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1 INDICATIONS AND USAGE Ephedrine sulfate injection is indicated for the treatment of clinically important hypotension occurring in the setting of anesthesia. Ephedrine Sulfate Injection, USP, is an alpha- and beta- adrenergic agonist and a norepinephrine-releasing agent indicated for the treatment of clinically important hypotension occurring in the setting of anesthesia. (1)

2 DOSAGE AND ADMINISTRATION Treatment of hypotension developing during anesthesia: Bolus intravenous injection: 5 to 10 mg as needed, not to exceed 50 mg. Dilute before use. See Full Prescribing Information for instructions on administration and preparation for injection. (2) 2.1 General Dosage and Administration Instructions Ephedrine sulfate injection must be diluted before administration to achieve the desired concentration as an intravenous bolus or intravenous infusion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is colored or cloudy, or if it contains particulate matter. 2.2 Dosing for the Treatment of Clinically Important Hypotension in the Setting of Anesthesia The recommended dosage 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 Preparation of 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 Sodium Chloride Injection. Withdraw an appropriate dose of the 5 mg/mL solution prior to bolus intravenous administration.

3 DOSAGE FORMS AND STRENGTHS Ephedrine sulfate injection is available as a single-dose 1 mL vial that contains 50 mg/mL ephedrine sulfate, equivalent to 38 mg ephedrine base. Injection: 50 mg/mL ephedrine sulfate in single-dose vial (3)

5 WARNINGS AND PRECAUTIONS • Pr e ssor Effect with Concomitant Oxytocic Drugs : Pressor effect of sympathomimetic pressor amines is potentiated (5.1) • T ach y ph y l a x i s and Tolerance : Repeated administration of ephedrine may cause tachyphylaxis (5.2) 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.

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 C ardiac disorders : Tachycardia, palpitations (thumping heart), reactive hypertension, bradycardia, ventricular ectopics, R-R variability N e rvous system disorders : Dizziness Psychiatric disorders : Restlessness For medical advice about adverse reactions, contact your medical professional. To report SUSPECTED ADVERSE REACTIONS, contact Par Health at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Most common adverse reactions during treatment: nausea, vomiting, and tachycardia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Par Health at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS I nteractions that Augment the Pressor Effect Oxytocin and oxytocic drugs C linical 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. I ntervention: Carefully monitor the blood pressure of individuals who have received both ephedrine and an oxytocic. Clonidine, propofol, monoamine oxidase inhibitors (MAOIs), atropine C linical Impact: These drugs augment the pressor effect of ephedrine. I ntervention: Carefully monitor the blood pressure of individuals who have received both ephedrine and any of these drugs. I nteractions that Antagonize the Pressor Effect C linical Impact: These drugs antagonize the pressor effect of ephedrine. I ntervention: 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 G u anethidine C linical Impact: Ephedrine may inhibit the neuron blockage produced by guanethidine, resulting in loss of antihypertensive effectiveness. I ntervention: Clinician should monitor patient for blood pressor response and adjust the dosage or choice of pressor accordingly. Rocuronium C linical Impact: Ephedrine may reduce the onset time of neuromuscular blockade when used for intubation with rocuronium if administered simultaneously with anesthetic induction. I ntervention: Be aware of this potential interaction. No treatment or other interventions are needed. Ep idural anesthesia C linical Impact: Ephedrine may decrease the efficacy of epidural blockade by hastening the regression of sensory analgesia. I ntervention: Monitor and treat the patient according to clinical practice. Th e ophylline C linical Impact: Concomitant use of ephedrine may increase the frequency of nausea, nervousness, and insomnia. I ntervention: Monitor patient for worsening symptoms and manage symptoms according to clinical practice. Cardiac glycosides C linical Impact: Giving ephedrine with a cardiac glycoside, such as digitalis, may increase the possibility of arrhythmias. I ntervention: Carefully monitor patients on cardiac glycosides who are also administered ephedrine. • I nt e r a ctio n s t ha t Augment the Pressor Effect : clonidine, oxytocin and oxytocic drugs, propofol, monoamine oxidase inhibitors (MAOIs), and atropine. Monitor blood pressure. (7) • I nt e r acti o n s that Antagonize the Pressor Effect : Antagonistic effects with α-adrenergic antagonists, β-adrenergic antagonists, reserpine, quinidine, mephentermine. Monitor blood pressure. (7) • G uan e t h i d in e : 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. (7) • R o cu roni u m : 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. (7) • 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.

