BIORPHEN- phenylephrine hydrochloride injection, solution

Biorphen by

Drug Labeling and Warnings

Biorphen by is a Prescription medication manufactured, distributed, or labeled by Eton Pharmaceuticals, Inc., SINTETICA SA, SINTETICA-BIOREN SA. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    BIORPHEN is indicated for the treatment of clinically important hypotension resulting primarily from vasodilation in the setting of anesthesia.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 General Dosage and Administration Instructions

    BIORPHEN MUST NOT BE DILUTED before administration as an intravenous bolus. It is supplied as READY-TO-USE formulation.

    During BIORPHEN administration:

    • Correct intravascular volume depletion.
    • Correct acidosis. Acidosis may reduce the effectiveness of phenylephrine.

    Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if the solution is colored or cloudy, or if it contains particulate matter. Discard any unused portion.

    2.2 Dosing for Treatment of Hypotension during Anesthesia

    The following are the recommended dosages for the treatment of hypotension during anesthesia.

    • The recommended initial dose is 40 to 100 mcg administered by intravenous bolus. Additional boluses may be administered every 1-2 minutes as needed; not to exceed a total dosage of 200 mcg.
    • Adjust dosage according to the blood pressure goal.
  • 3 DOSAGE FORMS AND STRENGTHS

    BIORPHEN (phenylephrine hydrochloride) injection USP, 0.1 mg/mL, for intravenous use, is a clear and colorless solution available in a type I one point cut, clear, colorless glass, 5 mL single-dose ampule containing 5 mL of solution for injection, corresponding to 0.5 mg of phenylephrine hydrochloride per ampule, equivalent to 0.41 mg of phenylephrine base.

  • 4 CONTRAINDICATIONS

    None

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Exacerbation of Angina, Heart Failure, or Pulmonary Arterial Hypertension

    Because of its increasing blood pressure effects, BIORPHEN can precipitate angina in patients with severe arteriosclerosis or history of angina, exacerbate underlying heart failure, and increase pulmonary arterial pressure.

    5.2 Peripheral and Visceral Ischemia

    BIORPHEN can cause excessive peripheral and visceral vasoconstriction and ischemia to vital organs, particularly in patients with extensive peripheral vascular disease.

    5.3 Skin and Subcutaneous Necrosis

    Extravasation of BIORPHEN can cause necrosis or sloughing of tissue. Avoid extravasation by checking infusion site for free flow.

    5.4 Bradycardia

    BIORPHEN can cause severe bradycardia and decreased cardiac output.

    5.5 Renal Toxicity

    BIORPHEN can increase the need for renal replacement therapy in patients with septic shock. Monitor renal function.

    5.6 Risk of Augmented Pressor Affect in Patients with Autonomic Dysfunction

    The increasing blood pressure response to adrenergic drugs, including BIORPHEN, can be increased in patients with autonomic dysfunction, as may occur with spinal cord injuries.

    5.7 Pressor Effect with Concomitant Oxytocic Drugs

    Oxytocic drugs potentiate the increasing blood pressure effect of sympathomimetic pressor amines including BIORPHEN [see Drug Interactions (7.1)], with the potential for hemorrhagic stroke.

  • 6 ADVERSE REACTIONS

    Adverse reactions to BIORPHEN are primarily attributable to excessive pharmacologic activity. Adverse reactions reported in published clinical studies, observational trials, and case reports of BIORPHEN are listed below by body system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.

    Cardiac disorders: Reflex bradycardia, lowered cardiac output, ischemia, hypertension, arrhythmias

    Gastrointestinal disorders: Epigastric pain, vomiting, nausea

    Nervous system disorders: Headache, blurred vision, neck pain, tremors

    Vascular disorders: Hypertensive crisis

    Respiratory, Thoracic and Mediastinal Disorders: Dyspnea

    Skin and subcutaneous tissue disorders: Pruritis

  • 7 DRUG INTERACTIONS

    7.1 Interactions that Augment Pressor Effect

    The increasing blood pressure effect of BIORPHEN is increased in patients receiving:

    • Monoamine oxidase inhibitors (MAOI)
    • Oxytocin and oxytocic drugs
    • Tricyclic antidepressants
    • Angiotensin, aldosterone
    • Atropine
    • Steroids, such as hydrocortisone
    • Norepinephrine transporter inhibitors, such as atomoxetine
    • Ergot alkaloids, such as methylergonovine maleate

