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

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.

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.

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 [see Warnings and Precautions (5.1)]. 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 Including arterial and venous thrombotic events

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.

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 Angiotensin II.
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 Angiotensin II 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 Angiotensin II 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 Angiotensin II.

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 Angiotensin II arm who reached the target MAP at Hour 3, the median time to reach the target MAP endpoint was approximately 5 minutes.  Angiotensin II 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 Angiotensin II.
Metabolism and Excretion:
No specific studies were conducted that examined the metabolism and excretion of Angiotensin II.
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 Angiotensin II in the following specific populations.
Renal Impairment
The clearance of angiotensin II is not dependent on renal function. Therefore, the pharmacokinetics of Angiotensin II 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 Angiotensin II are not expected to be influenced by hepatic impairment.
Age
The effect of age was analyzed in the 163 patients receiving Angiotensin II 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 Angiotensin II in ATHOS-3.  There were no significant differences in pharmacokinetics between male and female patients.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

13.2. Animal Toxicology and/or Pharmacology

No animal toxicology studies were conducted with Angiotensin II.

13.3. Safety Pharmacology

In a cardiovascular safety pharmacology study in normotensive dogs, Angiotensin II doses of 150, 450, and 1800 ng/kg (5, 15 and 60 ng/kg/min) were infused intravenously for 30 minutes each. At ≥ 450 ng/kg, Angiotensin II caused significantly elevated MAP and systemic vascular resistance, as expected.  The 1800 ng/kg dose also caused increased heart rate, increased systemic vascular resistance, increased left ventricular systolic and end-diastolic pressures, and PR interval prolongation.  Angiotensin II did not significantly alter respiratory rate or cause electrocardiographic changes in QRS duration or QTc.

14.1. 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 to Angiotensin II or placebo.  Doses of Angiotensin II or placebo were titrated to a target mean arterial pressure (MAP) of ≥ 75 mmHg during the first 3 hours of treatment while doses of other vasopressors were maintained. From Hour 3 to Hour 48, Angiotensin II 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 Angiotensin II compared to 23% of placebo subjects; 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 vasopressors 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 Angiotensin II -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 Angiotensin II 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 Angiotensin II when added to maximum doses of other vasopressors is unknown.
Mortality through Day 28 was 46% on Angiotensin II and 54% on placebo (hazard ratio 0.78; 95% confidence interval 0.57 – 1.07).

16.1. How Supplied

Angiotensin II Injection is a clear, aqueous solution for administration by intravenous infusion supplied as a single dose vial as follows:
• 2.5 mg/mL vial: NDC 68083-553-01: A carton of one 1 mL single dose vial containing 2.5 mg angiotensin II (as a sterile liquid).

16.2. Storage and Handling

• Angiotensin II Injection vials should be stored in the refrigerator (36-46°F, 2-8°C).
• Discard prepared diluted solution after 24 hours at room temperature or under refrigeration.

Manufactured by:
Gland Pharma Limited
Hyderabad -502307, INDIA
Revised: September, 2022