aneously with anesthetic induction. Be aware of this potential interaction. No treatment or other interventions are needed. (7) • 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. (7) • T h e o ph yll in e : 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. (7) • Ca rd i a c 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. (7)

<table><col/><col/><tbody><tr><td colspan="2"> <paragraph><content styleCode="bold">I</content><content styleCode="bold">nteractions that Augment the Pressor Effect</content></paragraph></td></tr><tr><td colspan="2" styleCode=" Toprule"> <paragraph><content styleCode="bold">Oxytocin and oxytocic drugs</content></paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">C</content><content styleCode="italics">linical Impact:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>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).

>C</content><content styleCode="italics">linical Impact:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>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.</paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">I</content><content styleCode="italics">ntervention:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>Carefully monitor the blood pressure of individuals who have received both ephedrine and an oxytocic.</paragraph></td></tr><tr><td colspan="2" styleCode=" Toprule"> <paragraph><content styleCode="bold">Clonidine, propofol, monoamine oxidase inhibitors (MAOIs), atropine</content></paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">C</content><content styleCode="italics">linical Impact:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>These drugs augment the pressor effect of ephedrine.</paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">I</content><content styleCode="italics">ntervention:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>Carefully monitor the blood pressure of individuals who have received both ephedrine and any of these drugs.</paragraph></td></tr><tr><td colspan="2" styleCode=" Toprule"> <paragraph><content styleCode="bold">I</content><content styleCode="bold">nteractions that Antagonize the Pressor Effect</content></paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">C</content><content styleCode="italics">linical Impact:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>These drugs antagonize the pressor effect of ephedrine.</paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">I</content><content styleCode="italics">ntervention:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>Carefully monitor the blood pressure of individuals who have received both ephedrine and any of these drugs.</paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">Examples:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>&#x3B1;-adrenergic antagonists, &#x3B2;-adrenergic receptor antagonists,</paragraph><paragraph>reserpine, quinidine, mephentermine</paragraph></td></tr><tr><td colspan="2" styleCode=" Toprule"> <paragraph><content styleCode="bold">Other Drug Interactions</content></paragraph></td></tr><tr><td colspan="2" styleCode=" Toprule"> <paragraph><content styleCode="bold">G</content><content styleCode="bold">u</content><content styleCode="bold">anethidine</content></paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">C</content><content styleCode="italics">linical Impact:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>Ephedrine may inhibit the neuron blockage produced by</paragraph><paragraph>guanethidine, resulting in loss of antihypertensive effectiveness.</paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">I</content><content styleCode="italics">ntervention:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>Clinician should monitor patient for blood pressor response and adjust the dosage or choice of pressor accordingly.</paragraph></td></tr><tr><td colspan="2" styleCode=" Toprule"> <paragraph><content styleCode="bold">Rocuronium</content></paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">C</content><content styleCode="italics">linical Impac

nd adjust the dosage or choice of pressor accordingly.</paragraph></td></tr><tr><td colspan="2" styleCode=" Toprule"> <paragraph><content styleCode="bold">Rocuronium</content></paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">C</content><content styleCode="italics">linical Impac t:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>Ephedrine may reduce the onset time of neuromuscular blockade when used for intubation with rocuronium if administered simultaneously with anesthetic induction.</paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">I</content><content styleCode="italics">ntervention:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>Be aware of this potential interaction.

