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.

Risk Summary

Available data from randomized studies, case series, and reports of ephedrine sulfate use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, there are clinical considerations due to underlying conditions (see Clinical Considerations). In animal reproduction studies, decreased fetal survival and fetal body weights were observed in the presence of maternal toxicity after normotensive pregnant rats were administered 60 mg/kg intravenous ephedrine sulfate (12 times the maximum recommended human dose (MRHD) of 50 mg/day). No malformations or embryo-fetal adverse effects were observed when pregnant rats or rabbits were treated with intravenous bolus doses of ephedrine sulfate during organogenesis at doses 1.9 and 7.7 times the MRHD, respectively [see data].

The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Storage Conditions

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature]. Store in carton until time of use. For single dose only. Discard unused portion.

Sterile, Nonpyrogenic, Preservative-free.

The container closure is not made with natural rubber latex.

SAGENT^®

Mfd. for SAGENT Pharmaceuticals

Schaumburg, IL 60195 (USA)

Made in Germany

©2022 Sagent Pharmaceuticals, Inc.

August 2022

SAGENT Pharmaceuticals^®

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label

NDC 25021-836-01

Rx only

Ephedrine Sulfate Injection, USP

50 mg per mL

Must Be Diluted

For Intravenous Use

1 mL Single-Dose Vial

Discard Unused Portion

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.

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. 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 is freely soluble in water and ethanol, very slightly soluble in chloroform, and practically insoluble in ether.

Each mL of the 50 mg per mL strength contains ephedrine sulfate 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. The 50 mg per mL vial must be diluted before intravenous administration.

The safety and effectiveness of ephedrine sulfate in pediatric patients have not been established.

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.

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.

None

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

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.

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 (5.2)].

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)].

Ephedrine Sulfate Injection is indicated for the treatment of clinically important hypotension occurring in the setting of anesthesia.

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.

• 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)

• Should be administered by trained healthcare providers (2.1)
• Ephedrine sulfate injection, 50 mg per mL, must be diluted before administration as an intravenous bolus dose. (2.1)
• Bolus intravenous injection: 5 to 10 mg as needed, not to exceed 50 mg. (2.1)

Ephedrine Sulfate Injection, USP is a clear, colorless, sterile solution for intravenous injection available as:

single-dose 1 mL vial that contains 50 mg per mL ephedrine sulfate, equivalent to 38 mg per mL of ephedrine base.

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

Ephedrine Sulfate Injection, USP is supplied as follows:

Ephedrine Sulfate Injection, USP is a clear, colorless, sterile solution for intravenous injection.

Ephedrine sulfate injection, 50 mg per mL 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.

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.

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

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

• Withdraw 50 mg (1 mL of 50 mg per 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 per mL solution prior to bolus intravenous administration.

Ephedrine sulfate injection should be administered by trained healthcare providers.

The recommended dosages for the treatment of clinically important hypotension in the setting of anesthesia is an initial dose of 5 mg 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).

Risk Summary

Available data from randomized studies, case series, and reports of ephedrine sulfate use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, there are clinical considerations due to underlying conditions (see Clinical Considerations). In animal reproduction studies, decreased fetal survival and fetal body weights were observed in the presence of maternal toxicity after normotensive pregnant rats were administered 60 mg/kg intravenous ephedrine sulfate (12 times the maximum recommended human dose (MRHD) of 50 mg/day). No malformations or embryo-fetal adverse effects were observed when pregnant rats or rabbits were treated with intravenous bolus doses of ephedrine sulfate during organogenesis at doses 1.9 and 7.7 times the MRHD, respectively [see data].

The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Storage Conditions

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature]. Store in carton until time of use. For single dose only. Discard unused portion.

Sterile, Nonpyrogenic, Preservative-free.

The container closure is not made with natural rubber latex.

SAGENT^®

Mfd. for SAGENT Pharmaceuticals

Schaumburg, IL 60195 (USA)

Made in Germany

©2022 Sagent Pharmaceuticals, Inc.

August 2022

SAGENT Pharmaceuticals^®

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label

NDC 25021-836-01

Rx only

Ephedrine Sulfate Injection, USP

50 mg per mL

Must Be Diluted

For Intravenous Use

1 mL Single-Dose Vial

Discard Unused Portion

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.

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. 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 is freely soluble in water and ethanol, very slightly soluble in chloroform, and practically insoluble in ether.

Each mL of the 50 mg per mL strength contains ephedrine sulfate 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. The 50 mg per mL vial must be diluted before intravenous administration.

The safety and effectiveness of ephedrine sulfate in pediatric patients have not been established.

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.

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.

None

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

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.

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 (5.2)].

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)].

Ephedrine Sulfate Injection is indicated for the treatment of clinically important hypotension occurring in the setting of anesthesia.

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.

• 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)

• Should be administered by trained healthcare providers (2.1)
• Ephedrine sulfate injection, 50 mg per mL, must be diluted before administration as an intravenous bolus dose. (2.1)
• Bolus intravenous injection: 5 to 10 mg as needed, not to exceed 50 mg. (2.1)

Ephedrine Sulfate Injection, USP is a clear, colorless, sterile solution for intravenous injection available as:

single-dose 1 mL vial that contains 50 mg per mL ephedrine sulfate, equivalent to 38 mg per mL of ephedrine base.

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

Ephedrine Sulfate Injection, USP is supplied as follows:

Ephedrine Sulfate Injection, USP is a clear, colorless, sterile solution for intravenous injection.

Ephedrine sulfate injection, 50 mg per mL 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.

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.

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

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

• Withdraw 50 mg (1 mL of 50 mg per 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 per mL solution prior to bolus intravenous administration.

Ephedrine sulfate injection should be administered by trained healthcare providers.

The recommended dosages for the treatment of clinically important hypotension in the setting of anesthesia is an initial dose of 5 mg 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).