Phenylephrine hydrochloride

Description

Phenylephrine is an alpha-1 adrenergic receptor agonist. Phenylephrine hydrochloride injection 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. The structural formula is provided below.

Phenylephrine hydrochloride, USP appears as a white or practically white, odorless powder, which is freely soluble in water, alcohol, and glycerol. Each mL of the injection contains 10 mg of phenylephrine hydrochloride USP, along with 1 mg of citric acid monohydrate, 3.5 mg of sodium chloride, 2 mg of sodium metabisulfite, and 4 mg of trisodium citrate dihydrate, all in water for injection. The pH of the solution is adjusted with hydrochloric acid and/or sodium hydroxide 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

The medication is administered via intravenous injection, which can be delivered either as a bolus or as a continuous infusion in a dilute solution.

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

In the case of intravenous infusion, the initial rate should be set between 10 mcg/min and 35 mcg/min. The infusion rate may be titrated to achieve the desired pressor response, with a maximum allowable rate of 200 mcg/min.

Healthcare professionals should adjust the dosage based on the patient's response to the medication, ensuring that titration is performed to achieve the optimal therapeutic effect.

Contraindications

There are no identified contraindications for the use of this product. It is deemed safe for use in the absence of specific conditions or situations that would warrant avoidance.

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 crucial to ensure proper intravenous technique and monitor the injection site closely to prevent this adverse effect.

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 monitor patients accordingly to mitigate potential risks 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 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 can occur due to extravasation during intravenous administration, potentially resulting in necrosis or sloughing of tissue. Severe bradycardia and decreased cardiac output have also been noted as serious adverse reactions.

In cases of overdose, symptoms may include headache, vomiting, hypertension, reflex bradycardia, a sensation of fullness in the head, tingling of the extremities, and cardiac arrhythmias, which may manifest as ventricular extrasystoles and ventricular tachycardia.

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

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 combination may result in an increased blood pressure response.

• Angiotensin and Aldosterone: These hormones can 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 drugs can augment the blood pressure response.

• Ergot Alkaloids: Co-administration may lead to increased blood pressure effects.

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: The combination 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: Co-administration may result in decreased blood pressure response.

• Benzodiazepines: These agents can lower the blood pressure effects of phenylephrine.

• ACE Inhibitors: The combination may lead to a reduction in the 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 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 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 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 2-4% and 15-20%, 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, 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. 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

Lactating mothers may excrete phenylephrine in breast milk, although specific data on the concentration of phenylephrine in human milk is not available. In animal studies, decreased pup weights were observed in a pre- and postnatal development toxicity study involving normotensive pregnant rats administered phenylephrine via continuous intravenous infusion during gestation and lactation. Despite this, 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, including mortality late in gestation and during the lactation period, as well as decreased food consumption and body weight, were reported at doses of 1 and 3 mg/kg/day of phenylephrine, which correspond to 1 and 2.9 times the human daily dose (HDD), respectively.

Healthcare professionals should weigh the potential risks and benefits when considering the use of phenylephrine in lactating mothers.

Renal Impairment

Patients with renal impairment have no specific information regarding dosage adjustments, special monitoring, or safety considerations provided in the text. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing to this population. Regular assessment of renal function may be warranted to ensure safe and effective use of the medication in patients with reduced kidney function.

Hepatic Impairment

There is no available information 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 caution and consider the lack of data when prescribing this medication to patients with liver problems.

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 rhythm is essential, and 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 follow established protocols for the management of overdose situations, ensuring that all interventions are tailored to the individual patient's needs.

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 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 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 the use of the product. These include hypertension, reflex bradycardia, and arrhythmias. Additional adverse reactions reported include headache, dizziness, and anxiety.

Severe allergic reactions, including anaphylaxis, have also been documented. Furthermore, there have been reports of extravasation leading to tissue necrosis. During postmarketing surveillance, some patients experienced elevated blood pressure and heart rate.

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 the safe and effective use of phenylephrine hydrochloride injection.

Storage and Handling

Phenylephrine hydrochloride injection USP, 10 mg/mL, is supplied in 1 mL vials designated for single use, as well as in 5 mL and 10 mL vials intended for pharmacy bulk packages. The product 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 vials from light and to keep them in their original carton until they are 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 Camber Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)