Phenylephrine Hydrochloride

6 ADVERSE REACTIONS The following adverse reactions associated with the use of phenylephrine hydrochloride 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. Cardiac disorders: Bradycardia, AV block, ventricular extrasystoles, myocardial ischemia Gastrointestinal disorders: Nausea, vomiting General disorders and administrative site conditions : Chest pain, extravasation Immune system disorders: Sulfite sensitivity Nervous system disorders: Headache, nervousness, paresthesia, tremor Psychiatric disorders: Excitability Respiratory: Pulmonary edema, rales Skin and subcutaneous tissue disorders: Diaphoresis, pallor, piloerection, skin blanching, skin necrosis with extravasation Vascular disorders: Hypertensive crisis Most common adverse reactions: nausea and vomiting, headache, nervousness ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact BE Pharmaceuticals Inc. at 1-877-648-9517 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

4 CONTRAINDICATIONS The use of Phenylephrine Hydrochloride Injection 10 mg/mL is contraindicated in patients with: Hypersensitivity to the products or any of their components Hypersensitivity to the products or any of their components ( 4 )

11 DESCRIPTION Phenylephrine Hydrochloride Injection contains 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 freely soluble in water and alcohol. Phenylephrine hydrochloride is sensitive to light. 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. phenylephrinestructure

2 DOSAGE AND ADMINISTRATION 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 (2.4) - Intravenous continuous infusion: 0.5 mcg/kg/minute to 1.4 mcg/kg/minute titrated to effect (2.4) Dosing for Patients with Vasodilatory Shock - Intravenous continuous infusion: 0.5 mcg/kg/minute to 6 mcg/kg/minute titrated to effect (2.5) 2.1 General Administration Instructions Phenylephrine Hydrochloride Injection 10 mg/mL formulation (10 mg/mL, 50 mg/5mL, and 100 mg/10 mL) MUST BE DILUTED before administration as an intravenous bolus or for continuous intravenous infusion. 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). Parenteral drug products should be inspected for particulate matter and discoloration prior to administration. Discard any unused portion. During Phenylephrine Hydrochloride Injection 10 mg/mL administration: Correct intravascular volume depletion. Correct acidosis. Acidosis may reduce the effectiveness of phenylephrine. 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: 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.

1 INDICATIONS AND USAGE Phenylephrine Hydrochloride Injection 10 mg/mL is indicated for increasing blood pressure in adults with clinically important hypotension resulting primarily from vasodilation in the settings of anesthesia and septic shock. Phenylephrine Hydrochloride Injection 10 mg/mL is alpha-1 adrenergic receptor agonist indicated for increasing blood pressure in adults with clinically important hypotension resulting primarily from vasodilation in the settings of anesthesia and septic shock.

10 OVERDOSAGE Overdose of phenylephrine hydrochloride injection 10 mg/mL can cause a rapid rise in blood pressure. Symptoms of overdose include headache, vomiting, hypertension, reflex bradycardia, and cardiac arrhythmias including ventricular extrasystoles and ventricular tachycardia, and may cause a sensation of fullness in the head and tingling of the extremities. Consider using an α-adrenergic antagonist.

7 DRUG INTERACTIONS Agonistic effects with monoamine oxidase inhibitors (MAOI), β-adrenergic blocking agents, α-2 adrenergic agonists, steroids, tricyclic antidepressants, norepinephrine transport inhibitors, ergot alkaloids, centrally-acting sympatholytic agents and atropine sulfate ( 7.1 ) Antagonistic effects on and by α-adrenergic blocking agents ( 7.2 ) 7.1 Agonists The pressor effect of phenylephrine hydrochloride is increased in patients receiving: Monoamine oxidase inhibitors (MAOI), such as selegiline. β-adrenergic blockers α-2 adrenergic agonists, such as clonidine Steroids Tricyclic antidepressants Norepinephrine transport inhibitors, such as atomoxetine Ergot alkaloids, such as methylergonovine maleate Centrally-acting sympatholytic agents, such as guanfacine or reserpine Atropine sulfate 7.2 Antagonists α-adrenergic blocking agents, including phenothiazines (e.g., chlorpromazine) and amiodarone block phenylephrine and are in turn blocked by phenylephrine.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Phenylephrine hydrochloride is an α-1 adrenergic receptor agonist. 12.2 Pharmacodynamics Phenylephrine is the active moiety. Metabolites are inactive at both the α-1and α-2 adrenergic receptors. Following parenteral administration of phenylephrine hydrochloride, increases in systolic blood pressure, diastolic blood pressure, mean arterial blood pressure, and total peripheral vascular resistance are observed. The onset of blood pressure increase following an intravenous bolus phenylephrine hydrochloride administration is rapid and the effect may persist for up to 20 minutes. As mean arterial pressure increases following parenteral doses, vagal activity also increases, resulting in reflex bradycardia. Most vascular beds are constricted, including renal, splanchnic, and hepatic. 12.3 Pharmacokinetics Following an intravenous infusion of phenylephrine hydrochloride, the effective half-life was approximately 5 minutes. The steady-state volume of distribution (340 L) exceeded the body volume by a factor of 5, suggesting a high distribution into certain organ compartments. The average total serum clearance (2095 mL/min) was close to one-third of the cardiac output. A mass balance study showed that phenylephrine is extensively metabolized by the liver with only 12% of the dose excreted unchanged in the urine. Deamination by monoamino oxidase is the primary metabolic pathway resulting in the formation of the major metabolite (m-hydroxymandelic acid) which accounts for 57% of the total administered dose.

