CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The evidence for the efficacy of ephedrine injection is derived from the published literature. Increases in blood pressure following administration of ephedrine were observed in 14 studies, including where ephedrine was used in pregnant women undergoing neuraxial anesthesia during Cesarean delivery, study in non-obstetric surgery under neuraxial anesthesia, and studies in patients undergoing surgery under general anesthesia. Ephedrine has been shown to raise systolic and mean blood pressure when administered as bolus dose following the development of hypotension during anesthesia.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None. None (4).

ADVERSE REACTIONS SECTION.

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 population of uncertain size, it is not always possible to estimate their frequency reliably or to establish causal relationship to drug exposure.Gastrointestinal disorders: Nausea, vomiting Cardiac disorders: Tachycardia, palpitations (thumping heart), reactive hypertension, bradycardia, ventricular ectopics, R-R variabilityNervous system disorders: DizzinessPsychiatric 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis: Two-year feeding studies in rats and mice conducted under the National Toxicology Program (NTP) demonstrated no evidence of carcinogenic potential with ephedrine sulfate at doses up to 10 mg/kg/day and 27 mg/kg/day (approximately times and times the maximum human recommended dose on mg/m2 basis, respectively).Mutagenesis: Ephedrine sulfate tested negative in the in vitro bacterial reverse mutation assay, the in vitro mouse lymphoma assay, the in vitro sister chromatid exchange, the in vitro chromosomal aberration assay, and the in vivo rat bone marrow micronucleus assay.Impairment of Fertility: There was no impact on fertility or early embryonic development in study in which male rats were administered intravenous bolus doses of 0, 2, 10, or 60 mg/kg ephedrine sulfate (up to 12 times the maximum recommended human dose of 50 mg based on body surface area) for 28 days prior to mating and through gestation and females were treated for 14 days prior to mating through Gestation Day 7.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Ephedrine sulfate is sympathomimetic amine that directly acts as an agonist at and -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 result, ephedrine usually increases blood pressure. Stimulation of the -adrenergic receptors of smooth muscle cells in the bladder base may increase the resistance to the outflow of urine. Activation of -adrenergic receptors in the lungs promotes bronchodilation.The overall cardiovascular effect from ephedrine is the result of balance among -1 adrenoceptor-mediated vasoconstriction, -2 adrenoceptor-mediated vasoconstriction, and -2 adrenoceptor-mediated vasodilatation. Stimulation of the -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 (5.2)].. 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 hours.Ephedrine crosses the placental barrier [see Use in Specific Populations (8.1)].

DESCRIPTION SECTION.

