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. 

 

10. OVERDOSAGE

 

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. 

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 1 mL 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.

 

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.

 

Chemical Structure 

 

Molecular formula: C50H71N13O12 ∙ (C2H4O2)n; (n= number of acetate molecules; theoretical n = 3) 

 

Average molecular weight: 1046.2 (as free base).

 

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 Ca2+/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.