Emerphed PFS

1. INDICATIONS AND USAGE EMERPHED and EMERPHED-PFS is indicated for the treatment of clinically important hypotension occurring in the setting of anesthesia. EMERPHED and EMERPHED-PFS 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 )

2. DOSAGE AND ADMINISTRATION This is a premixed formulation. Do not dilute prior to use. Discard any unused portion of EMERPHED or EMERPHED-PFS. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. EMERPHED and EMERPHED-PFS is a clear, colorless solution. Do not use if the solution is not clear or if particulate matter is present. The single-dose prefilled syringe is intended for use in one patient during one surgical procedure. 2.1 General Dosage and Administration Instructions This is a premixed formulation. Do not dilute prior to use. Discard any unused portion of EMERPHED. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The single-dose prefilled syringe is intended for use in one patient during one surgical procedure. EMERPHED is a clear, colorless solution. Do not use if the solution is not clear or if particulate matter is present. 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 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 Instructions for Use of Prefilled Syringe The proper method of administration of EMERPHED-PFS injection is described in the following instructions. For each single-dose prefilled syringe: Remove syringe from tray and check that it is not damaged or leaking. Inspect drug product in glass syringe for any visible particulate matter or discoloration prior to use. Discard if particulate matter or discoloration is present. Do not remove the tamper evident seal. Push plunger rod slightly in to break the stopper loose while tip cap is still on. Hold the syringe upright on the syringe barrel (C). With the other hand, take hold of the cap (A) and twist off cap counterclockwise from syringe tip (see Figure 1). Once cap (A) is off, DO NOT TOUCH THE STERILE SYRINGE TIP (Luer-Lok) (B) (see Figure 2). Discard the tip cap. Expel air bubble. Adjust dose into sterile material (if applicable). 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). Depress plunger rod to deliver medication. Ensure that pressure is maintained on the plunger rod during the entire administration. 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 Figure 1 Figure 2

4. CONTRAINDICATIONS None None ( 4 )

5. 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 EMERPHED and EMERPHED-PFS 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 EMERPHED and EMERPHED-PFS and an oxytocic. 5.2 Tolerance and Tachyphylaxis Data indicate that repeated administration of ephedrine can result in tachyphylaxis. Be aware of this possibility when treating anesthesia-induced hypotension with EMERPHED and EMERPHED-PFS and 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.

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. Intervention: Carefully monitor the blood pressure of individuals who have received both EMERPHED and EMERPHED-PFS 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 EMERPHED and EMERPHED-PFS and any of these drugs. Drugs that Antagonize the Pressor Effect α-adrenergic antagonists, β-adrenergic receptor antagonists, reserpine, quinidine, mephentermine Clinical Impact: These drugs antagonize the pressor effect of ephedrine. Intervention: Carefully monitor the blood pressure of individuals who have received both EMERPHED and EMERPHED-PFS and any of these drugs. Other Drug Interactions Guanethidine Clinical Impact: EMERPHED and EMERPHED-PFS 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: EMERPHED and EMERPHED-PFS 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: EMERPHED and EMERPHED-PFS 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 EMERPHED and EMERPHED-PFS 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 EMERPHED and EMERPHED-PFS 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: EMERPHED and EMERPHED-PFS 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: EMERPHED and EMERPHED-PFS 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: EMERPHED and EMERPHED-PFS 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 EMERPHED and EMERPHED-PFS may increase the frequency of nausea, nervousness, and insomnia. Monitor patient for worsening symptoms and manage symptoms according to clinical practice. Cardiac glycosides: Giving EMERPHED and EMERPHED-PFS with a cardiac glycoside, such as digitalis, may increase the possibility of arrhythmias. Carefully monitor patients on cardiac glycosides who are also administered EMERPHED and EMERPHED-PFS.

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 Most common adverse reactions during treatment : nausea, vomiting, and tachycardia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Nexus Pharmaceuticals at (855) 642-2594 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 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. 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).