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Angiotensin II (Giapreza®) - Intravenous Therapy for the Treatment of Septic Shock

Monday, November 26, 2018  
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Joyce Jung, PharmD Candidate 2019, Philadelphia College of Pharmacy

Oludamilola Olugbile, PharmD, Clinical Pharmacist, Magee Rehabilitation Hospital


Sepsis refers to a systemic inflammatory response to an infectious cause.1,2 Septic shock is a fatal acute organ dysfunction due to severe hypotension or hyperlactatemia complicated by sepsis.1 Severe hypotension occurs in response to infection when the body’s inflammatory response triggers the release of  large amounts of pro-inflammatory cytokines and causes vasodilation.1 According to Angus et al., there are about 750,000 cases of severe sepsis or septic shock that leads to hospitalization each year.1 Severe sepsis or septic shock accounts for 2% of all hospital admissions and 10% of all ICU admissions in the United States.1

Sepsis can be developed from either community-acquired or hospital-acquired infections such as pneumonia, urinary tract infection, intra-abdominal infection, and more.1 Prevalence is highest in African-American males 65 years of age and older. Patients with chronic diseases, cancer, or immunosuppression are also at a high risk of developing sepsis.1,3 Moreover, patients who have previously been admitted to the hospital, especially to the ICU, have a greater risk of developing sepsis from nosocomial infection.3

Although highly variable and nonspecific, clinical presentations of sepsis include hypotension (mean arterial pressure (MAP) <70 mmHg), tachypnea (>20 breaths/minute), altered mental status, and signs and symptoms specific to the site of infection1,3 These presentations can be quickly assessed using a sequential organ failure assessment (SOFA) to diagnose sepsis and predict its severity. 4 Because sepsis is a medical emergency, treatment is immediately initiated based on the clinical presentation to empirically and aggressively manage the infection. Identifying and managing sepsis at earlier stage is an important key to improve overall outcomes and increase chance of survival. According to Rivers E, et al., early goal-directed therapy for sepsis, consisting of immediate initiation of oxygen supply, fluid replenishment, and vasopressor and/or blood transfusion, resulted in significantly lower in-hospital mortality than the standard therapy (30.5% vs 46.5% respectively, p=0.009). 5

As per Rhodes et al., currently three possible pharmacological interventions can be made for treating severe sepsis or septic shock.6 Initial intervention is intravenous antibiotic administration. Empiric antibiotic therapy should cover the most common pathogens such as Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Klebsiella spp, and/or Pseudomonas aeruginosa.1,2 Also, appropriate fluid resuscitation should be followed to replenish hypo-perfused organs and tissues. Current guidelines recommend administering 30 mL/kg of intravenous crystalloids. 2 If the fluid resuscitation fails and the patient continues to have severe hypotension (MAP <70 mmHg), an appropriate vasopressor is used. Current guidelines recommend norepinephrine as a first-line therapy to target MAP ≥65 mmHg within one hour.2,6 As a second line therapy, usually epinephrine or vasopressin with or without norepinephrine is used to increase MAP.2,6 Dopamine may be an alternative agent to norepinephrine in selected patients.2,6

In December 2017, the U.S. Food and Drug Administration approved angiotensin II (Giapreza®) as a new intravenous vasopressor to increase blood pressure in adults with septic or other vasodilatory shock. Giapreza® is chemically synthesized angiotensin II that works by activating the renin-angiotensin-aldosterone system (RAAS). Angiotensin II increases MAP by triggering the adrenal cortex to release aldosterone and constrict arteries.7 Angiotensin II may be given as an intravenous infusion through a central venous line. Initial dose of 20 ng/kg/minute is recommended and can be titrated by increments of up to 15 ng/kg/minute every 5 minutes as needed.7  Initial dose should not exceed 80 ng/kg/minute during the first 3 hours of treatment and maintenance dose should not exceed 40 ng/kg/minutes.7  In terms of pharmacokinetics, the half-life of angiotensin II is less than one minute.6 However, other formal studies on pharmacokinetics, drug interactions, and special population have not been conducted.

Angiotensin II is available as a 1 mL sterile liquid vial (2.5 mg/1 mL or 5 mg/2 mL) which is further diluted with sterile 0.9% sodium chloride to be administrated as an intravenous infusion. If the patient is not fluid restricted, 1 mL of angiotensin II should be diluted with 500 mL of 0.9% sodium chloride to have a final concentration of 5,000 ng/mL. If the patient is fluid restricted, 1 mL of angiotensin II should be diluted with 250 mL of 0.9% sodium chloride to have a final concentration of 10,000 ng/mL. Diluted solution is stable for up to 24 hours either at room temperature or under refrigeration.7

ATHOS-3 trial is a phase III, randomized, control trial that was designed to determine the efficacy of angiotensin II in improving blood pressure in patients with septic or vasodilatory shock. ATHOS-3 trial included patients 18 years of age and older who were admitted to the ICU due to vasodilatory shock but refractory to fluid resuscitation and vasopressors in the previous 24 hours. Patients with severe conditions such as burns, acute coronary syndrome, bronchospasm, or liver failure were excluded. The study randomized 344 patients into 1:1 ratio to received either angiotensin II or placebo.

