ANGIOTENSIN II: 181 Adverse Event Reports & Safety Profile

11.

Description

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

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 )

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.

4.

Contraindications

None. None (4.1)

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . 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

AND PRECAUTIONS

• There is a potential for venous and arterial thrombotic and thromboembolic events in patients who receive Angiotensin II. Use concurrent venous thromboembolism (VTE) prophylaxis. ( 5.1 , 6.1 )

5.1 Risk for Thrombosis The safety of Angiotensin II 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 Angiotensin II 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.

INTERACTIONS

• Angiotensin converting enzyme (ACE) inhibitors ACE inhibitors may increase response to Angiotensin II. ( 7.1 )
• Angiotensin II Receptor Blockers (ARB) ARBs may reduce response to Angiotensin II. ( 7.2 ) 7.1.

Angiotensin Converting

Enzyme (ACE)

Inhibitors

Concomitant use of angiotensin converting enzyme (ACE) inhibitors may increase the response to Angiotensin II. 7.2. Angiotensin II Receptor Blockers (ARB) Concomitant use of angiotensin II blockers (ARBs) may decrease the response to Angiotensin II.