Biorphen

Description

Phenylephrine is an alpha-1 adrenergic receptor agonist. The chemical name of phenylephrine hydrochloride is (-)-m-hydroxy-α-(methylamino)methylbenzyl alcohol hydrochloride, with a molecular formula of C9H13NO2 · HCl and a molecular weight of 203.67 g/mol. Phenylephrine hydrochloride is soluble in water and ethanol, but insoluble in chloroform and ethyl ether.

BIORPHEN (phenylephrine hydrochloride) injection is available in two concentrations: 0.1 mg/mL and 10 mg/mL. The 0.1 mg/mL formulation is a sterile, nonpyrogenic, clear and colorless solution intended for intravenous use and must not be diluted prior to administration as an intravenous bolus. Each mL contains 0.1 mg of phenylephrine hydrochloride (equivalent to 0.08 mg of phenylephrine base) and 9.0 mg of sodium chloride in water for injection. The pH is adjusted with hydrochloric acid if necessary, maintaining a range of 3.0 to 5.0.

The 10 mg/mL formulation is also a sterile, nonpyrogenic, clear and colorless solution for intravenous use, but it must be diluted before administration, either as an intravenous bolus or for continuous intravenous infusion. Each mL contains 10 mg of phenylephrine hydrochloride (equivalent to 8.2 mg of phenylephrine base) and 6.0 mg of sodium chloride in water for injection, with the pH similarly adjusted to a range of 3.0 to 5.0.

Uses and Indications

BIORPHEN 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 BIORPHEN injection.

Dosage and Administration

BIORPHEN 0.1 mg/mL injection is supplied as a ready-to-use formulation and must not be diluted prior to administration. It is intended for intravenous bolus administration.

For the treatment of hypotension during anesthesia, the recommended dosing for bolus intravenous injection is as follows: an initial dose of 40 mcg to 100 mcg may be administered. Additional boluses of up to 200 mcg can be given every 1 to 2 minutes as necessary, with the dose adjusted according to the pressor response, titrating to effect.

For BIORPHEN 10 mg/mL injection, which requires dilution before administration, the following dosing guidelines apply:

• Bolus intravenous injection: The initial dose is the same as for the 0.1 mg/mL formulation, ranging from 40 mcg to 100 mcg, with additional boluses of up to 200 mcg every 1 to 2 minutes as needed, titrating to effect based on the pressor response.

• Continuous intravenous infusion: The infusion rate should be set between 10 mcg/min to 35 mcg/min, with titration to effect. The infusion rate must not exceed 200 mcg/min.

Healthcare professionals should ensure proper preparation and administration techniques are followed to achieve the desired therapeutic outcomes.

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

BIORPHEN has several critical warnings and precautions that healthcare professionals must consider when prescribing and administering this medication.

Exacerbation of Angina, Heart Failure, or Pulmonary Arterial Hypertension BIORPHEN may precipitate angina in patients with severe arteriosclerosis or a history of angina. It is important to monitor patients for signs of exacerbation of underlying heart failure and increased pulmonary arterial pressure, as these conditions may worsen with the use of this medication.

Peripheral and Visceral Ischemia The administration of BIORPHEN can lead to excessive peripheral and visceral vasoconstriction, resulting in ischemia to vital organs. Clinicians should be vigilant in assessing patients for symptoms indicative of ischemia and consider appropriate interventions if such symptoms arise.

Skin and Subcutaneous Necrosis Extravasation during intravenous administration of BIORPHEN may result in necrosis or sloughing of tissue. It is essential to ensure proper intravenous technique and to monitor the injection site closely for any signs of extravasation.

Bradycardia BIORPHEN has the potential to cause severe bradycardia and decreased 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 to implement appropriate monitoring strategies to ensure patient safety during the use of BIORPHEN.

Side Effects

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

Common adverse reactions reported include nausea, vomiting, and headache. These reactions are generally mild but should be monitored in patients.

Serious adverse reactions associated with BIORPHEN 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, BIORPHEN may lead to excessive peripheral and visceral vasoconstriction, resulting in ischemia to vital organs.

Skin and subcutaneous necrosis has been observed in cases of extravasation during intravenous administration, which may cause necrosis or sloughing of tissue. Furthermore, severe bradycardia and decreased cardiac output have been reported, necessitating careful monitoring of cardiac function in patients.

