Label: EPHEDRINE SULFATE- ephedrine sulfate injection

  • NDC Code(s): 0781-3269-71, 0781-3269-95
  • Packager: Sandoz Inc
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Abbreviated New Drug Application

Drug Label Information

Updated September 28, 2018

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use EPHEDRINE SULFATE INJECTION safely and effectively. See full prescribing information for EPHEDRINE SULFATE INJECTION.
    EPHEDRINE SULFATE injection, for intravenous use
    Initial U.S. Approval: 2016

    INDICATIONS AND USAGE

    Ephedrine sulfate injection is an alpha- and beta- adrenergic agonist and a norepinephrine-releasing agent that is indicated for the treatment of clinically important hypotension occurring in the setting of anesthesia. (1)

    DOSAGE AND ADMINISTRATION

    Ephedrine sulfate injection, 50 mg/mL, (equivalent to 38 mg ephedrine base) is injected intravenously as a bolus. Dilute before administration. ( 2)
    Bolus intravenous injection: 5 to 10 mg as needed, not to exceed 50 mg. ( 2)

    DOSAGE FORMS AND STRENGTHS

    Injection: 50 mg/mL ephedrine sulfate in single-dose vial (3)

    CONTRAINDICATIONS

    None (4)

    WARNINGS AND PRECAUTIONS

    Pressor Effects with Concomitant Use with Oxytocic Drugs: Pressor effect of sympathomimetic pressor amines is potentiated ( 5.1)
    Tachyphylaxis and Tolerance: Repeated administration of ephedrine may cause tachyphylaxis ( 5.2)

    ADVERSE REACTIONS

    Most common adverse reactions during treatment: nausea, vomiting, and tachycardia. (6)

    To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    DRUG INTERACTIONS

    Interactions that Augment Pressor Effect: clonidine, oxytocin and oxytocic drugs, propofol, monoamine oxidase inhibitors (MAOIs), and atropine. Monitor blood pressure. ( 7)
    Interactions that Antagonize the Pressor Effect: Antagonistic effects with α-adrenergic antagonists, β-adrenergic antagonists, reserpine, quinidine, mephentermine. Monitor blood pressure. ( 7)
    Guanethidine: Ephedrine may inhibit the neuron blockage produced by guanethidine, resulting in loss of antihypertensive effectiveness. Monitor blood pressure and adjust the dosage of pressor accordingly.
    Rocuronium: Ephedrine may reduce the onset time of neuromuscular blockade when used for intubation with rocuronium if administered simultaneously with anesthetic induction. Be aware of this potential interaction. No treatment or other interventions are needed.
    Epidural anesthesia: Ephedrine may decrease the efficacy of epidural blockade by hastening the regression of sensory analgesia. Monitor and treat the patient according to clinical practice.
    Theophylline: Concomitant use of ephedrine may increase the frequency of nausea, nervousness, and insomnia. Monitor patient for worsening symptoms and manage symptoms according to clinical practice.
    Cardiac glycosides: Giving ephedrine with a cardiac glycoside, such as digitalis, may increase the possibility of arrhythmias. Carefully monitor patients on cardiac glycosides who are also administered ephedrine.

    Revised: 9/2018

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  • FULL PRESCRIBING INFORMATION: CONTENTS*
  • 1 INDICATIONS AND USAGE

    Ephedrine sulfate injection is indicated for the treatment of clinically important hypotension occurring in the setting of anesthesia.

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  • 2 DOSAGE AND ADMINISTRATION

    2.1 General Dosage and Administration Instructions

    Ephedrine sulfate injection must be diluted before administration as an intravenous bolus to achieve the desired concentration. Dilute with normal saline or 5% dextrose in water.

    Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

    2.2 Dosing for the Treatment of Clinically Important Hypotension in the Setting of Anesthesia

    The recommended dosages for the treatment of clinically important hypotension in the setting of anesthesia is an initial dose of 5 to 10 mg administered by intravenous bolus. Administer additional boluses as needed, not to exceed a total dosage of 50 mg.

