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.

Each mL of the injection contains 10 mg of phenylephrine hydrochloride, 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. The solution is sensitive to light.

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 to 35 mcg/min, with titration based on the patient's pressor response. The infusion rate should not exceed 200 mcg/min.

Healthcare professionals are advised to adjust the dosage according to the individual patient's response to the medication, ensuring effective management of hypotension.

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 and precautions that healthcare professionals must consider to ensure patient safety.

Cardiovascular Risks Phenylephrine hydrochloride may exacerbate angina in patients with severe arteriosclerosis or a history of angina. It is crucial to monitor patients for signs of angina and to assess their cardiovascular status regularly. Additionally, this medication can worsen underlying heart failure and elevate pulmonary arterial pressure, necessitating careful evaluation of patients with pre-existing heart conditions.

Ischemic Events The use of phenylephrine hydrochloride can lead to excessive peripheral and visceral vasoconstriction, resulting in ischemia to vital organs. Healthcare providers should be vigilant in monitoring for symptoms of ischemia, particularly in patients with compromised vascular health.

Tissue Necrosis Extravasation during intravenous administration of phenylephrine hydrochloride poses a risk of skin and subcutaneous necrosis. It is imperative to ensure proper intravenous technique and to monitor the injection site closely for any signs of extravasation, which may necessitate immediate intervention to prevent tissue damage.

Bradycardia Phenylephrine hydrochloride has the potential to induce severe bradycardia and decrease cardiac output. Continuous cardiac monitoring is recommended for patients receiving this medication, particularly those with existing bradycardia or other cardiac conditions.

Healthcare professionals should remain alert to these risks and implement appropriate monitoring strategies to mitigate potential adverse effects associated with 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 warnings associated with phenylephrine hydrochloride include the potential for 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.

Extravasation during intravenous administration of phenylephrine hydrochloride poses a risk of skin and subcutaneous necrosis, which may result in tissue necrosis or sloughing. Furthermore, severe bradycardia and decreased cardiac output have been observed, necessitating careful monitoring of patients.

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. It is crucial for healthcare providers to be aware of these potential adverse reactions and to monitor patients accordingly.

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 oxytocic drugs, tricyclic antidepressants, angiotensin and aldosterone, atropine, steroids, norepinephrine transporter inhibitors, and ergot alkaloids. Clinicians should consider monitoring blood pressure closely when these agents are co-administered with phenylephrine hydrochloride, as dosage adjustments may be necessary to mitigate the risk of excessive hypertension.

Conversely, antagonistic interactions that may reduce 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 monitor blood pressure and assess the therapeutic efficacy of phenylephrine hydrochloride when these medications are used concurrently, as adjustments in dosage may be warranted to achieve the desired clinical effect.

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. Careful monitoring of these patients is recommended to ensure safety and efficacy.

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 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 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, although this dose was associated with some maternal toxicity. 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. Despite maternal toxicities observed at higher doses, no adverse effects on growth and development (including learning and memory, sexual development, and fertility) were noted in the offspring at any tested dose.

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. Additionally, potential adverse effects on the breastfed infant from phenylephrine hydrochloride or from the underlying maternal condition should be considered.

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 warranted based on clinical judgment.

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 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 postmarketing experience details are available in the provided text.

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 pre-existing health issues or ongoing treatments that the patient may have, as these factors can influence the response to the medication.

Providers are encouraged to ensure that patients understand the significance of sharing their complete medical history and current medication regimen, including over-the-counter drugs and supplements. This communication is essential for optimizing treatment outcomes and minimizing potential risks associated with the 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). It is essential to protect the product from light and to keep it in its carton until it is time 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 Amneal Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)