PRINCIPAL DISPLAY PANEL – Phenylephrine HCl Injection, USP 10 mg per mL

Carton

NDC 71288-807-02

Rx Only

Phenylephrine HCl Injection, USP

10 mg per mL

For Intravenous Use

Dilute Before Use

25 x 1 mL Single-Dose Vials

DISCARD UNUSED PORTION

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 per 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 per mL [see Drug Interactions (7.1)], with the potential for hemorrhagic stroke.

5.6 Allergic Reactions

Phenylephrine hydrochloride injection 10 mg per 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 per 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 per mL can increase the need for renal replacement therapy in patients with septic shock. Monitor renal function.

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.

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-1 and 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.

2 DOSAGE AND ADMINISTRATION

2.1 General Administration Instructions

• Phenylephrine hydrochloride injection 10 mg per mL formulation (10 mg per 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° 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 per 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 per mL Solution for Intravenous Bolus Administration

For intravenous bolus administration, withdraw 10 mg (1 mL of a 10 mg per mL concentration) of phenylephrine hydrochloride injection 10 mg per 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 per mL. Withdraw an appropriate dose from the 100 mcg per mL solution prior to intravenous bolus administration.

Preparing a 20 mcg per mL Solution for Continuous Intravenous Infusion

For continuous intravenous infusion, withdraw 10 mg (1 mL of 10 mg per mL concentration) of phenylephrine hydrochloride injection 10 mg per 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 per mL).

Dosing for Perioperative Setting

In adult patients undergoing surgical procedures with either neuraxial anesthesia or general anesthesia:

• Phenylephrine hydrochloride injection 10 mg per mL (diluted to 100 mcg per 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 per mL (diluted to 20 mcg per 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 per 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.

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Phenylephrine Hydrochloride Injection, USP, 10 mg per 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. 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° to 8°C). Discard any unused portion.

** Sterile, Nonpyrogenic.**
** The container closure is not made with natural rubber latex.**