Angiotensin II (Giapreza)

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# Overview
Angiotensin II (Giapreza) is a naturally occurring peptide hormone of the renin-angiotensin-aldosterone system (RAAS) that causes vasoconstriction and an increase in blood pressure that is FDA approved for the treatment of septic or other distributive shock.   Common adverse reactions include thromboembolic events.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Angiotensin II (Giapreza) increases blood pressure in adults with septic or other distributive shock.

### Dosage
Dosage Form
- Injection: 2.5 mg/mL angiotensin II (Giapreza) and 5 mg/2 mL angiotensin II (Giapreza) (2.5 mg/mL) in a vial.
Preparation
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Angiotensin II (Giapreza) must be administered as an intravenous infusion. Angiotensin II (Giapreza) must be diluted in 0.9% sodium chloride prior to use. Dilute the contents of one vial of angiotensin II (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.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding angiotensin II (Giapreza) Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding angiotensin II (Giapreza) Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Angiotensin II (Giapreza) FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding angiotensin II (Giapreza) Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding angiotensin II (Giapreza) Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
- None

# Warnings
- The safety of angiotensin II (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 angiotensin II (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.

# Adverse Reactions

## 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.
- The safety of angiotensin II (Giapreza) was evaluated in ATHOS-3. Patients in ATHOS-3 were receiving other vasopressors in addition to angiotensin II (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 angiotensin II (Giapreza) and with a rate of at least 1.5% higher with angiotensin II (Giapreza) than with placebo.

## Postmarketing Experience
There is limited information regarding Angiotensin II (Giapreza) Postmarketing Experience in the drug label.

# Drug Interactions
- Angiotensin Converting Enzyme (ACE) Inhibitors
- Angiotensin II (Giapreza) Receptor Blockers (ARB)
- Concomitant use of angiotensin converting enzyme (ACE) inhibitors may increase the response to angiotensin II (Giapreza).
- Concomitant use of angiotensin II (Giapreza) blockers (ARBs) may decrease the response to angiotensin II (Giapreza).

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):

### Risk Summary
- The published data on angiotensin II (Giapreza) 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 (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.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Angiotensin II (Giapreza) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Angiotensin II (Giapreza) during labor and delivery.

### Nursing Mothers
- It is not known whether angiotensin II (Giapreza) is present in human milk. No data are available on the effects of angiotensin II (Giapreza) on the breastfed child or the effects on milk production.

### Pediatric Use
- The safety and efficacy of angiotensin II (Giapreza) in pediatric patients have not been established.

### Geriatic 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 (Giapreza).

### Gender
There is no FDA guidance on the use of Angiotensin II (Giapreza) with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Angiotensin II (Giapreza) with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Angiotensin II (Giapreza) in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Angiotensin II (Giapreza) in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Angiotensin II (Giapreza) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Angiotensin II (Giapreza) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- The recommended starting dosage of angiotensin II (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 angiotensin II (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.

### Monitoring
- An increase in blood pressure is indicative of efficacy
- Blood pressure: Monitor response to therapy

# IV Compatibility
There is limited information regarding the compatibility of Angiotensin II (Giapreza) and IV administrations.

# Overdosage
- Overdose of angiotensin II (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 (Giapreza) is less than one minute.

# Pharmacology

## Mechanism of Action
- Angiotensin II (Giapreza) raises blood pressure by vasoconstriction and increased aldosterone release. Direct action of angiotensin II (Giapreza) on the vessel wall is mediated by binding to the G-protein-coupled angiotensin II (Giapreza) receptor type 1 on vascular smooth muscle cells, which stimulates Ca2+/calmodulin-dependent phosphorylation of myosin and causes smooth muscle contraction.

## Structure

## Pharmacodynamics
- For the 114 (70%) patients in the angiotensin II (Giapreza) arm who reached the target MAP at Hour 3, the median time to reach the target MAP endpoint was approximately 5 minutes. Angiotensin II (Giapreza) is titrated to effect for each individual patient.

## Pharmacokinetics
- Following intravenous infusion of angiotensin II (Giapreza) in adults with septic or other distributive shock, serum levels of angiotensin II (Giapreza) 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 (Giapreza) precursor peptide) is reduced by approximately 40%.

### Distribution:
- No specific studies were conducted that examined the distribution of angiotensin II (Giapreza).

### Metabolism and Excretion:
- No specific studies were conducted that examined the metabolism and excretion of angiotensin II (Giapreza).
- The plasma half-life of IV administered angiotensin II (Giapreza) is less than one minute. It is metabolized by aminopeptidase A and angiotensin converting enzyme 2 to angiotensin-(2-8)  and angiotensin-(1-7), respectively in plasma, erythrocytes and many of the major organs (i.e., intestine, kidney, liver and lung). Angiotensin II (Giapreza) type 1 receptor (AT1) mediated activity of angiotensin III is approximately 40% of angiotensin II (Giapreza); however, aldosterone synthesis activity is similar to angiotensin II (Giapreza). Angiotensin-(1-7) exerts the opposite effects of angiotensin II (Giapreza) on AT1 receptors and causes vasodilation.

### Specific Populations
- No formal pharmacokinetic studies were conducted with angiotensin II (Giapreza) in the following specific populations.
Renal Impairment
- The clearance of angiotensin II (Giapreza) is not dependent on renal function. Therefore, the pharmacokinetics of angiotensin II (Giapreza) are not expected to be influenced by renal impairment.
Hepatic Impairment
- The clearance of angiotensin II (Giapreza) is not dependent on hepatic function. Therefore, the pharmacokinetics of angiotensin II (Giapreza) are not expected to be influenced by hepatic impairment.
Age
- The effect of age was analyzed in the 163 patients receiving angiotensin II (Giapreza) 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 (Giapreza) in ATHOS-3. There were no significant differences in pharmacokinetics between male and female patients.

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No genetic toxicity studies have been conducted with angiotensin II (Giapreza). No carcinogenicity or fertility studies with angiotensin II (Giapreza) have been conducted in animals.

### Animal Toxicology and/or Pharmacology
- No animal toxicology studies were conducted with angiotensin II (Giapreza).

### Safety Pharmacology
- In a cardiovascular safety pharmacology study in normotensive dogs, angiotensin II (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, angiotensin II (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. Angiotensin II (Giapreza) did not significantly alter respiratory rate or cause electrocardiographic changes in QRS duration or QTc.

# Clinical Studies
- The angiotensin II (Giapreza) 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 (Giapreza) or placebo. Doses of angiotensin II (Giapreza) 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 (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 angiotensin II (Giapreza) 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.

# How Supplied
- Angiotensin II (Giapreza) (angiotensin II) Injection is a clear, aqueous solution for administration by intravenous infusion supplied as a single dose vial in two strengths:
- 2.5 mg/mL vial: NDC 68547-501-02: A carton of one 1 mL single dose vial containing 2.5 mg angiotensin II (Giapreza)(as a sterile liquid).
- 5 mg/2 mL vial: NDC 68547-002-05: A carton of one 2 mL single dose vial containing 5 mg (2.5 mg/mL) angiotensin II (Giapreza) (as a sterile liquid).

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

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
There is limited information regarding Angiotensin II (Giapreza) Patient Counseling Information in the drug label.

# Precautions with Alcohol
Alcohol-Angiotensin II (Giapreza) interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
- Giapreza

# Look-Alike Drug Names
There is limited information regarding Angiotensin II (Giapreza) Look-Alike Drug Names in the drug label.

# Drug Shortage Status
Drug Shortage

# Price