenous infusion rate of 0.05 mcg/kg/min to 2 mcg/kg/min, titrated
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`to achieve desired mean arterial pressure (2.1)
`o Wean gradually. (2.1)
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` Intraocular surgery:
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`o Dilute 1 mL with 100 to 1000 mL of an ophthalmic irrigation fluid, for
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`ophthalmic irrigation or intracameral injection. (2.2)
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`---------------------DOSAGE FORMS AND STRENGTHS----------------------
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`2 mL ampule containing 1 mg/1 mL epinephrine (1:1,000 Injection, USP). (3)
`-------------------------------CONTRAINDICATIONS------------------------------
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`None. (4)
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`-----------------------WARNINGS AND PRECAUTIONS------------------------
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` Correct blood volume depletion. (5.1)
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` Titrate carefully while patient vital signs are continuously monitored.
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`(5.2)
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` Avoid extravasation into tissues, which can cause local necrosis. (5.3)
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` Potential for pulmonary edema, which may be fatal (5.4)
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` May constrict renal blood vessels and decrease urine formation. (5.5)
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` May induce potentially serious cardiac arrhythmias in patients. (5.6)
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` MAO inhibitors and antidepressants may prolong hypertension. (5.7)
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` Undiluted ophthalmic administration: associated with corneal endothelial
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`damage. (5.8)
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`------------------------------ADVERSE REACTIONS-------------------------------
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`Most common adverse reactions (incidence > 1%) to systemically
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`administered epinephrine are headache; anxiety; restlessness; tremor;
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`weakness; dizziness; sweating; palpitations; pallor; peripheral coldness;
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`nausea/vomiting; and/or respiratory difficulties. (6)
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`To report SUSPECTED ADVERSE REACTIONS, contact Belcher
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`Pharmaceuticals at (727) 471-0850 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
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`------------------------------DRUG INTERACTIONS-------------------------------
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` Drugs that counter the pressor effects of epinephrine include alpha
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`blockers, vasodilators such as nitrates, diuretics, and antihypertensives.
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`(7.1)
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` Drugs that potentiate the pressor effects of epinephrine include
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`sympathomimetics, beta blockers, tricyclic antidepressants, MAO
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`inhibitors, COMT inhibitors, clonidine, doxapram, and oxytocin. (7.2)
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` Drugs that increase the arrhythmogenic potential of epinephrine include
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`beta blockers, cyclopropane and halogenated hydrocarbon anesthetics,
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`antihistamines, exogenous thyroid hormones, diuretics, and digitalis
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`glycosides. (7.2)
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` Potassium-depleting drugs, including corticosteroids, diuretics, and
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`theophylline, potentiate the hypokalemic effects of epinephrine. (7.2)
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`-----------------------USE IN SPECIFIC POPULATIONS------------------------
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` Pregnancy: Epinephrine may lead to fetal anoxia, spontaneous abortion
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`or both. (8.1)
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` Avoid breast-feeding with epinephrine infusion. (8.3)
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`See 17 for PATIENT COUNSELING INFORMATION
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`Revised: June 2015
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`2
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`FULL PRESCRIBING INFORMATION: CONTENTS*
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`INDICATIONS AND USAGE
`1
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`1.1 Hypotension associated with septic shock
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`Induction and maintenance of mydriasis during intraocular
`1.2
`surgery
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`DOSAGE AND ADMINISTRATION
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`2.1 Hypotension associated with septic shock
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`Induction and maintenance of mydriasis during intraocular
`2.2
`surgery
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`3
`DOSAGE FORMS AND STRENGTHS
`4
`CONTRAINDICATIONS
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`5 WARNINGS AND PRECAUTIONS
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`5.1 Blood Volume Replacement
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`5.2 Acute Hypertension
`5.3 Extravasation
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`Pulmonary Edema
`5.4
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`5.5 Renal Impairment
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`5.6 Cardiac Arrhythmias
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`Prolonged Hypertension
`5.7
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`Injury with Undiluted Intraocular Solution
`5.8
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`ADVERSE REACTIONS
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`6.1 Adverse Reactions Associated with Infusion (for Hypotension
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`Associated with Septic Shock)
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`6.2 Adverse Reactions Associated with Intraocular Use (for
`Mydriasis)
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`DRUG INTERACTIONS
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`7.1 Epinephrine’s Effects on Other Drugs
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`6
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`7
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`8
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`7.2 Effects of Other Drugs on Epinephrine
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`USE IN SPECIFIC POPULATIONS
`Pregnancy
`8.1
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`8.2 Labor and Delivery
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`8.3 Nursing Mothers
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`Pediatric Use
`8.4
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`8.5 Geriatric Use
`10 OVERDOSAGE
`10.1 Overdosage associated with Infusion (for Hypotension
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`associated with Septic Shock)
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`DESCRIPTION
`CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`13.2 Animal Toxicology and/or Pharmacology
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`CLINICAL STUDIES
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`14.1 Treating Hypotension from Septic Shock with Epinephrine
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`Induction and Maintenance of Mydriasis during Intraocular
`14.2
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`Surgery
`16 HOW SUPPLIED/STORAGE AND HANDLING
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`PATIENT COUNSELING INFORMATION
`17
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`*Sections or subsections omitted from the full prescribing information are not
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`listed.
