5. WARNINGS AND PRECAUTIONS

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

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
Including arterial and venous thrombotic events
Thromboembolic 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%)

2. DOSAGE AND ADMINISTRATION

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.

12. CLINICAL PHARMACOLOGY

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.

12.2. Pharmacodynamics

For the 114 (70%) patients in the GIAPREZA arm who reached the target MAP at Hour 3, the median time to reach the target MAP endpoint was approximately 5 minutes. GIAPREZA is titrated to effect for each individual patient.

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 GIAPREZA.

Metabolism and Excretion:

No specific studies were conducted that examined the metabolism and excretion of GIAPREZA.

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 GIAPREZA in the following specific populations.

Renal Impairment

The clearance of angiotensin II is not dependent on renal function. Therefore, the pharmacokinetics of GIAPREZA 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 GIAPREZA are not expected to be influenced by hepatic impairment.

Age

The effect of age was analyzed in the 163 patients receiving GIAPREZA 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 GIAPREZA in ATHOS-3. There were no significant differences in pharmacokinetics between male and female patients.

16. HOW SUPPLIED/STORAGE AND HANDLING

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.