te 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

use 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 biorphen can cause necrosis or sloughing of tissue. avoid extravasation by checking infusion site for free flow. 5.4 bradycardia biorphen can cause severe bradycardia and decreased cardiac output. 5.5 renal toxicity biorphen 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 biorphen, 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 biorphen [see drug interactions (7.1) ] , with the potential for hemorrhagic stroke.

ld 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. 2.2 dosing for treatment of hypotension during anesthesia 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. 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.

., at 1-888-375-3784 or fda at 1-800-fda-1088 or www.fda.gov/medwatch .

te 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

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 development, and fertility) were noted in the offspring of pregnant rats at any dose tested. maternal toxicities (mortality late in gestation and during lactation period, decreased food consumption and body weight) occurred at 1 and 3 mg/kg/day of phenylephrine (equivalent to and 2.9 times the hdd, respectively). 8.2 lactation 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. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 8.5 geriatric use 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. 8.6 hepatic impairment 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. 8.7 renal impairment 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.

e 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 development, and fertility) were noted in the offspring of pregnant rats at any dose tested. maternal toxicities (mortality late in gestation and during lactation period, decreased food consumption and body weight) occurred at 1 and 3 mg/kg/day of phenylephrine (equivalent to and 2.9 times the hdd, respectively).

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.

es are considered not pharmacologically active.

ty: phenylephrine did not impair mating, fertility, or reproductive outcome in normotensive male rats treated with 3 mg/kg/day phenylephrine via continuous intravenous infusion over 1 hour (2.9 times the hdd) for 28 days prior to mating and for a minimum of 63 days prior to sacrifice and female rats treated with the same dosing regimen for 14 days prior to mating and through gestation day 6. this dose was associated with increased mortality in both male and female rats and decreased body weight gain in treated males. there were decreased caudal sperm density and increased abnormal sperm reported in males treated with 3 mg/kg/day phenylephrine (2.9 times the hdd).

impair mating, fertility, or reproductive outcome in normotensive male rats treated with 3 mg/kg/day phenylephrine via continuous intravenous infusion over 1 hour (2.9 times the hdd) for 28 days prior to mating and for a minimum of 63 days prior to sacrifice and female rats treated with the same dosing regimen for 14 days prior to mating and through gestation day 6. this dose was associated with increased mortality in both male and female rats and decreased body weight gain in treated males. there were decreased caudal sperm density and increased abnormal sperm reported in males treated with 3 mg/kg/day phenylephrine (2.9 times the hdd).