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`11
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`14
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`Reference ID: 3837416
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`4
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` NDA 205029/S-001
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` Page 5
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` FULL PRESCRIBING INFORMATION
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`1
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`INDICATIONS AND USAGE
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`1.1 Hypotension associated with septic shock
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`Epinephrine Injection USP, 1 mg/mL (1:1,000) is indicated to increase mean arterial blood
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`pressure in hypotension associated with septic shock.
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`1.2
`Induction and maintenance of mydriasis during intraocular surgery
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`Induction and maintenance of mydriasis during intraocular surgery.
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`2
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`DOSAGE AND ADMINISTRATION
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`2.1 Hypotension associated with septic shock
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`Parenteral drug products should be inspected visually for particulate matter and discoloration
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`prior to administration, whenever solution and container permit. Discard any unused portion.
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`Dilute epinephrine in 5 percent dextrose solution or 5 percent dextrose and sodium chloride
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`solution. These dextrose containing fluids provide protection against significant loss of potency
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`by oxidation. Administration in saline solution alone is not recommended. Whole blood or
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`plasma, if indicated to increase blood volume, should be administered separately.
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`Add 1 mL (1 mg) of epinephrine from its ampule to 1,000 mL of a 5 percent dextrose containing
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`solution. Each mL of this dilution contains 1 mcg of epinephrine.
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`Blood volume depletion should always be corrected as fully as possible before any vasopressor is
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`administered. When, as an emergency measure, intraaortic pressures must be maintained to
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`prevent cerebral or coronary artery ischemia, epinephrine can be administered before and
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`concurrently with blood volume replacement.
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`Whenever possible, give infusions of epinephrine into a large vein. Avoid using a catheter tie-in
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`technique, because the obstruction to blood flow around the tubing may cause stasis and
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`increased local concentration of the drug. Occlusive vascular diseases (for example,
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`atherosclerosis, arteriosclerosis, diabetic endarteritis, Buerger’s disease) are more likely to occur
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`in the lower than in the upper extremity; therefore, avoid the veins of the leg in elderly patients
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`or in those suffering from such disorders. There is potential for gangrene in a lower extremity
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`when infusions of catecholamine are given in an ankle vein.
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`To provide hemodynamic support in septic shock associated hypotension in adult patients, the
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`suggested dosing infusion rate of intravenously administered epinephrine is 0.05 mcg/kg/min to
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`2 mcg/kg/min, and is titrated to achieve a desired mean arterial pressure (MAP). The dosage may
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`be adjusted periodically, such as every 10 - 15 minutes, in increments of 0.05 mcg/kg/min to
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`0.2 mcg/kg/min, to achieve the desired blood pressure goal.
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`Continuous epinephrine infusion is generally required over several hours or days until the
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`patient’s hemodynamic status improves. The duration of perfusion or total cumulative dose
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`After hemodynamic stabilization, wean incrementally over time, such as by decreasing doses of
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`epinephrine every 30 minutes over a 12- to 24-hour period.
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`Reference ID: 3837416
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`5
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` NDA 205029/S-001
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` Page 6
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`2.2
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` Induction and maintenance of mydriasis during intraocular surgery
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` Epinephrine must be diluted prior to intraocular use. Dilute 1 mL of epinephrine 1 mg/mL
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` (1:1000) in 100 to 1000 mL of an ophthalmic irrigation fluid to create an epinephrine
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` concentration of 1:100,000 to 1:1,000,000 (10 mcg/mL to 1 mcg/mL). Use the irrigating solution
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` as needed for the surgical procedure.
