PHENYLEPHRINE HYDROCHLORIDE injection

phenylephrine hydrochloride by

Drug Labeling and Warnings

phenylephrine hydrochloride by is a Prescription medication manufactured, distributed, or labeled by Heritage Pharmaceuticals Inc. d/b/a Avet Pharmaceuticals Inc., Emcure Pharmaceuticals Limited. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 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.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 General Administration Instructions

    There is ONE formulation of this product:

    • Phenylephrine Hydrochloride Injection 10 mg/mL formulation 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 to 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).

    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.
  • 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 below vial size:

    • 10 mg in 1 mL (10 mg/mL) of Phenylephrine hydrochloride in a single-dose vial 
  • 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
  • 5 WARNINGS AND PRECAUTIONS

    5.1 Exacerbation 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

    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 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

    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

    Phenylephrine Hydrochloride Injection 10 mg/mL can increase the need for renal replacement therapy in patients with septic shock. Monitor renal function.

  • 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

  • 7 DRUG INTERACTIONS

    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.

  • 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.

  • 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.

  • 11 DESCRIPTION

    Phenylephrine Hydrochloride 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:

    structure

    Phenylephrine hydrochloride is freely soluble in water and ethanol. Phenylephrine hydrochloride is sensitive to light.

    Phenylephrine Hydrochloride Injection, USP, 10 mg/mL:

    Phenylephrine Hydrochloride injection, USP is a clear, colorless solution 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 USP (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 NF, 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.

  • 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 (2,095 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.

  • 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.

  • 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.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Phenylephrine Hydrochloride injection, USP, 10 mg/mL, is supplied as follows:

    • NDC: 23155-620-41: 1 mL single dose vials packaged in cartons containing 25 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 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 to 8°C). Discard any unused portion.

  • 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

    Manufactured by:

    Emcure Pharmaceuticals Ltd.,

    Plot No. SM-14, 15 & 16/1, GIDC, Sanand - II, Charal,

    Tal - Sanand, Ahmedabad, Gujarat 382110, India.         

    Manufactured for:

    Avet Pharmaceuticals Inc.

    East Brunswick, NJ 08816

    1.866.901.DRUG (3784)

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    Revised: 03/2023                                                                                         

  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

    NDC 23155-620-31

    Phenylephrine HCl Injection, USP

    10 mg/mL

    For Intravenous Use

    Dilute Before Use

    1 mL Single Dose Vial

    DISCARD UNUSED PORTION

    PROTECT FROM LIGHT

    label


    NDC 23155-620-41

    Phenylephrine HCl Injection, USP

    10 mg/mL

    For Intravenous Use

    Dilute Before Use

    25 x 1 mL Single Dose Vials

    DISCARD UNUSED PORTION

    carton

  • INGREDIENTS AND APPEARANCE
    PHENYLEPHRINE HYDROCHLORIDE 
    phenylephrine hydrochloride injection
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 23155-620
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    PHENYLEPHRINE HYDROCHLORIDE (UNII: 04JA59TNSJ) (PHENYLEPHRINE - UNII:1WS297W6MV) PHENYLEPHRINE HYDROCHLORIDE10 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    SODIUM CHLORIDE (UNII: 451W47IQ8X) 3.5 mg  in 1 mL
    CITRIC ACID MONOHYDRATE (UNII: 2968PHW8QP) 1 mg  in 1 mL
    TRISODIUM CITRATE DIHYDRATE (UNII: B22547B95K) 4 mg  in 1 mL
    WATER (UNII: 059QF0KO0R)  
    SODIUM METABISULFITE (UNII: 4VON5FNS3C) 2 mg  in 1 mL
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 23155-620-4125 in 1 CARTON02/28/2023
    1NDC: 23155-620-311 mL in 1 VIAL; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA20996802/28/2023
    Labeler - Heritage Pharmaceuticals Inc. d/b/a Avet Pharmaceuticals Inc. (780779901)
    Registrant - AVET LIFESCIENCES PRIVATE LIMITED (853181664)
    Establishment
    NameAddressID/FEIBusiness Operations
    Emcure Pharmaceuticals Limited675467924ANALYSIS(23155-620) , MANUFACTURE(23155-620) , PACK(23155-620) , LABEL(23155-620)
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