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, with a chemical designation of C9H14ClNO2 and a molecular weight of 203.66 g/mol. Phenylephrine hydrochloride is soluble in water and ethanol, but insoluble in chloroform and ethyl ether. Each mL of the solution contains 10 mg of phenylephrine hydrochloride, 3.5 mg of sodium chloride, 4 mg of sodium citrate dihydrate, 1 mg of citric acid monohydrate, and 2 mg of sodium metabisulfite in water for injection. The pH range of the solution is 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

The medication is administered intravenously, either as a bolus injection or as a continuous infusion in a dilute solution. Prior to administration, the solution must be diluted appropriately.

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

Bolus Intravenous Injection: Administer a dose ranging from 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.

It is essential to adjust the dosage according to the pressor response, titrating to achieve the desired effect.

Contraindications

There are no contraindications associated with the use of this product.

Warnings and Precautions

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

Cardiovascular Risks The use of Phenylephrine Hydrochloride Injection may lead to exacerbation of angina, heart failure, or pulmonary arterial hypertension. Patients with severe arteriosclerosis or a history of angina are particularly at risk, as the medication can precipitate angina attacks and worsen underlying heart failure. Additionally, there is a potential for increased pulmonary arterial pressure, which necessitates careful monitoring in susceptible individuals.

Ischemic Events Healthcare providers should be aware that Phenylephrine Hydrochloride Injection can induce excessive peripheral and visceral vasoconstriction, potentially resulting in ischemia to vital organs. This risk underscores the importance of monitoring patients for signs of ischemia during and after administration.

Tissue Necrosis Extravasation of Phenylephrine Hydrochloride Injection during intravenous administration poses a risk of skin and subcutaneous necrosis. It is crucial to ensure proper intravenous placement and to monitor the injection site closely to prevent tissue damage.

Bradycardia The administration of Phenylephrine Hydrochloride Injection may lead to severe bradycardia and a decrease in cardiac output. Continuous cardiac monitoring is recommended to detect and manage any significant changes in heart rate or output.

In summary, healthcare professionals should exercise caution when using Phenylephrine Hydrochloride Injection, particularly in patients with cardiovascular conditions, and should remain vigilant for potential adverse effects, including ischemia and tissue necrosis.

Side Effects

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

Serious adverse reactions associated with Phenylephrine Hydrochloride Injection 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. Extravasation during intravenous administration has been reported to cause skin and subcutaneous necrosis, resulting in tissue necrosis or sloughing. Severe bradycardia and decreased cardiac output are also potential serious adverse reactions.

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

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 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 to 4% and 15 to 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, including increased mortality and significant body weight loss. 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 in normotensive pregnant rats 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, including learning and memory, sexual development, and fertility, were observed 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

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 injection in lactating mothers. Additionally, potential adverse effects on the breastfed infant from phenylephrine hydrochloride injection or from the underlying maternal condition should be evaluated.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to this patient population.

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 overdose with Phenylephrine Hydrochloride Injection, a rapid increase in blood pressure is a significant concern. 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

• 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 rate. If hypertension occurs, appropriate antihypertensive measures should be initiated. In cases of significant cardiac arrhythmias, advanced cardiac life support protocols may be necessary.

Prompt recognition and intervention are critical to mitigate the potential complications associated with Phenylephrine Hydrochloride Injection 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. The studies utilized the dietary route of administration, revealing 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 assessed for mutagenic potential and tested negative 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

No postmarketing experience details are available in the provided text.

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 to facilitate safe and effective use of Phenylephrine Hydrochloride Injection.

Storage and Handling

Phenylephrine Hydrochloride Injection, USP, 10 mg/mL is supplied in a suitable packaging configuration. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F) and must be protected from light. The product should remain in its carton until it is ready for use.

Once diluted, the solution should not be held at room temperature for more than 4 hours. If refrigerated, the diluted solution must be used within 24 hours. 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 Par Health USA, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)