HIGHLIGHTS OF PRESCRIBING INFORMATION ___________________ ADVERSE REACTIONS ___________________

These highlights do not include all the information needed to use Most common adverse reactions during treatment: nausea, vomiting, and
AKOVAZTM safely and effectively. See full prescribing information for tachycardia. (6)
AKOVAZ.
To report SUSPECTED ADVERSE REACTIONS, contact Éclat
AKOVAZ (ephedrine sulfate injection, USP) for intravenous use Pharmaceuticals at 1-877-622-2320 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
Initial U.S. Approval: 2016
___________________ DRUG INTERACTIONS____________________
__________________ INDICATIONS AND USAGE _________________
• Intreractions that Augment the Pressor Effect: clonidine, oxytocin and
AKOVAZ injection is an alpha- and beta- adrenergic agonist and a oxytocic drugs, propofol, monoamine oxidase inhibitors (MAOIs), and
norepinephrine-releasing agent that is indicated for the treatment of clinically atropine. Monitor blood pressure. (7)
important hypotension occurring in the setting of anesthesia. (1) • Interactions that Antagonize the Pressor Effect: Antagonistic effects
with α-adrenergic antagonists, β-adrenergic antagonists, reserpine,
_______________DOSAGE AND ADMINISTRATION ______________
quinidine, mephentermine. Monitor blood pressure. (7)
• AKOVAZ injection, 50 mg/mL, (equivalent to 38 mg ephedrine base) is • Guanethidine: Ephedrine may inhibit the neuron blockage produced by
injected intravenously as a bolus. Dilute before administration. (2) guanethidine, resulting in loss of antihypertensive effectiveness. Monitor
blood pressure and adjust the dosage of pressor accordingly.
• Bolus intravenous injection: 5 to 10 mg as needed, not to exceed 50 mg. • Rocuronium: Ephedrine may reduce the onset time of neuromuscular
(2) blockade when used for intubation with rocuronium if administered
simultaneously with anesthetic induction. Be aware of this potential
______________ DOSAGE FORMS AND STRENGTHS _____________
interaction. No treatment or other interventions are needed.
Injection: 50 mg/mL ephedrine sulfate in single-use vial (3) • Epidural anesthesia: Ephedrine may decrease the efficacy of epidural
___________________ CONTRAINDICATIONS ___________________ blockade by hastening the regression of sensory analgesia. Monitor and
treat the patient according to clinical practice.
None (4)
_______________ WARNINGS AND PRECAUTIONS_______________ • Theophylline: Concomitant use of ephedrine may increase the frequency
of nausea, nervousness, and insomnia. Monitor patient for worsening
• Pressor Effect with Concomitant Oxytocic Drugs: Pressor effect of symptoms and manage symptoms according to clinical practice.
sympathomimetic pressor amines is potentiated (5.1) • Cardiac glycosides: Giving ephedrine with a cardiac glycoside, such as
• Tachyphylaxis and Tolerance: Repeated administration of ephedrine digitalis, may increase the possibility of arrhythmias. Carefully monitor
may cause tachyphylaxis (5.2) patients on cardiac glycosides who are also administered ephedrine.

Revised: 04/2016

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE 8.5 Geriatric Use

2 DOSAGE AND ADMINISTRATION 8.6 Renal Impairment
2.1 General Dosage and Administration Instructions 10 OVERDOSAGE
2.2 Dosing for the Treatment of Clinically Important Hypotension in 11 DESCRIPTION
the Setting of Anesthesia 12 CLINICAL PHARMACOLOGY
2.3 Prepare a 5 mg/mL Solution for Bolus Intravenous
12.1 Mechanism of Action
Administration
12.2 Pharmacodynamics
3 DOSAGE FORMS AND STRENGTHS 12.3 Pharmacokinetics
4 CONTRAINDICATIONS 13 NONCLINICAL TOXICOLOGY
5 WARNINGS AND PRECAUTIONS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5.1 Pressor Effect with Concomitant Oxytocic Drugs 14 CLINICAL STUDIES
5.2 Tolerance and Tachyphylaxis 16 HOW SUPPLIED/STORAGE AND HANDLING
5.3 Risk of Hypertension When Used Prophylactically
6 ADVERSE REACTIONS
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
*Sections or subsections omitted from the full prescribing information
8.1 Pregnancy
are not listed.
8.2 Lactation
8.4 Pediatric Use

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 FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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

2 DOSAGE AND ADMINISTRATION

2.1 General Dosage and Administration Instructions

AKOVAZ (ephedrine sulfate injection) must be diluted before administration as an intravenous
bolus to achieve the desired concentration. Dilute with normal saline or 5% dextrose in water.
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
The recommended dosages for the treatment of clinically important hypotension in the setting of
anesthesia is an initial dose of 5 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.

3 DOSAGE FORMS AND STRENGTHS

AKOVAZ (ephedrine sulfate injection) is available as a single-dose 1 mL vial that contains 50
mg/mL ephedrine sulfate, equivalent to 38 mg ephedrine base.

4 CONTRAINDICATIONS
None

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 5 WARNINGS AND PRECAUTIONS

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.

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 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

7 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.

Reference ID: 3924387

 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

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 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy
Risk Summary
Limited published data on the use of ephedrine sulfate are insufficient to determine a drug
associated risk of major birth defects or miscarriage. However, there are clinical considerations
[see Clinical Considerations]. Animal reproduction studies have not been conducted with
ephedrine sulfate.
In the U.S. general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
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.

8.2 Lactation
Risk Summary
Limited published literature reports 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.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 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.

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 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.

10 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.

11 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. It must be diluted before intravenous administration. The chemical name of ephedrine
sulfate is (1R,2S)-(-)-2-methylamine-1-phenylpropan-1-ol sulfate, 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 slighly soluble in chloroform, and
practically insoluble in ether. Each mL 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 necesssary. The pH range is 4.5 to 7.0.

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 12 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 5.3].

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 8.1].

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 2 times and 3 times the
maximum human recommended dose on a 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, and the in vitro
chromosomal aberration assay.

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 Impairment of Fertility: Studies to evaluate the effect of ephedrine on fertility have not been
conducted.

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 9 where ephedrine was used in pregnant women undergoing neuraxial anesthesia
during Cesarean delivery, 1 study in non-obstetric surgery under neuraxial anesthesia, and 4
studies in patients undergoing surgery under general anesthesia. Ephedrine has been shown to
raise systolic and mean blood pressure when administered as a bolus dose following the
development of hypotension during anesthesia.

16 HOW SUPPLIED/STORAGE AND HANDLING

AKOVAZ (ephedrine sulfate injection), 50 mg/mL, is supplied as follows:

NDC Strength How Supplied

76014-005-25 50 mg/mL 1 mL clear glass vial; for single use (supplied in

packages of 25)

Vial stoppers are not manufactured with natural rubber latex. Store AKOVAZ (ephedrine sulfate
injection), 50 mg/mL, 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 use only.
Discard unused portion.

Manufactured for:
Éclat Pharmaceuticals
Chesterfield, MO 63005 USA

Rev. 04/16

Reference ID: 3924387