Phenylephrine hydrochloride

Description

Phenylephrine is an alpha-1 adrenergic receptor agonist. Phenylephrine hydrochloride injection, USP 10 mg/mL is a clear, colorless or slightly yellow, 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 chemical designation of C9H13NO2·HCl and a molecular weight of 203.67 g/mol. Its structural formula is provided below. Phenylephrine hydrochloride is soluble in water and ethanol, while being insoluble in chloroform and ethyl ether. The injection is sensitive to light.

Each mL of the solution contains phenylephrine hydrochloride 10 mg, sodium chloride 3.5 mg, sodium citrate dihydrate 4 mg, citric acid monohydrate 1 mg, and sodium metabisulfite 2 mg 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 3.5-5.5.

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

The medication is administered intravenously, either as a bolus injection or as a continuous infusion in a dilute solution. Prior to administration, the solution must be diluted appropriately.

For the treatment of hypotension during anesthesia, the following dosing guidelines apply:

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

Intravenous Infusion: Initiate the infusion at a rate of 10 mcg/min and may titrate up to 35 mcg/min based on the patient's response. The infusion rate should not exceed 200 mcg/min.

It is essential to adjust the dosage according to the pressor response, titrating to achieve the desired effect.

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, no specific instructions regarding avoidance or non-use are necessary.

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 phenylephrine hydrochloride.

Side Effects

Patients receiving phenylephrine hydrochloride may experience a range of adverse reactions, which can be categorized into common and serious events.

Common adverse reactions reported include nausea, vomiting, and headache. These reactions are typically mild and may resolve without the need for medical intervention.

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 has been observed as a result of extravasation during intravenous administration, which may cause necrosis or sloughing of tissue. Bradycardia is another serious concern, as phenylephrine hydrochloride can induce severe bradycardia and decreased cardiac output.

In cases of overdose, patients may experience a rapid rise in blood pressure, accompanied by symptoms such as 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. Monitoring and management of these symptoms are critical in the event of an overdose.

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), oxytocin and other oxytocic drugs, tricyclic antidepressants, angiotensin and aldosterone, atropine, steroids, norepinephrine transporter inhibitors, and ergot alkaloids. Clinicians should monitor blood pressure closely when these agents are co-administered with phenylephrine hydrochloride, as dosage adjustments may be necessary based on the patient's response.

Conversely, antagonistic interactions that may diminish the blood pressure effects of phenylephrine hydrochloride can occur with α-adrenergic antagonists, phosphodiesterase Type 5 inhibitors, mixed α- and β-receptor antagonists, calcium channel blockers, benzodiazepines, ACE inhibitors, and centrally acting sympatholytic agents. It is advisable to assess the patient's blood pressure regularly and consider dosage modifications of phenylephrine hydrochloride when these medications are used concurrently, to ensure adequate therapeutic efficacy.

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 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 injection 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 injection to other similar agents in pregnant women during Cesarean sections have not identified 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 injection exposure 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 injection.

In animal studies, no clear malformations or fetal toxicity were reported when normotensive pregnant rabbits were 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. This dose, which did not demonstrate maternal toxicity, was associated with evidence of developmental delay (altered ossification of sternebra). However, 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 clearly maternally toxic. An increase in the incidence of limb malformation 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 when normotensive pregnant rats were treated with up to 3 mg/kg/day of phenylephrine. This treatment was associated with some maternal toxicity, including decreased food consumption and body weight. 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. However, no adverse effects on growth and development, including learning and memory, sexual development, and fertility, were noted in the offspring at any tested dose. Maternal toxicities occurred at doses of 1 and 3 mg/kg/day, which were equivalent to and 2.9 times the HDD, respectively.

Lactation

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

When considering the use of phenylephrine hydrochloride in lactating mothers, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for the medication. Additionally, potential adverse effects on the breastfed infant from phenylephrine hydrochloride or from the underlying maternal condition should be taken into account.

Renal Impairment

There is no information available regarding renal impairment, dosage adjustments, special monitoring, or safety considerations for patients with reduced kidney function. Healthcare professionals should exercise caution and consider individual patient factors when treating patients with renal impairment, as specific recommendations are not provided in the current prescribing information.

Hepatic Impairment

There is no information available regarding the use of this medication in patients with hepatic impairment. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions specified for individuals with compromised liver function. Healthcare professionals should exercise clinical judgment when considering the use of this medication in patients with liver problems, as the absence of specific guidance necessitates careful evaluation of the patient's overall health status and liver function.

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 toxicology resources for further management strategies in cases of phenylephrine hydrochloride overdose.

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. These studies utilized the dietary route of administration. The results indicated 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

Postmarketing experience has identified several adverse reactions associated with phenylephrine hydrochloride injection. These include hypertension, reflex bradycardia, arrhythmias, headache, nausea, vomiting, anxiety, tremors, palpitations, peripheral ischemia, and tissue necrosis at the injection site.

Additionally, reports of allergic reactions, including anaphylaxis, as well as skin reactions such as rash and urticaria have been noted.

The safety profile of phenylephrine hydrochloride injection may evolve as further postmarketing data is collected and analyzed.

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 disclose their complete medical history and any other medications they are currently taking to ensure safe and effective use of phenylephrine hydrochloride injection.

Storage and Handling

Phenylephrine hydrochloride injection, USP 10 mg/mL should be stored 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). It is essential to protect the product from light and to keep it in its original carton until it is ready for use.

Once diluted, the solution must 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 should be discarded to ensure safety and efficacy.

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 Sandoz Inc. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)