ocuronium if administered simultaneously with anesthetic induction.</paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">I</content><content styleCode="italics">ntervention:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>Be aware of this potential interaction. No treatment or other interventions are needed.</paragraph></td></tr><tr><td colspan="2" styleCode=" Toprule"> <paragraph><content styleCode="bold">Ep</content><content styleCode="bold">idural anesthesia</content></paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">C</content><content styleCode="italics">linical Impact:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>Ephedrine may decrease the efficacy of epidural blockade by hastening the regression of sensory analgesia.</paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">I</content><content styleCode="italics">ntervention:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>Monitor and treat the patient according to clinical practice.</paragraph></td></tr><tr><td colspan="2" styleCode=" Toprule"> <paragraph><content styleCode="bold">Th</content><content styleCode="bold">e</content><content styleCode="bold">ophylline</content></paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">C</content><content styleCode="italics">linical Impact:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>Concomitant use of ephedrine may increase the frequency of nausea, nervousness, and insomnia.</paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">I</content><content styleCode="italics">ntervention:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>Monitor patient for worsening symptoms and manage symptoms according to clinical practice.</paragraph></td></tr><tr><td colspan="2" styleCode=" Toprule"> <paragraph><content styleCode="bold">Cardiac glycosides</content></paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">C</content><content styleCode="italics">linical Impact:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>Giving ephedrine with a cardiac glycoside, such as digitalis, may increase the possibility of arrhythmias.</paragraph></td></tr><tr><td styleCode=" Toprule"> <paragraph><content styleCode="italics">I</content><content styleCode="italics">ntervention:</content></paragraph></td><td styleCode=" Toprule Lrule"> <paragraph>Carefully monitor patients on cardiac glycosides who are also administered ephedrine.</paragraph></td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy R isk 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. The estimated background risk of major birth defects and miscarriage for the indicated population is 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. C linical 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 R isk 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.

8.1 Pregnancy R isk 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. The estimated background risk of major birth defects and miscarriage for the indicated population is 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. C linical 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 .

8.5 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.

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.

11 DESCRIPTION Ephedrine sulfate 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. Each mL contains ephedrine sulfate 50 mg in water for injection as a single-dose product. The pH range is 4.5 to 7.0. The drug product must be diluted before intravenous administration. The chemical name of ephedrine sulfate is (1R,2S)-(-)-2-methylamine-1-phenylpropan-1-ol sulfate (2:1) (salt). Its molecular weight is 428.54. The structural formula is: Ephedrine sulfate darkens on exposure to light. It is freely soluble in water and ethanol, very slightly soluble in chloroform, and practically insoluble in ether. Chemical Structure

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 ].

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 ].

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility C arc inogenesis : 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/m 2 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, and the in vitro chromosomal aberration assay. I mpairment of Fertility : Studies to evaluate the effect of ephedrine on fertility have not been conducted.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility C arc inogenesis : 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/m 2 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, and the in vitro chromosomal aberration assay. I mpairment of Fertility : Studies to evaluate the effect of ephedrine on fertility have not been conducted.

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Ephedrine Sulfate Injection, USP, 50 mg/mL, is supplied as follows: NDC S tre n gth How Supplied 42023-216-25 50 mg/mL 1 mL clear glass vial; for single use (supplied in packages of 25) Vial stoppers are not manufactured with natural rubber latex. Store ephedrine sulfate injection, 50 mg/mL, at 20° to 25°C (68° to 77°F), with excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature.] Protect from light. Store in carton until time of use. For single use only. Discard unused portion.

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1 INDICATIONS AND USAGE Ephedrine sulfate injection is indicated for the treatment of clinically important hypotension occurring in the setting of anesthesia. 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 )

2 DOSAGE AND ADMINISTRATION • This is a pre-mixed formulation. Do not dilute before administration. ( 2 ) • 5 mg to 10 mg administered by intravenous bolus. Additional boluses as needed, not to exceed a total dose of 50 mg. ( 2 ) 2.1 General Dosage and Administration Instructions • This is a premixed formulation. Do not dilute prior to use. • Discard any unused portion of Ephedrine sulfate injection. • 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 the solution is not clear or if particulate matter is present 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 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).

3 DOSAGE FORMS AND STRENGTHS Ephedrine Sulfate Injection, USP is a clear, colorless solution available as: A single-dose vial that contains 50 mg/10 mL (5 mg/mL) ephedrine sulfate, equivalent to 38 mg/10 mL (3.8 mg/mL) ephedrine base. Injection: 50 mg/10 mL ephedrine sulfate, equivalent to 38 mg/10 mL ephedrine base in a single-dose vial (5 mg/mL ephedrine sulfate, equivalent to 3.8 mg/mL ephedrine base). ( 3 )

5 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 sulfate injection may cause tachyphylaxis ( 5.2 ) 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 sulfate injection and an oxytocic. 5.2 Tolerance and Tachyphylaxis Data indicate that repeated administration of ephedrine can result in tachyphylaxis. Be aware of this possibility when treating anesthesia-induced hypotension with ephedrine sulfate injection and 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.

