Ephedrine Sulfate

1 INDICATIONS AND USAGE Ephedrine Sulfate Injection, USP 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 that is indicated for the treatment of clinically important hypotension occurring in the setting of anesthesia. ( 1 )

2 DOSAGE AND ADMINISTRATION 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. 2.1 General Dosage and Administration Instructions 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. 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). 2.3 Instructions for Use of Single-Dose Prefilled Syringe 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 Kab …

3 DOSAGE FORMS AND STRENGTHS 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. Injection: 5 mg/mL ephedrine sulfate in a 10 mL single-dose prefilled syringe, (50 mg/10 mL, equivalent to 38 mg ephedrine base) 5 mL single-dose prefilled syringe; (25 mg/5 mL, equivalent to 19 mg ephedrine base) ( 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 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 AuroMedics Pharma LLC at 1-866-850-2876 or www.auromedics.com 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. • 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 w …

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 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 2-4% and 15-20%, 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 6-17. 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 6-20. 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 Injection, USP and any potential adverse effects on the breastfed child from Ephedrine Sulfate Injection, USP or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of Ephedrine Sulfate Inject …

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. It must be diluted before intravenous administration. 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 methanol, slightly soluble in ethanol, very slightly soluble in chloroform, practically insoluble in ether. Each mLof the 50 mg/mL strength contains ephedrine sulfate, USP 50 mg (equivalent to 38 mg ephedrine base) in water for injection. The pH is adjusted with sodium hydroxide and/or glacial acetic acid if necessary. The pH range is 4.5 to 7.0.The 50 mg/mL vial must be diluted before intravenous administration. structural formula

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.

16 HOW SUPPLIED/STORAGE AND HANDLING 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: Product Code Unit of Sale Strength Each RF382505 NDC 65219-546-05 Unit of 10 25 mg/5 mL (5 mg/mL) NDC 65219-546-01 5 mL Single-Dose Prefilled Syringe This product contains an RFID. RF386510 NDC 65219-548-10 Unit of 10 50 mg/10 mL (5 mg/mL) NDC 65219-548-01 10 mL Single-Dose Prefilled Syringe This product contains an RFID. 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 Fresenius Kabi Logo