    7.2 Interactions that Antagonize the Pressor Effect

    The increasing blood pressure effect of BIORPHEN is decreased in patients receiving:

    • α-adrenergic antagonists
    • Phosphodiesterase Type 5 inhibitors
    • Mixed α- and β-receptor antagonists
    • Calcium channel blockers, such as nifedipine
    • Benzodiazepines
    • ACE inhibitors
    • Centrally acting sympatholytic agents, such as reserpine, guanfacine
  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    Data from randomized controlled trials and meta-analyses with phenylephrine hydrochloride injection use in pregnant women during caesarean section have not established a drug-associated risk of major birth defects and miscarriage. These studies have not identified an adverse effect on maternal outcomes or infant Apgar scores [see Data]. There are no data on the use of phenylephrine during the first or second trimester. In animal reproduction and development studies in normotensive animals, evidence of fetal malformations was noted when phenylephrine was administered during organogenesis via a 1-hour infusion at 1.2 times the human daily dose (HDD) of 10 mg/60 kg/day. Decreased pup weights were noted in offspring of pregnant rats treated with 2.9 times the HDD [See Data].

    The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, 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 2-4% and 15-20%, respectively.

    Clinical Considerations

    Disease-Associated Maternal and/or Embryofetal Risk

    Untreated hypotension associated with spinal anesthesia for cesarean section is associated with an increase in maternal nausea and vomiting. A sustained decrease in uterine blood flow due to maternal hypotension may result in fetal bradycardia and acidosis.

    Data

    Human Data

    Published randomized controlled trials over several decades, which compared the use of phenylephrine injection to other similar agents in pregnant women during cesarean section, have not identified adverse maternal or infant outcomes. At recommended doses, phenylephrine does not appear to affect fetal heart rate or fetal heart variability to a significant degree.

    There are no studies on the safety of phenylephrine injection exposure during the period of organogenesis, and therefore, it is not possible to draw any conclusions on the risk of birth defects following exposure to phenylephrine injection during pregnancy. In addition, there are no data on the risk of miscarriage following fetal exposure to phenylephrine injection.

    Animal Data

    No clear malformations or fetal toxicity were reported when normotensive pregnant rabbits were treated with phenylephrine via continuous intravenous infusion over 1 hour (0.5 mg/kg/day; approximately equivalent to a HDD based on body surface area) from Gestation Day 7 to 19. At this dose, which demonstrated no maternal toxicity, there was evidence of developmental delay (altered ossification of sternebra).

    In a non-GLP dose range-finding study in normotensive pregnant rabbits, fetal lethality and cranial, paw, and limb malformations were noted following treatment with 1.2 mg/kg/day of phenylephrine via continuous intravenous infusion over 1 hour (2.3-times the HDD). This dose was clearly maternally toxic (increased mortality and significant body weight loss). An increase in the incidence of limb malformation (hyperextension of the forepaw) coincident with high fetal mortality was noted in a single litter at 0.6 mg/kg/day (1.2-times the HDD) 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 phenylephrine via continuous intravenous infusion over 1 hour (2.9-times the HDD) from Gestation Day 6 to 17. This dose was associated with some maternal toxicity (decreased food consumption and body weights).

    Decreased pup weights were reported in a pre- and postnatal development toxicity study in which normotensive pregnant rats were administered phenylephrine via continuous intravenous infusion over 1 hour (0.3, 1.0, or 3.0 mg/kg/day; 0.29, 1, or 2.9 times the HDD) from Gestation Day 6 through Lactation Day 21). No adverse effects on growth and development (learning and memory, sexual development, and fertility) were noted in the offspring of pregnant rats at any dose tested. Maternal toxicities (mortality late in gestation and during lactation period, decreased food consumption and body weight) occurred at 1 and 3 mg/kg/day of phenylephrine (equivalent to and 2.9 times the HDD, respectively).

    8.2 Lactation

    Risk summary

    There are no data on the presence of Phenylephrine Hydrochloride Injection or its metabolite in human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for phenylephrine hydrochloride injection and any potential adverse effects on the breastfed infant from phenylephrine hydrochloride injection or from the underlying maternal condition.