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` After dilution in an ophthalmic irrigating fluid, epinephrine may also be injected intracamerally
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` 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).
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` 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.
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` DOSAGE FORMS AND STRENGTHS
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`3
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` 2 mL clear glass ampule containing 1 mg/1 mL epinephrine as the hydrochloride in a sterile,
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` preservative free/sulfite free solution, marked Epinephrine Injection USP, 1 mg/mL (1:1,000)
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` [see Dosage and Administration (2)].
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`CONTRAINDICATIONS
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`4
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` None.
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` 5 WARNINGS AND PRECAUTIONS
` 5.1 Blood Volume Replacement
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` Correct blood volume depletion before any vasopressor is administered.
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` 5.2 Acute Hypertension
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` Titrate epinephrine infusion while monitoring vital signs. Invasive arterial blood pressure
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` monitoring and central venous pressure monitoring are recommended. Because of varying
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` response to epinephrine, dangerously high blood pressure may occur.
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` 5.3 Extravasation
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` The infusion site should be checked frequently for free flow. Avoid extravasation of epinephrine
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` into the tissues, to prevent local necrosis. Blanching along the course of the infused vein,
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` sometimes without obvious extravasation, may be attributed to vasa vasorum constriction with
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` increased permeability of the vein wall, permitting some leakage. This also may progress on rare
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` Antidote for Extravasation Ischemia: To prevent sloughing and necrosis in areas in which
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` extravasation has taken place, infiltrate the area with 10 mL to 15 mL of saline solution
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` containing from 5 mg to 10 mg of phentolamine, an adrenergic blocking agent. Use a syringe
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` with a fine hypodermic needle, with the solution being infiltrated liberally throughout the area,
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` which is easily identified by its cold, hard, and pallid appearance. Sympathetic blockade with
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` phentolamine causes immediate and conspicuous local hyperemic changes if the area is
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` infiltrated within 12 hours.
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`Reference ID: 3837416
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`6
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`
` NDA 205029/S-001
`
` Page 7
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`5.4
` Pulmonary Edema
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` There is risk of pulmonary edema because of the peripheral constriction and cardiac stimulation
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` produced.
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` 5.5 Renal Impairment
` Intravenously administered epinephrine initially may produce constriction of renal blood vessels
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` 5.6 Cardiac Arrhythmias
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` Epinephrine may induce cardiac arrhythmias in patients, especially those patients suffering from
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` heart disease, organic heart disease, or who are receiving drugs that sensitize the myocardium.
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`5.7
`Prolonged Hypertension
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`Patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or
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`imipramine types may experience severe, prolonged hypertension when given epinephrine.
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`5.8
`Injury with Undiluted Intraocular Solution
`Epinephrine must be diluted before intraocular use. Other products of epinephrine containing
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`sodium bisulfite have been associated with corneal endothelial damage when used in the eye at
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`undiluted concentrations (1 mg/mL). Although this Epinephrine product contains no sulfites and
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`is sulfite-free/preservative-free, warning is still advised [see Dosage and Administration (2.2)].
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`6
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`ADVERSE REACTIONS
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`6.1 Adverse Reactions Associated with Infusion (for Hypotension Associated with
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`Septic Shock)
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`The following adverse reactions associated with the use of epinephrine were identified in the
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`literature. Because these reactions are reported voluntarily from a population of uncertain size, it
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`is not always possible to estimate their frequency reliably or to establish a causal relationship to
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`drug exposure.
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`Cardiovascular disorders: tachycardia, supraventricular tachycardia, ventricular arrhythmias,
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`myocardial ischemia, myocardial infarction, limb ischemia, pulmonary edema
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`Gastrointestinal disorders: Nausea, vomiting
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`General disorders and administrative site conditions: Chest pain, extravasation,
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`Metabolic: hypoglycemia, hyperglycemia, insulin resistance, hypokalemia, lactic acidosis
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`Nervous system disorders: Headache, nervousness, paresthesia, tremor, stroke, central nervous
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`system bleeding
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`Psychiatric disorders: Excitability
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`Renal disorders: Renal insufficiency
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`Respiratory: Pulmonary edema, rales
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`Skin and subcutaneous tissue disorders: Diaphoresis, pallor, piloerection, skin blanching, skin
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`necrosis with extravasation
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`Reference ID: 3837416
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`7
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` NDA 205029/S-001
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` Page 8
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` 6.2 Adverse Reactions Associated with Intraocular Use (for Mydriasis)
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` Epinephrine containing sodium bisulfite has been associated with corneal endothelial damage
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` when used in the eye at undiluted concentrations (1 mg/mL). Although this Epinephrine product
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` contains no sulfites and is sulfite-free/preservative-free, warning is still advised [see Warnings
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` and Precautions (5.8)].
