Angiotensin Ii

1 INDICATIONS AND USAGE Angiotensin II Injection increases blood pressure in adults with septic or other distributive shock. Angiotensin II Injection is a vasoconstrictor to increase blood pressure in adults with septic or other distributive shock. (1)

2 DOSAGE AND ADMINISTRATION Dilute Angiotensin II Injection in 0.9% sodium chloride prior to use. See Full Prescribing Information for instructions on preparation and administration of injection. Diluted solution may be stored at room temperature or under refrigeration and should be discarded after 24 hours. Angiotensin II Injection must be administered as an intravenous infusion. ( 2.1 ) • Start Angiotensin II Injection intravenously at 20 nanograms (ng)/kg/min. Titrate as frequently as every 5 minutes by increments of up to 15 ng/kg/min as needed. During the first 3 hours, the maximum dose should not exceed 80 ng/kg/min. Maintenance dose should not exceed 40 ng/kg/min. ( 2.2 ) 2.1. Preparation Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Angiotensin II Injection must be administered as an intravenous infusion. Angiotensin II Injection must be diluted in 0.9% sodium chloride prior to use. Dilute the contents of one vial of Angiotensin II Injection in 0.9% saline to achieve a final concentration of 5,000 ng/mL or 10,000 ng/mL. Discard vial and any unused portion of the drug product after use. Table 1: Preparation of Diluted Solution F l u i d Restricted? V i al Strength Withdraw Amount (m L ) I n f usion Bag Size (mL) Final Concentration (ng/mL) No 2.5 mg/mL 1 500 5,000 Yes 2.5 mg/mL 1 250 10,000 Diluted solution may be stored at room temperature or under refrigeration. Discard prepared solution after 24 hours at room temperature or under refrigeration. 2.2. Administration The recommended starting dosage of Angiotensin II Injection is 20 nanograms (ng)/kg/min via continuous intravenous infusion. Administration through a central venous line is recommended. Monitor blood pressure response and titrate Angiotensin II Injection every 5 minutes by increments of up to 15 ng/kg/min as needed to achieve or maintain target blood pressure. Do not exceed 80 ng/kg/min during the first 3 hours of treatment. Maintenance doses should not exceed 40 ng/kg/min. Doses as low as 1.25 ng/kg/min may be used. Once the underlying shock has sufficiently improved, down-titrate every 5 to 15 minutes by increments of up to 15 ng/kg/min based on blood pressure.

6 ADVERSE REACTIONS The most common adverse reactions reported in greater than 10% in Angiotensin II treated patients were thromboembolic events. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma at (609)-250‐7990 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. ATHOS-3 The safety of Angiotensin II was evaluated in ATHOS-3 [see Warnings and Precautions (5.1) ] . Patients in ATHOS-3 were receiving other vasopressors in addition to Angiotensin II or placebo, which were titrated to effect on mean arterial pressure (MAP). Table 2 summarizes adverse reactions with an incidence of at least 4% among patients treated with Angiotensin II and with a rate of at least 1.5% higher with Angiotensin II than with placebo. Table 2: Adverse Reactions Occurring in ≥ 4% of Patients Treated with Angiotensin II and ≥ 1.5% More Often than in Placebo-treated Patients in ATHOS-3 A dverse Event Angiotensin II N= 163 Placebo N= 158 Thromboembolic events a 21 (12.9%) 8 (5.1%) Deep vein thrombosis 7 (4.3%) 0 (0.0%) Thrombocytopenia 16 (9.8%) 11 (7.0%) Tachycardia 14 (8.6%) 9 (5.7%) Fungal infection 10 (6.1%) 2 (1.3%) Delirium 9 (5.5%) 1 (0.6%) Acidosis 9 (5.5%) 1 (0.6%) Hyperglycemia 7 (4.3%) 4 (2.5%) Peripheral ischemia 7 (4.3%) 4 (2.5%) a Including arterial and venous thrombotic events

12.3 Pharmacokinetics Following intravenous infusion of angiotensin II in adults with septic or other distributive shock, serum levels of angiotensin II are similar at Baseline and Hour 3 after intravenous infusion. After 3 hours of treatment, however, the serum level of angiotensin I (the angiotensin II precursor peptide) is reduced by approximately 40%. Distribution: No specific studies were conducted that examined the distribution of Angiotensin II. Metabolism and Excretion: No specific studies were conducted that examined the metabolism and excretion of Angiotensin II. The plasma half-life of IV administered angiotensin II is less than one minute. It is metabolized by aminopeptidase A and angiotensin converting enzyme 2 to angiotensin-(2-8) [angiotensin III] and angiotensin-(1-7), respectively in plasma, erythrocytes and many of the major organs (i.e., intestine, kidney, liver and lung). Angiotensin II type 1 receptor (AT1) mediated activity of angiotensin III is approximately 40% of angiotensin II; however, aldosterone synthesis activity is similar to angiotensin II. Angiotensin-(1-7) exerts the opposite effects of angiotensin II on AT1 receptors and causes vasodilation. Specific Populations No formal pharmacokinetic studies were conducted with Angiotensin II in the following specific populations. Renal Impairment The clearance of angiotensin II is not dependent on renal function. Therefore, the pharmacokinetics of Angiotensin II are not expected to be influenced by renal impairment. Hepatic Impairment The clearance of angiotensin II is not dependent on hepatic function. Therefore, the pharmacokinetics of Angiotensin II are not expected to be influenced by hepatic impairment. Age The effect of age was analyzed in the 163 patients receiving Angiotensin II in ATHOS-3. There were no significant differences in pharmacokinetics between age groups (< 65 years / ≥ 65 years). Male and Female Patients The effect of sex was analyzed in the 163 patients receiving Angiotensin II in ATHOS-3. There were no significant differences in pharmacokinetics between male and female patients.