    8.4 Pediatric Use

    Safety and effectiveness in pediatric patients have not been established.

    8.5 Geriatric Use

    Clinical studies of phenylephrine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

    8.6 Hepatic Impairment

    In patients with liver cirrhosis [Child Pugh Class B and Class C], dose-response data indicate decreased responsiveness to phenylephrine. Start dosing in the recommended dose range but more phenylephrine may be needed in this population.

    8.7 Renal Impairment

    In patients with end stage renal disease (ESRD), dose-response data indicate increased responsiveness to phenylephrine. Consider starting at the lower end of the recommended dose range, and adjusting dose based on the target blood pressure goal.

  • 10 OVERDOSAGE

    Overdose of BIORPHEN (phenylephrine hydrochloride) can cause a rapid rise in blood pressure. Symptoms of overdose include 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.

  • 11 DESCRIPTION

    Phenylephrine is an alpha-1 adrenergic receptor agonist. BIORPHEN (phenylephrine hydrochloride) injection, 0.1 mg/mL, is a sterile, nonpyrogenic, clear and colorless solution for intravenous use. It MUST NOT BE DILUTED before administration as an intravenous bolus. The chemical name of phenylephrine hydrochloride is (-)-m-hydroxy-α-[(methylamino) methyl] benzyl alcohol hydrochloride, its molecular formula is C9H13NO2· HCl (Molecular Weight: 203.67) and its structural formula is depicted below:

    Chemical Structure

    Phenylephrine hydrochloride is soluble in water and ethanol, and insoluble in chloroform and ethyl ether.

    Each mL contains: phenylephrine hydrochloride 0.1 mg (equivalent to 0.08 mg of phenylephrine base), sodium chloride 9.0 mg, in water for injection. The pH is adjusted with hydrochloric acid if necessary. The pH range is 3.0 -5.0.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Phenylephrine hydrochloride is an α-1 adrenergic receptor agonist.

    12.2 Pharmacodynamics

    Interaction of phenylephrine with α-1 adrenergic receptors on vascular smooth muscle cells causes activation of the cells and results in vasoconstriction. Following phenylephrine hydrochloride intravenous administration, increases in systolic and diastolic blood pressures, mean arterial blood pressure, and total peripheral vascular resistance are observed. The onset of blood pressure increase following an intravenous bolus phenylephrine hydrochloride administration is rapid, typically within minutes. As blood pressure increases following intravenous administration, vagal activity also increases, resulting in reflex bradycardia. Phenylephrine has activity on most vascular beds, including renal, pulmonary, and splanchnic arteries.

    12.3 Pharmacokinetics

    Following an intravenous infusion of phenylephrine hydrochloride, the observed effective half-life was approximately 5 minutes. The steady-state volume of distribution of approximately 340 L suggests a high distribution into organs and peripheral tissues. The average total serum clearance is approximately 2100 mL/min. The observed phenylephrine plasma terminal elimination half-life was 2.5 hours.

    Phenylephrine is metabolized primarily by monoamine oxidase and sulfotransferase. After intravenous administration of radiolabeled phenylephrine, approximately 80% of the total dose was eliminated within first 12 h; and approximately 86% of the total dose was recovered in the urine within 48 h.

    The excreted unchanged parent drug was 16% of the total dose in the urine at 48 h post intravenous administration. There are two major metabolites, with approximately 57 and 8% of the total dose excreted as m-hydroxymandelic acid and sulfate conjugates, respectively. The metabolites are considered not pharmacologically active.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenesis: Long-term animal studies that evaluated the carcinogenic potential of orally administered phenylephrine hydrochloride in F344/N rats and B6C3F1 mice were completed by the National Toxicology Program using the dietary route of administration. There was no evidence of carcinogenicity in mice administered approximately 270 mg/kg/day (131 times the human daily dose (HDD) of 10 mg/60 kg/day based on body surface area) or rats administered approximately 50 mg/kg/day (48 times the HDD).

    Mutagenesis: Phenylephrine hydrochloride tested negative in the in vitro bacterial reverse mutation assay (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. Positive results were reported in only one of two replicates of the in vitro mouse lymphoma assay.

