Phenylephrine hydrochloride

Description

Phenylephrine Hydrochloride Injection contains phenylephrine as the active pharmaceutical ingredient in the form of its hydrochloride salt. Phenylephrine is a synthetic sympathomimetic agent provided in a sterile formulation for parenteral administration. The chemical structure of phenylephrine hydrochloride is represented as (-)-m-Hydroxy-α-(methylamino)methylbenzyl alcohol hydrochloride. This compound exhibits high solubility in water, is freely soluble in ethanol, and is insoluble in chloroform and ethyl ether. It is also sensitive to light.

The injection is presented as a clear, colorless, aqueous solution that is essentially free of visible foreign matter. Prior to administration, it must be diluted for either bolus intravenous infusion or continuous intravenous infusion. Each milliliter of the solution contains 10 mg of phenylephrine hydrochloride, 3.5 mg of sodium chloride, 4 mg of sodium citrate dihydrate, and 1 mg of citric acid, all in water for injection. The pH of the solution may be adjusted to a range of 3.5 to 5.5 using sodium hydroxide and/or hydrochloric acid, if necessary.

Uses and Indications

Phenylephrine Hydrochloride Injection 10 mg/mL is indicated for increasing blood pressure in adults experiencing clinically important hypotension primarily due to vasodilation in the contexts of anesthesia and septic shock.

Limitations of Use: There are no reported teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

Prior to administration, the medication must be diluted appropriately.

For the management of perioperative hypotension, the recommended dosing is as follows: an intravenous bolus of 50 mcg to 250 mcg may be administered. Alternatively, a continuous intravenous infusion can be initiated at a rate of 0.5 mcg/kg/minute to 1.4 mcg/kg/minute, with titration based on the patient's response.

In patients experiencing vasodilatory shock, the dosing regimen involves a continuous intravenous infusion starting at 0.5 mcg/kg/minute, which may be increased up to 6 mcg/kg/minute, also titrated to achieve the desired clinical effect.

Healthcare professionals should monitor the patient's response closely and adjust the infusion rate as necessary to ensure optimal therapeutic outcomes.

Contraindications

Use of this product is contraindicated in individuals with a known hypersensitivity to the product or any of its components.

Warnings and Precautions

Severe bradycardia and decreased cardiac output are significant risks associated with the use of this medication. Healthcare professionals should closely monitor patients for these cardiovascular effects, particularly in those with pre-existing heart conditions or those receiving other medications that may exacerbate these issues.

Extravasation during intravenous administration poses a serious risk, as it may lead to necrosis or sloughing of tissue. It is imperative that healthcare providers ensure proper intravenous technique and monitor the infusion site closely to prevent this complication.

Caution is advised when administering this medication in conjunction with oxytocic drugs, as the pressor effect of sympathomimetic pressor amines may be potentiated. This interaction necessitates careful consideration of the patient's overall medication regimen and vigilant monitoring of blood pressure and heart rate.

While no specific general precautions or laboratory tests are outlined, healthcare professionals should remain vigilant and apply clinical judgment in the management of patients receiving this treatment. Regular assessment of cardiovascular status and infusion site integrity is recommended to mitigate potential risks.

Side Effects

Patients may experience a range of adverse reactions associated with the use of this medication. The most common adverse reactions reported include nausea and vomiting, headache, and nervousness.

Serious side effects have been observed, including severe bradycardia and decreased cardiac output. Extravasation during intravenous administration may lead to necrosis or sloughing of tissue. Additionally, caution is advised when using this medication concomitantly with oxytocic drugs, as the pressor effect of sympathomimetic pressor amines may be potentiated.

Allergic reactions, including hypersensitivity to the product or any of its components, have also been reported.

In cases of overdosage, symptoms may include headache, vomiting, hypertension, reflex bradycardia, and cardiac arrhythmias such as ventricular extrasystoles and ventricular tachycardia. Patients may also report a sensation of fullness in the head and tingling of the extremities.

Furthermore, animal reproductive and developmental studies have indicated decreased fetal body weights at 0.4 times the human daily dose (HDD) of 10 mg. While no malformations were reported, an increased incidence of agenesis of the intermediate lobe of the lung, a visceral variation, was noted at levels as low as 0.08 times the HDD.

