Akovaz

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

2 DOSAGE AND ADMINISTRATION • Should be administered by trained healthcare providers • AKOVAZ injection, 50 mg/mL, must be diluted before administration as an intravenous bolus dose. • AKOVAZ injection, 5 mg/mL in a pre-filled syringe, is a premixed formulation. Do not dilute prior to use. • Bolus intravenous injection: 5 mg to 10 mg as needed, not to exceed 50 mg.

2.1General Dosage and Administration Instructions

AKOVAZ (ephedrine sulfate injection), 50 mg/mL must be diluted before administration as an intravenous bolus to achieve the desired concentration. Dilute with normal saline or 5% dextrose in water. AKOVAZ (ephedrine sulfate injection), 25 mg/5 mL (5 mg/mL) in a prefilled syringe, is a premixed formulation.

Do not dilute prior to use. The single-dose prefilled syringe is intended for use in one patient during one surgical procedure. Discard any unused portion. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.2Dosing for the Treatment of Clinically Important Hypotension

in the Setting of Anesthesia AKOVAZ 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).

2.3Prepare 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 AKOVAZ (ephedrine sulfate injection): • Withdraw 50 mg (1 mL of 50 mg/mL) of AKOVAZ (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/mL solution prior to bolus intravenous administration.

2.4Instructions for Use of Prefilled Syringe

1. Perform visual inspection on the syringe by verifying: • Absence of syringe damage • Absence of external particles • Absence of internal particles • Proper drug color • Drug name • Drug strength • Fill volume • Route of administration • Expiration date to be sure the drug has not expired 2. Do not remove tamper evident seal.

Push plunger rod slightly in to break the stopper loose while tip cap is still on. 3. Remove tip cap and tamper evident seal by twisting off. : Figure 1. 4. Discard the tip cap. 5. Expel air bubble. 6. Adjust dose into sterile material (if applicable). 7. Connect the syringe to an appropriate intravenous connection. • Before injection, ensure that the syringe is securely attached to the needle or needleless luer access device (NLAD). 8.

Depress plunger rod to deliver medication. Ensure that pressure is maintained on the plunger rod during the entire administration. 9. Remove syringe from NLAD (if applicable) and discard into appropriate receptacle. • To prevent needle stick injuries, do not recap needle when needle is connected to syringe.

NOTE : All steps must be done sequentially • Do not re-sterilize syringe • Do not use this product on a sterile field • Do not introduce any other fluid into the syringe at any time • This product is for single dose only opening syringe pictorial

5 WARNINGS AND PRECAUTIONS • Pressor Effects with Concomitant Use with Oxytocic Drugs : Pressor effect of sympathomimetic pressor amines is potentiated • Tachyphylaxis and Tolerance : Repeated administration of ephedrine may cause tachyphylaxis

5.1Pressor 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) . Some of these patients experienced a stroke. Carefully monitor the blood pressure of individuals who have received both ephedrine and an oxytocic.

5.2Tolerance and Tachyphylaxis Data

indicate that repeated administration of ephedrine can result in tachyphylaxis. Clinicians treating anesthesia-induced hypotension with AKOVAZ (ephedrine sulfate injection) should be aware of the possibility of tachyphylaxis and should be prepared with an alternative pressor to mitigate unacceptable responsiveness.

5.3Risk 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.

None None

8.1Pregnancy 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 . 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 . 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 . 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).

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.

To report SUSPECTED ADVERSE REACTIONS, contact Exela Pharma Sciences, LLC at 1-888-451-4321 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .