Phenylephrine Hydrochloride

IMMPHENTIV Injection 100 mcg/mL: Do NOT dilute prior to administration (2.1) Dosing for Perioperative Hypotension - Intravenous bolus administration: 50 mcg to 250 mcg (2.2) Phenylephrine Hydrochloride Injection 10 mg/mL: MUST BE DILUTED before administration. (2.1) Dosing for Perioperative Hypotension Intravenous bolus administration: 50 mcg to 250 mcg (2.2) Intravenous continuous infusion: 0.5 mcg/kg/minute to 1.4 mcg/kg/minute titrated to effect (2.2) Dosing for Patients with Vasodilatory Shock Intravenous continuous infusion: 0.5 mcg/kg/minute to 6 mcg/kg/minute titrated to effect (2.2)

2.1General Administration Instructions Phenylephrine Hydrochloride

Injection is injected by bolus intravenous infusion or in dilute solution as a continuous intravenous infusion. 2.2 Preparation of Phenylephrine Hydrochloride Injection Preparing a 100 mcg/mL Solution for Intravenous Bolus Administration For intravenous bolus administration, withdraw 10 mg (1 mL of a 10 mg/mL concentration) of Phenylephrine Hydrochloride Injection 10 mg/mL and dilute with 99 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP. This will yield a final concentration of 100 mcg/mL. Withdraw an appropriate dose from the 100 mcg/mL solution prior to intravenous bolus administration. Preparing a 20 mcg/mL Solution for Continuous Intravenous Infusion For continuous intravenous infusion, withdraw 10 mg (1 mL of 10 mg/mL concentration) of phenylephrine hydrochloride injection 10 mg/mL and add to 500 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (providing a final concentration of 20 mcg/mL). Directions for Dispensing from Phenylephrine Hydrochloride Injection 10 mg/mL Pharmacy Bulk Vial The Pharmacy Bulk Vial is intended for dispensing of single doses to multiple patients in a pharmacy admixture program and is restricted to the preparation of admixtures for infusion. Each closure shall be penetrated only one time with a suitable sterile transfer device or dispensing set that allows measured dispensing of the contents. The Pharmacy Bulk Vial is to be used only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area). Dispensing from a pharmacy bulk vial should be completed within 4 hours after the vial is penetrated. Dosing for Perioperative Setting In adult patients undergoing surgical procedures with either neuraxial anesthesia or general anesthesia: IMMPHENTIV Injection 100 mcg/mL and Phenylephrine Hydrochloride Injection 10 mg/mL (diluted to 100 mcg/mL): 50 mcg to 250 mcg by intravenous bolus administration. The most frequently reported initial bolus dose is 50 mcg or 100 mcg. Phenylephrine Hydrochloride Injection 10 mg/mL (diluted to 20 mcg/mL): 0.5 mcg/kg/min to 1.4 mcg/kg/min by intravenous continuous infusion, titrated to blood pressure goal. Dosing for Septic or Other Vasodilatory Shock (Phenylephrine Hydrochloride Injection 10 mg/mL only) In adult patients with septic or other vasodilatory shock: No bolus. 0.5 mcg/kg/min to 6 mcg/kg/min by intravenous continuous infusion, titrated to blood pressure goal. Doses above 6 mcg/kg/min do not show significant incremental increase in blood pressure.

Severe bradycardia and decreased cardiac output: (5.2) Extravasation: during intravenous administration may cause necrosis or sloughing of tissue (5.4) Concomitant use with oxytocic drugs: pressor effect of sympathomimetic pressor amines is potentiated (5.5) Allergic-type reactions with Phenylephrine Hydrochloride Injection 10 mg/mL: Sulfite (5.6)