Demographics were similar in both groups. Participants in the study were a median age of 64 years old with a mean initial MAP of 66.3 mmHg. 8 About 80.7% of all patients had a vasodilatory shock due to sepsis and others due to potential sepsis, pancreatitis, postoperative vasoplegia, and other multifactorial causes. 8 As a result, 69.9% of patients treated with angiotensin II with the standard of care (i.e. catecholamine) were able to reach to the target MAP (>75 mmHg or >10 mmHg increase from the baseline) at hour 3, as compared to only 23.4% of the patients treated with placebo and the standard of care vasopressor (OR 7.95, 95% CI 4.76-13.3, p<0.001%).8 These results showed that patients treated with angiotensin II, who significantly reached their target MAP within 5 minutes of infusion initiation, continued the effect for 3 hours.7,8 Moreover, patients on angiotensin II required less vasopressors (i.e. norepinephrine) than patients on placebo (-0.03 ± 0.10 vs. 0.03 ± 0.23, p<0.001).8

The safety profile of patients treated with angiotensin II and those with placebo was similar. In this trial, 87.1% of patients who received angiotensin II and 91.8% of patients who received placebo experienced adverse effects.8 Discontinuation due to severe adverse events occurred in 14.1% of patients who received angiotensin II and 21.5% in those who received placebo. 8 These adverse events included infection such as pneumonia, multiorgan failure, cardiac arrest, respiratory failure, and more. 8 In ATHOS-3 study, patients who received angiotensin II had a greater incidence of thromboembolic events such as deep venous thrombosis than those who received placebo.8 Therefore, a concurrent use of venous thromboembolism prophylaxis is recommended in patients who receive angiotensin II.7

Giapreza® comes in a single-dose vial (2.5 mg/1 mL or 5 mg/2 mL) with the average manufacturer price costs of $1,800.8 Giapreza® is about 17 times more expensive than norepinephrine, 10 times than epinephrine, and 1.5 times than vasopressin (Table 1)9.

Table1. Cost analysis of commercially available intravenous vasopressors for the treatment of severe hypotension in patients with sepsis or septic shock9

Treatment Options


Vial Size

AWP Package(Vial) Price


2.5 mg/1 mL

1 mL vial



20 u/1 mL

1 mL vial



1 mg/1 mL

1 mL vial



1 mg/1 mL

4 mL vial



80 mg/1 mL

5 mL vial


AWP, average wholesale price; u, units

Angiotensin II (Giapreza®) is a new therapeutic option in the treatment of septic shock that is refractory to initial vasopressors. Clinical studies have shown that angiotensin II (Giapreza®) is an efficacious add-on vasopressor to increase dangerously low blood pressure in patients with septic or other vasodilatory shock. Along with the standard of care, angiotensin II effectively increase MAP in 3 hours to the target MAP. Cost analysis shows that Giapreza® is the most expensive choice of vasopressors. Moreover, lack of drug interaction and pharmacokinetic data should be taken into account when encountering this medication. Further research should be conducted to determine drug interactions and evaluate longer term safety profile.                                                                                                                                                                                                              


1.       Angus DC, Poll TVD. Severe Sepsis and Septic Shock. N Engl J Med.2013;369(9):840-51.

2.       Levy MM, Evans LE, Rhodes A. The surviving sepsis campaign bundle: 2018 update. Crit Care Med. 2018; 46(6):997-1000.

3.       Neviere R.  Sepsis syndromes in adults: epidemiology, definitions, clinical presentation, diagnosis, and prognosis. In: Parsons PE, editor. UpToDate. [Internet]. Waltham, Mass.: UpToDate; 2018 [cited Octorber 16, 2018]. Available from:

4.       Jones AE, Trzeciak S, Kline JA. The sequential organ failure assessment score for predicting outcome in patients with severe sepsis and evidence of hypoperfusion at the time of emergency department presentation. Crit Care Med. 2009. 37(5): 1649-1654.

5.       Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368–77

6.       Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonella M, Ferrer R, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017 Mar; 43(3);304-377.

7.       Giapreza® (angiotensin II) [prescribing information]. San Diego, La Jolla Pharmaceutical Company; December2017.

8.       Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, et al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017; 377(5):419-30.

9.       IBM Micromedex RED BOOK [Internet]. Greenwood Village (CO): Truven Health Analytics; 2018 [cited 2018 Oct 2].

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