Phenylephrine hydrochloride

Description

Phenylephrine is an alpha-1 adrenergic receptor agonist. Phenylephrine Hydrochloride Injection, USP, is formulated as a clear, colorless, sterile, nonpyrogenic solution for intravenous use, with a concentration of 10 mg/mL. Prior to administration, it must be diluted for intravenous bolus or continuous intravenous infusion. The chemical name of Phenylephrine hydrochloride is (-)-m-hydroxy-α-(methylamino)methylbenzyl alcohol hydrochloride, and it is chemically designated as C9H14ClNO2, with a molecular weight of 203.67 g/mol.

The structural formula is provided below. Phenylephrine hydrochloride is soluble in water and ethanol, but insoluble in chloroform and ethyl ether. The injection is sensitive to light. Each mL of the solution contains 10 mg of phenylephrine hydrochloride, 3.5 mg of sodium chloride, 4 mg of sodium citrate dihydrate, and 1 mg of citric acid, all 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 as per the available data.

Dosage and Administration

The medication is administered intravenously, either as a bolus injection or as a continuous infusion in a dilute solution.

For bolus intravenous injection, the recommended dosage ranges from 40 mcg to 100 mcg, administered every 1 to 2 minutes as needed. The total dosage should not exceed 200 mcg.

For intravenous infusion, the initial rate should be set between 10 mcg/min and 35 mcg/min, with titration based on the desired pressor response. The infusion rate must not exceed 200 mcg/min.

Prior to administration, it is essential to dilute the medication appropriately. Adjustments to the dosage should be made according to the patient's response to the treatment.

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 or 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. It may also 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 monitoring for signs of ischemia, particularly in patients 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 to monitor the injection site closely for any signs of extravasation.

Bradycardia Phenylephrine Hydrochloride can induce severe bradycardia and decrease 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 implement appropriate monitoring strategies to mitigate 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 side effects 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.

Extravasation during intravenous administration of Phenylephrine Hydrochloride has been associated with skin and subcutaneous necrosis, which may result in necrosis or sloughing of tissue. Severe bradycardia and decreased cardiac output are also potential serious adverse reactions.

In cases of overdose, patients may present with 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.

No additional adverse reactions have been reported in the specified sections.

Drug Interactions

Agonistic interactions that may enhance the blood pressure effects of Phenylephrine Hydrochloride include the following drug classes:

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

• Oxytocin and Oxytocic Drugs: These agents may potentiate the hypertensive effects of Phenylephrine.

• Tricyclic Antidepressants: The combination can result in an increased blood pressure response.

• Angiotensin and Aldosterone: These substances may contribute to elevated blood pressure when used concurrently.

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

• Steroids: Corticosteroids may increase blood pressure effects when administered with Phenylephrine.

• Norepinephrine Transporter Inhibitors: These agents can lead to an increased blood pressure response.

• Ergot Alkaloids: Co-administration may result in enhanced hypertensive effects.

Conversely, antagonistic interactions that may diminish the blood pressure effects of Phenylephrine Hydrochloride include:

• α-Adrenergic Antagonists: These agents may counteract the pressor effects of Phenylephrine.

• Phosphodiesterase Type 5 Inhibitors: The combination may lead to reduced blood pressure response.

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

• Calcium Channel Blockers: Co-administration may result in decreased blood pressure effects.

• Benzodiazepines: These agents may reduce the efficacy of Phenylephrine in raising blood pressure.

• ACE Inhibitors: The combination may lead to diminished blood pressure response.

• Centrally Acting Sympatholytic Agents: These medications may antagonize the hypertensive 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 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 a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experiences have 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

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 did not identify 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 2-4% and 15-20%, respectively.

At recommended doses, Phenylephrine does not appear to significantly affect fetal heart rate or fetal heart rate variability. However, there are no studies assessing the safety of Phenylephrine 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 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. This dose did not result in maternal toxicity; however, evidence of developmental delay was noted, specifically altered ossification of sternebra. Conversely, in a non-GLP dose range-finding study, fetal lethality and cranial, paw, and limb malformations were observed following treatment with 1.2 mg/kg/day of Phenylephrine, which was associated with maternal toxicity, including increased mortality and significant body weight loss. An increase in limb malformation incidence was noted at a lower dose of 0.6 mg/kg/day in the absence of maternal toxicity.

In studies involving normotensive pregnant rats, no malformations or embryo-fetal toxicity were reported when treated with up to 3 mg/kg/day of Phenylephrine, although this dose 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 with doses of 0.3, 1.0, or 3.0 mg/kg/day administered 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 doses of 1 and 3 mg/kg/day of Phenylephrine.

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.

Healthcare professionals should consider the developmental and health benefits of breastfeeding alongside 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 taken into account when making treatment decisions.

Renal Impairment

There is no information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution and consider the lack of specific guidance when prescribing to patients with reduced kidney function.

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 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 assessed for mutagenic potential and tested negative 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 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 through Gestation Day 6. Although this dose was associated with increased mortality in both male and female rats and decreased body weight gain in treated males, it was noted that there were decreased caudal sperm density and an increase in abnormal sperm in males treated with 3 mg/kg/day Phenylephrine, which is 2.9 times the HDD.

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 from postmarketing surveillance have noted severe allergic reactions, cardiac arrest, myocardial ischemia, and pulmonary edema.

It is important for healthcare professionals to monitor patients for these adverse reactions during and after the administration of Phenylephrine Hydrochloride Injection.

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 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 the injection.

Storage and Handling

Phenylephrine Hydrochloride Injection, USP 10 mg/mL is supplied in a suitable container that 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 at room temperature for more than 4 hours. If stored under refrigerated conditions, the diluted solution should not be kept for more than 24 hours. 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 Fresenius Kabi USA, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)