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. The chemical name of phenylephrine hydrochloride is (-)-m-hydroxy-α-(methylamino)methylbenzyl alcohol hydrochloride. It is chemically designated as C9H14ClNO2, with a molecular weight of 203.66 g/mol. Phenylephrine hydrochloride is soluble in water and ethanol, and insoluble in chloroform and ethyl ether. 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 3.5 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 intravenously, either as a bolus injection or as a continuous infusion in a dilute solution.

For bolus intravenous injection, the recommended dosage ranges from 40 mcg to 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 effect, with a maximum allowable rate of 200 mcg/min.

Healthcare professionals should adjust the dosage based on the patient's pressor response, ensuring that the administration is tailored 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. Therefore, the product can be used without specific restrictions related to contraindications.

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 that healthcare providers monitor the administration site closely to prevent and address any complications promptly.

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 underlying cardiac conditions.

Healthcare professionals are advised to remain alert to these warnings and to implement appropriate monitoring strategies to ensure patient safety during the use of phenylephrine hydrochloride.

Side Effects

Patients receiving phenylephrine hydrochloride may experience a range of adverse reactions. 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 has been noted as a potential consequence of extravasation during intravenous administration, which may result in necrosis or sloughing of tissue. Bradycardia is another serious concern, as phenylephrine hydrochloride can cause severe bradycardia and decreased cardiac output.

In cases of overdose, patients may experience a rapid rise in blood pressure, with symptoms including 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.

Healthcare professionals should monitor patients closely for these adverse reactions and manage them appropriately.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

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 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 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 some maternal toxicity was noted at this dose. 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 were noted in the offspring at any tested dose, although maternal toxicities occurred at higher doses.

Given the available data, healthcare professionals should weigh the potential benefits of phenylephrine use against the unknown risks during pregnancy, particularly in the absence of comprehensive safety data during the first and second trimesters.

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 phenylephrine hydrochloride or from the underlying maternal condition should be evaluated.

Renal Impairment

In patients with end stage renal disease (ESRD), dose-response data indicate increased responsiveness to phenylephrine. It is advisable to consider starting at the lower end of the recommended dose range for these patients. Dosing should be adjusted based on the target blood pressure goal to ensure optimal therapeutic outcomes while minimizing the risk of adverse effects associated with reduced kidney function. Regular monitoring of blood pressure and renal function is recommended to guide appropriate dosing adjustments.

Hepatic Impairment

In patients with hepatic impairment, particularly those with liver cirrhosis classified as Child-Pugh Class B and Class C, there is evidence suggesting a decreased responsiveness to phenylephrine. Consequently, while it is recommended to initiate treatment within the standard dosing range, it may be necessary to adjust the dosage to achieve the desired therapeutic effect in this population. Careful monitoring of the patient's response to treatment is advised to ensure optimal dosing and efficacy.

Overdosage

In cases of phenylephrine hydrochloride 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 phenylephrine hydrochloride overdose should focus on the immediate assessment of the patient's cardiovascular status. Continuous monitoring of blood pressure and heart rhythm is essential. If hypertension is present, appropriate antihypertensive measures should be initiated. In cases of severe arrhythmias, advanced cardiac life support protocols may be necessary.

Healthcare providers are advised to ensure that supportive care is provided, and symptomatic treatment is administered as required. Prompt recognition and intervention are critical to mitigate the potential complications associated with 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

No postmarketing experience details are available in the provided data.

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 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 and to keep it in its original 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

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)