Phenylephrine hydrochloride

Description

Phenylephrine is an alpha-1 adrenergic receptor agonist. 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 g/mol. Phenylephrine hydrochloride is soluble in water and ethanol, but insoluble in chloroform and ethyl ether.

The formulation is provided as a sterile, nonpyrogenic injection containing 500 mcg of phenylephrine hydrochloride per 5 mL (100 mcg/mL), presented as a clear and colorless solution for intravenous use. It is critical that the solution is not diluted prior to administration as an intravenous bolus. Each mL of the injection contains 100 mcg of phenylephrine hydrochloride (equivalent to 80 mcg of phenylephrine base) and 9.0 mg of sodium chloride, in water for injection. The pH of the solution is adjusted with hydrochloric acid as necessary, maintaining a pH range of 3.0 to 5.0.

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 is supplied as a ready-to-use formulation at a concentration of 500 mcg/5 mL (100 mcg/mL) and must not be diluted prior to administration.

For the treatment of hypotension during anesthesia, the recommended dosing is as follows:

• Initial Dose: Administer an intravenous bolus of 40 mcg to 100 mcg.

• Subsequent Doses: Additional boluses of up to 200 mcg may be given every 1 to 2 minutes as necessary.

Healthcare professionals should adjust the dosage based on the patient's pressor response, titrating to effect as required.

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 Injection is associated with several significant warnings that healthcare professionals must consider when administering this medication.

Exacerbation of Angina, Heart Failure, or Pulmonary Arterial Hypertension This medication 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 Phenylephrine Hydrochloride Injection 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 Injection may result in necrosis or sloughing of tissue. It is crucial to ensure proper intravenous placement and to monitor the injection site closely for any signs of extravasation.

Bradycardia The use of Phenylephrine Hydrochloride Injection can induce severe bradycardia and a decrease in cardiac output. Continuous cardiac monitoring is recommended for patients receiving this medication, especially those with underlying 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 Injection.

Side Effects

Patients receiving Phenylephrine Hydrochloride Injection may experience a range of adverse reactions. The most common adverse reactions reported include nausea, vomiting, and headache.

Serious warnings associated with Phenylephrine Hydrochloride Injection 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 Injection poses a risk of skin and subcutaneous necrosis, which may result in tissue necrosis or sloughing. Furthermore, the injection can cause severe bradycardia and decreased cardiac output, 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 vigilant in monitoring for these adverse reactions and to manage them appropriately.

Drug Interactions

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

• Monoamine Oxidase Inhibitors (MAOIs): Co-administration may lead to increased blood pressure response.

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

• Tricyclic Antidepressants: The combination may result in an augmented blood pressure response.

• Angiotensin and Aldosterone: These substances may contribute to increased blood pressure effects.

• Atropine: Co-administration may enhance the blood pressure response.

• Steroids: The use of steroids may lead to an increased hypertensive effect.

• Norepinephrine Transporter Inhibitors: These agents can also potentiate the blood pressure effects.

• Ergot Alkaloids: Co-administration may result in an increased blood pressure response.

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

• α-Adrenergic Antagonists: These agents may reduce the efficacy of Phenylephrine.

• Phosphodiesterase Type 5 Inhibitors: Co-administration may lead to a decreased blood pressure response.

• Mixed α- and β-Receptor Antagonists: These may antagonize the blood pressure effects of Phenylephrine.

• Calcium Channel Blockers: The use of these agents may result in a reduced blood pressure effect.

• Benzodiazepines: Co-administration may lead to diminished blood pressure response.

• ACE Inhibitors: These agents may antagonize the hypertensive effects of Phenylephrine.

• Centrally Acting Sympatholytic Agents: The use of these agents may result in a decreased blood pressure response.

Monitoring of blood pressure is advised when Phenylephrine Hydrochloride Injection 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 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 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 is 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 for 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 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 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. However, this dose demonstrated evidence of developmental delay, specifically altered ossification of sternebra. In a non-GLP dose range-finding study, fetal lethality and cranial, paw, and limb malformations were noted at a dose of 1.2 mg/kg/day (2.3 times the HDD), which was associated with maternal toxicity. An increase in limb malformation incidence was observed at 0.6 mg/kg/day (1.2 times the HDD) in the absence of maternal toxicity.

In contrast, no malformations or embryo-fetal toxicity were reported in normotensive pregnant rats treated with up to 3 mg/kg/day of phenylephrine (2.9 times the HDD) from Gestation Day 6 to 17, although some maternal toxicity was noted. 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 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 (equivalent to and 2.9 times the HDD, respectively).

Lactation

Lactating mothers may be exposed to phenylephrine, as it has been shown to cross into breast milk. In a pre-and postnatal development toxicity study involving normotensive pregnant rats, decreased pup weights were observed when phenylephrine was administered via continuous intravenous infusion during gestation and lactation. The doses tested were 0.3, 1.0, or 3.0 mg/kg/day, which correspond to 0.29, 1, or 2.9 times the human daily dose (HDD).

Despite the noted decrease in pup weights, no adverse effects on growth and development, including learning and memory, sexual development, and fertility, were reported in the offspring at any dose tested. However, maternal toxicities, such as mortality late in gestation and during the lactation period, as well as decreased food consumption and body weight, were observed at doses of 1 and 3 mg/kg/day (equivalent to and 2.9 times the HDD, respectively).

Healthcare professionals should consider these findings when advising lactating mothers regarding the use of phenylephrine, weighing the potential risks to both the mother and the breastfed infant.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

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 prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In cases of phenylephrine hydrochloride injection overdose, a significant and rapid increase in blood pressure may occur. Healthcare professionals should be vigilant for the following symptoms associated with overdose: headache, vomiting, hypertension, reflex bradycardia, a sensation of fullness in the head, tingling of the extremities, and various cardiac arrhythmias, which may include ventricular extrasystoles and ventricular tachycardia.

Management of an overdose should focus on the immediate stabilization of the patient. Continuous monitoring of vital signs is essential, particularly blood pressure and heart rhythm. If hypertension is present, appropriate antihypertensive measures should be initiated. In cases of severe arrhythmias, advanced cardiac life support protocols may be necessary. It is crucial to provide supportive care and consider the administration of intravenous fluids to maintain hemodynamic stability.

Prompt recognition and intervention are vital to mitigate the potential complications associated with 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, also showed no signs of carcinogenicity.

In terms of mutagenesis, phenylephrine hydrochloride was tested across several assays. It demonstrated negative results in the in vitro bacterial reverse mutation assay using S. typhimurium strains TA98, TA100, TA1535, and TA1537, as well as in the in vitro chromosomal aberrations assay and the in vitro sister chromatid exchange assay. Additionally, the in vivo rat micronucleus assay yielded negative results. 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

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, nausea, vomiting, and anxiety.

Skin reactions, such as rash and urticaria, have also been documented. Furthermore, rare cases of myocardial ischemia and infarction have been reported in the postmarketing setting. Some patients have experienced peripheral ischemia following administration.

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 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, to optimize the therapeutic outcomes and minimize potential risks associated with the use of phenylephrine hydrochloride injection.

Storage and Handling

Phenylephrine hydrochloride injection USP is supplied in a concentration of 500 mcg/5 mL (100 mcg/mL). It 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 to maintain its stability and efficacy. Any unused portion of the injection must be discarded to ensure safety and compliance with handling protocols.

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 Somerset Therapeutics, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)