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` To report SUSPECTED ADVERSE REACTIONS, contact Belcher Pharmaceuticals at (727)
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` 471-0850 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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`7
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` DRUG INTERACTIONS
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` 7.1 Epinephrine’s Effects on Other Drugs
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` Antihypertensives: Epinephrine may antagonize the neuronal blockade produced by
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` guanethidine resulting in decreased antihypertensive effect and requiring increased dosage of the
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`latter.
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` 7.2 Effects of Other Drugs on Epinephrine
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` Drugs antagonizing pressor effects
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` α-blockers, such as phentolamine
` Vasodilators, such as nitrates
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` Diuretics
` Antihypertensives
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`Drugs potentiating pressor effects
` Sympathomimetics
` β-blockers
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` Tricyclic anti-depressants
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` Monoamine oxidase (MAO) inhibitors
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` Catechol-O-methyl transferase (COMT) inhibitors, such as entacapone
` Clonidine
` Doxapram
` Oxytocin
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`Drugs potentiating arrhythmogenic effects
` β-blockers
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` Cyclopropane or halogenated hydrocarbon anesthetics, such as halothane
` Antihistamines
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` Thyroid hormones
` Diuretics
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` Digitalis glycosides
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`Drugs potentiating hypokalemic effects
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` Potassium depleting diuretics
` Corticosteroids
` Theophylline
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`Reference ID: 3837416
`
`8
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` NDA 205029/S-001
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` Page 9
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`
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` USE IN SPECIFIC POPULATIONS
`8
`8.1
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`Pregnancy
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` Pregnancy Category C: Epinephrine has been shown to have developmental effects in rabbits at a
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` subcutaneous dose of 1.2 mg/kg (approximately 30 times the maximum recommended daily
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` subcutaneous or intramuscular dose on a mg/m2 basis), in mice at a subcutaneous dose of 1
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` mg/kg (approximately 7 times the maximum recommended daily subcutaneous or intramuscular
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` dose on a mg/m2 basis), and in hamsters at a subcutaneous dose of 0.5 mg/kg (approximately 5
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` times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis).
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` These effects were not seen in mice at a subcutaneous dose of 0.5 mg/kg (approximately 3 times
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` the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis).
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` Although there are no adequate and well-controlled studies in pregnant women, epinephrine
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` crosses the placenta (but not the blood-brain barrier) and could lead to fetal anoxia, spontaneous
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` abortion or both. Data from animal studies have shown that epinephrine interferes with ovum
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` implantation and fetus survival in rabbits and has teratogenic potential.
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` Epinephrine has been shown to have teratogenic effects (including gastroschisis and embryonic
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` lethality) when administered subcutaneous in rabbits at approximately 15 times the maximum
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` recommended intramuscular or subcutaneous dose (on a mg/m2 basis at a maternal subcutaneous
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`dose of 1.2 mg/kg/day for two to three days).
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`In mice, teratogenic effects (including embryonic lethality) were observed at approximately 3
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`times the maximum recommended intramuscular or subcutaneous dose (on a mg/m2 basis at
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`maternal subcutaneous dose of 1 mg/kg/day for 10 days). These effects were not seen in mice at
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`approximately 2 times the maximum recommended daily intramuscular or subcutaneous dose
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`(on a mg/m2 basis at a subcutaneous maternal dose of 0.5 mg/kg/day for 10 days).
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`In hamsters, teratogenic effects were observed at approximately 2 times the maximum
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`recommended intramuscular or subcutaneous dose (on a mg/m2 basis at a maternal subcutaneous
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`dose of 0.5 mg/kg/day for 4 days).
