PHENYLEPHRINE HYDROCHLORIDE

Phenylephrine is an alpha-1 adrenergic receptor agonist. Phenylephrine hydrochloride injection USP, 10 mg/mL, is a clear, colorless, sterile, nonpyrogenic solution for intravenous use. It must be diluted before administration as an intravenous bolus or continuous intravenous infusion. The chemical name of phenylephrine hydrochloride is (-)- m -hydroxy-α-[(methylamino)methyl]benzyl alcohol hydrochloride, and its structural formula is depicted below: Phenylephrine hydrochloride, USP is a white or practically white crystals with a molecular formula of C 9 H 13 NO 2 • HCl and a molecular weight of 203.67. It is freely soluble in water and in alcohol. Phenylephrine hydrochloride injection USP, 10 mg/mL is sensitive to light. Each mL contains: phenylephrine hydrochloride, USP 10 mg, sodium chloride 3.5 mg, trisodium citrate dihydrate 4 mg, citric acid monohydrate 1 mg, and sodium metabisulfite 2 mg in water for injection. The pH is adjusted with sodium hydroxide and/or hydrochloric acid if necessary. The pH range is 3.5 to 5.5. 1

Phenylephrine hydrochloride injection, 10 mg/mL is indicated for the treatment of clinically important hypotension resulting primarily from vasodilation in the setting of anesthesia. Phenylephrine hydrochloride injection is an alpha-1 adrenergic receptor agonist indicated for the treatment of clinically important hypotension resulting primarily from vasodilation in the setting of anesthesia. ( 1 )

Phenylephrine hydrochloride injection, 10 mg/mL, is injected intravenously either as a bolus or in a dilute solution as a continuous infusion. Dilute before administration. ( 2 ) Dosing for treatment of hypotension during anesthesia Bolus intravenous injection: 40 mcg to 100 mcg every 1 to 2 minutes as needed, not to exceed 200 mcg. ( 2 ) Intravenous infusion: 10 mcg/min to 35 mcg/min, titrating to effect, not to exceed 200 mcg/min. ( 2 ) Adjust the dose according to the pressor response (i.e. titrate to effect). ( 2 ) 2.1 General Dosage and Administration Instructions Phenylephrine hydrochloride injection, 10 mg/mL 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. 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. The diluted solution should not be held for more than 4 hours at room temperature or for more than 24 hours under refrigerated conditions. Discard any unused portion. During phenylephrine hydrochloride injection administration: Correct intravascular volume depletion. Correct acidosis. Acidosis may reduce the effectiveness of phenylephrine. 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 to 2 minutes as needed; not to exceed a total dosage of 200 mcg. If blood pressure is below the target goal, start a continuous intravenous infusion with an infusion rate of 10 to 35 mcg/minute; not to exceed 200 mcg/minute. Adjust dosage according to the blood pressure goal. 2.3 Prepare a 100 mcg/mL Solution for Bolus Intravenous Administration For bolus intravenous administration, prepare a solution containing a final concentration of 100 mcg/mL of phenylephrine hydrochloride injection: Withdraw 10 mg (1 mL of 10 mg/mL) of phenylephrine hydrochloride 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. 2.4 Prepare a Solution for Continuous Intravenous Administration For continuous intravenous infusion, prepare a solution containing a final concentration of 20 mcg/mL of phenylephrine hydrochloride in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP: Withdraw 10 mg (1 mL of 10 mg/mL) of phenylephrine hydrochloride and dilute with 500 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP.

None None ( 4 )

Adverse reactions to phenylephrine hydrochloride are primarily attributable to excessive pharmacologic activity. Adverse reactions reported in published clinical studies, observational trials, and case reports of phenylephrine hydrochloride 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 Most common adverse reactions during treatment: nausea, vomiting, and headache. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Agonistic effects (increase in phenylephrine hydrochloride blood pressure effect) can occur with monoamine oxidase inhibitors (MAOI), oxytocin and oxytocic drugs, tricyclic antidepressants, angiotensin and aldosterone, atropine, steroids, norepinephrine transporter inhibitors, ergot alkaloids. ( 7.1 ) Antagonistic effects (decrease in phenylephrine hydrochloride blood pressure effect) can occur with α-adrenergic antagonists, phosphodiesterase Type 5 inhibitors, mixed α- and β-receptor antagonists, calcium channel blockers, benzodiazepines and ACE inhibitors, centrally acting sympatholytic agents. ( 7.2 ) 7.1 Interactions that Augment Pressor Effect The increasing blood pressure effect of phenylephrine hydrochloride 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 phenylephrine hydrochloride 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