Phenylephrine hydrochloride

Description

Phenylephrine is an alpha-1 adrenergic receptor agonist. Phenylephrine hydrochloride injection USP, 10 mg/mL, is a clear, colorless, sterile, nonpyrogenic solution intended for intravenous use. Prior to administration, it must be diluted for either intravenous bolus or continuous intravenous infusion. The chemical name of phenylephrine hydrochloride is (-)-m-hydroxy-α-(methylamino)methylbenzyl alcohol hydrochloride, with a molecular formula of C9H13NO2 • HCl and a molecular weight of 203.67. The substance appears as white or practically white crystals and is freely soluble in water and alcohol.

Phenylephrine hydrochloride injection USP, 10 mg/mL, is sensitive to light. Each mL contains 10 mg of phenylephrine hydrochloride USP, 3.5 mg of sodium chloride, 4 mg of trisodium citrate dihydrate, 1 mg of citric acid monohydrate, and 2 mg of sodium metabisulfite in water for injection. The pH of the solution is adjusted with sodium hydroxide and/or hydrochloric acid as necessary, maintaining a pH range of 3.5 to 5.5.

Uses and Indications

Phenylephrine hydrochloride injection is indicated for the treatment of clinically important hypotension resulting primarily from vasodilation in the setting of anesthesia.

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

Dosage and Administration

Phenylephrine hydrochloride injection, 10 mg/mL, is intended for intravenous administration, either as a bolus injection or as a continuous infusion in a diluted solution. Prior to administration, the solution must be diluted appropriately.

For the treatment of hypotension during anesthesia, the following dosing guidelines should be adhered to:

Bolus Intravenous Injection: Administer 40 mcg to 100 mcg every 1 to 2 minutes as needed. The total dose should not exceed 200 mcg.

Intravenous Infusion: Initiate at a rate of 10 mcg/min and may be increased to a maximum of 35 mcg/min, with adjustments made based on the patient's pressor response. The infusion rate should not exceed 200 mcg/min.

Healthcare professionals are advised to titrate the dose to achieve the desired effect, ensuring careful monitoring of the patient's response throughout the administration process.

Contraindications

There are no contraindications associated with the use of this product. It is not classified as a controlled substance, and there are no identified risks of abuse, misuse, or dependence. Therefore, the product can be used without specific restrictions related to contraindications.

Warnings and Precautions

Phenylephrine hydrochloride is associated with several significant warnings that healthcare professionals must consider when prescribing and administering this medication.

Exacerbation of Angina, Heart Failure, or Pulmonary Arterial Hypertension Phenylephrine hydrochloride has the potential to precipitate angina in patients with severe arteriosclerosis or a history of angina. Additionally, it may exacerbate underlying heart failure and increase pulmonary arterial pressure, necessitating careful monitoring of patients with these conditions.

Peripheral and Visceral Ischemia The use of phenylephrine hydrochloride can lead to excessive peripheral and visceral vasoconstriction, resulting in ischemia to vital organs. Clinicians should be vigilant in assessing patients for signs of ischemia, particularly in those with pre-existing vascular conditions.

Skin and Subcutaneous Necrosis Extravasation during intravenous administration of phenylephrine hydrochloride may result in necrosis or sloughing of tissue. It is imperative to ensure proper intravenous technique and monitor the injection site closely to prevent this adverse effect.

Bradycardia Phenylephrine hydrochloride may induce severe bradycardia and a decrease in cardiac output. Continuous cardiac monitoring is recommended for patients receiving this medication, especially those with pre-existing cardiac conditions.

Healthcare professionals are advised to remain alert to these warnings and to monitor patients accordingly to mitigate potential risks associated with the use of phenylephrine hydrochloride.

Side Effects

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

Serious adverse reactions associated with phenylephrine hydrochloride include exacerbation of angina, heart failure, or pulmonary arterial hypertension. This medication can precipitate angina in patients with severe arteriosclerosis or a history of angina, exacerbate underlying heart failure, and increase pulmonary arterial pressure. Additionally, excessive peripheral and visceral vasoconstriction may lead to ischemia of vital organs.

Skin and subcutaneous necrosis can occur as a result of extravasation during intravenous administration, potentially causing necrosis or sloughing of tissue. Bradycardia is another serious concern, as it can lead to severe bradycardia and decreased cardiac output.

