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 (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 embryofetal 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.

PACKAGE LABEL - PRINCIPAL DISPLAY – Ephedrine Sulfate 5 mL RFID Syringe Label

Rx only        NDC 65219-546-01

Ephedrine

Sulfate Injection, USP

25 mg/5 mL

(5 mg/mL)

RFID logo

For Intravenous Use Only        Ready-To-Use        Protect from light

Single-Dose prefilled syringe

Discard unused portion.

Store at 25°C (77°F)

Recommended Dosage:

See prescribing information.

Simplist logo

Mfd. For: Fresenius Kabi

Lake Zurich, IL 60047

Made in Austria

M088650/00 US

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 5 mg/mL is a clear, colorless, sterile, ready-to-use solution for intravenous injection. The chemical name of ephedrine sulfate is benzenemethanol, α-[1-(methylamino)ethyl]-, [R-(R*,S*)]-, sulfate (2:1) (salt), and the molecular weight is 428.5 g/mol. Its molecular formula is (C₁₀H₁₅NO)₂ · H₂SO₄ and 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 contains ephedrine sulfate 5 mg (equivalent to 3.8 mg ephedrine base), sodium chloride 8.6 mg, trisodium citrate dihydrate 1.25 mg, citric acid anhydrous 0.25 mg and sodium hydroxide and/or glacial acetic acid for pH adjustment, if necessary. The pH range is 5.0 to 7.0.

Safety and effectiveness 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 β-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, β-2 adrenoceptor-mediated vasoconstriction, and β-2 adrenoceptor-mediated vasodilatation. Stimulation of the β-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 β-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)

• Bolus intravenous injection: 5 mg to 10 mg (equivalent to 3.8 to 7.6 mg ephedrine base) as needed, not to exceed 50 mg. (2)
• Ready-to-Use formulation. Do not dilute.

Ephedrine Sulfate Injection, USP, 5 mg/mL is a clear, colorless solution available in:

• a single-dose, 10 mL prefilled syringe that contains 50 mg/10 mL ephedrine sulfate, equivalent to 38 mg ephedrine base;
• a single-dose, 5 mL prefilled syringe that contains 25 mg/5 mL ephedrine sulfate, equivalent to 19 mg ephedrine base.

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.

Ephedrine Sulfate Injection, USP 5 mg/mL (equivalent to 3.8 mg/mL ephedrine base), is a clear, colorless solution and is supplied as follows:

Syringe plunger stoppers and Luer lock tip caps are not manufactured with natural rubber latex. Store Ephedrine Sulfate Injection, USP 5 mg/mL at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in carton until time of use. For single use only. Discard unused portion.

Protect from Light

Contains No Preservatives

Manufactured for:

www.fresenius-kabi.com/us

Made in Austria

451838

Ready to Use formulation. Do not dilute.

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Ephedrine Sulfate Injection is a clear, colorless solution. Do not use if discolored.

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.

INSTRUCTIONS FOR USE

Important Administration Information

• Ephedrine Sulfate Injection is administered undiluted by slow intravenous injection.
• The syringe should be administered with clean gloved hands.
• Check the compatibility of Ephedrine Sulfate Injection with all other medications and any intravenous fluids the patent is currently receiving.
• This product is for single dose only; discard unused portion.
• Do not introduce any other fluid into the syringe at any time.
• Do not re-sterilize the syringe.
• Do not use this product on a sterile field.

Figure 1: Outer Packaging and Prefilled Syringe

• Inspect the outer packaging (flow wrap) to confirm the integrity of the packaging. Do not use if the flow wrap or the prefilled syringe has been damaged.
• Remove the syringe from the outer packaging. (See Figure 2)

  Figure 2

• • Examine syringe for damage or cracks and ensure the Luer cap is intact.
    
    DO NOT USE if the Luer cap is missing, loose or damaged.
  • Inspect and ensure the EPHEDRINE liquid in the prefilled syringe is clear and colorless.
    
    DO NOT USE if the liquid looks discolored, cloudy, or if the liquid contains any particulate matter.
  • Check the expiration date on the syringe and confirm product has not expired.
    
    DO NOT USE if the expiration date has passed.
• Check the intravenous site for signs of infiltration from fluid or medications leaking into surrounding tissue. If signs of infiltration are observed, existing IV administration should be discontinued. A new IV administration site should be established.
  
  Thoroughly cleanse the injection port closest to the patient with alcohol prep pad.
• Push plunger rod slightly to break stopper loose while tip cap is still on.
• Twist the tip cap to open. (Figure 3).

• Remove air from the syringe if necessary.
  • -
    With the tip of the syringe pointing up, tap the syringe barrel to make air bubbles rise to the top.
  • -
    Expel air and excess medication by pushing the plunger up until the edge of the plunger is at the graduation mark that corresponds to volume of the prescribed dose. (Figure 4).

  Figure 4

• Connect the syringe to the injection port.
• If the intravenous line does not have a backflow protection, pinch/clamp the intravenous tubing between intravenous bag and injection port.
• Press down on the plunger of the prefilled syringe to administer the medication by intravenous bolus. Inject 5 mg to 10 mg by intravenous bolus at a time.
  • -
    Adjust dosage according to the blood pressure goal (i.e., titrate to effect).
  • -
    DO NOT exceed a total dosage of 50 mg.
• Remove the syringe from injection port.
• If necessary, release the pinched intravenous tubing ensuring continuous flow of intravenous fluid.
  
  Alternatively, manually flush the line after administration of Ephedrine Sulfate Injection so there is no residual drug in the intravenous tubing.
• Dispose of used syringe. Safely throw away syringe(s) immediately after use into an appropriate medical waste container.

For more information concerning this drug, please call Fresenius Kabi USA, LLC at 1-800-551-7176.