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 Most common adverse reactions during treatment: nausea, vomiting, and tachycardia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS contact Gland Pharma Limited at 609-250‐7990 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 sulfate injection 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 sulfate injection and any of these drugs. Drugs that Antagonize the Pressor Effect α-adrenergic antagonists, β-adrenergic receptor antagonists, reserpine, quinidine, mephentermine Clinical Impact: These drugs antagonize the pressor effect of ephedrine. Intervention: Carefully monitor the blood pressure of individuals who have received both ephedrine sulfate injection and any of these drugs. Other Drug Interactions Guanethidine Clinical Impact: Ephedrine sulfate injection 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 sulfate injection 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 sulfate injection 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 sulfate injection 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 sulfate injection 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. • 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 sulfate injection 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 sulfate injection 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.

ust the dosage of pressor accordingly. • Rocuronium : Ephedrine sulfate injection 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 sulfate injection 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 sulfate injection 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 sulfate injection with a cardiac glycoside, such as digitalis, may increase the possibility of arrhythmias. Carefully monitor patients on cardiac glycosides who are also administered ephedrine sulfate injection.

<table cellspacing="0" cellpadding="0" border="0" width="800.66"><colgroup><col width="20.4318936877076%"/><col width="79.5681063122924%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="center" valign="top"><content styleCode="bold">Interactions that Augment the Pressor Effect</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" valign="top"><content styleCode="bold">Oxytocin and oxytocic drugs</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="italics">Clinical Impact:</content> </td><td styleCode="Rrule" align="justify" valign="top">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. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="italics">Intervention:</content> </td><td styleCode="Rrule" align="justify" valign="top">Carefully monitor the blood pressure of individuals who have received both ephedrine sulfate injection and an oxytocic. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="justify" valign="top"><content styleCode="bold">Clonidine, propofol, monoamine oxidase inhibitors (MAOIs), atropine</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="italics">Clinical Impact:</content> </td><td styleCode="Rrule" align="justify" valign="top">These drugs augment the pressor effect of ephedrine. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="italics">Intervention: </content> </td><td styleCode="Rrule" align="justify" valign="top">Carefully monitor the blood pressure of individuals who have received both ephedrine sulfate injection and any of these drugs. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="center" valign="top"><content styleCode="bold">Drugs that Antagonize the Pressor Effect</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="center" valign="top"><content styleCode="bold">&#x3B1;-adrenergic antagonists, &#x3B2;-adrenergic receptor antagonists, reserpine, quinidine,</content> <content styleCode="bold">mephentermine</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="italics">Clinical Impact:</content> </td><td styleCode="Rrule" align="justify" valign="top">These drugs antagonize the pressor effect of ephedrine. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="italics">Intervention:</content> </td><td styleCode="Rrule" align="justify" valign="top">Carefully monitor the blood pressure of individuals who have received both ephedrine sulfate injection and any of these drugs.

/tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="italics">Intervention:</content> </td><td styleCode="Rrule" align="justify" valign="top">Carefully monitor the blood pressure of individuals who have received both ephedrine sulfate injection and any of these drugs. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="center" valign="top"><content styleCode="bold">Other Drug Interactions</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="justify" valign="top"><content styleCode="bold">Guanethidine </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="italics">Clinical Impact:</content> </td><td styleCode="Rrule" align="justify" valign="top">Ephedrine sulfate injection may inhibit the neuron blockage produced by guanethidine, resulting in loss of antihypertensive effectiveness. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="italics">Intervention: </content> </td><td styleCode="Rrule" align="justify" valign="top">Clinician should monitor patient for blood pressor response and adjust the dosage or choice of pressor accordingly. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="justify" valign="top"><content styleCode="bold">Rocuronium </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle"><content styleCode="italics">Clinical Impact:</content> </td><td styleCode="Rrule" align="justify" valign="top">Ephedrine sulfate injection may reduce the onset time of neuromuscular blockade when used for intubation with rocuronium if administered simultaneously with anesthetic induction. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="italics">Intervention:</content> </td><td styleCode="Rrule" align="justify" valign="top">Be aware of this potential interaction. No treatment or other interventions are needed. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="justify" valign="top"><content styleCode="bold">Epidural anesthesia</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="italics">Clinical Impact:</content> </td><td styleCode="Rrule" align="justify" valign="top">Ephedrine sulfate injection may decrease the efficacy of epidural blockade by hastening the regression of sensory analgesia. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="italics">Intervention:</content> </td><td styleCode="Rrule" align="justify" valign="top">Monitor and treat the patient according to clinical practice. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="justify" valign="top"><content styleCode="bold">Theophylline</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="italics">Clinical Impact:</content> </td><td styleCode="Rrule" align="justify" valign="top">Concomitant use of ephedrine sulfate injection may increase the frequency of nausea, nervousness, and insomnia. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="italics">Intervention:</content> </td><td styleCode="Rrule" align="justify" valign="top">Monitor patient for worsening symptoms and manage symptoms according to clinical practice.