In cases of overdose, patients may present with a rapid rise in blood pressure, headache, vomiting, hypertension, reflex bradycardia, a sensation of fullness in the head, tingling of the extremities, and cardiac arrhythmias, including ventricular extrasystoles and ventricular tachycardia. These symptoms highlight the importance of monitoring patients closely during treatment with phenylephrine hydrochloride.

Drug Interactions

Agonistic interactions that may enhance the blood pressure effects of phenylephrine hydrochloride have been observed with several drug classes. These include:

• Monoamine Oxidase Inhibitors (MAOIs): Co-administration may lead to increased blood pressure due to enhanced sympathomimetic activity.

• Oxytocin and Oxytocic Drugs: These agents can potentiate the hypertensive effects of phenylephrine.

• Tricyclic Antidepressants: The interaction may result in elevated blood pressure.

• Angiotensin and Aldosterone: These hormones can contribute to increased blood pressure when used concurrently.

• Atropine: This anticholinergic agent may enhance the pressor response.

• Steroids: Corticosteroids may also increase blood pressure effects.

• Norepinephrine Transporter Inhibitors: These drugs can lead to heightened blood pressure responses.

• Ergot Alkaloids: Co-administration may result in increased blood pressure.

In contrast, antagonistic interactions that may diminish the blood pressure effects of phenylephrine hydrochloride include:

• α-Adrenergic Antagonists: These agents can counteract the pressor effects of phenylephrine.

• Phosphodiesterase Type 5 Inhibitors: Co-administration may lead to reduced blood pressure response.

• Mixed α- and β-Receptor Antagonists: These drugs can attenuate the hypertensive effects.

• Calcium Channel Blockers: The use of these agents may result in decreased blood pressure response.

• Benzodiazepines: These medications may also lower the blood pressure effects of phenylephrine.

• ACE Inhibitors: Co-administration may lead to a reduction in blood pressure response.

• Centrally Acting Sympatholytic Agents: These agents can diminish the pressor effects of phenylephrine.

Monitoring of blood pressure is advised when phenylephrine hydrochloride is used in conjunction with any of the aforementioned agents, and dosage adjustments may be necessary based on the clinical scenario and patient response.

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 sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, other reported clinical experience has not identified significant differences in responses between elderly patients and younger patients.

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. Monitoring for efficacy and safety is recommended to ensure appropriate therapeutic outcomes in this population.

Pregnancy

Data from randomized controlled trials and meta-analyses involving the use of phenylephrine hydrochloride in pregnant women during Cesarean sections have not established a drug-associated risk of major birth defects or miscarriage. These studies have not identified any adverse effects on maternal outcomes or infant Apgar scores. However, there are no data available regarding the use of phenylephrine during the first or second trimester of pregnancy.

Animal reproduction and development studies have shown evidence of fetal malformations when phenylephrine was administered during organogenesis via a 1-hour infusion at a dose of 1.2 times the human daily dose (HDD) of 10 mg/60 kg/day. Additionally, decreased pup weights were observed in offspring of pregnant rats treated with 2.9 times the HDD. It is important to note that the estimated background risk of major birth defects and miscarriage for the indicated population remains unknown, although 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.

Untreated hypotension associated with spinal anesthesia during Cesarean sections can lead to increased maternal nausea and vomiting. A sustained decrease in uterine blood flow due to maternal hypotension may result in fetal bradycardia and acidosis. Published randomized controlled trials over several decades comparing phenylephrine hydrochloride injection to other similar agents in pregnant women during Cesarean sections have not identified any adverse maternal or infant outcomes. At recommended doses, phenylephrine does not appear to significantly affect fetal heart rate or fetal heart rate variability.

There are no studies assessing the safety of phenylephrine hydrochloride injection during the period of organogenesis, making it impossible to draw conclusions regarding the risk of birth defects following exposure during pregnancy. Furthermore, there are no data available on the risk of miscarriage following fetal exposure to phenylephrine hydrochloride injection.

In studies involving normotensive pregnant rabbits, no clear malformations or fetal toxicity were reported when treated with phenylephrine via continuous intravenous infusion over 1 hour at a dose of 0.5 mg/kg/day (approximately equivalent to a HDD based on body surface area) from Gestation Day 7 to 19. However, this dose demonstrated evidence of developmental delay, specifically altered ossification of sternebra. In a non-GLP dose range-finding study, fetal lethality and cranial, paw, and limb malformations were noted following treatment with 1.2 mg/kg/day of phenylephrine, which was associated with maternal toxicity. An increase in limb malformation incidence was observed at a lower dose of 0.6 mg/kg/day in the absence of maternal toxicity.

