Angiotensin Ii

1. INDICATIONS AND USAGE 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 )

3. DOSAGE FORMS AND STRENGTHS Injection: 0.5 mg/mL angiotensin II and 2.5 mg/mL angiotensin II in a vial. GIAPREZA is a clear, aqueous solution. Injection: 0.5 mg/mL and 2.5 mg/mL in a vial.

4. CONTRAINDICATIONS None. None (4.1)

5. WARNINGS AND PRECAUTIONS 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.

6. ADVERSE REACTIONS 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%)

7. DRUG INTERACTIONS 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.

8. USE IN SPECIFIC POPULATIONS 8.1. Pregnancy 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. 8.2. Lactation Risk Summary It is not known whether GIAPREZA is present in human milk. No data are available on the effects of angiotensin II on the breastfed child or the effects on milk production. 8.4. Pediatric Use The safety and efficacy of GIAPREZA in pediatric patients have not been established. 8.5. Geriatric Use 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 .

12.1. Mechanism of Action Angiotensin II raises blood pressure by vasoconstriction and increased aldosterone release. Direct action of angiotensin II on the vessel wall is mediated by binding to the G-protein-coupled angiotensin II receptor type 1 on vascular smooth muscle cells, which stimulates Ca 2+ /calmodulin-dependent phosphorylation of myosin and causes smooth muscle contraction.