a, nervousness, and insomnia. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="italics">Intervention:</content> </td><td styleCode="Rrule" align="justify" valign="top">Monitor patient for worsening symptoms and manage symptoms according to clinical practice. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="justify" valign="top"><content styleCode="bold">Cardiac glycosides</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="italics">Clinical Impact:</content> </td><td styleCode="Rrule" align="justify" valign="top">Giving ephedrine sulfate injection with a cardiac glycoside, such as digitalis, may increase the possibility of arrhythmias. </td></tr><tr><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="italics">Intervention:</content> </td><td styleCode="Rrule" align="justify" valign="top">Carefully monitor patients on cardiac glycosides who are also administered ephedrine. </td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 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 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 is 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. Clinical Considerations Disease-associated maternal and/or embryofetal risk Untreated hypotension associated with spinal anesthesia for cesarean section is associated with an increase in maternal nausea and vomiting. A decrease in uterine blood flow due to maternal hypotension may result in fetal bradycardia and acidosis. 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. Data Animal Data Decreased fetal body weights were observed when pregnant rats were administered intravenous bolus doses of 60 mg/kg ephedrine sulfate (12 times the maximum recommended human dose (MRHD) of 50 mg based on body surface area) from Gestation Day 6 to 17. This dose was associated with evidence of maternal toxicity (decreased body weight of dams and abnormal head movements). No malformations or fetal deaths were noted at this dose. No effects on fetal body weight were noted at 10 mg/kg (1.9 times the MRHD of 50 mg). No evidence of malformations or embryo-fetal toxicity were noted in pregnant rabbits administered intravenous bolus doses up to 20 mg/kg ephedrine sulfate (7.7 times the maximum recommended human dose (MRHD) of 50 mg based on body surface area) from Gestation Day 6 to 20. This dose was associated with expected pharmacological maternal effects (increased respiration rate, dilated pupils, piloerection). Decreased fetal survival and body weights in the presence of maternal toxicity (increased mortality) were noted when pregnant dams were administered intravenous bolus doses of 60 mg/kg epinephrine sulfate (approximately 12 times the MRHD based on body surface area) from GD 6 through Lactation Day 20. No adverse effects were noted at 10 mg/kg (1.9 times the MRHD).

the presence of maternal toxicity (increased mortality) were noted when pregnant dams were administered intravenous bolus doses of 60 mg/kg epinephrine sulfate (approximately 12 times the MRHD based on body surface area) from GD 6 through Lactation Day 20. No adverse effects were noted at 10 mg/kg (1.9 times the MRHD). 8.2 Lactation Risk Summary A single published case report indicates 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 of ephedrine sulfate injection in pediatric patients have not been established. Animal Toxicity Data In a study in which juvenile rats were administered intravenous bolus doses of 2, 10, or 60 mg/kg ephedrine sulfate daily from Postnatal Day 35 to 56, an increased incidence of mortality was noted at the high dose of 60 mg/kg. The no-adverse-effect level was 10 mg/kg (approximately 1.9 times a maximum daily dose of 50 mg in a 60 kg person based on body surface area). 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.

