Ephedrine Sulfate

Ephedrine sulfate injection 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 indicated for the treatment of clinically important hypotension occurring in the setting of anesthesia. (1)

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. Injection: 50 mg/mL ephedrine sulfate in single-dose vial (3)

None None (4)

• Pr e ssor Effect with Concomitant Oxytocic Drugs : Pressor effect of sympathomimetic pressor amines is potentiated (5.1)
• T ach y ph y l a x i s 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 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.

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

I nteractions that Augment the Pressor Effect Oxytocin and oxytocic drugs C linical 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. I ntervention: Carefully monitor the blood pressure of individuals who have received both ephedrine and an oxytocic. Clonidine, propofol, monoamine oxidase inhibitors (MAOIs), atropine C linical Impact: These drugs augment the pressor effect of ephedrine. I ntervention: Carefully monitor the blood pressure of individuals who have received both ephedrine and any of these drugs. I nteractions that Antagonize the Pressor Effect C linical Impact: These drugs antagonize the pressor effect of ephedrine. I ntervention: 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 G u anethidine C linical Impact: Ephedrine may inhibit the neuron blockage produced by guanethidine, resulting in loss of antihypertensive effectiveness. I ntervention: Clinician should monitor patient for blood pressor response and adjust the dosage or choice of pressor accordingly. Rocuronium C linical Impact: Ephedrine may reduce the onset time of neuromuscular blockade when used for intubation with rocuronium if administered simultaneously with anesthetic induction. I ntervention: Be aware of this potential interaction. No treatment or other interventions are needed. Ep idural anesthesia C linical Impact: Ephedrine may decrease the efficacy of epidural blockade by hastening the regression of sensory analgesia. I ntervention: Monitor and treat the patient according to clinical practice. Th e ophylline C linical Impact: Concomitant use of ephedrine may increase the frequency of nausea, nervousness, and insomnia. I ntervention: Monitor patient for worsening symptoms and manage symptoms according to clinical practice. Cardiac glycosides C linical Impact: Giving ephedrine with a cardiac glycoside, such as digitalis, may increase the possibility of arrhythmias. I ntervention: Carefully monitor patients on cardiac glycosides who are also administered ephedrine.

• I nt e r a ctio n s t ha t Augment the Pressor Effect : clonidine, oxytocin and oxytocic drugs, propofol, monoamine oxidase inhibitors (MAOIs), and atropine. Monitor blood pressure. (7)
• I nt e r acti o n s that Antagonize the Pressor Effect : Antagonistic effects with α-adrenergic antagonists, β-adrenergic antagonists, reserpine, quinidine, mephentermine. Monitor blood pressure. (7)
• G uan e t h i d in e : 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. (7)
• R o cu roni u m : 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. (7)
• 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. (7)
• T h e o ph yll in e : 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. (7)
• Ca rd i a c 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. (7)

8.1 Pregnancy R isk 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. The estimated background risk of major birth defects and miscarriage for the indicated population is 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 to 4% and 15 to 20%, respectively. C linical 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 R isk 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 ephedrine sulfate injection and any potential adverse effects on the breastfed child from 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. 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.

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.