Biorphen

1 INDICATIONS AND USAGE BIORPHEN is indicated for the treatment of clinically important hypotension resulting primarily from vasodilation in the setting of anesthesia. BIORPHEN 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 BIORPHEN 500 mcg/5 mL (100 mcg/mL)/mL injection MUST NOT BE DILUTED before administration as an intravenous bolus. It is supplied as a READY-TO-USE formulation. ( 2 ) BIORPHEN 10 mg/mL injection MUST BE DILUTED before administration as an intravenous bolus or continuous intravenous infusion to achieve the desired concentration. ( 2 ) 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. ( 2 ) Adjust the dose according to the pressor response (i.e., titrate to effect). ( 2 ) Biorphen 10 mg/mL Only: Continuous intravenous infusion: 10 mcg/min to 35 mcg/min, titrating to effect, not to exceed 200 mcg/min. ( 2 ) 2.1 General Dosage and Administration Instructions 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 500 mcg/5 mL (100 mcg/mL) and 10 mg/mL Injection have important differences in administration instructions: Administration Instructions for BIORPHEN 500 mcg/5 mL (100 mcg/mL) Injection: BIORPHEN 500 mcg/5 mL (100 mcg/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. 2.2 Dosing for Treatment of Hypotension during Anesthesia The following are the recommended dosages for the treatment of hypotension during anesthesia. BIORPHEN 500 mcg/5 mL (100 mcg/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. 2.3 Preparation of a 100 mcg/mL Solution for Bolus Intravenous Administration from BIORPHEN 10 mg/mL Injection 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. 2.4 Preparation of Solution for Continuous Intravenous Administration from BIORPHEN 10 mg/mL Injection 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.

3 DOSAGE FORMS AND STRENGTHS BIORPHEN 500 mcg/5 mL (100 mcg/mL) Injection: Ampule BIORPHEN injection, 500 mcg/5 mL (100 mcg/mL), for intravenous use, is a clear and colorless solution available in a type I one point cut clear colorless glass 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). Vial BIORPHEN injection, 500 mcg/5 mL (100 mcg/mL), for intravenous use, is a clear and colorless solution available in a type I clear colorless glass single-dose vial containing 5 mL of solution for injection, corresponding to 0.5 mg of phenylephrine hydrochloride per vial (equivalent to 0.41 mg of phenylephrine base). BIORPHEN 10 mg/mL Injection: BIORPHEN injection, 10 mg/mL, for intravenous use, is a clear and colorless solution available in a type I one point cut clear colorless glass single-dose ampule containing 1 mL of solution for injection, corresponding to 10 mg of phenylephrine hydrochloride per ampule (equivalent to 8.2 mg of phenylephrine base). Biorphen 500 mcg/5 mL (100 mcg/mL) Injection: Single-dose ampule containing 5 mL of solution for injection corresponding to 0.5 mg of phenylephrine hydrochloride per ampule. ( 3 ) Biorphen 500 mcg/5 mL (100 mcg/mL) Injection: Single-dose vial containing 5 mL of solution for injection corresponding to 0.5 mg of phenylephrine hydrochloride per vial.( 3 ) Biorphen 10 mg/mL Injection: Single-dose ampule containing 1 mL of solution for injection corresponding to 10 mg of phenylephrine hydrochloride per ampule. ( 3 )

4 CONTRAINDICATIONS None. None ( 4 )

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 Most common adverse reactions during treatment: nausea, vomiting, and headache. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy's Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

7 DRUG INTERACTIONS Agonistic Effects (increase in BIORPHEN 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 BIORPHEN 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 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 (learni …

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

11 DESCRIPTION Phenylephrine is an alpha-1 adrenergic receptor agonist. The chemical name of phenylephrine hydrochloride is (-)- m -hydroxy-α-[(methylamino) methyl] benzyl alcohol hydrochloride, its molecular formula is C 9 H 13 NO 2 · HCl (Molecular Weight: 203.67g/mol). Its structural formula is depicted below: Phenylephrine hydrochloride is soluble in water and ethanol, and insoluble in chloroform and ethyl ether. BIORPHEN Injection, 500 mcg/5 mL (100 mcg/mL): BIORPHEN (phenylephrine hydrochloride) injection, 500 mcg/5 mL (100 mcg/mL),, is a sterile, nonpyrogenic, clear and colorless solution for intravenous use. It MUST NOT BE DILUTED before administration as an intravenous bolus. Each mL contains: phenylephrine hydrochloride 100 mcg (equivalent to 80 mcg 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 to 5.0. BIORPHEN Injection, 10 mg/mL: BIORPHEN (phenylephrine hydrochloride) injection, 10 mg/mL, is a sterile, nonpyrogenic, clear and colorless solution for intravenous use. It MUST BE DILUTED before administration as an intravenous bolus or continuous intravenous infusion. Each mL contains: phenylephrine hydrochloride 10 mg (equivalent to 8.2 mg of phenylephrine base), sodium chloride 6.0 mg in water for injection. The pH is adjusted with hydrochloric acid if necessary. The pH range is 3.0 to 5.0. Chemical Structure

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.

16 HOW SUPPLIED/STORAGE AND HANDLING BIORPHEN (phenylephrine hydrochloride) injection is supplied as follows: Unit of Sale Strength Each NDC No. 43598-172-25 5mL single-dose vial 500 mcg/5mL (100 mcg/mL) NDC No. 43598-172-25 5mL single-dose vial NDC No. 43598-172-15 Pack of 10 single-dose ampules 500 mcg/5mL (100 mcg/mL) NDC No. 43598-172-05 5 mL single-dose ampule NDC No. 43598-199-10 Pack of 10 single-dose ampules 10 mg/mL NDC No. 43598-199-01 1 mL single-dose ampule 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.