11 DESCRIPTION. Ephedrine is an alpha- and beta-adrenergic agonist and norepinephrine-releasing agent. AKOVAZ (ephedrine sulfate injection) is clear, colorless, sterile solution for intravenous injection. The chemical name of ephedrine sulfate is benzenemethanol, -[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 mL single-dose prefilled syringe contains mg (equivalent to 3.8 mg ephedrine base) and mg Sodium Chloride, USP in Water for Injection. The pH range is 4.5 to 6.5. structural formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oShould be administered by trained healthcare providers (2.1)oAKOVAZ injection, 50 mg/mL, must be diluted before administration as an intravenous bolus dose. (2.1)oAKOVAZ injection, mg/mL in pre-filled syringe, is premixed formulation. Do not dilute prior to use. (2.1)oBolus intravenous injection: mg to 10 mg as needed, not to exceed 50 mg. (2.1). oShould be administered by trained healthcare providers (2.1). oAKOVAZ injection, 50 mg/mL, must be diluted before administration as an intravenous bolus dose. (2.1). oAKOVAZ injection, mg/mL in pre-filled syringe, is premixed formulation. Do not dilute prior to use. (2.1). oBolus intravenous injection: 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 prefilled syringe, is 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 mg to 10 mg administered by intravenous bolus. Administer additional boluses as needed, not to exceed total dosage of 50 mg.oAdjust dosage according to the blood pressure goal (i.e., titrate to effect).. oAdjust dosage according to the blood pressure goal (i.e., titrate to effect).. 2.3 Prepare 5 mg/mL Solution for Bolus Intravenous Administration. For bolus intravenous administration, prepare solution containing final concentration of mg/mL of AKOVAZ (ephedrine sulfate injection):oWithdraw 50 mg (1 mL of 50 mg/mL) of AKOVAZ (ephedrine sulfate injection) and dilute with mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection.oWithdraw an appropriate dose of the mg/mL solution prior to bolus intravenous administration.. oWithdraw 50 mg (1 mL of 50 mg/mL) of AKOVAZ (ephedrine sulfate injection) and dilute with mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection.. oWithdraw an appropriate dose of the 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:oAbsence of syringe damageoAbsence of external particlesoAbsence of internal particlesoProper drug coloroDrug nameoDrug strengthoFill volumeoRoute of administrationoExpiration date to be sure the drug has not expired2. 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. oBefore 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. oTo prevent needle stick injuries, do not recap needle when needle is connected to syringe.NOTE: All steps must be done sequentiallyoDo not re-sterilize syringeoDo not use this product on sterile fieldoDo not introduce any other fluid into the syringe at any timeoThis product is for single dose only. oAbsence of syringe damage. oAbsence of external particles. oAbsence of internal particles. oProper drug color. oDrug name. oDrug strength. oFill volume. oRoute of administration. oExpiration date to be sure the drug has not expired. oBefore injection, ensure that the syringe is securely attached to the needle or needleless luer access device (NLAD).. oTo prevent needle stick injuries, do not recap needle when needle is connected to syringe.. oDo not re-sterilize syringe. oDo not use this product on sterile field. oDo not introduce any other fluid into the syringe at any time. oThis product is for single dose only. opening syringe pictorial.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. AKOVAZ (ephedrine sulfate injection) is clear, colorless, sterile solution for intravenous injection available as: single-dose mL vial that contains 50 mg/mL ephedrine sulfate, equivalent to 38 mg/mL of ephedrine base single-dose mL prefilled syringe that contains 25 mg/ 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 5 mL single-dose prefilled syringe (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Interactions that Augment the Pressor EffectOxytocin and oxytocic drugsClinical Impact: Serious postpartum hypertension has been described in patients who received both vasopressor (i.e., methoxamine, phenylephrine, ephedrine) and an oxytocic (i.e., methylergonovine, ergonovine). Some of these patients experienced stroke. Intervention: Carefully monitor the blood pressure of individuals who have received both ephedrine and an oxytocic.Clonidine, propofol, monoamine oxidase inhibitors (MAOIs), atropineClinical 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 EffectClinical 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: -adrenergic antagonists, -adrenergic receptor antagonists, reserpine, quinidine, mephentermineOther Drug InteractionsGuanethidineClinical 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.RocuroniumClinical 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 anesthesiaClinical 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.TheophyllineClinical 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 glycosidesClinical Impact: Giving ephedrine with cardiac glycoside, such as digitalis, may increase the possibility of arrhythmias.Intervention: Carefully monitor patients on cardiac glycosides who are also administered ephedrine.. oInteractions that Augment Pressor Effect: clonidine, oxytocin and oxytocic drugs, propofol, monoamine oxidase inhibitors (MAOIs), and atropine. Monitor blood pressure. (7)oInteractions that Antagonize the Pressor Effect: Antagonistic effects with -adrenergic antagonists, -adrenergic antagonists, reserpine, quinidine, mephentermine. Monitor blood pressure. (7)oGuanethidine: 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.oRocuronium: 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.oEpidural 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.oTheophylline: 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.oCardiac glycosides: Giving ephedrine with cardiac glycoside, such as digitalis, may increase the possibility of arrhythmias. Carefully monitor patients on cardiac glycosides who are also administered ephedrine.. oInteractions that Augment Pressor Effect: clonidine, oxytocin and oxytocic drugs, propofol, monoamine oxidase inhibitors (MAOIs), and atropine. Monitor blood pressure. (7). oInteractions that Antagonize the Pressor Effect: Antagonistic effects with -adrenergic antagonists, -adrenergic antagonists, reserpine, quinidine, mephentermine. Monitor blood pressure. (7). oGuanethidine: 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.. oRocuronium: 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.. oEpidural 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.. oTheophylline: 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.. oCardiac glycosides: Giving ephedrine with cardiac glycoside, such as digitalis, may increase the possibility of arrhythmias. Carefully monitor patients on cardiac glycosides who are also administered ephedrine.

GERIATRIC USE SECTION.

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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. AKOVAZ (ephedrine sulfate injection) is clear, colorless, sterile solution for intravenous injection supplied as follows:NDCStrengthHow Supplied 51754-4200-450 mg/mL of ephedrine sulfate equivalent to 38 mg/mL of ephedrine base1 mL clear glass vial; for single-dose (supplied in packages of 25)51754-4250-325 mg/ mL (5 mg/mL) of ephedrine sulfate equivalent to 19 mg/5 mL (3.8 mg/mL) of ephedrine base5 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 25C (77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. Store in carton until time of use. For single dose only. Discard unused portion. The single-dose mL prefilled syringe is intended for use in one patient during one surgical procedure. Manufactured for:Exela Pharma Sciences, LLC Lenoir, NC 28645. 51754-4200-4. EXELA LOGO.