    Adjust dosage according to the blood pressure goal (i.e., titrate to effect).

    2.3 Prepare a 5 mg/mL Solution for Bolus Intravenous Administration

    For bolus intravenous administration, prepare a solution containing a final concentration of 5 mg/mL of ephedrine sulfate injection:

    Withdraw 50 mg (1 mL of 50 mg/mL) of ephedrine sulfate injection and dilute with 9 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection.
    Withdraw an appropriate dose of the 5 mg/mL solution prior to bolus intravenous administration.
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  • 3 DOSAGE FORMS AND STRENGTHS

    Ephedrine sulfate injection, USP is available as a single-dose 1 mL vial that contains 50 mg/mL ephedrine sulfate, equivalent to 38 mg ephedrine base.

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  • 4 CONTRAINDICATIONS

    None

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  • 5 WARNINGS AND PRECAUTIONS

    5.1 Pressor Effect with Concomitant Oxytocic Drugs

    Serious postpartum hypertension has been described in patients who received both a vasopressor (i.e., methoxamine, phenylephrine, ephedrine) and an oxytocic (i.e., methylergonovine, ergonovine) [see Drug Interactions (7)]. Some of these patients experienced a stroke. Carefully monitor the blood pressure of individuals who have received both ephedrine and an oxytocic.

    5.2 Tolerance and Tachyphylaxis

    Data indicate that repeated administration of ephedrine can result in tachyphylaxis. Clinicians treating anesthesia-induced hypotension with ephedrine sulfate injection should be aware of the possibility of tachyphylaxis and should be prepared with an alternative pressor to mitigate unacceptable responsiveness.

    5.3 Risk of Hypertension When Used Prophylactically

    When used to prevent hypotension, ephedrine has been associated with an increased incidence of hypertension compared with when ephedrine is used to treat hypotension.

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  • 6 ADVERSE REACTIONS

    The following adverse reactions associated with the use of ephedrine sulfate 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.

    Gastrointestinal disorders: Nausea, vomiting

    Cardiac disorders: Tachycardia, palpitations (thumping heart), reactive hypertension, bradycardia, ventricular ectopics, R-R variability

    Nervous system disorders: Dizziness

    Psychiatric disorders: Restlessness

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  • 7 DRUG INTERACTIONS

    Interactions that Augment the Pressor Effect

    Oxytocin and oxytocic drugs

    Clinical Impact:

    Serious postpartum hypertension has been described in patients who received both a vasopressor (i.e., methoxamine, phenylephrine, ephedrine) and an oxytocic (i.e., methylergonovine, ergonovine). Some of these patients experienced a stroke.

    Intervention:

    Carefully monitor the blood pressure of individuals who have received both ephedrine and an oxytocic.

    Clonidine, propofol, monoamine oxidase inhibitors (MAOIs), atropine

    Clinical Impact:

    These drugs augment the pressor effect of ephedrine.

    Intervention:

    Carefully monitor the blood pressure of individuals who have received both ephedrine and any of these drugs.

    Interactions that Antagonize the Pressor Effect

    Clinical Impact:

    These drugs antagonize the pressor effect of ephedrine.

    Intervention:

    Carefully monitor the blood pressure of individuals who have received both ephedrine and any of these drugs.

    Examples:

    α-adrenergic antagonists, β-adrenergic receptor antagonists, reserpine, quinidine, mephentermine

    Other Drug Interactions

    Guanethidine

    Clinical Impact:

    Ephedrine may inhibit the neuron blockage produced by guanethidine, resulting in loss of antihypertensive effectiveness.

    Intervention:

    Clinician should monitor patient for blood pressor response and adjust the dosage or choice of pressor accordingly.

    Rocuronium

    Clinical Impact:

    Ephedrine may reduce the onset time of neuromuscular blockade when used for intubation with rocuronium if administered simultaneously with anesthetic induction.

    Intervention:

    Be aware of this potential interaction. No treatment or other interventions are needed.

    Epidural anesthesia

    Clinical Impact:

    Ephedrine may decrease the efficacy of epidural blockade by hastening the regression of sensory analgesia.