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`8.2 Labor and Delivery
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`Epinephrine usually inhibits spontaneous or oxytocin induced contractions of the pregnant
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`human uterus and may delay the second stage of labor. Avoid epinephrine during the second
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`stage of labor. In dosage sufficient to reduce uterine contractions, the drug may cause a
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`prolonged period of uterine atony with hemorrhage. Avoid epinephrine in obstetrics when
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`maternal blood pressure exceeds 130/80 mmHg.
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`8.3 Nursing Mothers
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`Epinephrine is distributed into breast milk. Avoid breast-feeding in mothers receiving infusion of
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`epinephrine.
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`8.4
`Pediatric Use
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`Safety and effectiveness of epinephrine in pediatric patients with septic shock have not been
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`established.
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`Reference ID: 3837416
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`9
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` NDA 205029/S-001
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` Page 10
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` The safety and effectiveness of epinephrine (at a dilution of 1:100,000 to 1:400,000) for
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` induction and maintenance of mydriasis during intraocular surgery have been established in
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` pediatric patients. Use of epinephrine for induction and maintenance of mydriasis during
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` intraocular surgery in pediatric patients is supported by adequate and well controlled studies in
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` adults and uncontrolled studies in pediatric patients.
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` 8.5 Geriatric Use
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` Clinical studies of epinephrine for the treatment of hypotension associated with septic shock did
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` not include sufficient numbers of subjects aged 65 and over to determine whether they respond
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` differently from younger subjects. Other reported clinical experience has not identified
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` differences in responses between the elderly and younger patients. In general, dose selection for
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` an elderly patient should be cautious, usually starting at the low end of the dosing range,
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` reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of
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` concomitant disease or other drug therapy.
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` For induction and maintenance of mydriasis during intraocular surgery, no overall differences
` have been observed between elderly and other patients.
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`OVERDOSAGE
`10
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` Overdosage associated with Infusion (for Hypotension associated with Septic
`10.1
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`Shock)
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` Myocardial ischemia and infarction, cardiomyopathy, pulmonary edema, and renal insufficiency
` were observed in literature reports of accidental overdoses.
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` Toxic effects of overdosage can be counteracted by injection of an alpha-adrenergic blocker
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` (such as phentolamine mesylate) and a beta-adrenergic blocker (such as propranolol). Rapid-
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` acting vasodilators such as nitrites, or alpha-adrenergic blocking agents can be given to
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` counteract the marked pressor effect of large doses of epinephrine causing a sharp rise in the
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` blood pressure. Treatment of acute toxicity is mainly supportive since epinephrine is rapidly
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` inactivated in the body.
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` Epinephrine overdosage can also cause transient bradycardia followed by tachycardia, and these
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` may be accompanied by potentially fatal cardiac arrhythmias. Premature ventricular contractions
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` may appear within one minute after injection and may be followed by multifocal ventricular
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` tachycardia (prefibrillation rhythm). Subsidence of the ventricular effects may be followed by
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` atrial tachycardia and occasionally by atrioventricular block. Treatment of arrhythmias consists
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` of administration of a beta-adrenergic blocking drug such as propranolol.
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`11
`DESCRIPTION
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` Epinephrine Injection USP, 1 mg/mL (1:1,000) is supplied as a sterile aqueous solution that is
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` colorless and nonpyrogenic. Each milliliter contains 1 mg Epinephrine base (as the
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` hydrochloride), Sodium Chloride 9 mg (for isotonicity), and Water for Injection, USP, qs.
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` Contains no sulfites. May contain Hydrochloric Acid for pH adjustment.
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` The solution contains no preservatives such as sulfites. This sterile solution is to be diluted prior
` to intravenous or ocular use.
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`Reference ID: 3837416
`
`10
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` NDA 205029/S-001
`
` Page 11
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` Epinephrine, USP is a sympathomimetic catecholamine (adrenergic agent) designated chemically
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` as 4-[1-hydroxy-2 (methylamino) ethyl]-1,2 benzenediol, a white, microcrystalline powder. It
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`has the following structural formula:
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`The molecular weight of epinephrine is 183.2.
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`Epinephrine solution deteriorates rapidly on exposure to air or light, turning pink from oxidation
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`to adrenochrome and brown from the formation of melanin.
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`12
`CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`Epinephrine acts on both alpha (α)- and beta (β)-adrenergic receptors. The mechanism of the rise
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`in blood pressure is 3-fold: a direct myocardial stimulation that increases the strength of
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`ventricular contraction (positive inotropic action), an increased heart rate (positive chronotropic
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`action), and peripheral vasoconstriction.