To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 (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 embryofetal 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.

PACKAGE LABEL - PRINCIPAL DISPLAY – Ephedrine Sulfate 5 mL RFID Syringe Label

Rx only        NDC 65219-546-01

Ephedrine

Sulfate Injection, USP

25 mg/5 mL

(5 mg/mL)

RFID logo

For Intravenous Use Only        Ready-To-Use        Protect from light

Single-Dose prefilled syringe

Discard unused portion.

Store at 25°C (77°F)

Recommended Dosage:

See prescribing information.

Simplist logo

Mfd. For: Fresenius Kabi

Lake Zurich, IL 60047

Made in Austria

M088650/00 US

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 5 mg/mL is a clear, colorless, sterile, ready-to-use solution for intravenous injection. The chemical name of ephedrine sulfate is benzenemethanol, α-[1-(methylamino)ethyl]-, [R-(R*,S*)]-, sulfate (2:1) (salt), and the molecular weight is 428.5 g/mol. Its molecular formula is (C₁₀H₁₅NO)₂ · H₂SO₄ and 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 contains ephedrine sulfate 5 mg (equivalent to 3.8 mg ephedrine base), sodium chloride 8.6 mg, trisodium citrate dihydrate 1.25 mg, citric acid anhydrous 0.25 mg and sodium hydroxide and/or glacial acetic acid for pH adjustment, if necessary. The pH range is 5.0 to 7.0.

Safety and effectiveness 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 β-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, β-2 adrenoceptor-mediated vasoconstriction, and β-2 adrenoceptor-mediated vasodilatation. Stimulation of the β-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 β-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)

• Bolus intravenous injection: 5 mg to 10 mg (equivalent to 3.8 to 7.6 mg ephedrine base) as needed, not to exceed 50 mg. (2)
• Ready-to-Use formulation. Do not dilute.

Ephedrine Sulfate Injection, USP, 5 mg/mL is a clear, colorless solution available in:

• a single-dose, 10 mL prefilled syringe that contains 50 mg/10 mL ephedrine sulfate, equivalent to 38 mg ephedrine base;
• a single-dose, 5 mL prefilled syringe that contains 25 mg/5 mL ephedrine sulfate, equivalent to 19 mg ephedrine base.

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.

Ephedrine Sulfate Injection, USP 5 mg/mL (equivalent to 3.8 mg/mL ephedrine base), is a clear, colorless solution and is supplied as follows:

Syringe plunger stoppers and Luer lock tip caps are not manufactured with natural rubber latex. Store Ephedrine Sulfate Injection, USP 5 mg/mL at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in carton until time of use. For single use only. Discard unused portion.

Protect from Light

Contains No Preservatives

Manufactured for:

www.fresenius-kabi.com/us

Made in Austria

451838

Ready to Use formulation. Do not dilute.

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Ephedrine Sulfate Injection is a clear, colorless solution. Do not use if discolored.

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.

INSTRUCTIONS FOR USE

Important Administration Information

• Ephedrine Sulfate Injection is administered undiluted by slow intravenous injection.
• The syringe should be administered with clean gloved hands.
• Check the compatibility of Ephedrine Sulfate Injection with all other medications and any intravenous fluids the patent is currently receiving.
• This product is for single dose only; discard unused portion.
• Do not introduce any other fluid into the syringe at any time.
• Do not re-sterilize the syringe.
• Do not use this product on a sterile field.

Figure 1: Outer Packaging and Prefilled Syringe

• Inspect the outer packaging (flow wrap) to confirm the integrity of the packaging. Do not use if the flow wrap or the prefilled syringe has been damaged.
• Remove the syringe from the outer packaging. (See Figure 2)

  Figure 2

• • Examine syringe for damage or cracks and ensure the Luer cap is intact.
    
    DO NOT USE if the Luer cap is missing, loose or damaged.
  • Inspect and ensure the EPHEDRINE liquid in the prefilled syringe is clear and colorless.
    
    DO NOT USE if the liquid looks discolored, cloudy, or if the liquid contains any particulate matter.
  • Check the expiration date on the syringe and confirm product has not expired.
    
    DO NOT USE if the expiration date has passed.
• Check the intravenous site for signs of infiltration from fluid or medications leaking into surrounding tissue. If signs of infiltration are observed, existing IV administration should be discontinued. A new IV administration site should be established.
  
  Thoroughly cleanse the injection port closest to the patient with alcohol prep pad.
• Push plunger rod slightly to break stopper loose while tip cap is still on.
• Twist the tip cap to open. (Figure 3).

• Remove air from the syringe if necessary.
  • -
    With the tip of the syringe pointing up, tap the syringe barrel to make air bubbles rise to the top.
  • -
    Expel air and excess medication by pushing the plunger up until the edge of the plunger is at the graduation mark that corresponds to volume of the prescribed dose. (Figure 4).

  Figure 4

• Connect the syringe to the injection port.
• If the intravenous line does not have a backflow protection, pinch/clamp the intravenous tubing between intravenous bag and injection port.
• Press down on the plunger of the prefilled syringe to administer the medication by intravenous bolus. Inject 5 mg to 10 mg by intravenous bolus at a time.
  • -
    Adjust dosage according to the blood pressure goal (i.e., titrate to effect).
  • -
    DO NOT exceed a total dosage of 50 mg.
• Remove the syringe from injection port.
• If necessary, release the pinched intravenous tubing ensuring continuous flow of intravenous fluid.
  
  Alternatively, manually flush the line after administration of Ephedrine Sulfate Injection so there is no residual drug in the intravenous tubing.
• Dispose of used syringe. Safely throw away syringe(s) immediately after use into an appropriate medical waste container.

For more information concerning this drug, please call Fresenius Kabi USA, LLC at 1-800-551-7176.

To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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).