Drug Interactions

The use of this medication may result in significant drug interactions, categorized primarily into agonistic and antagonistic effects.

Agonistic interactions are observed with the following classes of drugs:

• Monoamine Oxidase Inhibitors (MAOIs): Co-administration may enhance the pharmacological effects, potentially leading to increased risk of hypertensive crises or serotonin syndrome.

• β-Adrenergic Blocking Agents: Concurrent use may amplify the effects on cardiovascular parameters, necessitating careful monitoring of heart rate and blood pressure.

• α-2 Adrenergic Agonists: The combination may lead to enhanced sedation or hypotensive effects.

• Steroids: There may be an increased risk of side effects due to synergistic effects on metabolic pathways.

• Tricyclic Antidepressants: Co-administration may increase the risk of serotonin syndrome or other central nervous system effects.

• Norepinephrine Transport Inhibitors: The interaction may potentiate sympathomimetic effects, requiring close observation for signs of excessive stimulation.

• Ergot Alkaloids: The combination may lead to increased vasoconstriction and risk of ergotism.

• Centrally-Acting Sympatholytic Agents: Enhanced central nervous system depression may occur, warranting monitoring for sedation and respiratory depression.

• Atropine Sulfate: Co-administration may lead to increased anticholinergic effects, necessitating vigilance for signs of toxicity.

Antagonistic interactions are noted with α-Adrenergic Blocking Agents. The concurrent use of these agents may diminish the therapeutic effects of the medication, potentially requiring dosage adjustments or alternative therapies to achieve the desired clinical outcomes.

Healthcare professionals should consider these interactions when prescribing this medication and may need to adjust dosages or enhance monitoring protocols based on the specific combinations used.

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

In animal reproductive and developmental studies, decreased fetal body weights were observed at doses of phenylephrine hydrochloride equivalent to 0.4 times the human daily dose (HDD) of 10 mg. While no malformations were reported, there was an increased incidence of agenesis of the intermediate lobe of the lung, a visceral variation, at doses as low as 0.08 times the HDD.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. It is important to note that 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.

In studies involving normotensive pregnant rats, no malformations were noted when treated with intravenous doses of phenylephrine hydrochloride ranging from 50 mcg to 300/200 mcg/kg from Gestation Day 6 to 17, with the highest dose being 0.3/0.2 times the HDD based on body surface area. However, maternal toxicity, including mortality, was observed at the highest tested dose. Similarly, in normotensive pregnant rabbits treated with doses of 40 mcg to 200 mcg/kg from Gestation Day 7 to 19, decreased fetal body weights were reported, along with maternal toxicity indicated by decreased food consumption and body weight gain. An increased incidence of agenesis of the intermediate lobe of the lung was also noted in all treatment groups compared to controls.

No adverse effects on the offspring were reported when pregnant rats were treated with a single daily intravenous bolus dose of up to 200 mcg/day phenylephrine hydrochloride (0.2 times the HDD based on body surface area) from Gestation Day 6 to Lactation Day 20. Given these findings, healthcare professionals should weigh the potential risks and benefits when considering the use of phenylephrine hydrochloride in pregnant patients.

Lactation

There are no reported adverse effects on breastfed infants when lactating mothers are treated with phenylephrine hydrochloride. In animal studies, pregnant rats administered a single daily intravenous bolus dose of up to 200 mcg/day (0.2 times the human equivalent dose based on body surface area) from Gestation Day 6 to Lactation Day 20 did not show any negative outcomes in their offspring.

Healthcare professionals should consider this information when evaluating the use of phenylephrine hydrochloride in lactating mothers.

Renal Impairment

In patients with end stage renal disease (ESRD) undergoing hemodialysis, dose-response data indicates increased responsiveness to phenylephrine. Therefore, it is advisable to consider using lower doses of phenylephrine hydrochloride in this patient population to mitigate the risk of adverse effects associated with heightened sensitivity. Monitoring and dose adjustments are essential for ensuring safe and effective treatment in patients with reduced kidney function.