8.1 Pregnancy 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 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 is 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. Clinical Considerations Disease-associated maternal and/or embryofetal risk Untreated hypotension associated with spinal anesthesia for cesarean section is associated with an increase in maternal nausea and vomiting. A decrease in uterine blood flow due to maternal hypotension may result in fetal bradycardia and acidosis. 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. Data Animal Data Decreased fetal body weights were observed when pregnant rats were administered intravenous bolus doses of 60 mg/kg ephedrine sulfate (12 times the maximum recommended human dose (MRHD) of 50 mg based on body surface area) from Gestation Day 6 to 17. This dose was associated with evidence of maternal toxicity (decreased body weight of dams and abnormal head movements). No malformations or fetal deaths were noted at this dose. No effects on fetal body weight were noted at 10 mg/kg (1.9 times the MRHD of 50 mg). No evidence of malformations or embryo-fetal toxicity were noted in pregnant rabbits administered intravenous bolus doses up to 20 mg/kg ephedrine sulfate (7.7 times the maximum recommended human dose (MRHD) of 50 mg based on body surface area) from Gestation Day 6 to 20. This dose was associated with expected pharmacological maternal effects (increased respiration rate, dilated pupils, piloerection). Decreased fetal survival and body weights in the presence of maternal toxicity (increased mortality) were noted when pregnant dams were administered intravenous bolus doses of 60 mg/kg epinephrine sulfate (approximately 12 times the MRHD based on body surface area) from GD 6 through Lactation Day 20. No adverse effects were noted at 10 mg/kg (1.9 times the MRHD).

8.4 Pediatric Use Safety and effectiveness of ephedrine sulfate injection in pediatric patients have not been established. Animal Toxicity Data In a study in which juvenile rats were administered intravenous bolus doses of 2, 10, or 60 mg/kg ephedrine sulfate daily from Postnatal Day 35 to 56, an increased incidence of mortality was noted at the high dose of 60 mg/kg. The no-adverse-effect level was 10 mg/kg (approximately 1.9 times a maximum daily dose of 50 mg in a 60 kg person based on body surface area).

10 OVERDOSAGE Overdose of ephedrine sulfate injection 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.

11 DESCRIPTION Ephedrine sulfate is a sympathomimetic amine. Ephedrine Sulfate Injection, USP is a clear, colorless, sterile 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 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, USP 5 mg (equivalent to 3.8 mg ephedrine base), 0.9% sodium chloride, USP in water for injection.The pH range is 4.5 to 7.0. ephedrine-spl-structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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. 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 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 ]. 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 ] .

12.1 Mechanism of Action 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.

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 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 ].

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 ] .

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/m 2 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: There was no impact on fertility or early embryonic development in a study in which male rats were administered intravenous bolus doses of 0, 2, 10, or 60 mg/kg ephedrine sulfate (up to 12 times the maximum recommended human dose of 50 mg based on body surface area) for 28 days prior to mating and through gestation and females were treated for 14 days prior to mating through Gestation Day 7.

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/m 2 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: There was no impact on fertility or early embryonic development in a study in which male rats were administered intravenous bolus doses of 0, 2, 10, or 60 mg/kg ephedrine sulfate (up to 12 times the maximum recommended human dose of 50 mg based on body surface area) for 28 days prior to mating and through gestation and females were treated for 14 days prior to mating through Gestation Day 7.

14 CLINICAL STUDIES The evidence for the efficacy of ephedrine sulfate 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Ephedrine sulfate injection, USP is a clear, colorless solution available as a single-dose vial that contains 50 mg/10 mL (5 mg/mL) ephedrine sulfate, equivalent to 38 mg/10 mL (3.8 mg/mL) ephedrine base and is supplied as follows: NDC Presentation 68083-610-10 10 mL clear glass, single-dose vials; strength 50 mg/10 mL (5 mg/mL) packaged in a carton of 10 Ephedrine Sulfate Injection, USP 50 mg/10 mL (5 mg/mL) is not made with natural rubber latex. Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Store in carton until time of use. For single dose only. Discard unused portion. Manufactured by: Gland Pharma Limited D.P.Pally, Dundigal Post Hyderabad-500 043, India. Revised: 06/2024

<table cellspacing="0" cellpadding="0" border="0" width="508.6585"><colgroup><col width="44.4110341221075%"/><col width="55.5889658778925%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">NDC</content> </td><td styleCode="Rrule" align="justify" valign="top"><content styleCode="bold">Presentation</content> </td></tr><tr><td styleCode="Lrule Rrule" align="justify" valign="top">68083-610-10 </td><td styleCode="Rrule" align="justify" valign="top">10 mL clear glass, single-dose vials; strength 50 mg/10 mL (5 mg/mL) packaged in a carton of 10 </td></tr></tbody></table>