Akovaz (ephedrine sulfate): Uses, Dosage, Side Effects & Warnings

Uses

(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. ( 1 )

Dosage and administration

• Should be administered by trained healthcare providers ( 2.1 )
• AKOVAZ injection, 50 mg/mL, must be diluted before administration as an intravenous bolus dose. ( 2.1 )
• AKOVAZ injection, 5 mg/mL in a pre-filled syringe, is a premixed formulation. Do not dilute prior to use. ( 2.1 )
• Bolus intravenous injection: 5 mg to 10 mg as needed, not to exceed 50 mg. ( 2.1 ) 2.1 General 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. 2.2 Dosing 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). 2.3 Prepare 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. 2.4 Instructions 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. (See Figure 1): 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

Dosage forms and strengths

(ephedrine sulfate injection) is a clear, colorless, sterile solution for intravenous injection available as: single-dose 1 mL vial that contains 50 mg/mL ephedrine sulfate, equivalent to 38 mg/mL of ephedrine base single-dose 5 mL prefilled syringe that contains 25 mg/ 5 mL (5 mg/mL) ephedrine sulfate equivalent to 19 mg/5 mL (3.8 mg/mL) of ephedrine base Injection: 50 mg/mL ephedrine sulfate in single-dose vial and 25 mg/5 mL (5 mg/mL) ephedrine sulfate in a 5 mL single-dose prefilled syringe ( 3 )

Contraindications

None None ( 4 )

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 AKOVAZ (ephedrine sulfate injection) should be aware of the possibility of tachyphylaxis and should be prepared with an alternative pressor to mitigate unacceptable responsiveness. 5.3 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.

Side effects

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 Exela Pharma Sciences, LLC at 1-888-451-4321 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 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 and any of these drugs. Interactions that Antagonize the Pressor Effect Clinical Impact: These drugs antagonize the pressor effect of ephedrine. Intervention: 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 Guanethidine Clinical Impact: Ephedrine 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 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 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 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 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 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 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 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 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 with a cardiac glycoside, such as digitalis, may increase the possibility of arrhythmias. Carefully monitor patients on cardiac glycosides who are also administered ephedrine.

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 AKOVAZ (ephedrine sulfate injection) and any potential adverse effects on the breastfed child from AKOVAZ (ephedrine sulfate injection) or from the underlying maternal condition. 8.3 Pediatric Use The safety and effectiveness of AKOVAZ in pediatric patients have not been established. Animal Toxicity Data In a study in which juvenile rats were administered intravenous bolus doses of 2, 10, or 60 mg/kg ephedrine sulfate daily from Postnatal Day 35 to 56, an increased incidence of mortality was noted at the high dose of 60 mg/kg. The no-adverse-effect level was 10 mg/kg (approximately 1.9 times a maximum daily dose of 50 mg in a 60 kg person based on body surface area). 8.4 Geriatric Use Clinical studies of ephedrine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Renal Impairment Ephedrine and its metabolite are excreted in urine. In patients with renal impairment, excretion of ephedrine is likely to be affected with a corresponding increase in elimination half-life, which will lead to slow elimination of ephedrine and consequently prolonged pharmacological effect and potentially adverse reactions. Monitor patients with renal impairment carefully after the initial bolus dose for adverse events.

Pregnancy

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).

Pediatric use

8.3 Pediatric Use The safety and effectiveness of AKOVAZ in pediatric patients have not been established. Animal Toxicity Data In a study in which juvenile rats were administered intravenous bolus doses of 2, 10, or 60 mg/kg ephedrine sulfate daily from Postnatal Day 35 to 56, an increased incidence of mortality was noted at the high dose of 60 mg/kg. The no-adverse-effect level was 10 mg/kg (approximately 1.9 times a maximum daily dose of 50 mg in a 60 kg person based on body surface area).

Geriatric use

8.4 Geriatric Use Clinical studies of ephedrine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

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.

Description

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

Mechanism of action

12.1 Mechanism of Action Ephedrine sulfate is a sympathomimetic amine that directly acts as an agonist at α- and β-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.

How supplied

(ephedrine sulfate injection) is a clear, colorless, sterile solution for intravenous injection supplied as follows: NDC Strength How Supplied 51754-4200-4 50 mg/mL of ephedrine sulfate equivalent to 38 mg/mL of ephedrine base 1 mL clear glass vial; for single-dose (supplied in packages of 25) 51754-4250-3 25 mg/ 5 mL (5 mg/mL) of ephedrine sulfate equivalent to 19 mg/5 mL (3.8 mg/mL) of ephedrine base 5 mL single-dose prefilled syringe (supplied in packages of 10) Vial stoppers are not manufactured with natural rubber latex. Store AKOVAZ (ephedrine sulfate injection), at 25°C (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 dose only. Discard unused portion. The single-dose 5 mL prefilled syringe is intended for use in one patient during one surgical procedure. Manufactured for: Exela Pharma Sciences, LLC Lenoir, NC 28645 EXELA LOGO

Active ingredients

Ephedrine Sulfate in 2 products

Akovaz NDC products (2)

NDC	Strength & form	Labeler	Type
51754-4200	Ephedrine Sulfate 50 mg/mL Injection	Exela Pharma Sciences, LLC	NDA
51754-4250	Ephedrine Sulfate 5 mg/mL Injection	Exela Pharma Sciences, LLC	NDA

Frequently asked questions

What is Akovaz used for?

(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. ( 1 )

What are the side effects of Akovaz?

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,… See the full label for the complete list.

Who makes Akovaz?

Akovaz is listed by 1 labeler in the FDA NDC directory, including Exela Pharma Sciences, LLC.