Phenylephrine hydrochloride

Description

Phenylephrine Hydrochloride Injection contains phenylephrine as the active pharmaceutical ingredient in the form of its hydrochloride salt. It is a synthetic sympathomimetic agent provided in a sterile formulation for parenteral administration. The chemical name of phenylephrine hydrochloride is (-)-m-Hydroxy-α-(methylamino)methylbenzyl alcohol hydrochloride, and its structural formula is represented accordingly.

This injection is freely soluble in water and alcohol, but it is sensitive to light. Phenylephrine Hydrochloride Injection, USP, is available at a concentration of 10 mg/mL and is presented as a clear, colorless, aqueous solution that is essentially free of visible foreign matter. Prior to administration, it must be diluted for either bolus intravenous infusion or continuous intravenous infusion.

Each milliliter of the injection contains 10 mg of phenylephrine hydrochloride (equivalent to 8.2 mg of phenylephrine base), along with 3.5 mg of Sodium Chloride USP as a tonicity agent, 1 mg of Citric Acid Monohydrate USP and 4 mg of Sodium Citrate Dihydrate USP as buffering agents, and 2 mg of Sodium Metabisulfite USP as an antioxidant. Sodium Hydroxide NF and Hydrochloric Acid NF are included as pH adjusters in Water for Injection. The pH range of the phenylephrine hydrochloride injection is between 3.0 and 6.5.

Uses and Indications

Phenylephrine Hydrochloride Injection is indicated for increasing blood pressure in adults experiencing clinically important hypotension primarily due to vasodilation in the contexts of anesthesia and septic shock.

There are no teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

Prior to administration, the solution must be diluted.

For the management of perioperative hypotension, the recommended dosing is as follows: an intravenous bolus of 50 mcg to 250 mcg may be administered. Alternatively, a continuous intravenous infusion can be initiated at a rate of 0.5 mcg/kg/minute to 1.4 mcg/kg/minute, with titration based on the patient's response.

In cases of vasodilatory shock, the dosing regimen involves a continuous intravenous infusion ranging from 0.5 mcg/kg/minute to 6 mcg/kg/minute, also titrated to achieve the desired therapeutic effect.

Contraindications

Use of this product is contraindicated in individuals with hypersensitivity to the product or any of its components. This contraindication is due to the potential for severe allergic reactions, which may pose significant health risks.

Warnings and Precautions

Severe bradycardia and decreased cardiac output have been observed with the use of this medication. Healthcare professionals should monitor patients closely for signs of bradycardia and assess cardiac output, particularly in those with pre-existing cardiovascular conditions.

Extravasation during intravenous administration of this medication may lead to serious complications, including necrosis or sloughing of tissue. It is imperative to ensure proper intravenous placement and to monitor the infusion site closely for any signs of extravasation. Immediate intervention is required if extravasation occurs to mitigate potential tissue damage.

Caution is advised when administering this medication concomitantly with oxytocic drugs, as the pressor effect of sympathomimetic pressor amines may be potentiated. Healthcare providers should evaluate the potential risks and benefits of such combinations and monitor patients for enhanced hypertensive responses.

Allergic-type reactions have been reported with Phenylephrine Hydrochloride Injection 10 mg/mL, particularly in individuals sensitive to sulfites. It is essential to inquire about a patient's history of sulfite sensitivity prior to administration and to remain vigilant for any signs of an allergic reaction during and after the administration of the injection.

Side Effects

Patients receiving treatment may experience a range of adverse reactions. The most common adverse reactions reported include nausea and vomiting, headache, and nervousness.

Serious side effects have also been observed. These include severe bradycardia and decreased cardiac output, which require careful monitoring. Extravasation during intravenous administration may lead to necrosis or sloughing of tissue, necessitating prompt intervention. Additionally, the concomitant use of this treatment with oxytocic drugs can potentiate the pressor effect of sympathomimetic pressor amines, which may pose significant risks. Allergic-type reactions have been noted with Phenylephrine Hydrochloride Injection 10 mg/mL, particularly in patients with sulfite sensitivity.

