Phenylephrine Hydrochloride

RECENT MAJOR CHANGES Dosage and Administration ( 2.1 , 2.2 )---------------------------------------03/2023

1 INDICATIONS AND USAGE Phenylephrine hydrochloride injection is an alpha-1 adrenergic receptor agonist indicated for increasing blood pressure in adults with clinically important hypotension resulting primarily from vasodilation, in such settings as septic shock or anesthesia. Phenylephrine hydrochloride injection is an alpha-1 adrenergic receptor agonist indicated for increasing blood pressure in adults with clinically important hypotension resulting primarily from vasodilation, in such settings as septic shock or anesthesia. ( 1 )

2 DOSAGE AND ADMINISTRATION 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. 2.5 Directions for Dispensing from Pharmacy Bulk Vial The Pharmacy Bulk Vial is intended for dispensing of single-doses to multiple patients in a pharmacy admixture program and is restricted to the preparation of admixtures for infusion. Each closure shall be penetrated only one time with a suitable sterile transfer device or dispensing set that allows measured dispensing of the contents. The Pharmacy Bulk Vial is to be used only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area). Dispensing from a pharmacy bulk vial should be completed within 4 hours after the vial is penetrated.

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 mat …

3 DOSAGE FORMS AND STRENGTHS Phenylephrine hydrochloride injection, USP 10 mg/mL, for intravenous use is available in three vial sizes: • Injection: 10 mg/mL as a clear, colorless or slightly yellow solution in a single-dose 1 mL vial (10 mg of phenylephrine hydrochloride per vial) • Injection: 10 mg/mL as a clear, colorless or slightly yellow solution in Pharmacy Bulk Package 5 mL vial (50 mg of phenylephrine hydrochloride per vial) that will provide five 1 mL single doses • Injection: 10 mg/mL as a clear, colorless or slightly yellow solution in Pharmacy Bulk Package 10 mL vial (100 mg of phenylephrine hydrochloride per vial) that will provide ten 1 mL single doses Injection ( 3 ) • 1 mL single-dose vials containing 10 mg phenylephrine hydrochloride (10 mg/mL) ( 3 ) • 5 mL pharmacy bulk package vials containing 50 mg phenylephrine hydrochloride (10 mg/mL) ( 3 ) • 10 mL pharmacy bulk package vials containing 100 mg phenylephrine hydrochloride (10 mg/mL) ( 3 )

4 CONTRAINDICATIONS The use of phenylephrine hydrochloride injection 10 mg per mL is contraindicated in patients with: Hypersensitivity to the products or any of their components Hypersensitivity to the products or any of their components ( 4 )

6 ADVERSE REACTIONS Adverse reactions to Phenylephrine hydrochloride injection are primarily attributable to excessive pharmacologic activity. Adverse reactions reported in published clinical studies, observational trials, and case reports of Phenylephrine hydrochloride injection 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 Provepharm Inc., at 1–833-727-6556 or safety-us@provepharm.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS Agonistic effects (increase in phenylephrine hydrochloride injection 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 injection 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 Press or Effect The increasing blood pressure effect of phenylephrine hydrochloride injection 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 Press or Effect The increasing blood pressure effect of phenylephrine hydrochloride injection 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 Cesarean 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 hydrochloride during the first or second trimester. In animal reproduction and development studies in normotensive animals, evidence of fetal malformations was noted when phenylephrine hydrochloride 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 are 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 hydrochloride injection to other similar agents in pregnant women during Cesarean section, have not identified adverse maternal or infant outcomes. At recommended doses, phenylephrine hydrochloride does not appear to affect fetal heart rate or fetal heart rate variability to a significant degree. There are no studies on the safety of phenylephrine hydrochloride 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 hydrochloride injection during pregnancy. In addition, there are no data on the risk of miscarriage following fetal exposure to phenylephrine hydrochloride injection. Animal Data No clear malformations or fetal toxicity were reported when normotensive pregnant rabbits were treated with phenylephrine hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride via continuous intravenous infusion over 1 hour (0 …

12.1 Mechanism of Action Phenylephrine hydrochloride is an α-1 adrenergic receptor agonist.

11 DESCRIPTION Phenylephrine hydrochloride injection contain active pharmaceutical ingredient phenylephrine in the form of hydrochloride salt. Phenylephrine is a synthetic sympathomimetic agent in sterile form for parenteral injection. Phenylephrine hydrochloride chemical name is (-)- m -Hydroxy-α-[(methylamino)methyl]benzyl alcohol hydrochloride and has the following structural formula: Phenylephrine hydrochloride USP is white or practically white powder. Phenylephrine hydrochloride is very soluble in water, freely soluble in ethanol, and insoluble in chloroform and ethyl ether. Phenylephrine hydrochloride is sensitive to light. Phenylephrine Hydrochloride Injection, USP, 10 mg/mL : Phenylephrine hydrochloride injection, USP is a clear, colorless, aqueous solution that is essentially free of visible foreign matter. It MUST BE DILUTED before administration as bolus intravenous infusion or continuous intravenous infusion. Each mL contains: 10 mg of phenylephrine hydrochloride USP, (equivalent to 8.2 mg of phenylephrine base); 3.5 mg of Sodium Chloride USP as tonicity agent; 1 mg of Citric Acid Monohydrate USP and 4 mg of Sodium Citrate Dihydrate USP, as buffering agents; 2 mg of Sodium Metabisulfite NF, as antioxidant, and Sodium Hydroxide NF and Hydrochloric Acid NF, as pH adjusters in Water for Injection. Phenylephrine hydrochloride injection pH range is 3.5 to 5.5. Phenylephrine Hydrochloride Chemical Structure

10 OVERDOSAGE Overdose of phenylephrine hydrochloride injection 10 mg/mL can cause a rapid rise in blood pressure. Symptoms of overdose include headache, vomiting, hypertension, reflex bradycardia, and cardiac arrhythmias including ventricular extrasystoles and ventricular tachycardia, and may cause a sensation of fullness in the head and tingling of the extremities. Consider using an α-adrenergic antagonist. Consider using an α-adrenergic antagonist.

16 HOW SUPPLIED/STORAGE AND HANDLING Phenylephrine hydrochloride Injection, 10 mg/mL is a clear, colorless, aqueous solution free from visible particles supplied as follows; NDC No. Strength How Supplied NDC 70594- 063 -02 10 mg/mL 1 mL vial; for single use (supplied in packages of 25) NDC 70594- 064 -02 50 mg/5 mL (10 mg/mL) 5 mL vial; Pharmacy Bulk Package (supplied in packages of 10) NDC 70594- 065 -01 100 mg/10 mL (10 mg/mL) 10 mL vial; Pharmacy Bulk Package (supplied as a single unit) NDC 70594- 065 -02 100 mg/10 mL (10 mg/mL) 10 mL vial; Pharmacy Bulk Package (supplied in packages of 10) Vial stoppers are not manufactured with natural rubber latex. Store phenylephrine hydrochloride Injection, 10 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]. Protect from light. Store in carton until time of use. The 1 mL vials are for single use only; the 5 and 10 mL vials are pharmacy bulk packages. 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.