In contrast, no malformations or embryo-fetal toxicity were reported in normotensive pregnant rats treated with up to 3 mg/kg/day of phenylephrine, although some maternal toxicity was noted at this dose. Decreased pup weights were reported in a pre-and postnatal development toxicity study involving normotensive pregnant rats administered phenylephrine from Gestation Day 6 through Lactation Day 21. Importantly, no adverse effects on growth and development, including learning and memory, sexual development, and fertility, were noted in the offspring of pregnant rats at any tested dose. Maternal toxicities, including mortality late in gestation and during the lactation period, as well as decreased food consumption and body weight, occurred at higher doses of phenylephrine.

Lactation

There are no data on the presence of phenylephrine hydrochloride or its metabolite in human or animal milk, nor are there any known effects on breastfed infants or on milk production.

The developmental and health benefits of breastfeeding should be weighed against the clinical need for phenylephrine hydrochloride in lactating mothers, as well as any potential adverse effects on the breastfed infant resulting from either phenylephrine hydrochloride or the underlying maternal condition.

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 outlined 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 phenylephrine hydrochloride overdose, a rapid increase in blood pressure is a significant concern. Healthcare professionals should be vigilant for a range of symptoms that may manifest following an overdose.

Symptoms of Overdosage Patients may present with a variety of symptoms, including but not limited to:

• Headache

• Vomiting

• Hypertension

• Reflex bradycardia

• A sensation of fullness in the head

• Tingling of the extremities

• Cardiac arrhythmias, which may include ventricular extrasystoles and ventricular tachycardia

Management Procedures In the event of an overdose, immediate medical intervention is recommended. Monitoring of blood pressure and cardiac function is essential. Appropriate measures should be taken to manage hypertension and any arrhythmias that may arise. Supportive care should be provided as necessary, and symptomatic treatment should be initiated based on the clinical presentation of the patient.

Healthcare professionals are advised to consult relevant clinical guidelines and consider contacting a poison control center for further assistance in managing phenylephrine hydrochloride overdose cases.

Nonclinical Toxicology

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 utilized the dietary route of administration and found no evidence of carcinogenicity in mice receiving approximately 270 mg/kg/day, which is 131 times the human daily dose (HDD) of 10 mg/60 kg/day based on body surface area. Similarly, rats administered approximately 50 mg/kg/day, equivalent to 48 times the HDD based on body surface area comparisons, also showed no signs of carcinogenicity.

Phenylephrine hydrochloride was tested for mutagenicity and demonstrated negative results in several assays, including the in vitro bacterial reverse mutation assay using 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. However, positive results were observed in one of two replicates of the in vitro mouse lymphoma assay.

In terms of reproductive toxicity, phenylephrine did not impair mating, fertility, or reproductive outcomes in normotensive male rats treated with 3 mg/kg/day via continuous intravenous infusion over 1 hour (2.9 times the HDD) for 28 days prior to mating and for a minimum of 63 days prior to sacrifice. Female rats received the same dosing regimen for 14 days prior to mating and continued through Gestation Day 6. It is important to note that this dose was associated with increased mortality in both male and female rats, as well as decreased body weight gain in treated males. Additionally, males treated with 3 mg/kg/day phenylephrine exhibited decreased caudal sperm density and an increase in abnormal sperm.

Postmarketing Experience

No specific postmarketing experience details are available. As such, there are no additional adverse events or rare case reports to report at this time.

Patient Counseling

Healthcare providers should inform patients, family members, or caregivers that certain medical conditions and medications may affect the efficacy of phenylephrine hydrochloride injection. It is important to discuss any existing health issues or ongoing treatments that the patient may have, as these factors could influence the response to the medication. Providers should encourage patients to provide a comprehensive medical history and to disclose all medications they are currently taking, including over-the-counter drugs and supplements. This information is crucial for ensuring safe and effective use of phenylephrine hydrochloride injection.

Storage and Handling

Phenylephrine hydrochloride injection USP, 10 mg/mL, is supplied in a suitable packaging configuration. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F). The product must be protected from light and should remain in its carton until it is time for use.

Once diluted, the solution should not be held for more than 4 hours at room temperature or for more than 24 hours when refrigerated. Any unused portion of the diluted solution must be discarded.

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 Amneal Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)