In the event of an overdose, symptoms may include 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 such as ventricular extrasystoles and ventricular tachycardia. These symptoms highlight the importance of adhering to prescribed dosages and monitoring patients closely for signs of overdose.

Drug Interactions

Agonistic interactions that may enhance the blood pressure effect of BIORPHEN 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 BIORPHEN.

• Tricyclic Antidepressants: The combination may result in elevated blood pressure.

• Angiotensin and Aldosterone: These substances can contribute to increased blood pressure when used with BIORPHEN.

• Atropine: This anticholinergic agent may enhance the blood pressure response.

• Steroids: Corticosteroids can lead to increased blood pressure when administered concurrently.

• Norepinephrine Transporter Inhibitors: These drugs may augment the hypertensive effects of BIORPHEN.

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

Conversely, antagonistic interactions that may diminish the blood pressure effect of BIORPHEN include:

• α-Adrenergic Antagonists: These agents can reduce the hypertensive response to BIORPHEN.

• Phosphodiesterase Type 5 Inhibitors: The use of these medications may lead to a decrease in blood pressure effects.

• Mixed α- and β-Receptor Antagonists: Co-administration may result in reduced blood pressure response.

• Calcium Channel Blockers: These drugs can antagonize the blood pressure effects of BIORPHEN.

• Benzodiazepines: The sedative effects may counteract the hypertensive response.

• ACE Inhibitors: These agents may lead to a decrease in blood pressure effects when used with BIORPHEN.

• Centrally Acting Sympatholytic Agents: Co-administration may result in diminished blood pressure response.

Monitoring of blood pressure is advised when BIORPHEN is used in conjunction with any of the aforementioned agents, and dosage adjustments may be necessary based on the clinical response.

Packaging & NDC

The table below lists all NDC Code configurations of Biorphen (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, as there is insufficient data to support its use in these populations.

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 is 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 for cesarean section 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 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 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 via continuous intravenous infusion from Gestation Day 6 to 17. 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. 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 breastfed infants or on milk production.

The developmental and health benefits of breastfeeding should be weighed against 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 considered.

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, dose-response data indicate a decreased responsiveness to phenylephrine. Therefore, while it is recommended to initiate dosing 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 efficacy and safety.

Overdosage

In the event of an overdose of BIORPHEN (phenylephrine hydrochloride), healthcare professionals should be aware that a significant increase in blood pressure may occur. This hypertensive response can lead to a range of symptoms that require immediate attention.

Symptoms of Overdose Patients experiencing an overdose may present with various 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 manifest as ventricular extrasystoles and ventricular tachycardia

Management Procedures In cases of suspected overdose, it is crucial to monitor the patient's vital signs closely, particularly blood pressure and heart rate. Immediate medical intervention may be necessary to manage hypertension and any associated cardiac arrhythmias. Supportive care should be provided as needed, and specific treatment protocols should be followed based on the severity of the symptoms presented.

Healthcare professionals are advised to consult relevant clinical guidelines and consider contacting a poison control center for further assistance in managing overdose cases effectively.

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, also showed no signs of carcinogenicity.

In terms of mutagenesis, phenylephrine hydrochloride demonstrated a negative outcome 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 the 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 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. Although this dose was associated with increased mortality in both male and female rats and decreased body weight gain in treated males, it did not impair reproductive performance. Notably, 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, and tissue necrosis at the injection site.

Additional safety information from postmarketing experience includes reports of severe allergic reactions, cardiac arrest, and ischemic events. It is important to monitor patients for these adverse reactions during and after the administration of BIORPHEN.

Patient Counseling

Healthcare providers should inform patients, as well as their family members or caregivers, that certain medical conditions and medications may affect the efficacy of BIORPHEN injection. It is important to discuss any pre-existing health issues or ongoing treatments that the patient is undergoing, as these factors could influence the response to the medication. Encouraging open communication about the patient's complete medical history will help ensure safe and effective use of BIORPHEN injection.

Storage and Handling

BIORPHEN (phenylephrine hydrochloride) injection is supplied in a manner that ensures optimal storage and handling. It 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) in accordance with USP Controlled Room Temperature guidelines.

Healthcare professionals are advised to discard any unused portion of the injection 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 Biorphen as submitted by Eton Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)