Ephedrine

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 )

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 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 patient is currently receiving This product is for single dose only; discard unused portion FIGURE A. PREFILLED SYRINGE Figure A Step 1 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. Step 2 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. Step 3 Thoroughly cleanse the injection port closest to the patient with alcohol prep pad. Step 4 Twist the tip cap to open. See Figure B. Figure B Step 5 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. See Figure C Figure C Step 6 Connect the syringe to the injection port. Step 7 If the intravenous line does not have backflow protection, pinch/clamp the intravenous tubing between intravenous bag and injection port. Step 8 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. Step 9 Remove the syringe from injection port. Step 10 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. Step 11 Dispose of used syringe. Safely throw away syringe(s) immediately after use into an appropriate medical waste container. Figure A Figure B This is an image of Figure C.

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 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.

4. CONTRAINDICATIONS None None ( 4 )

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 who are also administered ephedrine sulfate injection.

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.

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- 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- 8.1].