The following Structured Product Label (SPL) was submitted to the FDA by Hikma Pharmaceuticals Usa Inc. for the product Immphentiv (NDC 0641-6245). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1 indications and usage, 2.1 general administration instructions, 2.2 preparation of phenylephrine hydrochloride injection, 3 dosage forms and strengths, 4 contraindications, 5.1 exacerbation of angina, heart failure, or pulmonary arterial hypertension, 5.2 bradycardia, 5.3 risk in patients with autonomic dysfunction, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
IMMPHENTIV injection 100 mcg/mL is indicated for increasing blood pressure in adults with clinically important hypotension resulting primarily from vasodilation in the setting of anesthesia.
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 is injected by bolus intravenous infusion or in dilute solution as a continuous intravenous infusion.
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:
Dosing for Septic or Other Vasodilatory Shock (Phenylephrine Hydrochloride Injection 10 mg/mL only)
In adult patients with septic or other vasodilatory shock:
IMMPHENTIV® injection, USP: 100 mcg/mL phenylephrine hydrochloride is a clear, colorless, essentially free of visible foreign matter sterile parenteral solution, available in two vial sizes:
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:
The use of IMMPHENTIV 100 mcg/mL and Phenylephrine Hydrochloride Injection 10 mg/mL is contraindicated in patients with:
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.
IMMPHENTIV 100 mcg/mL and Phenylephrine Hydrochloride Injection 10 mg/mL can cause severe bradycardia and decreased cardiac output.
The pressor response to adrenergic drugs, including phenylephrine, can be increased in patients with autonomic dysfunction, as may occur with spinal cord injuries.
Extravasation of phenylephrine can cause necrosis or sloughing of tissue.
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.
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.
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.
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.
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
The pressor effect of phenylephrine hydrochloride is increased in patients receiving:
α-adrenergic blocking agents, including phenothiazines (e.g., chlorpromazine) and amiodarone block phenylephrine and are in turn blocked by phenylephrine.
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.
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
Safety and effectiveness in pediatric patients have not been established.
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.
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.
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.
Overdose of IMMPHENTIV 100 mcg/mL and 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.
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:
Structural Formula (Phenylephrine Hydrochloride Injection Usp Nda 1)
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.
Phenylephrine hydrochloride is an α-1 adrenergic receptor agonist.
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.
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.
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.
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.
IMMPHENTIV® injection, USP, 100 mcg/mL Ready-to-Use vials is supplied as follows:
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:
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.
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:
Manufactured by:
Hikma Pharmaceuticals USA Inc.
Berkeley Heights, NJ 07922
Revised: March 2023
462-664-05
NDC 0641-6142-01
Phenylephrine
HCl Injection, USP
10 mg/mL
For Intravenous
Use
Dilute before use
Protect from light
1 mL Single Dose Vial
Phenylephrine Hci Injection, Usp 1 mL Sdv Container Label (Phenylephrine Hydrochloride Injection Usp Nda 2)
NDC 0641-6142-25 Rx only
Phenylephrine
HCl Injection, USP
10 mg/mL
For Intravenous Use
Dilute before use
25 x 1 mL Single Dose Vials
Discard unused portion
Phenylephrine Hci Injection, Usp 1 mL Sdv Carton Label (Phenylephrine Hydrochloride Injection Usp Nda 3)
NDC 0641-6188-01 Rx only
Phenylephrine
HCl Injection, USP
50 mg/5 mL (10 mg/mL)
Pharmacy Bulk Package
Not for Direct Infusion
For Intravenous Use
Must Be Diluted
Protect From Light 5 mL Vial
Vial Label (Phenylephrine Hydrochloride Injection Usp Nda 4) 
NDC 0641-6188-10 Rx only
Phenylephrine
HCl Injection, USP
50 mg/5 mL (10 mg/mL)
Pharmacy Bulk Package
Not for Direct Infusion
For Intravenous Use
Must Be Diluted - Protect From Light
Store in carton until time of use
10 x 5 mL Vials
Carton Label (Phenylephrine Hydrochloride Injection Usp Nda 5) 
NDC 0641-6189-01 Rx only
Phenylephrine
HCl Injection, USP
100 mg/10 mL (10 mg/mL)
Pharmacy Bulk Package
Not for Direct Infusion
For Intravenous Use
Must Be Diluted
Protect From Light
10 mL Vial
Vial Label (Phenylephrine Hydrochloride Injection Usp Nda 6) 
NDC 0641-6189-10 Rx only
Phenylephrine
HCl Injection, USP
100 mg/10 mL (10 mg/mL)
Pharmacy Bulk Package
Not for Direct Infusion
For Intravenous Use
Must Be Diluted - Protect From Light
Store in carton until time of use
10 x 10 mL vials
Carton Label (Phenylephrine Hydrochloride Injection Usp Nda 7)
NDC 0641-6245-01 Rx only
IMMPHENTIV
Phenylephrine HCl Injection, USP
500 mcg per 5 mL (100 mcg/mL)
For Intravenous Use
Ready to Use - Do NOT Dilute
Immphentiv Rtu 5 mL Container Label (Phenylephrine Hydrochloride Injection Usp Nda 8)
NDC 0641-6245-10 Rx only
IMMPHENTIV
Phenylephrine HCl Injection, USP
500 mcg per 5 mL (100 mcg/mL)
For Intravenous Use
Ready to Use - Do NOT Dilute
10 x 5 mL Single-Dose Vials
462-991-00 Immphentiv 5 mL Rtu Carton Label (Phenylephrine Hydrochloride Injection Usp Nda 9)
NDC 0641-6246-01 Rx only
IMMPHENTIV
Phenylephrine HCl Injection, USP
1,000 mcg per 10 mL (100 mcg/mL)
For Intravenous Use
Ready to Use - Do NOT Dilute
Immphentiv Rtu 10 mL Container Label (Phenylephrine Hydrochloride Injection Usp Nda 10)
NDC 0641-6246-10 Rx only
IMMPHENTIV
Phenylephrine HCl Injection, USP
1,000 mcg per 10 mL (100 mcg/mL)
For Intravenous Use
Ready to Use - Do NOT Dilute
10 x 10 mL Single-Dose Vials
462-993-00 Immphentiv 10 mL Rtu Carton Label (Phenylephrine Hydrochloride Injection Usp Nda 11)
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