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 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.

Phenylephrine hydrochloride is soluble in water and ethanol, but 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. The structural formula is depicted below.

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 appropriately.

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

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 increased to a maximum of 35 mcg/min, titrating the dose to achieve the desired pressor response. The infusion rate should not exceed 200 mcg/min.

Healthcare professionals should adjust the dosage based on the individual patient's response to the medication, titrating to effect as necessary.

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, no specific instructions regarding avoidance or non-use are necessary.

Warnings and Precautions

Phenylephrine hydrochloride is associated with several significant warnings and precautions that healthcare professionals must consider to ensure patient safety.

Cardiovascular Risks Phenylephrine hydrochloride 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 pre-existing cardiovascular conditions for any signs of exacerbation.

Ischemic Events 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 symptoms of ischemia, particularly in those with compromised vascular health.

Tissue Necrosis Extravasation during intravenous administration of phenylephrine hydrochloride 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 Phenylephrine hydrochloride has the potential to induce severe bradycardia and decrease cardiac output. Continuous cardiac monitoring is recommended for patients receiving this medication, especially those with existing bradyarrhythmias or other cardiac conditions.

In summary, careful consideration and monitoring are essential when administering phenylephrine hydrochloride to mitigate the risks of cardiovascular complications, ischemic events, tissue necrosis, and bradycardia.

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, excessive peripheral and visceral vasoconstriction may lead to ischemia of vital organs. Skin and subcutaneous necrosis can occur if extravasation happens during intravenous administration, potentially resulting in necrosis or sloughing of tissue. Severe bradycardia and decreased cardiac output have also been observed in some 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, which may manifest as ventricular extrasystoles and ventricular tachycardia.

No additional adverse reactions have been reported in clinical trials or postmarketing experiences.

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 hormones can contribute to elevated blood pressure when used concurrently.

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

• Steroids: Corticosteroids may increase blood pressure, potentially leading to an additive effect.

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

• Ergot Alkaloids: Co-administration may lead to increased blood pressure effects.

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 hydrochloride.

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

• Mixed α- and β-Receptor Antagonists: These medications may attenuate the hypertensive effects.

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

• Benzodiazepines: These central nervous system depressants may reduce the effectiveness of Phenylephrine hydrochloride.

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

• Centrally Acting Sympatholytic Agents: These agents can antagonize the pressor effects of Phenylephrine hydrochloride.

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 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 2-4% 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 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 when normotensive pregnant rats were treated with up to 3 mg/kg/day of phenylephrine, although this dose 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 were observed at doses of 1 and 3 mg/kg/day, which correspond to the HDD.

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 the phenylephrine hydrochloride or 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. Regular monitoring of blood pressure and renal function is recommended to guide dosing adjustments in this population.

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. Therefore, while it is recommended to initiate treatment within the standard dosing range, it may be necessary to adjust the dose upward to achieve the desired therapeutic effect in this population. Close monitoring of the patient's response to treatment is advised to ensure optimal dosing and efficacy.

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 experience 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 essential. Monitoring of blood pressure and cardiac function should be prioritized. Appropriate measures may include the administration of antihypertensive agents to manage elevated blood pressure and supportive care to address any arrhythmias. Continuous cardiac monitoring is recommended to detect and manage any potential complications effectively.

Healthcare professionals are advised to follow established protocols for the management of drug overdoses and to consult relevant clinical guidelines for further treatment options.

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 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.

In terms of mutagenesis, phenylephrine hydrochloride 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.

Regarding impairment of fertility, phenylephrine did not adversely affect 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 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 such as anaphylaxis and severe allergic reactions have been reported. There have also been cases of myocardial ischemia and infarction in patients with pre-existing cardiovascular disease.

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, 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 Xellia Pharmaceuticals USA LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)