Phenylephrine Hydrochloride

1 INDICATIONS AND USAGE Phenylephrine hydrochloride injection 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 )

2 DOSAGE AND ADMINISTRATION Phenylephrine hydrochloride injection 500 mcg/5 mL (100 mcg/mL) MUST NOT BE DILUTED before administration as an intravenous bolus. It is supplied as a READY-TO-USE formulation. Dosing for treatment of hypotension during anesthesia Bolus intravenous injection: Initial dose is 40 mcg to 100 mcg. Additional boluses up to 200 mcg may be administered every 1 to 2 minutes as needed. Adjust the dose according to the pressor response (i.e., titrate to effect). 2.1 General Dosage and Administration Instructions During Phenylephrine Hydrochloride Injection 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. Administration Instructions for Phenylephrine Hydrochloride Injection, 500 mcg/5 mL (100 mcg/mL): Phenylephrine Hydrochloride Injection, 500 mcg/5 mL (100 mcg/mL) MUST NOT BE DILUTED before administration as an intravenous bolus. It is supplied as READY-TO-USE formulation. 2.2 Dosing for Treatment of Hypotension during Anesthesia The following are the recommended dosages for the treatment of hypotension during anesthesia. Phenylephrine Hydrochloride Injection, 500 mcg/5 mL (100 mcg/mL): 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.

5 WARNINGS AND PRECAUTIONS Exacerbation of Angina, Heart Failure, or Pulmonary Arterial Hypertension : Phenylephrine Hydrochloride Injection can precipitate angina in patients with severe arteriosclerosis or history of angina, exacerbate underlying heart failure, and increase pulmonary arterial pressure. ( 5.1 ) Peripheral and Visceral Ischemia : Phenylephrine Hydrochloride Injection can cause excessive peripheral and visceral vasoconstriction and ischemia to vital organs. ( 5.2 ) Skin and Subcutaneous Necrosis : Extravasation during intravenous administration may cause necrosis or sloughing of tissue. ( 5.3 ) Bradycardia: Phenylephrine Hydrochloride Injection can cause severe bradycardia and decreased cardiac output. ( 5.4 ) 5.1 Exacerbation of Angina, Heart Failure, or Pulmonary Arterial Hypertension Because of its increasing blood pressure effects, phenylephrine hydrochloride injection 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 Phenylephrine hydrochloride injection 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 phenylephrine hydrochloride injection can cause necrosis or sloughing of tissue. Avoid extravasation by checking infusion site for free flow. 5.4 Bradycardia Phenylephrine hydrochloride injection can cause severe bradycardia and decreased cardiac output. 5.5 Renal Toxicity Phenylephrine hydrochloride injection 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 phenylephrine hydrochloride injection, 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 phenylephrine hydrochloride injection [see Drug Interactions ( 7.1 )] , with the potential for hemorrhagic stroke.

4 CONTRAINDICATIONS None ( 4 ) None ( 4 )

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 the Pressor 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 Pressor 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

8.1 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 developmen…

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 Somerset Therapeutics, LLC at 1-800-417-9175 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .