Phenylephrine hydrochloride

Description

Phenylephrine is an alpha-1 adrenergic receptor agonist. Phenylephrine hydrochloride Injection, 10 mg/mL, is a clear, colorless, sterile, non-pyrogenic 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)methyl benzyl alcohol hydrochloride, with a chemical designation of C9H14ClNO2 and a molecular weight of 203.66 g/mol.

The structural formula is provided below. Phenylephrine hydrochloride is soluble in water and ethanol, while being insoluble in chloroform and ethyl ether. This injection is sensitive to light. Each mL 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 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.

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 and titrate to effect, with a maximum infusion rate of 35 mcg/min. The dose should be adjusted based on the pressor response, ensuring that the total infusion rate does not exceed 200 mcg/min.

Healthcare professionals are advised to closely monitor the patient's response and adjust the dosage accordingly 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.

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. Additionally, it may exacerbate underlying heart failure and increase pulmonary arterial pressure. Healthcare providers should closely monitor patients with these conditions for any signs of worsening symptoms. (5.1)

Peripheral and Visceral Ischemia The administration of phenylephrine hydrochloride can lead to excessive peripheral and visceral vasoconstriction, resulting in ischemia to vital organs. It is crucial for healthcare professionals to assess and monitor patients for signs of ischemia, particularly in those with pre-existing vascular conditions. (5.2)

Skin and Subcutaneous Necrosis Extravasation during intravenous administration of phenylephrine hydrochloride may result in necrosis or sloughing of tissue at the injection site. Careful administration techniques should be employed, and the injection site should be monitored for any signs of extravasation to prevent tissue damage. (5.3)

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 a history of cardiac issues or those who are at risk for bradycardia. (5.4)

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 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 reported as a serious consequence of extravasation during intravenous administration, which may result in necrosis or sloughing of tissue. Furthermore, severe bradycardia and decreased cardiac output can occur, posing significant risks to patients.

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, such as ventricular extrasystoles and ventricular tachycardia. These symptoms necessitate immediate medical attention to mitigate potential complications.

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 hydrochloride.

• Tricyclic Antidepressants: The interaction may result in an increased blood pressure response.

• Angiotensin and Aldosterone: These substances may contribute to elevated blood pressure when used concurrently.

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

• Steroids: Corticosteroids may increase blood pressure effects when administered with Phenylephrine hydrochloride.

• Norepinephrine Transporter Inhibitors: These agents can lead to an increased blood pressure response.

• Ergot Alkaloids: Co-administration may result in enhanced blood pressure effects.

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

• α-Adrenergic Antagonists: These agents may reduce the efficacy of Phenylephrine hydrochloride in elevating blood pressure.

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

• Mixed α- and β-Receptor Antagonists: These medications can counteract the hypertensive effects of Phenylephrine hydrochloride.

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

• Benzodiazepines: These drugs may antagonize the blood pressure-raising effects of Phenylephrine hydrochloride.

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

• Centrally Acting Sympatholytic Agents: These agents may reduce the effectiveness of Phenylephrine hydrochloride in increasing blood pressure.

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 these elderly patients respond differently from younger subjects. However, other reported clinical experience has not identified significant differences in responses between geriatric patients and their younger counterparts.

In general, dose selection for elderly 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 is recommended to ensure safety and efficacy 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 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 any 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 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 following treatment with 1.2 mg/kg/day of phenylephrine, which was associated with maternal toxicity. An increase in limb malformation incidence 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. This treatment was associated with some maternal toxicity, including decreased food consumption and body weight. 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 occurred at higher doses, including mortality late in gestation and during the lactation period, as well as decreased food consumption and body weight.

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 in lactating mothers. Additionally, potential adverse effects on the breastfed infant from either phenylephrine hydrochloride or the underlying maternal condition should be taken into account when making treatment decisions.

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 of these patients.

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 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 Overdose 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 should be provided as necessary, and symptomatic treatment should be initiated based on the clinical presentation of the patient.

Healthcare professionals are advised to consult relevant clinical guidelines and toxicology resources for further management strategies in cases of 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 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 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 phenylephrine hydrochloride injection. These include hypertension, reflex bradycardia, and arrhythmias. Additional adverse reactions reported include headache, anxiety, and nausea.

There have also been reports of extravasation leading to tissue necrosis. Furthermore, cases of severe allergic reactions, including anaphylaxis, have been documented. The safety profile of phenylephrine hydrochloride injection continues to be monitored through postmarketing surveillance.

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 essential 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 importance of disclosing their complete medical history and current medication regimen, including over-the-counter drugs and supplements. This information will help in assessing the appropriateness of phenylephrine hydrochloride Injection for the patient and in monitoring for potential interactions or side effects.

Storage and Handling

Phenylephrine hydrochloride Injection, 10 mg/mL is supplied in 1 mL vials designated for single use only, as well as in 5 mL and 10 mL vials which are intended as pharmacy bulk packages. The product 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 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 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 Somerset Therapeutics, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)