Giapreza

. 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.

. 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.

. Pregnancy

. Lactation

. Pediatric Use

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

. 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.

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.

. 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.

. Angiotensin Converting Enzyme (ACE) Inhibitors

Concomitant use of angiotensin converting enzyme (ACE) inhibitors may increase the response to GIAPREZA.

. Angiotensin II Receptor Blockers (ARB)

Concomitant use of angiotensin II receptor blockers (ARBs) may decrease the response to GIAPREZA.

. 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.

. 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.

. 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%.

. Carcinogenesis, Mutagenesis, Impairment of Fertility

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

. Animal Toxicology and/or Pharmacology

No animal toxicology studies were conducted with GIAPREZA.

. Safety Pharmacology

In a cardiovascular safety pharmacology study in normotensive dogs, GIAPREZA doses of 150, 450, and 1,800 ng/kg (5, 15, and 60 ng/kg/min) were infused intravenously for 30 minutes each. At ≥ 450 ng/kg, GIAPREZA caused significantly elevated MAP and systemic vascular resistance, as expected. The 1,800 ng/kg dose also caused increased heart rate, increased systemic vascular resistance, increased left ventricular systolic and end-diastolic pressures, and PR interval prolongation. GIAPREZA did not significantly alter respiratory rate or cause electrocardiographic changes in QRS duration or QTc.

. ATHOS-3

The Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) trial was a double-blind study in which 321 adults with septic or other distributive shock who remained hypotensive despite fluid and vasopressor therapy were randomized 1:1 and treated with either GIAPREZA or placebo, both in addition to background vasopressor therapy. Doses of GIAPREZA or placebo were titrated to a target MAP of ≥ 75 mmHg during the first 3 hours of treatment while doses of other vasopressors were maintained. From Hour 3 to Hour 48, GIAPREZA or placebo were titrated to maintain MAP between 65 and 70 mmHg while reducing doses of other vasopressors. The primary endpoint was the percentage of subjects who achieved either a MAP ≥ 75 mmHg or a ≥ 10 mmHg increase in MAP without an increase in baseline vasopressor therapy at 3 hours.

91% of subjects had septic shock; the remaining subjects had other forms of distributive shock such as neurogenic shock. At the time of study drug administration, 97% of subjects were receiving norepinephrine, 67% vasopressin, 15% phenylephrine, 13% epinephrine, and 2% dopamine. 83% of subjects had received two or more vasopressors and 47% three or more vasopressors prior to study drug administration. 61% of subjects were male, 80% were White, 10% were Black, and 10% were other races. The median age of subjects was 64 years (range: 22-89 years). Patients requiring high doses of steroids, patients with a history of asthma or bronchospasm, and patients with Raynaud's syndrome were not included.

The primary endpoint was achieved by 70% of patients randomized to GIAPREZA compared to 23% of placebo patients; p < 0.0001 (a treatment effect of 47%). Figure 1 shows the results in all patients and in selected subgroups.

Figure 1: ATHOS-3: Primary Endpoint – Overall Result and Results in Selected Subgroups

NE Equiv = norepinephrine equivalent dose: the sum of all vasopressor doses with each vasopressor dose converted to the clinically equivalent norepinephrine dose.

Note: The figure above presents effects in various subgroups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made and may not reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

In the GIAPREZA-treated group, the median time to reach the target MAP endpoint was 5 minutes. The effect on MAP was sustained for at least the first three hours of treatment. The median dose of GIAPREZA was 10 ng/kg/min at 30 minutes. Of the 114 responders at Hour 3, only 2 (1.8%) received more than 80 ng/kg/min.

Patients were not necessarily on maximum doses of other vasopressors at the time of randomization. The effect of GIAPREZA when added to maximum doses of other vasopressors is unknown.

Mortality through Day 28 was 46% on GIAPREZA and 54% on placebo (hazard ratio 0.78; 95% confidence interval 0.57 – 1.07).

. 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).

. 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.