INDICATIONS & USAGE SECTION.

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 norepinephrine-releasing agent that is indicated for the treatment of clinically important hypotension occurring in the setting of anesthesia. (1).

LACTATION SECTION.

8.2 Lactation. Risk SummaryA 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 mothers 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.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis: Two-year feeding studies in rats and mice conducted under the National Toxicology Program (NTP) demonstrated no evidence of carcinogenic potential with ephedrine sulfate at doses up to 10 mg/kg/day and 27 mg/kg/day (approximately times and times the maximum human recommended dose on mg/m2 basis, respectively).Mutagenesis: Ephedrine sulfate tested negative in the in vitro bacterial reverse mutation assay, the in vitro mouse lymphoma assay, the in vitro sister chromatid exchange, the in vitro chromosomal aberration assay, and the in vivo rat bone marrow micronucleus assay.Impairment of Fertility: There was no impact on fertility or early embryonic development in study in which male rats were administered intravenous bolus doses of 0, 2, 10, or 60 mg/kg ephedrine sulfate (up to 12 times the maximum recommended human dose of 50 mg based on body surface area) for 28 days prior to mating and through gestation and females were treated for 14 days prior to mating through Gestation Day 7.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdose of ephedrine can cause 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL-1 mL Vial Label. NDC 51754-4200-1 Rx OnlyAkovaz(R)Ephedrine SulfateInjection, USP(50 mg/mL)Must Be DilutedFor Intravenous Use1 mL Single-Dose Vial. ml vial label.

PEDIATRIC USE SECTION.

8.3 Pediatric Use The safety and effectiveness of AKOVAZ in pediatric patients have not been established.Animal Toxicity DataIn 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 maximum daily dose of 50 mg in 60 kg person based on body surface area).

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Ephedrine stimulates heart rate and cardiac output and variably increases peripheral resistance; as result, ephedrine usually increases blood pressure. Stimulation of the -adrenergic receptors of smooth muscle cells in the bladder base may increase the resistance to the outflow of urine. Activation of -adrenergic receptors in the lungs promotes bronchodilation.The overall cardiovascular effect from ephedrine is the result of balance among -1 adrenoceptor-mediated vasoconstriction, -2 adrenoceptor-mediated vasoconstriction, and -2 adrenoceptor-mediated vasodilatation. Stimulation of the -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 (5.2)].

PHARMACOKINETICS SECTION.

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 hours.Ephedrine crosses the placental barrier [see Use in Specific Populations (8.1)].

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from randomized studies, case series, and reports of ephedrine sulfate use in pregnant women have not identified 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 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 ConsiderationsDisease-associated maternal and/or embryofetal riskUntreated hypotension associated with spinal anesthesia for cesarean section is associated with an increase in maternal nausea and vomiting. decrease in uterine blood flow due to maternal hypotension may result in fetal bradycardia and acidosis.Fetal/Neonatal Adverse ReactionsCases 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 infants acid-base status is warranted to ensure that an episode of acidosis is acute and reversible. DataAnimal DataDecreased 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 through Lactation Day 20. No adverse effects were noted at 10 mg/kg (1.9 times the MRHD).

SPL UNCLASSIFIED SECTION.

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 prefilled syringe, is 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable data from randomized studies, case series, and reports of ephedrine sulfate use in pregnant women have not identified 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 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 ConsiderationsDisease-associated maternal and/or embryofetal riskUntreated hypotension associated with spinal anesthesia for cesarean section is associated with an increase in maternal nausea and vomiting. decrease in uterine blood flow due to maternal hypotension may result in fetal bradycardia and acidosis.Fetal/Neonatal Adverse ReactionsCases 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 infants acid-base status is warranted to ensure that an episode of acidosis is acute and reversible. DataAnimal DataDecreased 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 through Lactation Day 20. No adverse effects were noted at 10 mg/kg (1.9 times the MRHD). 8.2 Lactation. Risk SummaryA 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 mothers 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 DataIn 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 maximum daily dose of 50 mg in 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 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oPressor Effects with Concomitant Use with Oxytocic Drugs: Pressor effect of sympathomimetic pressor amines is potentiated (5.1)oTachyphylaxis and Tolerance: Repeated administration of ephedrine may cause tachyphylaxis (5.2) oPressor Effects with Concomitant Use with Oxytocic Drugs: Pressor effect of sympathomimetic pressor amines is potentiated (5.1). oTachyphylaxis 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 vasopressor (i.e., methoxamine, phenylephrine, ephedrine) and an oxytocic (i.e., methylergonovine, ergonovine) [see Drug Interactions (7) ]. Some of these patients experienced 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.