Angiotensin Ii: Uses, Dosage, Side Effects & Warnings

Uses

Angiotensin II Injection increases blood pressure in adults with septic or other distributive shock. Angiotensin II Injection is a vasoconstrictor to increase blood pressure in adults with septic or other distributive shock. (1)

Dosage 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.

Dosage forms and strengths

Injection: 2.5 mg/mL angiotensin II in a vial. Angiotensin II Injection is a clear, aqueous solution. Injection: 2.5 mg/mL in a vial.

Contraindications

None. None (4.1)

Warnings 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.

Side effects

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 [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 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

Drug 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.

Use in specific populations

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.

Pregnancy

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.

Pediatric use

8.4 Pediatric Use The safety and efficacy of Angiotensin II in pediatric patients have not been established.

Geriatric use

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.

Overdosage

Overdose of Angiotensin II 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.

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. Angiotensin II Injection is a sterile, aqueous solution of synthetic human angiotensin II for intravenous administration by infusion. Each 1 mL of Angiotensin II Injection 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-L-tyrosyl-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: C50H71N13O12
• (C2H4O2) n; (n= number of acetate molecules; theoretical n= 3) Average molecular weight: 1046.2 (as free base). angiotensin-II-chemcial-structure

Mechanism of action

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.

How supplied

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 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).

Storage

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

Active ingredients

Angiotensin Ii in 1 product

Angiotensin Ii NDC products (1)

NDC	Strength & form	Labeler	Type
68083-553	Angiotensin Ii 2.5 mg/mL Injection	Gland Pharma Limited	ANDA

Frequently asked questions

What is Angiotensin Ii used for?

Angiotensin II Injection increases blood pressure in adults with septic or other distributive shock. Angiotensin II Injection is a vasoconstrictor to increase blood pressure in adults with septic or other distributive shock. (1)

What are the side effects of Angiotensin Ii?

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… See the full label for the complete list.

Who makes Angiotensin Ii?

Angiotensin Ii is listed by 1 labeler in the FDA NDC directory, including Gland Pharma Limited.