Vazculep

Description

Phenylephrine is an α-1 adrenergic receptor agonist. VAZCULEP (phenylephrine hydrochloride) Injection is formulated as a clear, colorless, sterile, nonpyrogenic solution for intravenous use, with a concentration of 10 mg/mL. 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)methylbenzyl alcohol hydrochloride, with a chemical designation of C9H14ClNO2 and a molecular weight of 203.66 g/mol. The structural formula is provided below. Phenylephrine hydrochloride is soluble in water and ethanol, while being insoluble in chloroform and ethyl ether.

VAZCULEP Injection is sensitive to light and each mL contains the following components: 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

VAZCULEP 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 VAZCULEP.

Dosage and Administration

VAZCULEP injection is administered intravenously, either as a bolus 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.

It is essential to adjust the dose according to the pressor response, 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, the product can be used without specific restrictions related to contraindications.

Warnings and Precautions

VAZCULEP has several critical warnings and precautions that healthcare professionals must consider to ensure patient safety.

Exacerbation of Angina, Heart Failure, or Pulmonary Arterial Hypertension VAZCULEP may precipitate angina in patients with severe arteriosclerosis or a history of angina. It is also known to exacerbate underlying heart failure and can lead to increased pulmonary arterial pressure. Close monitoring of patients with these conditions is essential.

Peripheral and Visceral Ischemia The administration of VAZCULEP can result in excessive peripheral and visceral vasoconstriction, potentially causing ischemia to vital organs. Healthcare providers should be vigilant in assessing patients for signs of ischemia during treatment.

Skin and Subcutaneous Necrosis Extravasation during intravenous administration of VAZCULEP may lead to necrosis or sloughing of tissue. It is crucial to ensure proper intravenous technique and monitor the injection site closely to prevent this adverse effect.

Bradycardia VAZCULEP has the potential to induce severe bradycardia and decrease cardiac output. Continuous cardiac monitoring is recommended for patients receiving this medication, particularly those with pre-existing cardiac conditions.

Healthcare professionals are advised to remain alert to these warnings and take appropriate measures to monitor and manage any adverse effects associated with VAZCULEP.

Side Effects

Patients receiving VAZCULEP may experience a range of adverse reactions, which can be categorized by their seriousness and frequency.

The most common adverse reactions reported include nausea, vomiting, and headache. These reactions are typically mild to moderate in severity.

Serious adverse reactions associated with VAZCULEP include exacerbation of angina, heart failure, or pulmonary arterial hypertension. The medication can precipitate angina in patients with severe arteriosclerosis or a history of angina, exacerbate underlying heart failure, and increase pulmonary arterial pressure. Additionally, VAZCULEP may lead to excessive peripheral and visceral vasoconstriction, resulting in ischemia to vital organs.

Other serious reactions include skin and subcutaneous necrosis, which may occur due to extravasation during intravenous administration, potentially causing necrosis or sloughing of tissue. Severe bradycardia and decreased cardiac output have also been observed in patients treated with VAZCULEP.

In cases of overdose, patients may present with a rapid rise in blood pressure, headache, vomiting, hypertension, reflex bradycardia, a sensation of fullness in the head, tingling of the extremities, and cardiac arrhythmias, including ventricular extrasystoles and ventricular tachycardia.

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

Drug Interactions

Agonistic interactions that may enhance the blood pressure effect of VAZCULEP have been observed with several drug classes. These include monoamine oxidase inhibitors (MAOIs), oxytocin and oxytocic drugs, tricyclic antidepressants, angiotensin and aldosterone, atropine, steroids, norepinephrine transporter inhibitors, and ergot alkaloids. Clinicians should monitor blood pressure closely when VAZCULEP is administered concurrently with these agents, as dosage adjustments may be necessary based on the patient's response.

Conversely, antagonistic interactions that may diminish the blood pressure effect of VAZCULEP can occur with α-adrenergic antagonists, phosphodiesterase Type 5 inhibitors, mixed α- and β-receptor antagonists, calcium channel blockers, benzodiazepines, ACE inhibitors, and centrally acting sympatholytic agents. It is advisable to assess blood pressure regularly in patients receiving VAZCULEP alongside these medications, and consider dosage modifications if a significant reduction in blood pressure is noted.

Packaging & NDC

The table below lists all NDC Code configurations of Vazculep (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 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 demonstrated no 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 coincided with high fetal mortality at a dose of 0.6 mg/kg/day 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. This treatment was associated with some maternal toxicity, including decreased food consumption and body weights. 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. 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 occurred at doses of 1 and 3 mg/kg/day, which were equivalent to and 2.9 times the HDD, respectively.

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.

The developmental and health benefits of breastfeeding should be considered alongside the clinical need for VAZCULEP in lactating mothers, as well as any potential adverse effects on the breastfed infant resulting from VAZCULEP or from the underlying maternal condition.

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 dose 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 the event of an overdose of VAZCULEP, healthcare professionals should be aware that a rapid rise in blood pressure may occur.

Symptoms of Overdose Patients experiencing an overdose may present with 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 Prompt recognition and management of these symptoms are crucial. Healthcare providers should monitor the patient's vital signs closely and initiate appropriate interventions to manage hypertension and any arrhythmias that may arise. Supportive care should be provided as necessary, and further treatment should be guided by the clinical presentation and severity of symptoms.

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 findings 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 evidence of carcinogenicity.

Phenylephrine hydrochloride was tested in various in vitro and in vivo assays for mutagenicity. The compound tested negative 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, it was negative in 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

Postmarketing experience has identified several adverse reactions associated with the use of the product. These include hypotension, bradycardia, and arrhythmias. Additional adverse reactions reported include headache, nausea, vomiting, and anxiety.

Severe allergic reactions, including anaphylaxis, have been documented. Cases of extravasation leading to tissue necrosis have also been reported. Some patients experienced elevated blood pressure and tachycardia. Furthermore, reports of visual disturbances, such as blurred vision and transient blindness, have been noted. Instances of pulmonary edema have been observed in patients receiving high doses.

Patient Counseling

Healthcare providers should inform patients, family members, or caregivers that certain medical conditions and medications may affect the efficacy of VAZCULEP (phenylephrine hydrochloride) Injection. It is important 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 should encourage patients to disclose their complete medical history and any other medications they are currently taking to ensure safe and effective use of VAZCULEP.

Storage and Handling

VAZCULEP (phenylephrine hydrochloride) Injection, 10 mg/mL is supplied in 1 mL vials intended for single use, as well as in 5 mL and 10 mL vials designated as pharmacy bulk packages.

This 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 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 Vazculep as submitted by Exela Phrama Sciences, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)