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. This compound appears as white or practically white crystals, with a molecular formula of C9H13NO2 • HCl and a molecular weight of 203.67. It is freely soluble in water and alcohol, and the injection is sensitive to light.

Each mL of the solution contains phenylephrine hydrochloride, USP 10 mg, sodium chloride 3.5 mg, trisodium 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 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. 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 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, 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.

Warnings and Precautions

Phenylephrine hydrochloride is associated with several significant warnings and precautions that healthcare professionals must consider to ensure patient safety.

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 administration 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 cause 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, which can be categorized into common and serious events.

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 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, peripheral and visceral ischemia may occur due to excessive vasoconstriction, potentially leading to ischemia of vital organs.

Skin and subcutaneous necrosis has been observed in cases of extravasation during intravenous administration, which may result in necrosis or sloughing of tissue. Furthermore, severe bradycardia and decreased cardiac output have been reported, necessitating careful monitoring of patients.

In the event of an 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 professionals should remain vigilant for these adverse reactions and manage them appropriately to ensure patient safety.

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 substances may contribute to increased blood pressure when used concurrently.

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

• Steroids: Corticosteroids can potentially amplify the blood pressure effects.

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

• Ergot Alkaloids: Co-administration may lead to an increase in blood pressure.

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 may attenuate the hypertensive effects of phenylephrine.

• Calcium Channel Blockers: These agents can decrease the blood pressure response to phenylephrine.

• Benzodiazepines: The sedative effects may interfere with the blood pressure response.

• ACE Inhibitors: These may reduce the efficacy of phenylephrine in raising blood pressure.

• Centrally Acting Sympatholytic Agents: These medications may diminish the pressor response of phenylephrine.

Monitoring of blood pressure is advised when phenylephrine hydrochloride is used in conjunction with these interacting 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 a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience has 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 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. In contrast, no clear malformations or fetal toxicity were reported in normotensive pregnant rabbits treated with phenylephrine at 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% to 4% and 15% to 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.

Published randomized controlled trials have not identified adverse maternal or infant outcomes when comparing phenylephrine hydrochloride injection to other similar agents in pregnant women during Cesarean sections. 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 hydrochloride injection during the period of organogenesis, making it impossible to draw 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 significant risks in clinical studies during Cesarean sections, caution is warranted due to the lack of data during the first and second trimesters and the potential for adverse effects observed in animal studies.

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.

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 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

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 essential. Monitoring of blood pressure and cardiac function should be prioritized. Appropriate measures may include the administration of antihypertensive agents to manage elevated blood pressure and supportive care to address any arrhythmias. Continuous cardiac monitoring is recommended to detect and manage potential complications effectively.

Healthcare professionals are advised to follow established protocols for the management of drug overdoses and to consult relevant guidelines for specific treatment recommendations.

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 evidence 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 the impairment of fertility, phenylephrine 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 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 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). It is essential to protect the product from light and to keep it in its 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

Patients, family members, or caregivers should be informed that certain medical conditions and medications may affect the efficacy of phenylephrine hydrochloride injection.

The product is manufactured by Amneal Pharmaceuticals Pvt. Ltd. at multiple locations in India, including Ahmedabad (382213 and 382110) and Mehsana (382165). Distribution is managed by Amneal Pharmaceuticals LLC, located in Bridgewater, NJ 08807.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Phenylephrine Hydrochloride as submitted by Henry Schein, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)