EPHEDRINE: 1,152 Adverse Event Reports & Safety Profile

Ephedrine is an alpha- and beta-adrenergic agonist and a norepinephrine-releasing agent. AKOVAZ (ephedrine sulfate injection) 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 of the 50 mg/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/mL vial must be diluted before intravenous administration. Each mL of the 5 mL single-dose prefilled syringe contains 5 mg (equivalent to 3.8 mg ephedrine base) and 9 mg Sodium Chloride, USP in Water for Injection. The pH range is 4.5 to 6.5. structural formula

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 )

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

Figure

1 Figure 2 Figure 3 Figure 4

4.

Contraindications

None None ( 4 )

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 Endo 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 Endo at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Asthma alert: Because asthma may be life threatening, see a doctor if you  are not better in 60 minutes  get worse  need more than 12 tablets in 24 hours  use more than 8 tablets in 24 hours for 3 or more days a week  have more than 2 asthma attacks in a week These may be signs that your asthma is getting worse.  This product will not give you asthma relief as quickly as an inhaled bronchodilator Do not use  unless a doctor said you have asthma  if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs taken for depression, psychiatric or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.  if you have ever had an allergic reaction to this product or any of its ingredients Ask a doctor before use if you have  ever been hospitalized for asthma  heart disease  high blood pressure  diabetes  thyroid disease  seizures  narrow angle glaucoma  a psychiatric or emotional condition  trouble urinating due to an enlarged prostate gland Ask a doctor or pharmacist before use if you are  taking prescription drugs for asthma, obesity, weight control, depression, or psychiatric or emotional conditions  taking any drug that contains phenylephrine, pseudoephedrine, ephedrine, or caffeine (such as for allergy, cough-cold, or pain) When using this product  your blood pressure or heart rate may go up. This could increase your risk of heart attack or stroke, which may cause death.  your risk of heart attack or stroke increases if you:  have a history of high blood pressure or heart disease  take this product more frequently or take more than the recommended dose  avoid foods or beverages that contain caffeine  avoid dietary supplements containing ingredients reported or claimed to have a stimulant effect Stop use and ask a doctor if  your asthma is getting worse (see Asthma alert)  you have difficulty sleeping  you have a rapid heart beat  you have tremors, nervousness, or seizure If pregnant or breast-feeding, ask a health professional before use. Keep out of the reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.

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.

Drug Facts Active ingredient (in each tablet)

Ephedrine Hydrochloride

12.5 mg

Inactive ingredients D&C yellow #10 aluminum lake, dibasic calcium phosphate dihydrate, FD&C yellow #6 aluminum lake, magnesium stearate, microcrystalline cellulose, silicon dioxide, sodium starch glycolate, stearic acid