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 contents of one vial of Giapreza 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.

Diluted solution may be stored at room temperature or under refrigeration. 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 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.

Injection: 2.5 mg/mL angiotensin II and 5 mg/2 mL angiotensin II (2.5 mg/mL) in a vial.

Giapreza is a clear, aqueous solution.

None.

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.

ATHOS-3

The safety of Giapreza was evaluated in ATHOS-3 [see Warnings and Precautions(5.1)]. Patients in ATHOS-3 were receiving other vasopressors in addition to Giapreza 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 Giapreza and with a rate of at least 1.5% higher with Giapreza than with placebo.

. 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 Giapreza.

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.

. Lactation

Risk Summary

It is not known whether Giapreza 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.

. 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.

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.

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.

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

Average molecular weight: 1046.2 (as free base).

. 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 1800 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 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. Giapreza did not significantly alter respiratory rate or cause electrocardiographic changes in QRS duration or QTc.

Contraindications

None.1

Warnings/Precautions

Risk for Thrombosis

The safety of angiotensin II acetate 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 acetate 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.1

Specific Populations

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 acetate.1

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.1

Disease-associated Maternal and/or Embryofetal 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.1

It is not known whether angiotensin II acetate is present in human milk. No data are available on the effects of angiotensin II on the breast-fed child or the effects on milk production.1

The safety and efficacy of angiotensin II acetate in pediatric patients have not been established.1

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 acetate.1

Common Adverse Effects

The most common adverse reactions reported in greater than 10% in angiotensin II acetate-treated patients were thromboembolic events.1

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Angiotensin-converting Enzyme (ACE) Inhibitors: ACE inhibitors may increase response to angiotensin II acetate.1

• Angiotensin II Receptor Blockers (ARBs): ARBs may reduce response to angiotensin II acetate.1