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 Injection is available in two formulations for intravenous use. The first formulation contains 500 mcg of phenylephrine hydrochloride per 5 mL (100 mcg/mL), equivalent to 80 mcg of phenylephrine base, and includes sodium chloride 9.0 mg in water for injection. The second formulation contains 10 mg of phenylephrine hydrochloride per mL (equivalent to 8.2 mg of phenylephrine base) and includes sodium chloride 6.0 mg in water for injection. Both formulations are sterile, nonpyrogenic, clear, and colorless solutions, with the pH adjusted with hydrochloric acid as necessary, maintaining a pH 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 500 mcg/5 mL (100 mcg/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 following dosing guidelines apply:

• Bolus Intravenous Injection: The initial dose is 40 mcg to 100 mcg. Additional boluses of up to 200 mcg may be administered every 1 to 2 minutes as needed. The dose should be adjusted according to the pressor response, titrating to effect.

• Biorphen 10 mg/mL Only: This formulation must be diluted before administration, either for intravenous bolus or continuous intravenous infusion to achieve the desired concentration. For continuous intravenous infusion, the dosing range is 10 mcg/min to 35 mcg/min, with titration to effect. The infusion rate must not exceed 200 mcg/min.

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 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 monitor the injection site closely to prevent this adverse effect.

Bradycardia Severe bradycardia and decreased cardiac output have been associated with BIORPHEN. 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 mitigate risks associated with the use of BIORPHEN.

Side Effects

Patients receiving BIORPHEN may experience a range of adverse reactions, which can be categorized into common and serious events.

Common adverse reactions reported include nausea, vomiting, and headache. These reactions are typically mild and may resolve without the need for medical intervention.

Serious side effects 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 as serious adverse reactions.

In the event of an 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.

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

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

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 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 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 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 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. An increase in limb malformation incidence 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 in normotensive pregnant rats treated with up to 3 mg/kg/day of phenylephrine, although some maternal toxicity was noted at this dose. 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.

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, there is evidence suggesting a decreased responsiveness to phenylephrine. Consequently, 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 optimal dosing and efficacy.

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 assessed 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, 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 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 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. Nonetheless, 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 the following adverse reactions reported voluntarily or through surveillance programs: hypertension, bradycardia, and arrhythmias. These events have been documented in the context of routine pharmacovigilance activities.

Patient Counseling

Healthcare providers should inform patients, 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. Providers should encourage patients to provide a comprehensive medical history and to disclose all medications they are currently taking, including over-the-counter drugs and supplements. This dialogue will help ensure safe and effective use of BIORPHEN injection.

Storage and Handling

BIORPHEN (phenylephrine hydrochloride) injection is supplied in a manner that ensures its integrity and efficacy. 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 product to maintain safety and effectiveness.

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 Dr. Reddy's Laboratories Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)