    Intervention:

    Monitor and treat the patient according to clinical practice.

    Theophylline

    Clinical Impact:

    Concomitant use of ephedrine may increase the frequency of nausea, nervousness, and insomnia.

    Intervention:

    Monitor patient for worsening symptoms and manage symptoms according to clinical practice.

    Cardiac glycosides

    Clinical Impact:

    Giving ephedrine with a cardiac glycoside, such as digitalis, may increase the possibility of arrhythmias.

    Intervention:

    Carefully monitor patients on cardiac glycosides who are also administered ephedrine.

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  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    Limited published data on the use of ephedrine sulfate are insufficient to determine a drug associated risk of major birth defects or miscarriage. However, there are clinical considerations [see Clinical Considerations]. Animal reproduction studies have not been conducted with ephedrine sulfate.

    In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

    Clinical Considerations

    Fetal/Neonatal Adverse Reactions

    Cases of potential metabolic acidosis in newborns at delivery with maternal ephedrine exposure have been reported in the literature. These reports describe umbilical artery pH of ≤7.2 at the time of delivery [see Clinical Pharmacology (12.3)]. Monitoring of the newborn for signs and symptoms of metabolic acidosis may be required. Monitoring of infant’s acid-base status is warranted to ensure that an episode of acidosis is acute and reversible.

    8.2 Lactation

    Risk Summary

    Limited published literature reports that ephedrine is present in human milk. However, no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ephedrine sulfate injection and any potential adverse effects on the breastfed child from ephedrine sulfate injection or from the underlying maternal condition.

    8.4 Pediatric Use

    Safety and effectiveness in pediatric patients have not been established.

    8.5 Geriatric Use

    Clinical studies of ephedrine 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. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

    8.6 Renal Impairment

    Ephedrine and its metabolite are excreted in urine. In patients with renal impairment, excretion of ephedrine is likely to be affected with a corresponding increase in elimination half-life, which will lead to slow elimination of ephedrine and consequently prolonged pharmacological effect and potentially adverse reactions. Monitor patients with renal impairment carefully after the initial bolus dose for adverse events.

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  • 10 OVERDOSAGE

    Overdose of ephedrine can cause a rapid rise in blood pressure. In the case of an overdose, careful monitoring of blood pressure is recommended. If blood pressure continues to rise to an unacceptable level, parenteral antihypertensive agents can be administered at the discretion of the clinician.

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  • 11 DESCRIPTION

    Ephedrine is an alpha- and beta-adrenergic agonist and a norepinephrine-releasing agent. Ephedrine sulfate injection, USP is a clear, colorless, sterile solution for intravenous injection. It must be diluted before intravenous administration. The chemical name of ephedrine sulfate is (1R,2S)-(-)-2-methylamine-1-phenylpropan-1-ol sulfate, and the molecular weight is 428.5 g/mol. Its structural formula is depicted below:

    Ephedrine Sulfate Chemical Structure

    Ephedrine sulfate is freely soluble in water and ethanol, very slightly soluble in chloroform, and practically insoluble in ether. Each mL contains ephedrine sulfate, USP 50 mg (equivalent to 38 mg ephedrine base) in water for injection. The pH is adjusted with sodium hydroxide and/or glacial acetic acid if necessary. The pH range is 4.5 to 7.0.

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  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Ephedrine sulfate is a sympathomimetic amine that directly acts as an agonist at α- and ß- adrenergic receptors and indirectly causes the release of norepinephrine from sympathetic neurons. Pressor effects by direct alpha- and beta-adrenergic receptor activation are mediated by increases in arterial pressures, cardiac output, and peripheral resistance. Indirect adrenergic stimulation is caused by norepinephrine release from sympathetic nerves.

    12.2 Pharmacodynamics

    Ephedrine stimulates heart rate and cardiac output and variably increases peripheral resistance; as a result, ephedrine usually increases blood pressure. Stimulation of the α-adrenergic receptors of smooth muscle cells in the bladder base may increase the resistance to the outflow of urine. Activation of ß-adrenergic receptors in the lungs promotes bronchodilation.