    Impairment of Fertility: Phenylephrine did not impair mating, fertility, or reproductive outcome in normotensive male rats treated with 3 mg/kg/day phenylephrine 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 and female rats treated with the same dosing regimen for 14 days prior to mating and through Gestation Day 6. This dose was associated with increased mortality in both male and female rats and decreased body weight gain in treated males. There were decreased caudal sperm density and increased abnormal sperm reported in males treated with 3 mg/kg/day phenylephrine (2.9 times the HDD).

  • 14 CLINICAL STUDIES

    The evidence for the efficacy of BIORPHEN, is derived from studies of phenylephrine hydrochloride in the published literature. The literature support includes 16 studies evaluating the use of intravenous phenylephrine to treat hypotension during anesthesia. The 16 studies include 9 studies where phenylephrine was used in low-risk (ASA 1 and 2) pregnant women undergoing neuraxial anesthesia during Cesarean delivery, 6 studies in non-obstetric surgery under general anesthesia, and 1 study in non-obstetric surgery under combined general and neuraxial anesthesia. Phenylephrine has been shown to raise systolic and mean blood pressure when administered either as a bolus dose or by continuous infusion following the development of hypotension during anesthesia.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    BIORPHEN (phenylephrine hydrochloride) injection USP, 0.1 mg/mL, for intravenous use, is a clear and colorless solution supplied as follows:

    Unit of SaleStrengthEach
    NDC No.71863-202-06
    pack of 10 ampules    		0.1 mg/mLNDC No. 71863-202-05
    5 mL ampule; for single use

    Store BIORPHEN (phenylephrine hydrochloride) injection USP, 0.1 mg/mL at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. The 5 mL ampule is for single use only.

    Discard any unused portion.

  • 17 PATIENT COUNSELING INFORMATION

    If applicable, inform patient, family member, or caregiver that certain medical conditions and medications might influence how BIORPHEN injection works.

  • SPL UNCLASSIFIED SECTION

    Manufactured for:
    Eton Pharmaceuticals, Inc.
    Deer Park, IL 60010
    USA
    Rev. 10/19

  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL - BIORPHEN (Phenylephrine Hydrochloride) Injection, USP 0.1 mg/ml Ampoule Label - NDC: 71863-202-05

    BIORPHEN (Phenylephrine Hydrochloride) Injection, USP 0.1 mg/ml Ampoule Label - NDC: <a href=/NDC/71863-202-05>71863-202-05</a>

    PRINCIPAL DISPLAY PANEL - BIORPHEN (Phenylephrine Hydrochloride) Injection, USP 0.1 mg/ml Ampoule Carton (10 Single Dose Ampules) - NDC: 71863-202-06

    BIORPHEN (Phenylephrine Hydrochloride) Injection, USP 0.1 mg/ml Ampoule Carton (10 Single Dose Ampules) - NDC: <a href=/NDC/71863-202-06>71863-202-06</a>
  • INGREDIENTS AND APPEARANCE
    BIORPHEN 
    phenylephrine hydrochloride injection, solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 71863-202
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    PHENYLEPHRINE HYDROCHLORIDE (UNII: 04JA59TNSJ) (PHENYLEPHRINE - UNII:1WS297W6MV) PHENYLEPHRINE HYDROCHLORIDE0.1 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    SODIUM CHLORIDE (UNII: 451W47IQ8X) 9 mg  in 1 mL
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    WATER (UNII: 059QF0KO0R)  
    NITROGEN (UNII: N762921K75)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 71863-202-0610 in 1 CARTON11/01/2019
    1NDC: 71863-202-055 mL in 1 AMPULE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA21290911/01/2019
    Labeler - Eton Pharmaceuticals, Inc. (080870465)
    Registrant - Eton Pharmaceuticals, Inc. (080870465)
    Establishment
    NameAddressID/FEIBusiness Operations
    SINTETICA SA480895478MANUFACTURE(71863-202) , ANALYSIS(71863-202) , LABEL(71863-202) , PACK(71863-202)
    Establishment
    NameAddressID/FEIBusiness Operations
    SINTETICA-BIOREN SA483148768ANALYSIS(71863-202)

    • Trademark Results [Biorphen]

    Mark Image

    Registration | Serial
    Company
    Trademark
    Application Date
    BIORPHEN
    BIORPHEN
    79221555 not registered Live/Pending
    Sintetica S.A.
    2017-08-30
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