12.1 Mechanism of Action Phenylephrine hydrochloride is an α-1 adrenergic receptor agonist.

12.2 Pharmacodynamics Phenylephrine is the active moiety. Metabolites are inactive at both the α-1and α-2 adrenergic receptors. Following parenteral administration of phenylephrine hydrochloride, increases in systolic blood pressure, diastolic blood pressure, mean arterial blood pressure, and total peripheral vascular resistance are observed. The onset of blood pressure increase following an intravenous bolus phenylephrine hydrochloride administration is rapid and the effect may persist for up to 20 minutes. As mean arterial pressure increases following parenteral doses, vagal activity also increases, resulting in reflex bradycardia. Most vascular beds are constricted, including renal, splanchnic, and hepatic.

12.3 Pharmacokinetics Following an intravenous infusion of phenylephrine hydrochloride, the effective half-life was approximately 5 minutes. The steady-state volume of distribution (340 L) exceeded the body volume by a factor of 5, suggesting a high distribution into certain organ compartments. The average total serum clearance (2095 mL/min) was close to one-third of the cardiac output. A mass balance study showed that phenylephrine is extensively metabolized by the liver with only 12% of the dose excreted unchanged in the urine. Deamination by monoamino oxidase is the primary metabolic pathway resulting in the formation of the major metabolite (m-hydroxymandelic acid) which accounts for 57% of the total administered dose.

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3 DOSAGE FORMS AND STRENGTHS Phenylephrine Hydrochloride Injection, USP: 10 mg/mL phenylephrine hydrochloride is a clear, colorless, essentially free of visible foreign matter sterile parenteral solution, available in three vial sizes: 10 mg in 1 mL (10 mg/mL) of Phenylephrine hydrochloride in a single-dose vial 50 mg in 5 mL (10 mg/mL) of Phenylephrine hydrochloride in a pharmacy bulk package vial 100 mg in 10 mL (10 mg/mL) of Phenylephrine hydrochloride in a pharmacy bulk package vial Phenylephrine Hydrochloride Injection: 10 mg in 1 mL (10 mg/mL) of Phenylephrine hydrochloride in a single-dose vial ( 3 ) 50 mg in 5 mL (10 mg/mL) of Phenylephrine hydrochloride in a pharmacy bulk package vial ( 3 ) 100 mg in 10 mL (10 mg/mL) of Phenylephrine hydrochloride in a pharmacy bulk package vial ( 3 )

Phenylephrine Hydrochloride Phenylephrine Hydrochloride Phenylephrine Hydrochloride Phenylephrine Sodium Chloride Trisodium Citrate Dihydrate Citric Acid Monohydrate Sodium Metabisulfite Sodium Hydroxide Hydrochloric Acid Water Phenylephrine Hydrochloride Phenylephrine Hydrochloride Phenylephrine Hydrochloride Phenylephrine Sodium Chloride Trisodium Citrate Dihydrate Citric Acid Monohydrate Sodium Metabisulfite Sodium Hydroxide Hydrochloric Acid Water Phenylephrine Hydrochloride Phenylephrine Hydrochloride Phenylephrine Hydrochloride Phenylephrine Sodium Chloride Trisodium Citrate Dihydrate Citric Acid Monohydrate Sodium Metabisulfite Sodium Hydroxide Hydrochloric Acid Water

