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 intravenous bolus or continuous intravenous infusion. The chemical name of phenylephrine hydrochloride, USP is (-)-m-hydroxy-α(methylamino)methylbenzyl alcohol hydrochloride, with a chemical designation of C9H13NO2•HCl and a molecular weight of 203.67 g/mol. The structural formula is provided below.

Phenylephrine hydrochloride, USP appears as white or practically white crystals and is freely soluble in water and alcohol. The injection 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 3.0-6.5.

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 intravenously, either as a bolus injection or as a continuous infusion in a dilute solution. It is essential to dilute the medication prior to administration.

For the treatment of hypotension during anesthesia, the following dosing guidelines apply:

Bolus Intravenous Injection: Administer a dose of 40 mcg to 100 mcg every 1 to 2 minutes as needed. The total dose should not exceed 200 mcg.

Intravenous Infusion: Initiate the infusion at a rate of 10 mcg/min and may titrate up to 35 mcg/min based on the patient's response. The infusion rate should not exceed 200 mcg/min.

Healthcare professionals should adjust the dosage according to the pressor response, titrating to achieve the desired effect.

Contraindications

There are no identified contraindications for the use of this product. It is deemed safe for use across various patient populations, as no specific conditions or situations have been outlined that would preclude its administration.

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. Additionally, it may 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 may 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 by seriousness and frequency.

The most common adverse reactions observed during treatment include nausea, vomiting, and headache. These reactions are typically mild but may affect patient comfort and adherence to therapy.

Serious adverse reactions associated with phenylephrine hydrochloride include exacerbation of angina, heart failure, or pulmonary arterial hypertension. The 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, which is a significant concern in susceptible populations.

Skin and subcutaneous necrosis may occur as a result of extravasation during intravenous administration, potentially leading to necrosis or sloughing of tissue. Bradycardia is another serious adverse reaction that can manifest as severe bradycardia and decreased cardiac output, necessitating careful monitoring of patients.

In cases of overdose, symptoms may include a rapid rise in blood pressure, headache, vomiting, hypertension, reflex bradycardia, a sensation of fullness in the head, tingling of the extremities, and cardiac arrhythmias, such as ventricular extrasystoles and ventricular tachycardia. These symptoms highlight the importance of adhering to recommended dosing guidelines to minimize the risk of overdose and its associated complications.

Healthcare providers should remain vigilant for these adverse reactions and manage them appropriately to ensure patient safety and therapeutic efficacy.

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.

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

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

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

• Norepinephrine Transporter Inhibitors: These drugs can 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 drugs may decrease the efficacy of phenylephrine.

• Calcium Channel Blockers: The interaction may result in a diminished blood pressure effect.

• Benzodiazepines: These agents may reduce the hypertensive response.

• ACE Inhibitors: Co-administration may lead to a decrease in blood pressure effects.

• Centrally Acting Sympatholytic Agents: These medications can antagonize the pressor 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 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 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 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. 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 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, 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, resulting in increased mortality and significant body weight loss. An increase in the incidence of limb malformation (hyperextension of the forepaw) was observed in a single litter at a dose of 0.6 mg/kg/day (1.2 times the HDD) without 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 via continuous intravenous infusion over 1 hour (2.9 times the HDD) from Gestation Day 6 to 17, although some maternal toxicity was noted (decreased food consumption and body weights). Decreased pup weights were reported in a pre- and postnatal development toxicity study in which normotensive pregnant rats were administered phenylephrine at doses of 0.3, 1.0, or 3.0 mg/kg/day (0.29, 1, or 2.9 times the HDD) 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 (equivalent to and 2.9 times the HDD, respectively).

Lactation

There are no data on the risk of miscarriage following fetal exposure to phenylephrine injection. In a pre- and postnatal development toxicity study, decreased pup weights were observed in normotensive pregnant rats administered phenylephrine via continuous intravenous infusion from Gestation Day 6 through Lactation Day 21 at doses of 0.3, 1.0, or 3.0 mg/kg/day (0.29, 1, or 2.9 times the human daily dose HDD). However, 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, were reported at doses of 1 and 3 mg/kg/day of phenylephrine, which are equivalent to and 2.9 times the HDD, respectively. Given the lack of specific data on excretion in human breast milk and the potential for maternal toxicity, caution is advised when considering the use of phenylephrine in lactating mothers.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of 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.

Overdosage

In cases of phenylephrine hydrochloride injection overdose, a rapid increase in blood pressure is a significant concern. Healthcare professionals should be vigilant for the following symptoms that may manifest in affected individuals: 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 occurs, 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.

Healthcare professionals are advised to consult local poison control centers or toxicology experts for further guidance on the management of phenylephrine hydrochloride overdose.

Nonclinical Toxicology

Long-term animal studies conducted by the National Toxicology Program assessed the carcinogenic potential of orally administered phenylephrine hydrochloride in F344/N rats and B6C3F1 mice. The studies revealed no evidence of carcinogenicity in mice receiving approximately 270 mg/kg/day, which corresponds to 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 mutagenicity, phenylephrine hydrochloride 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.

Regarding 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. 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 reported voluntarily or through surveillance programs. These include hypertension, reflex bradycardia, arrhythmias, headache, nausea, vomiting, anxiety, tremors, palpitations, peripheral ischemia, extravasation injury, and tissue necrosis at the injection site.

Additionally, there have been reports of severe allergic reactions, including anaphylaxis, as well as serious cardiovascular events such as cardiac arrest, stroke, and myocardial infarction.

Healthcare providers are advised to monitor patients for these adverse reactions and manage them appropriately.

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 can 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 10 mg/mL is supplied in 1 mL vials, which are intended for single-dose use only. Any unused portion must be discarded.

This product should be stored at a temperature range of 20º to 25ºC (68º to 77ºF), 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 the time of use.

Once diluted, the solution should not be held for more than 4 hours at room temperature or for more than 24 hours when refrigerated. Any unused diluted solution must also be discarded.

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 Lifestar Pharma LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)