Phenylephrine hydrochloride

Description

Phenylephrine is an alpha-1 adrenergic receptor agonist. Phenylephrine Hydrochloride Injection, USP, contains 10 mg of phenylephrine hydrochloride per mL in a sterile, nonpyrogenic solution intended for intravenous use. Prior to administration, the solution 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 C9H14ClNO2 and a molecular weight of 203.66 g/mol. The structural formula is provided below. This compound is soluble in water and ethanol, while being insoluble in chloroform and ethyl ether.

Phenylephrine Hydrochloride Injection, USP, appears as a clear, colorless solution that 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 as per the available data.

Dosage and Administration

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

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 titrate to effect, with a maximum infusion rate of 200 mcg/min.

It is essential to adjust the dosage based on the patient's pressor response, ensuring that the administration is titrated to achieve the desired therapeutic 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. 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 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 to monitor the injection site closely for any signs of extravasation.

Bradycardia Phenylephrine hydrochloride can 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 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, which can be categorized into common and serious side effects.

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

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.

Another serious concern is skin and subcutaneous necrosis, which can occur due to extravasation during intravenous administration, potentially resulting in necrosis or sloughing of tissue. Bradycardia is also a significant adverse reaction, as phenylephrine hydrochloride can cause severe bradycardia and decreased cardiac output.

In cases of overdose, patients may experience a rapid rise in blood pressure along 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.

Healthcare providers should monitor patients closely for these adverse reactions and manage them appropriately.

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 can potentiate the hypertensive effects of phenylephrine.

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

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

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

• Steroids: Corticosteroids may also augment the blood pressure effects.

• Norepinephrine Transporter Inhibitors: These drugs can increase the sympathomimetic effects of phenylephrine.

• Ergot Alkaloids: Co-administration may lead to increased blood pressure due to their vasoconstrictive properties.

Conversely, 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 may attenuate the hypertensive effects of phenylephrine.

• Calcium Channel Blockers: These agents can lower blood pressure and may interfere with phenylephrine's effects.

• Benzodiazepines: The sedative effects may reduce the efficacy of phenylephrine.

• ACE Inhibitors: These medications may lead to decreased blood pressure response.

• Centrally Acting Sympatholytic Agents: These drugs can diminish the pressor response 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, as there is insufficient data to support its use in these populations. Healthcare professionals are advised to consider the potential risks and benefits before prescribing this medication to pediatric patients.

Geriatric Use

Clinical studies of phenylephrine hydrochloride 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 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 hydrochloride during the first or second trimester of pregnancy.

Animal reproduction and development studies have shown evidence of fetal malformations when phenylephrine hydrochloride was administered during organogenesis at doses exceeding the human daily dose (HDD). Specifically, in normotensive animals, a 1-hour infusion at 1.2 times the HDD resulted in fetal malformations, while decreased pup weights were observed in offspring of pregnant rats treated with 2.9 times the HDD. Notably, no clear malformations or fetal toxicity were reported in normotensive pregnant rabbits treated with a dose equivalent to the HDD, although developmental delays were noted at this dose.

The estimated background risk of major birth defects and miscarriage in the general U.S. population is 2-4% and 15-20%, respectively. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. Untreated hypotension associated with spinal anesthesia during Cesarean sections can lead to increased maternal nausea and vomiting, and a sustained decrease in uterine blood flow due to maternal hypotension may result in fetal bradycardia and acidosis.

At recommended doses, phenylephrine hydrochloride does not appear to significantly affect fetal heart rate or heart rate variability. However, there are no studies assessing the safety of phenylephrine hydrochloride injection during the period of organogenesis, making it impossible to draw definitive conclusions regarding the risk of birth defects or miscarriage following fetal exposure to this medication.

In summary, while phenylephrine hydrochloride has not been associated with major birth defects or adverse maternal outcomes in clinical studies, caution is warranted due to the lack of data during early pregnancy and the potential for fetal effects observed in animal studies. Healthcare professionals should weigh the benefits against the risks when considering the use of phenylephrine hydrochloride in pregnant patients.

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 injection in lactating mothers. Additionally, potential adverse effects on the breastfed infant from phenylephrine hydrochloride injection or from the underlying maternal condition should be evaluated.

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

Patients with hepatic impairment have not been specifically studied in clinical trials for this medication. Consequently, there is no information available regarding 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 and symptomatic treatment should be provided as necessary to ensure patient safety and recovery.

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.

In terms of mutagenesis, phenylephrine hydrochloride demonstrated a negative outcome 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.

Regarding impairment of fertility, phenylephrine hydrochloride did not adversely affect 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 hydrochloride exhibited decreased caudal sperm density and an increase in abnormal sperm.

Postmarketing Experience

Postmarketing experience has identified several adverse reactions associated with the use of the product. These include hypertension, reflex bradycardia, and arrhythmias. Additional adverse reactions reported include headache, dizziness, and anxiety.

Rare cases of severe allergic reactions, including anaphylaxis, have also been documented. Instances of extravasation leading to tissue necrosis have been reported. Furthermore, some patients have experienced visual disturbances, such as blurred vision and diplopia. There have been reports of cardiac events, including myocardial infarction and stroke, noted in the postmarketing experience.

Patient Counseling

Healthcare providers should inform patients, as well as their family members or caregivers, that certain medical conditions and medications may affect the efficacy of phenylephrine hydrochloride. It is important to discuss any pre-existing health issues or ongoing treatments that the patient may have, as these factors could influence how the medication works in their specific case.

Providers are encouraged to ensure that patients understand the significance of sharing their complete medical history and current medication regimen to optimize treatment outcomes and minimize potential interactions.

Storage and Handling

The product is supplied in a carton to protect it from light and should be stored at a temperature range of 20° to 25°C (68° to 77°F). Temporary excursions are permissible between 15° to 30°C (59° to 86°F). It is essential to keep the product 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 Meitheal Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)