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`12.2
`Pharmacodynamics
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`Intravenous use for hypotension associated with septic shock:
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`Following intravenous administration of epinephrine, increases in systolic blood pressure and
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`heart rate are observed. Decreases in systemic vascular resistance and diastolic blood pressure
`are observed at low doses of epinephrine because of β2-mediated vasodilation, but are overtaken
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`by α1-mediated peripheral vasoconstriction at higher doses leading to increase in diastolic blood
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`pressure. The onset of blood pressure increase following an intravenous dose of epinephrine is
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`< 5 minutes and the time to offset blood pressure response occurs within 20 min. Most vascular
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`beds are constricted including renal, splanchnic, mucosal and skin.
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`Intraocular use for mydriasis
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`Epinephrine causes mydriasis when administered intraocularly or parenterally.
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`12.3
`Pharmacokinetics
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`Intravenous use for hypotension associated with septic shock:
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`Following intravenous injection, epinephrine is rapidly cleared from the plasma with an effective
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`half-life of < 5 min. A pharmacokinetic steady state following continuous intravenous infusion is
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`achieved within 10-15 min. In patients with septic shock, epinephrine displays dose-proportional
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`pharmacokinetics in the infusion dose range of 0.03 to 1.7 mcg/kg/min.
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`Reference ID: 3837416
`
`11
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` NDA 205029/S-001
`
` Page 12
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` Epinephrine is extensively metabolized with only a small amount excreted unchanged.
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` Epinephrine is rapidly degraded to vanillylmandelic acid, an inactive metabolite, by monoamine
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` oxidase and catechol-O-methyltransferase that are abundantly expressed in the liver, kidneys and
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` other extraneuronal tissues. The tissues with the highest contribution to removal of circulating
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` exogenous epinephrine are the liver (32%), kidneys (25%), skeletal muscle (20%), and
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` mesenteric organs (12%).
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` Special Populations
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`Elderly
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`In a pharmacokinetic study of 45-minute epinephrine infusions given to healthy men aged 20 to
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`25 years and healthy men aged 60 to 65 years, the mean plasma metabolic clearance rate of
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`epinephrine at steady state was greater among the older men (144.8 versus 78 mL/kg/min for a
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`14.3 ng/kg/min infusion).
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`Body Weight
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`Body weight has been found to influence epinephrine pharmacokinetics. Higher body weight
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`was associated with a higher plasma epinephrine clearance and a lower concentration plateau.
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`Intraocular use:
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`When administered intraocularly, epinephrine has a rapid onset and short duration of action.
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`The extent of human systemic exposure at the labeled intraocular dose has not been evaluated,
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`however, significant systemic concentrations or plasma exposure of epinephrine are not expected
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`when administered intraocularly.
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`13
`NONCLINICAL TOXICOLOGY
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`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
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`Adequate carcinogenesis studies have not been reported. An equivocal response of epinephrine
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`was found when tested in Salmonella typhimurium strain TA 100 in the absence of metabolic
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`activation system (S9) and negative in the presence of activation system (S9). There are no data
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`from either animal or human studies regarding potential for the impairment of fertility.
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`The potential for epinephrine to impair reproductive performance has not been evaluated, but
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`epinephrine has been shown to decrease implantation in female rabbits dosed subcutaneously
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`with 1.2 mg/kg/day (15-fold the highest human intramuscular or subcutaneous daily dose) during
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`gestation days 3 to 9.
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`There are no data from human studies regarding potential for the impairment of fertility.
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`13.2
`Animal Toxicology and/or Pharmacology
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`Epinephrine was associated with metabolic effects, decreased mesenteric, coronary and renal
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`conductance in a sheep model of septic shock. Data from hemolysis study have shown that
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`epinephrine at 1:1,000 dilution is non-hemolytic. Epinephrine infusion significantly increased the
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`MAP (69 vs. 86 mmHg) and cardiac output (6.4 vs. 7.1 L/min) and decreased renal blood flow
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`(330 vs. 247 mL/min).
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`Reference ID: 3837416
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`12
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` NDA 205029/S-001
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` Page 13
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`14
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` CLINICAL STUDIES
`14.1
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` Treating Hypotension from Septic Shock with Epinephrine
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` Fourteen clinical studies from the literature documented that epinephrine increases the mean
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