5.1Exacerbation of Angina, Heart Failure, or Pulmonary Arterial

Hypertension Because of its pressor effects, phenylephrine hydrochloride can precipitate angina in patients with severe arteriosclerosis or history of angina, exacerbate underlying heart failure, and increase pulmonary arterial pressure. 5.2 Bradycardia IMMPHENTIV 100 mcg/mL and Phenylephrine Hydrochloride Injection 10 mg/mL can cause severe bradycardia and decreased cardiac output. 5.3 Risk in Patients with Autonomic Dysfunction The pressor response to adrenergic drugs, including phenylephrine, can be increased in patients with autonomic dysfunction, as may occur with spinal cord injuries. 5.4 Skin and Subcutaneous Necrosis Extravasation of phenylephrine can cause necrosis or sloughing of tissue. 5.5 Pressor Effect with Concomitant Oxytocic Drugs Oxytocic drugs potentiate the pressor effect of sympathomimetic pressor amines including IMMPHENTIV 100 mcg/mL and Phenylephrine Hydrochloride Injection 10 mg/mL [see Drug Interactions (7.1)], with the potential for hemorrhagic stroke. 5.6 Allergic Reactions Phenylephrine Hydrochloride Injection 10 mg/mL contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. 5.7 Peripheral and Visceral Ischemia IMMPHENTIV 100 mcg/mL and Phenylephrine Hydrochloride Injection 10 mg/mL can cause excessive peripheral and visceral vasoconstriction and ischemia to vital organs, particularly in patients with extensive peripheral vascular disease. 5.8 Renal Toxicity IMMPHENTIV 100 mcg/mL and Phenylephrine Hydrochloride Injection 10 mg/mL can increase the need for renal replacement therapy in patients with septic shock. Monitor renal function.

8.1Pregnancy Risk Summary

In animal reproductive and developmental studies, decreased fetal body weights were noted at 0.4 times the human daily dose (HDD) of 10 mg. No malformations were reported, however, an increased incidence of agenesis of the intermediate lobe of the lung, a visceral variation, was reported at levels as low as 0.08 times the HDD. 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. Data Animal Data No malformations were noted when normotensive pregnant rats were treated with a single daily intravenous bolus dose of 50 mcg, 150 mcg, or 300/200 mcg/kg phenylephrine hydrochloride from Gestation Day 6 to 17 (high dose is 0.3/0.2 times the human daily dose (HDD) of 10 mg/day based on body surface area). Evidence of maternal toxicity, including mortality, was noted at the highest tested dose of 300/200 mcg/kg. Decreased fetal body weights but no clear treatment-related malformations were reported when normotensive pregnant rabbits were treated with a single daily intravenous bolus dose of 40 mcg, 100 mcg and 200 mcg/kg (0.08, 0.2, and 0.4 times the HDD based on body surface area) phenylephrine hydrochloride from Gestation Day 7 to 19. Maternal toxicity, as manifested by decreased food consumption and body weight gain at all doses. An increased incidence of agenesis of the intermediate lobe of the lung, a visceral variation, was noted in all treatment groups compared to controls. No adverse effects on the offspring were reported when pregnant rats were treated via a single daily intravenous bolus dose of up to 200 mcg/day phenylephrine hydrochloride (0.2 times the HDD based on body surface area) from Gestation Day 6 to Lactation Day 20. Pregnancy Category B Animal reproduction studies have not been conducted with phenylephrine. It is also not known whether phenylephrine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Phenylephrine should be given to a pregnant woman only if clearly needed. However, the safety of its use for the management of hypotension associated with neuraxial anesthesia in cesarean deliveries is well established. 71 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of phenylephrine 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. 8.6 Hepatic Impairment In patients with liver cirrhosis [Child Pugh Class A (n=3), Class B (n=5) and Class C (n=1)], dose-response data indicate decreased responsiveness to phenylephrine. Consider using larger doses than usual in hepatic impaired subjects. 8.7 Renal Impairment In patients with end stage renal disease (ESRD) undergoing hemodialysis, dose-response data indicates increased responsiveness to phenylephrine. Consider using lower doses of phenylephrine hydrochloride in ESRD patients.

Risk Summary In animal reproductive and developmental studies, decreased fetal body weights were noted at 0.4 times the human daily dose (HDD) of 10 mg. No malformations were reported, however, an increased incidence of agenesis of the intermediate lobe of the lung, a visceral variation, was reported at levels as low as 0.08 times the HDD. 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. Data Animal Data No malformations were noted when normotensive pregnant rats were treated with a single daily intravenous bolus dose of 50 mcg, 150 mcg, or 300/200 mcg/kg phenylephrine hydrochloride from Gestation Day 6 to 17 (high dose is 0.3/0.2 times the human daily dose (HDD) of 10 mg/day based on body surface area). Evidence of maternal toxicity, including mortality, was noted at the highest tested dose of 300/200 mcg/kg. Decreased fetal body weights but no clear treatment-related malformations were reported when normotensive pregnant rabbits were treated with a single daily intravenous bolus dose of 40 mcg, 100 mcg and 200 mcg/kg (0.08, 0.2, and 0.4 times the HDD based on body surface area) phenylephrine hydrochloride from Gestation Day 7 to 19. Maternal toxicity, as manifested by decreased food consumption and body weight gain at all doses. An increased incidence of agenesis of the intermediate lobe of the lung, a visceral variation, was noted in all treatment groups compared to controls. No adverse effects on the offspring were reported when pregnant rats were treated via a single daily intravenous bolus dose of up to 200 mcg/day phenylephrine hydrochloride (0.2 times the HDD based on body surface area) from Gestation Day 6 to Lactation Day 20. Pregnancy Category B Animal reproduction studies have not been conducted with phenylephrine. It is also not known whether phenylephrine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Phenylephrine should be given to a pregnant woman only if clearly needed. However, the safety of its use for the management of hypotension associated with neuraxial anesthesia in cesarean deliveries is well established. 71