Hepatic Impairment

In patients with hepatic impairment, particularly those with liver cirrhosis classified under Child Pugh Class A, Class B, and Class C, there is evidence suggesting a decreased responsiveness to phenylephrine. Given this reduced responsiveness, it may be necessary to consider using larger doses than usual in individuals with compromised liver function.

Monitoring of liver function is recommended in these patients to ensure appropriate dosing and to assess any potential adverse effects related to hepatic impairment. Careful evaluation of the patient's clinical status and response to treatment should guide any adjustments in dosing.

Overdosage

In cases of overdose with phenylephrine hydrochloride injection (10 mg/mL), healthcare professionals should be aware that a rapid rise in blood pressure may occur. This hypertensive response can lead to a range of symptoms that require prompt attention.

Symptoms of Overdose Patients experiencing an overdose may present with a variety of symptoms, including headache, vomiting, and significant hypertension. Additionally, reflex bradycardia may be observed, along with cardiac arrhythmias such as ventricular extrasystoles and ventricular tachycardia. Patients may also report a sensation of fullness in the head and tingling in the extremities.

Management of Overdose In the event of an overdose, it is advisable to consider the administration of an α-adrenergic antagonist to mitigate the effects of excessive phenylephrine. Continuous monitoring of the patient's cardiovascular status is essential, and appropriate supportive measures should be implemented as necessary.

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/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 was tested in various assays. It demonstrated negative results in the in vitro bacterial reverse mutation assay using S. typhimurium strains TA98, TA100, TA1535, and TA1537, as well as in the in vitro chromosomal aberrations assay and the in vitro sister chromatid exchange assay. Additionally, the in vivo rat micronucleus assay yielded negative results. However, positive results were observed in one of two replicates of the in vitro mouse lymphoma assay.

Regarding the impairment of fertility, no adverse effects were noted on fertility or early embryonic development when phenylephrine hydrochloride was administered at doses of 50 mcg, 100 mcg, or 200 mcg/kg/day. These doses, which are up to 0.2 times the HDD of 10 mg/60 kg/day based on body surface area, were given via single daily bolus injection for 28 days prior to mating in male rats and for 14 days prior to mating through Gestation Day 7 in female rats.

Postmarketing Experience

Postmarketing experience has identified several adverse events associated with the use of phenylephrine, reported voluntarily or through surveillance programs. The primary side effect noted is hypertension, which may, in rare instances, escalate to a hypertensive crisis. Additionally, bradycardia has been observed, with some cases leading to heart block or other cardiac arrhythmias.

Other reported events include extra ventricular beats, myocardial ischemia in patients with pre-existing cardiac conditions, and pulmonary edema, which may present as fluid accumulation in the lungs or rales.

Common, less serious symptoms reported include chest pain, skin or tissue damage resulting from extravasation of the drug from the venous catheter, headache, nervousness, tremor, and paresthesias (numbness or tingling) in the extremities. Gastrointestinal symptoms such as nausea and vomiting, along with excitability, dizziness, sweating, and flushing, have also been documented.

Patient Counseling

Healthcare providers should inform patients, families, or caregivers that the primary side effect of phenylephrine is hypertension, which may, in rare cases, lead to a hypertensive crisis. It is important to discuss the potential for bradycardia, which can result in heart block or other cardiac arrhythmias, as well as extra ventricular beats, myocardial ischemia in patients with pre-existing cardiac conditions, and pulmonary edema or rales.

Patients should be made aware of common, less serious symptoms that may occur, including chest pain, which could indicate complications. Providers should also explain the risk of skin or tissue damage if the medication leaks from the venous catheter into surrounding tissues. Other symptoms to discuss include headache, nervousness, tremor, and numbness or tingling (paresthesias) in the hands or feet. Additionally, patients may experience nausea, vomiting, excitability, dizziness, sweating, and flushing.

It is essential for healthcare providers to ensure that patients understand these potential side effects and symptoms, encouraging them to report any concerning changes or reactions during treatment.

Storage and Handling

The product is supplied in a configuration that allows for single use only. It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as defined by USP Controlled Room Temperature guidelines.

To ensure product integrity, it must be protected from light and kept covered in its original carton until the time of use. Any unused portion should be discarded to maintain 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 Fresenius Kabi USA, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)