    The overall cardiovascular effect from ephedrine is the result of a balance among α-1 adrenoceptor-mediated vasoconstriction, ß-2 adrenoceptor-mediated vasoconstriction, and ß-2 adrenoceptor-mediated vasodilatation. Stimulation of the ß-1 adrenoceptors results in positive inotrope and chronotrope action.

    Tachyphylaxis to the pressor effects of ephedrine may occur with repeated administration [see Warnings and Precautions (5.3)].

    12.3 Pharmacokinetics

    Publications studying pharmacokinetics of oral administration of (-)-ephedrine support that (-)- ephedrine is metabolized into norephedrine. However, the metabolism pathway is unknown. Both the parent drug and the metabolite are excreted in urine. Limited data after IV administration of ephedrine support similar observations of urinary excretion of drug and metabolite. The plasma elimination half-life of ephedrine following oral administration was about 6 hours.

    Ephedrine crosses the placental barrier [see Use in Specific Populations (8.1)].

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  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenesis: Two-year feeding studies in rats and mice conducted under the National Toxicology Program (NTP) demonstrated no evidence of carcinogenic potential with ephedrine sulfate at doses up to 10 mg/kg/day and 27 mg/kg/day (approximately 2 times and 3 times the maximum human recommended dose on a mg/m2 basis, respectively).

    Mutagenesis: Ephedrine sulfate tested negative in the in vitro bacterial reverse mutation assay, the in vitro mouse lymphoma assay, the in vitro sister chromatid exchange, the in vitro chromosomal aberration assay, and the in vivo rat bone marrow micronucleus assay.

    Impairment of Fertility: Studies to evaluate the effect of ephedrine on fertility have not been conducted.

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  • 14 CLINICAL STUDIES

    The evidence for the efficacy of ephedrine injection is derived from the published literature. Increases in blood pressure following administration of ephedrine were observed in 14 studies, including 9 where ephedrine was used in pregnant women undergoing neuraxial anesthesia during Cesarean delivery, 1 study in non-obstetric surgery under neuraxial anesthesia, and 4 studies in patients undergoing surgery under general anesthesia. Ephedrine has been shown to raise systolic and mean blood pressure when administered as a bolus dose following the development of hypotension during anesthesia.

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  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Ephedrine sulfate injection, USP, 50 mg/mL, is supplied as follows:

    NDC

    Strength

    How Supplied

    0781-3269-95

    50 mg/mL

    1 mL fill in 2 mL amber vial; for single use (supplied in packages of 10)

    Vial stoppers are not manufactured with natural rubber latex. Store ephedrine sulfate injection, USP, 50 mg/mL, at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Store in carton until time of use. For single use only. Discard unused portion.

    46238558

    Rev. September 2018

    Manufactured in Canada by

    Avara Boucherville Pharmaceutical Services, Inc. for

    Sandoz Inc., Princeton, NJ 08540

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  • 50mg/mL Carton

    ephedrine-carton

    NDC 0781-3269-95

    Ephedrine Sulfate

    Injection, USP

    50 mg/mL

    Must Be Diluted

    For Intravenous Use

    10 x 1 mL Single Dose Vials

    Rx Only

    SANDOZ A Novartis Division

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  • INGREDIENTS AND APPEARANCE
    EPHEDRINE SULFATE 
    ephedrine sulfate injection
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0781-3269
    Route of Administration INTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    EPHEDRINE SULFATE (UNII: U6X61U5ZEG) (EPHEDRINE - UNII:GN83C131XS) EPHEDRINE SULFATE 50 mg  in 1 mL
    Inactive Ingredients
    Ingredient Name Strength
    ACETIC ACID (UNII: Q40Q9N063P)  
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    WATER (UNII: 059QF0KO0R)  
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0781-3269-95 10 in 1 CARTON 10/01/2017
    1 NDC:0781-3269-71 1 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA209784 10/01/2017
    Labeler - Sandoz Inc (110342024)
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