Phenylephrine hydrochloride

Description

Phenylephrine is an alpha-1 adrenergic receptor agonist. Phenylephrine hydrochloride injection USP, at a concentration of 10 mg/mL, is a clear, colorless, sterile, nonpyrogenic 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)methylbenzyl alcohol hydrochloride, with a chemical designation of C₉H₁₄ClNO₂ and a molecular weight of 203.66 g/mol. Its structural formula is provided below. Phenylephrine hydrochloride is soluble in water and ethanol, while being insoluble in chloroform and ethyl ether. 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 3.5-5.5.

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

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

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 may be titrated up to 35 mcg/min based on the patient's response. The infusion rate should not exceed 200 mcg/min.

Dosing should be adjusted according to the pressor response, with careful titration to achieve the desired effect.

Contraindications

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

Warnings and Precautions

Phenylephrine hydrochloride injection carries several important warnings and precautions that healthcare professionals must consider to ensure patient safety.

Cardiovascular Risks Phenylephrine hydrochloride injection may exacerbate angina in patients with severe arteriosclerosis or a history of angina. It is also important to note that this medication can worsen underlying heart failure and elevate pulmonary arterial pressure. Healthcare providers should closely monitor patients with these conditions for any signs of deterioration.

Ischemic Events The use of phenylephrine hydrochloride injection can lead to excessive peripheral and visceral vasoconstriction, potentially resulting in ischemia of vital organs. Clinicians should be vigilant in assessing patients for symptoms of ischemia, particularly in those with pre-existing vascular conditions.

Tissue Injury Extravasation of phenylephrine hydrochloride during intravenous administration poses a risk of skin and subcutaneous necrosis. It is crucial for healthcare professionals to ensure proper intravenous placement and to monitor the injection site closely to prevent tissue damage.

Bradycardia Administration of phenylephrine hydrochloride injection may induce severe bradycardia and a decrease in cardiac output. Continuous cardiac monitoring is recommended for patients receiving this medication, particularly those with existing cardiac conditions or those at risk for bradycardia.

In summary, careful consideration of these warnings and precautions, along with appropriate monitoring, is essential for the safe use of phenylephrine hydrochloride injection in clinical practice.

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 can result in skin and subcutaneous necrosis, leading to tissue necrosis or sloughing. Furthermore, severe bradycardia and decreased cardiac output have been observed in some patients following administration.

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. It is crucial for healthcare providers to monitor patients closely for these adverse reactions and manage them appropriately.

Drug Interactions

Agonistic interactions that may enhance the blood pressure effect 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 effect.

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

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

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

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

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

Conversely, antagonistic interactions that may diminish the blood pressure effect of phenylephrine hydrochloride injection include:

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

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

• Mixed α- and β-Receptor Antagonists: These drugs 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 medications may antagonize the hypertensive effects of phenylephrine.

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

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 experience has 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 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 animal studies, no clear malformations or fetal toxicity were reported when normotensive pregnant rabbits were 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. An increase in the incidence of limb malformation coinciding with high fetal mortality was observed at a dose of 0.6 mg/kg/day (1.2 times the HDD) in the absence of maternal toxicity.

No malformations or embryo-fetal toxicity were reported when normotensive pregnant rats were 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 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, 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 studies on the safety of phenylephrine injection exposure during lactation, and therefore, it is not possible to draw any conclusions regarding its excretion in breast milk or the potential effects on breastfed infants.

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 from Gestation Day 6 through Lactation Day 21 at doses of 0.3, 1.0, or 3.0 mg/kg/day. However, 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, were reported at doses of 1 and 3 mg/kg/day.

Due to the lack of data on the safety of phenylephrine during lactation, healthcare professionals should exercise caution when considering the use of this medication in lactating mothers.

Renal Impairment

Patients with renal impairment may not have specific information regarding dosage adjustments, special monitoring, or safety considerations outlined in the prescribing information. Therefore, healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the lack of data necessitates careful clinical judgment and individualized patient assessment. Regular monitoring of renal function is advisable to ensure patient safety and optimal therapeutic outcomes.

Hepatic Impairment

There is no available information regarding the use of this medication in patients with hepatic impairment. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions specified for individuals with compromised liver function. Healthcare professionals should exercise caution and consider the individual patient's liver status when prescribing this medication.

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 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 assessment of the patient's cardiovascular status. Continuous monitoring of blood pressure and heart rhythm is essential. If hypertension occurs, appropriate antihypertensive measures should be initiated. In cases of significant cardiac arrhythmias, advanced cardiac life support protocols may be necessary. It is crucial to provide supportive care and consider the use of intravenous fluids to maintain hemodynamic stability.

Prompt recognition and intervention are vital 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 and found 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 evidence 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 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 vasoconstriction, extravasation injury, and tissue necrosis at the injection site.

Additionally, serious adverse reactions have been reported, including myocardial ischemia and infarction. Cases of severe allergic reactions, such as anaphylaxis, have also been documented.

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 existing health issues or ongoing treatments that the patient may have, as these factors can influence how the medication works in their specific situation. This conversation will help ensure that the patient receives the most appropriate care and management while using this medication.

Storage and Handling

Phenylephrine hydrochloride Injection USP, 10 mg/mL, is supplied in a suitable container that 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 carton until it is ready for use.

Once diluted, the solution must not be held at room temperature for more than 4 hours. If refrigerated, the diluted solution should not be stored for more than 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 Gland Pharma Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)