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, vomitingCardiac disorders: Tachycardia, palpitations (thumping heart), reactive hypertension, bradycardia, ventricular ectopics, R-R variabilityNervous system disorders: DizzinessPsychiatric disorders: RestlessnessFor medical advice about adverse reactions, contact your medical professional. To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical 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 Pharmaceutical at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis and Mutagenesis and 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, and the in vitro chromosomal aberration assay.Impairment of Fertility: Studies to evaluate the effect of ephedrine on fertility have not been conducted.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Ephedrine sulfate is sympathomimetic amine that directly acts as an agonist at 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 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 ss-adrenergic receptors in the lungs promotes bronchodilation.The overall cardiovascular effect from ephedrine is the result of balance among -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 hours.Ephedrine crosses the placental barrier [see Use in Specific Populations 8.1].

DESCRIPTION SECTION.

11 DESCRIPTION. Ephedrine sulfate is an alpha- and beta-adrenergic agonist and norepinephrine-releasing agent. Ephedrine sulfate injection, USP is clear, colorless, sterile solution for intravenous injection. Each mL contains ephedrine sulfate 50 mg in water for injection as single-dose product. The pH range is 4.5 to 7.0. The drug product must be diluted before intravenous administration. The chemical name of ephedrine sulfate is (1R,2S)-(-)-2-methylamine-1-phenylpropan-1-ol sulfate (2:1) (salt). Its molecular weight is 428.54. The structural formula is:Image 1Ephedrine sulfate darkens on exposure to light. It is freely soluble in water and ethanol, very slightly soluble in chloroform, and practically insoluble in ether. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Treatment of hypotension developing during anesthesia: Bolus intravenous injection: to 10 mg as needed, not to exceed 50 mg. Dilute before use. See Full Prescribing Information for instructions on administration and preparation for injection. (2) Treatment of hypotension developing during anesthesia: Bolus intravenous injection: to 10 mg as needed, not to exceed 50 mg. Dilute before use. See Full Prescribing Information for instructions on administration and preparation for injection. (2) 2.1 General Dosage andAdministration Instructions Ephedrine sulfate injection must be diluted before administration to achieve the desired concentration as an intravenous bolus or intravenous infusion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is colored or cloudy, or if it contains particulate matter.. 2.2 Dosingfor the Treatment of Clinically Important Hypotension in the Setting ofAnesthesia The recommended dosage for the treatment of clinically important hypotension in the setting of anesthesia is an initial dose of to 10 mg administered by intravenous bolus. Administer additional boluses as needed, not to exceed total dosage of 50 mg.Adjust dosage according to the blood pressure goal (i.e., titrate to effect).. 2.3 Preparation of 5 mg/mL Solution for BolusIntravenous Administration For bolus intravenous administration, prepare solution containing final concentration of mg/mL of ephedrine sulfate injection.Withdraw 50 mg (1 mL of 50 mg/mL) of ephedrine sulfate injection and dilute with mL of 5% Dextrose Injection or Sodium Chloride Injection.Withdraw an appropriate dose of the mg/mL solution prior to bolus intravenous administration.. Withdraw 50 mg (1 mL of 50 mg/mL) of ephedrine sulfate injection and dilute with mL of 5% Dextrose Injection or Sodium Chloride Injection.. Withdraw an appropriate dose of the mg/mL solution prior to bolus intravenous administration.

DRUG INTERACTIONS SECTION.

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 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), 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: -adrenergic antagonists, -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 cardiac glycoside, such as digitalis, may increase the possibility of arrhythmias. Intervention: Carefully monitor patients on cardiac glycosides who are also administered ephedrine. o nt r ctio s ha Augment the Pressor Effect: clonidine, oxytocin and oxytocic drugs, propofol, monoamine oxidase inhibitors (MAOIs), and atropine. Monitor blood pressure. (7) I nt r acti n that Antagonize the Pressor Effect: Antagonistic effects with -adrenergic antagonists, -adrenergic antagonists, reserpine, quinidine, mephentermine. Monitor blood pressure. (7) G uan t i 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 cu roni 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 e 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 a 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. (7).

GERIATRIC USE SECTION.

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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis and Mutagenesis and 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, and the in vitro chromosomal aberration assay.Impairment of Fertility: Studies to evaluate the effect of ephedrine on fertility have not been conducted.

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 ss-adrenergic receptors in the lungs promotes bronchodilation.The overall cardiovascular effect from ephedrine is the result of balance among -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].

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryLimited published data on the use of ephedrine sulfate are insufficient to determine 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 background risk of birth defect, loss, orother adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.Clinical ConsiderationsFetal/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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryLimited published data on the use of ephedrine sulfate are insufficient to determine 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 background risk of birth defect, loss, orother adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.Clinical ConsiderationsFetal/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. 8.2 Lactation. Risk SummaryLimited 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 mothers 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 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. Pr ssor Effect with Concomitant Oxytocic Drugs: Pressor effect of sympathomimetic pressor amines is potentiated (5.1) T ach ph l x s and Tolerance: Repeated administration of ephedrine may cause tachyphylaxis (5.2) 5.1 Pressor Effect withConcomitant 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 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 ofHypertension 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.