Other adverse reactions of clinical importance include hypersensitivity to the products or any of their components. In cases of overdose, symptoms may manifest as a rapid rise in blood pressure, headache, vomiting, hypertension, reflex bradycardia, and cardiac arrhythmias, including ventricular extrasystoles and ventricular tachycardia. Patients may also report a sensation of fullness in the head and tingling of the extremities. Monitoring for these reactions is essential to ensure patient safety and effective management of any adverse effects.

Drug Interactions

The interaction profile includes both agonistic and antagonistic effects with various drug classes.

Agonistic interactions are observed with the following agents: monoamine oxidase inhibitors (MAOIs), β-adrenergic blocking agents, α-2 adrenergic agonists, steroids, tricyclic antidepressants, norepinephrine transport inhibitors, ergot alkaloids, centrally-acting sympatholytic agents, and atropine sulfate. Clinicians should be aware of the potential for enhanced pharmacological effects when these agents are co-administered, which may necessitate careful monitoring of therapeutic outcomes and side effects.

Conversely, antagonistic interactions are noted with α-adrenergic blocking agents. The presence of these agents may diminish the therapeutic efficacy of the drug, and dosage adjustments or increased monitoring may be warranted to ensure optimal therapeutic response.

Healthcare professionals are advised to evaluate the clinical significance of these interactions and consider appropriate management strategies, including dosage adjustments and enhanced patient monitoring, as necessary.

Packaging & NDC

The table below lists all NDC Code configurations of Phenylephrine Hydrochloride, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Therefore, the use of this medication in children, infants, and adolescents should be approached with caution until further data is available.

Geriatric Use

Clinical studies of phenylephrine did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience has not identified significant differences in responses between elderly patients and their younger counterparts.

In general, dose selection for geriatric patients should be approached with caution. It is advisable to start at the low end of the dosing range, taking into account the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies. Careful monitoring of these patients is recommended to ensure safety and efficacy.

Pregnancy

In animal reproductive and developmental studies, decreased fetal body weights were observed at doses equivalent to 0.4 times the human daily dose (HDD) of 10 mg. While no malformations were reported, an increased incidence of agenesis of the intermediate lobe of the lung, a visceral variation, was noted 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. It is important to note that all pregnancies carry a background risk of birth defects, 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 approximately 2 to 4% and 15 to 20%, respectively.

In studies involving normotensive pregnant rats, no malformations were observed when treated with a single daily intravenous bolus dose of phenylephrine hydrochloride at doses of 50 mcg, 150 mcg, or 300/200 mcg/kg from Gestation Day 6 to 17, with the highest dose being 0.3/0.2 times the HDD based on body surface area. However, evidence of maternal toxicity, including mortality, was noted at the highest tested dose.

Similarly, in normotensive pregnant rabbits treated with phenylephrine hydrochloride at doses of 40 mcg, 100 mcg, and 200 mcg/kg (0.08, 0.2, and 0.4 times the HDD) from Gestation Day 7 to 19, decreased fetal body weights were reported, but no clear treatment-related malformations were observed. Maternal toxicity was evident, as indicated by decreased food consumption and body weight gain across all doses. An increased incidence of agenesis of the intermediate lobe of the lung was also noted in all treatment groups compared to controls.

Conversely, no adverse effects on the offspring were reported when pregnant rats were treated with a single daily intravenous bolus dose of up to 200 mcg/day phenylephrine hydrochloride (0.2 times the HDD) from Gestation Day 6 to Lactation Day 20.

Healthcare professionals should weigh the potential risks and benefits when considering the use of this medication in pregnant patients.

Lactation

Lactating mothers may receive phenylephrine hydrochloride; however, data on its excretion in human breast milk is not available. In animal studies, no adverse effects on offspring were reported when pregnant rats were treated with a single daily intravenous bolus dose of up to 200 mcg/day from Gestation Day 6 to Lactation Day 20. This dose corresponds to 0.2 times the human equivalent dose based on body surface area. Given the lack of human data, healthcare professionals should weigh the potential benefits against any unknown risks when considering the use of phenylephrine hydrochloride in lactating mothers.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In cases of overdose with phenylephrine hydrochloride injection at a concentration of 10 mg/mL, a rapid increase in blood pressure is a significant concern. Healthcare professionals should be vigilant for symptoms that may arise, which include headache, vomiting, hypertension, reflex bradycardia, and various cardiac arrhythmias such as ventricular extrasystoles and ventricular tachycardia.

