Angiotensin II

Angiotensin II is a naturally occurring peptide hormone of the renin-angiotensin-aldosterone system (RAAS) that causes vasoconstriction and an increase in blood pressure. GIAPREZA is a sterile, aqueous solution of synthetic human angiotensin II for intravenous administration by infusion. Each 2.5 mg/mL vial of GIAPREZA contains 2.5 mg angiotensin II equivalent to an average of 2.9 mg angiotensin II acetate, 25 mg mannitol, and Water for Injection adjusted with sodium hydroxide and/or hydrochloric acid to pH of 5.5. Each 0.5 mg/mL vial of GIAPREZA contains 0.5 mg angiotensin II equivalent to an average of 0.6 mg angiotensin II acetate, 25 mg mannitol, and Water for Injection adjusted with sodium hydroxide and/or hydrochloric acid to pH of 5.5. The chemical name of the synthetic angiotensin II acetate is L-Aspartyl-L-arginyl-L-valyl-Ltyrosyl-L-isoleucyl-L-histidyl-L-prolyl-L-phenylalanine, acetate salt. The counter ion acetate is present in a non-stoichiometric ratio. It is a white to off-white powder, soluble in water. The structure of angiotensin II acetate is shown below. Molecular formula: C 50 H 71 N 13 O 12 ∙ (C 2 H 4 O 2 ) n ; (n= number of acetate molecules; theoretical n = 3) Average molecular weight: 1046.2 (as free base). giapreza-structure

GIAPREZA increases blood pressure in adults with septic or other distributive shock [see Clinical Studies (14)] . GIAPREZA is a vasoconstrictor to increase blood pressure in adults with septic or other distributive shock. ( 1 )

16.1. How Supplied GIAPREZA (angiotensin II) Injection is a clear, aqueous solution for administration by intravenous infusion supplied as a single-dose vial: 2.5 mg/mL vial: NDC 68547-501-02: A carton of one 1 mL single-dose vial containing 2.5 mg angiotensin II (as a sterile liquid). 0.5 mg/mL vial: NDC 68547-005-05: A carton of five 1 mL single-dose vials (NDC 68547-005-01) containing 0.5 mg angiotensin II (as a sterile liquid). 0.5 mg/mL vial: NDC 68547-005-01: A carton of one 1 mL single-dose vial containing 0.5 mg angiotensin II (as a sterile liquid). 16.2. Storage and Handling GIAPREZA vials should be stored in the refrigerator between 2°C to 8°C (36°F to 46°F). Discard prepared diluted solution after 24 hours at room temperature or under refrigeration.

Dilute GIAPREZA 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. GIAPREZA must be administered as an intravenous infusion. ( 2.1 ) Start GIAPREZA 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. Doses as low as 1.25 ng/kg/min may be used.( 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. GIAPREZA must be administered as an intravenous infusion. GIAPREZA must be diluted in 0.9% sodium chloride prior to use. Dilute the appropriate amount of GIAPREZA in a normal saline (0.9% sodium chloride) infusion bag to achieve the desired final concentration of 5,000 ng/mL or 10,000 ng/mL. Discard vial and any unused portion of the drug product after use. Diluted solution may be stored at room temperature (20°C to 25°C [68°F to 77°F]) or under refrigeration (2°C to 8°C [36°F to 46°F]). Discard prepared solution after 24 hours at room temperature or under refrigeration. 2.2. Administration The recommended starting dosage of GIAPREZA is 20 nanograms (ng)/kg/min via continuous intravenous infusion. Administration through a central venous line is recommended. Monitor blood pressure response and titrate GIAPREZA as frequently as 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 dose 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.

None. None (4.1)

There is a potential for venous and arterial thrombotic and thromboembolic events in patients who receive GIAPREZA. Use concurrent venous thromboembolism (VTE) prophylaxis. ( 5.1 , 6.1 ) 5.1 Risk for Thrombosis The safety of GIAPREZA was evaluated in 321 adults with septic or other distributive shock in a randomized, double-blind, placebo-controlled study, ATHOS-3. There was a higher incidence of arterial and venous thrombotic and thromboembolic events in patients who received GIAPREZA compared to placebo-treated patients in the ATHOS-3 study (13% vs. 5%). The major imbalance was in deep venous thromboses. Use concurrent venous thromboembolism (VTE) prophylaxis.

Angiotensin converting enzyme (ACE) inhibitors ACE inhibitors may increase response to GIAPREZA. ( 7.1 ) Angiotensin II Receptor Blockers (ARB) ARBs may reduce response to GIAPREZA. ( 7.2 ) 7.1. Angiotensin Converting Enzyme (ACE) Inhibitors Concomitant use of angiotensin converting enzyme (ACE) inhibitors may increase the response to GIAPREZA. 7.2. Angiotensin II Receptor Blockers (ARB) Concomitant use of angiotensin II receptor blockers (ARBs) may decrease the response to GIAPREZA.

No genetic toxicity studies have been conducted with GIAPREZA. No carcinogenicity or fertility studies with GIAPREZA have been conducted in animals.

Risk Summary The published data on angiotensin II use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. Animal reproduction studies have not been conducted with GIAPREZA. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Septic or other distributive shock is a medical emergency that can be fatal if left untreated. Delaying treatment in pregnant women with hypotension associated with septic or other distributive shock is likely to increase the risk of maternal and fetal morbidity and mortality.

The safety and efficacy of GIAPREZA in pediatric patients have not been established.

In ATHOS-3, 48% of the total patient population was aged 65 years and older. There was no significant difference in safety or efficacy between patients less than 65 and those 65 years or older when treated with GIAPREZA .

The most common adverse reactions reported in greater than 10% of GIAPREZA treated patients were thromboembolic events. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact La Jolla Pharmaceutical Company at 1-800-651-3861 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 GIAPREZA was evaluated in ATHOS-3 [see Warnings and Precautions(5.1) ] . Patients in ATHOS-3 were receiving other vasopressors in addition to GIAPREZA or placebo, which were titrated to effect on mean arterial pressure (MAP). Table 1 summarizes adverse reactions with an incidence of at least 4% among patients treated with GIAPREZA and with a rate of at least 1.5% higher with GIAPREZA than with placebo. Table 1: Adverse Reactions Occurring in ≥ 4% of Patients Treated with GIAPREZA and ≥ 1.5% More Often than in Placebo-treated Patients in ATHOS-3 Adverse Event GIAPREZA N=163 Placebo N=158 Thromboembolic events Including arterial and venous thrombotic events 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%)

Overdose of GIAPREZA would be expected to result in hypertension, necessitating close monitoring and supportive care. Effects are expected to be brief because the half-life of angiotensin II is less than one minute.