Phenylephrine Hydrochloride Injection and IMMPHENTIV ® injection contain active pharmaceutical ingredient phenylephrine in the form of hydrochloride salt. Phenylephrine is a synthetic sympathomimetic agent in sterile form for parenteral injection. Phenylephrine hydrochloride chemical name is (-)- m -Hydroxy-α [(methylamino)methyl]benzyl alcohol hydrochloride and has the following structural formula: Phenylephrine hydrochloride is very soluble in water, freely soluble in ethanol, and insoluble in chloroform and ethyl ether. Phenylephrine hydrochloride is sensitive to light. IMMPHENTIV ® Injection, 100 mcg/mL: IMMPHENTIV ®, USP, is a clear, colorless, aqueous solution that is essentially free of visible foreign matter, and Ready-To-Use formulation. Each mL contains: 100 mcg of Phenylephrine Hydrochloride USP (equivalent to 82 mcg of phenylephrine base), 7.5 mg of Sodium Chloride USP as tonicity agent; 4 mg of Sodium Citrate Dihydrate USP, and 1 mg of Citric Acid Monohydrate USP, as buffering agents, 0.2 mg of Edetate Disodium USP as chelating agent, and Sodium Hydroxide NF and Hydrochloric Acid NF as pH adjusters, in Water for Injection USP. IMMPHENTIV ® injection pH range is 3.0 to 6.5. Phenylephrine Hydrochloride Injection, USP, 10 mg/mL: Phenylephrine Hydrochloride injection, USP is a clear, colorless, aqueous solution that is essentially free of visible foreign matter. It MUST BE DILUTED before administration as bolus intravenous infusion or continuous intravenous infusion. Each mL contains: 10 mg of Phenylephrine Hydrochloride (equivalent to 8.2 mg of phenylephrine base); 3.5 mg of Sodium Chloride USP as tonicity agent; 1 mg of Citric Acid Monohydrate USP and 4 mg of Sodium Citrate Dihydrate USP, as buffering agents; 2 mg of Sodium Metabisulfite USP, as antioxidant, and Sodium Hydroxide NF and Hydrochloric Acid NF, as pH adjusters in Water for Injection. Phenylephrine Hydrochloride injection pH range is 3.0 to 6.5. Structural formula

IMMPHENTIV ® injection, USP, 100 mcg/mL Ready-to-Use vials is supplied as follows: NDC 0641-6245-10: 500 mcg in 5 mL (100 mcg/mL) single-dose vials packaged in cartons containing 10 vials per carton NDC 0641-6246-10: 1,000 mcg in 10 mL (100 mcg/mL) single-dose vials packaged in cartons containing 10 vials per carton Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Discard any unused portion. Phenylephrine Hydrochloride injection, USP, 10 mg/mL, is supplied as follows: NDC 0641-6142-25: 10 mg in 1 mL fill (10 mg/mL) in 2 mL single-dose vials packaged in cartons containing 25 vials per carton NDC 0641-6188-10: 50 mg in 5 mL (10 mg/mL) Pharmacy Bulk Package vials packed in cartons containing 10 vials per carton NDC 0641-6189-10: 100 mg in 10 mL (10 mg/mL) Pharmacy Bulk Package vials packed in cartons containing 10 vials per carton Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from light. Keep covered in carton until time of use. The 1 mL vials are for single-dose only. Discard any unused portion. The 5 mL and 10 mL vials are pharmacy bulk packages. The diluted solution should not be held for more than 4 hours at room temperature or for more than 24 hours under refrigerated conditions (2°C - 8°C). Discard any unused portion.