Biorphen

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.

BIORPHEN 0.1 mg/mL and 10 mg/mL Injection have important differences in administration instructions:

Administration Instructions for BIORPHEN 0.1 mg/mL Injection:

BIORPHEN 0.1 mg/mL injection MUST NOT BE DILUTED before administration as an intravenous bolus. It is supplied as READY-TO-USE formulation.

Administration Instructions for BIORPHEN 10 mg/mL Injection:

BIORPHEN 10 mg/mL injection MUST BE DILUTED before administration as an intravenous bolus or continuous intravenous infusion to achieve the desired concentration:

    •  Bolus: Dilute with normal saline or 5% dextrose in water.
    •  Continuous infusion: Dilute with normal saline or 5% dextrose in water.

The diluted solution should not be held for more than 4 hours at room temperature or for more than 24 hours under refrigerated conditions.

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

BIORPHEN 0.1 mg/mL Injection:

• The recommended initial dose is 40 mcg to 100 mcg administered by intravenous bolus. Additional boluses up to 200 mcg may be administered every 1 to 2 minutes as needed.
• Adjust dosage according to the blood pressure goal.

BIORPHEN 10 mg/mL Injection:
    •  The recommended initial dose is 40 mcg to 100 mcg administered by intravenous bolus. Additional boluses up to 200 mcg may be administered every 1 to 2 minutes as needed.
    •  If blood pressure is below the target goal, start a continuous intravenous infusion with an infusion rate of 10 mcg/minute to 35 mcg/minute; not to exceed 200 mcg/minute.
    •  Adjust dosage according to the blood pressure goal.

For bolus intravenous administration, prepare a solution containing a final concentration of 100 mcg/mL of BIORPHEN 10 mg/mL Injection:

    •  Withdraw 10 mg i.e. 1 mL of BIORPHEN 10 mg/mL Injection and dilute with 99 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP.
    •  Withdraw an appropriate dose from the 100 mcg/mL solution prior to bolus intravenous administration.

For continuous intravenous infusion, prepare a solution containing a final concentration of 20 mcg/mL of BIORPHEN 10 mg/mL Injection in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP.

    •  Withdraw 10 mg i.e. 1 mL of BIORPHEN 10 mg/mL Injection and dilute with 500 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP.

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.

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

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

BIORPHEN can cause severe bradycardia and decreased cardiac output.

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

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.

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.

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

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

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.

Safety and effectiveness in pediatric patients have not been established.

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.

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.

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.

Phenylephrine hydrochloride is an α-1 adrenergic receptor agonist.

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.

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.

Store BIORPHEN (phenylephrine hydrochloride) injection 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].

Discard any unused portion.