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Long-term animal studies that evaluated the carcinogenic potential of orally administered phenylephrine hydrochloride in F344/N rats and B6C3F1 mice were completed by the National Toxicology Program using the dietary route of administration. There was no evidence of carcinogenicity in mice administered approximately 270 mg/kg/day (131-times the human daily dose (HDD) of 10 mg/day based on body surface area) or rats administered approximately 50 mg/kg/day (48-times the HDD based on body surface area comparisons). Mutagenesis: Phenylephrine hydrochloride tested negative in the in vitro bacterial reverse mutation assay (S. typhimurium strains TA98, TA100, TA1535 and TA1537), the in vitro chromosomal aberrations assay, the in vitro sister chromatid exchange assay, and the in vivo rat micronucleus assay. Positive results were reported in only one of two replicates of the in vitro mouse lymphoma assay. Impairment of Fertility: No adverse effects on fertility or early embryonic development were noted when phenylephrine hydrochloride was administered at doses of 50 mcg, 100 mcg, or 200 mcg/kg/day (up to 0.2 times HDD of 10 mg/60 kg/day based on body surface area) via single daily bolus injection for 28 days prior to mating to male rats or for 14 days prior to mating through Gestation Day 7 to female rats.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Long-term animal studies that evaluated the carcinogenic potential of orally administered phenylephrine hydrochloride in F344/N rats and B6C3F1 mice were completed by the National Toxicology Program using the dietary route of administration. There was no evidence of carcinogenicity in mice administered approximately 270 mg/kg/day (131-times the human daily dose (HDD) of 10 mg/day based on body surface area) or rats administered approximately 50 mg/kg/day (48-times the HDD based on body surface area comparisons). Mutagenesis: Phenylephrine hydrochloride tested negative in the in vitro bacterial reverse mutation assay (S. typhimurium strains TA98, TA100, TA1535 and TA1537), the in vitro chromosomal aberrations assay, the in vitro sister chromatid exchange assay, and the in vivo rat micronucleus assay. Positive results were reported in only one of two replicates of the in vitro mouse lymphoma assay. Impairment of Fertility: No adverse effects on fertility or early embryonic development were noted when phenylephrine hydrochloride was administered at doses of 50 mcg, 100 mcg, or 200 mcg/kg/day (up to 0.2 times HDD of 10 mg/60 kg/day based on body surface area) via single daily bolus injection for 28 days prior to mating to male rats or for 14 days prior to mating through Gestation Day 7 to female rats.

ANDA217521

Phenylephrine Hydrochloride

Phenylephrine Hydrochloride

71839-129

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Phenylephrine Hydrochloride Injection, USP 10 mg/mL - Vial Label Phenylephrine Hydrochloride Injection, USP 10 mg/mL - Carton Label Phenylephrine Hydrochloride Injection, USP 50 mg/5 mL (10 mg/mL) - Vial Label Phenylephrine Hydrochloride Injection, USP 50 mg/5 mL (10 mg/mL) - Carton Label Phenylephrine Hydrochloride Injection, USP 100 mg/10 mL (10 mg/mL) - Vial Label Phenylephrine Hydrochloride Injection, USP 100 mg/10 mL (10 mg/mL) - Carton Label phen1mlvial phen1mlcarton vial phen5mlcarton vial phen10mlcarton

Dosage and Administration ( 2.1 )………………………………03/2023

17 PATIENT COUNSELING INFORMATION Inform patients, families, or caregivers that the primary side effect of phenylephrine is hypertension and rarely, hypertensive crisis. Patients may experience bradycardia (slow heart rate), which in some cases may produce heart block or other cardiac arrhythmias, extra ventricular beats, myocardial ischemia in patients with underlying cardiac disease, and pulmonary edema (fluid in the lungs) or rales. Common, less serious symptoms include the following: chest pain skin or tissue damage if the drug leaks out of the venous catheter into the surrounding tissue headache, nervousness, tremor, numbness/tingling (paresthesias) in hands or feet nausea, vomiting excitability, dizziness, sweating, flushing Distributed by: BE Pharmaceuticals Inc. 203 New Edition Court Cary, NC 27511 Manufactured by: MSN Laboratories Private Limited Formulation Division, Unit-II, Survey Nos. 1277 & 1319 to 1324, Nandigama (Village & Mandal), Rangareddy District, Telangana 509228, India. Revised: May 2023

14 CLINICAL STUDIES Increases in systolic and mean blood pressure following administration of phenylephrine were observed in 42 literature-based studies in the perioperative setting, including 26 studies where phenylephrine was used in low-risk (ASA 1 and 2) pregnant women undergoing neuraxial anesthesia during cesarean delivery, 3 studies in non-obstetric surgery under neuraxial anesthesia, and 13 studies in patients undergoing surgery under general anesthesia. Mean arterial blood pressure increases were also observed in two double-blind, active-controlled studies in patients with septic shock.

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.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.1 Pregnancy 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 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. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Phenylephrine Hydrochloride Injection, USP, 10 mg/mL, is a clear colorless solution, free from visible particulate matter and supplied as follows: NDC No. Strength How Supplied NDC 71839-127-25 10 mg/mL 1 mL Single-dose vials packaged in cartons containing 25 vials per carton NDC 71839-128-10 50 mg/5 mL (10 mg/mL) 5 mL Pharmacy Bulk Package vials packed in cartons containing 10 vials per carton NDC 71839-129-10 100 mg/10 mL (10 mg/mL) 10 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 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.