Ephedrine Sulfate

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 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 ) 2.1 General Dosage and Administration Instructions 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. 2.2 Dosing for the Treatment of Clinically Important Hypotension in the Setting of Anesthesia 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). 2.3 Prepare a 5 mg per mL Solution for Bolus Intravenous Administration 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.

3 DOSAGE FORMS AND STRENGTHS 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. Ephedrine Sulfate Injection: 50 mg per mL ephedrine sulfate in single-dose vial ( 3 )

4 CONTRAINDICATIONS None None ( 4 )

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. (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)

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 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. Clinical Considerations Disease-associated maternal and/or embryo-fetal 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). 8.2 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 and any potential adverse effects on the breastfed child from ephedrine sulfate or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of ephedrine sulfate in pediatric patient …

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.

11 DESCRIPTION Ephedrine is an alpha- and beta-adrenergic agonist and a norepinephrine-releasing agent. Ephedrine Sulfate Injection, USP is a clear, colorless, sterile solution for intravenous injection. 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. Structural Formula

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Ephedrine Sulfate Injection, USP is supplied as follows: NDC Ephedrine Sulfate Injection, USP Package Factor 25021-836-01 50 mg per mL of ephedrine sulfate equivalent to 38 mg per mL of ephedrine base in a 1 mL Single-Dose Vial 25 vials per carton Ephedrine Sulfate Injection, USP is a clear, colorless, sterile solution for intravenous injection. 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 ®