Patients may also report a sensation of fullness in the head and tingling in the extremities, which can further indicate the severity of the overdose.

Management of phenylephrine overdose may involve the administration of an α-adrenergic antagonist to counteract the effects of excessive stimulation of adrenergic receptors. It is crucial for healthcare providers to monitor the patient closely and provide supportive care as needed, addressing any cardiovascular complications that may arise during the course of treatment.

Nonclinical Toxicology

No information regarding teratogenic effects is available.

Non-teratogenic effects were observed in studies where phenylephrine hydrochloride was administered at doses of 50 mcg, 100 mcg, or 200 mcg/kg/day via single daily bolus injection for 28 days prior to mating in male rats and for 14 days prior to mating through Gestation Day 7 in female rats. No adverse effects on fertility or early embryonic development were noted at these doses, which correspond to up to 0.2 times the human daily dose of 10 mg/60 kg/day based on body surface area.

Long-term animal studies conducted by the National Toxicology Program evaluated the carcinogenic potential of orally administered phenylephrine hydrochloride in F344/N rats and B6C3F1 mice. The studies revealed no evidence of carcinogenicity in mice receiving approximately 270 mg/kg/day, which is 131 times the human daily dose based on body surface area, or in rats receiving approximately 50 mg/kg/day, equivalent to 48 times the human daily dose based on body surface area comparisons.

Phenylephrine hydrochloride was tested in various genotoxicity assays. It tested negative in the in vitro bacterial reverse mutation assay using S. typhimurium strains TA98, TA100, TA1535, and TA1537, as well as in the in vitro chromosomal aberrations assay and the in vitro sister chromatid exchange assay. Additionally, it showed negative results in the in vivo rat micronucleus assay. However, positive results were reported in one of two replicates of the in vitro mouse lymphoma assay.

Postmarketing Experience

Postmarketing experience has identified hypertension as the primary side effect associated with phenylephrine, with rare occurrences of hypertensive crisis. Additionally, bradycardia has been reported, which may lead to heart block or other cardiac arrhythmias, as well as extra ventricular beats, myocardial ischemia in patients with pre-existing cardiac conditions, and pulmonary edema or rales.

Common, less serious adverse events include chest pain, skin or tissue damage resulting from extravasation of the drug from the venous catheter, headache, nervousness, tremor, and paresthesias (numbness or tingling) in the extremities. Other reported symptoms encompass nausea, vomiting, excitability, dizziness, sweating, and flushing.

Patient Counseling

Healthcare providers should inform patients, families, or caregivers that the primary side effect of phenylephrine is hypertension, which may rarely lead to a hypertensive crisis. It is important to discuss the potential for bradycardia, which can result in heart block or other cardiac arrhythmias, as well as extra ventricular beats, myocardial ischemia in patients with pre-existing cardiac conditions, and pulmonary edema or rales.

Patients should be made aware of common, less serious symptoms that may occur, including chest pain and the risk of skin or tissue damage if the drug leaks from the venous catheter into surrounding tissue. Other symptoms to discuss include headache, nervousness, tremor, and numbness or tingling (paresthesias) in the hands or feet. Additionally, patients may experience nausea, vomiting, excitability, dizziness, sweating, and flushing.

It is essential for healthcare providers to ensure that patients understand these potential side effects and symptoms, enabling them to recognize and report any concerning changes during treatment.

Storage and Handling

The product is supplied in 1 mL vials, which are intended for single-dose use only. Each vial should be discarded after use, and any unused portion must not be retained.

Storage conditions require the product to be maintained at a temperature range of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) in accordance with USP Controlled Room Temperature guidelines. It is essential to protect the vials from light and to keep them covered in their original carton until they are ready for use.

Once diluted, the solution should not be stored for more than 4 hours at room temperature or for more than 24 hours when refrigerated at 2°C to 8°C. Any unused diluted solution must be discarded after these timeframes.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Phenylephrine Hydrochloride as submitted by BE Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)