4.1. Therapeutic indications

Giapreza is indicated for the treatment of refractory hypotension in adults with septic or other distributive shock who remain hypotensive despite adequate volume restitution and application of catecholamines and other available vasopressor therapies (see section 5.1).

4.2. Posology and method of administration

Giapreza should be prescribed by a physician experienced in the treatment of shock and is intended for use in an acute and hospital setting.

Posology

The recommended starting dose of Giapreza is 20 nanograms (ng)/kg per minute via continuous intravenous infusion.

When initiating, it is important to closely monitor blood pressure response and adjust dose accordingly. Concurrent venous thromboembolism (VTE) prophylaxis should be used unless contraindicated during treatment with Giapreza (see section 4.4).

Once an infusion has been established, the dose may be titrated as frequently as every 5 minutes in steps of up to 15 ng/kg per minute, as needed, depending on the patient's condition and target mean arterial pressure. Approximately one in every four patients experienced transient hypertension with the angiotensin II 20 ng/kg per minute starting dose in clinical trials (see section 4.8), thus needing dose down-titration. For critically ill patients, the usual target mean arterial pressure is 65 – 75 mmHg. Do not exceed 80 ng/kg per minute during the first 3 hours of treatment. Maintenance doses should not exceed 40 ng/kg per minute. Doses as low as 1.25 ng/kg per minute may be used.

It is important to administer Giapreza at the lowest compatible dose to achieve or maintain adequate arterial blood pressure and tissue perfusion (see section 4.4). The median duration of treatment in clinical trials was 48 hours (range: 3.5 to 168 hours).

In order to minimise the risk of adverse events derived from prolonged vasoconstriction, treatment with Giapreza should be withdrawn once underlying shock is sufficiently improved. Down-titrate by gradual decrements of up to 15 ng/kg per minute, as needed, based on blood pressure, in order to avoid hypotension due to abrupt withdrawal (see section 4.4).

Special populations

Elderly

There are limited efficacy and safety data of Giapreza in patients > 75 years. No special dose adjustment is required in patients over 75 years. As for other age groups, it is important to closely monitor blood pressure response and adjust dose accordingly.

Renal or hepatic impairment

No special dose adjustment is required in patients with renal insufficiency or those with hepatic impairment (see section 5.2). As for other patient populations, it is important to closely monitor blood pressure response and adjust dose accordingly.

Paediatric population

The safety and efficacy of Giapreza in children less than 18 years old has not yet been established. No data are available.

Method of administration

Giapreza should only be administered by continuous intravenous infusion under close monitoring of haemodynamics and end-organ perfusion.

For intravenous use only after dilution. Giapreza is recommended to be administered via a central venous line.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

The clinical experience with Giapreza is limited to septic or other distributive shock. The use of Giapreza is not recommended in other types of shock (e.g. cardiogenic shock, etc) as patients with non-distributive shocks were excluded from clinical trials (see section 5.1).

Thromboembolic events

Thromboembolic events have been reported with the use of angiotensin II in clinical trials. The major imbalance compared to placebo was in venous thromboembolism (6.1% vs 0%) (see section 4.8). Concurrent venous thromboembolism (VTE) prophylaxis should be used unless contraindicated during treatment with Giapreza. Non-pharmacologic VTE prophylaxis may be considered where pharmacologic prophylaxis is contraindicated.

Peripheral ischaemia

Peripheral ischaemia has been reported with the use of angiotensin II (see section 4.8). It is important to administer Giapreza at the lowest compatible dose to achieve or maintain adequate mean arterial pressure and tissue perfusion.

Withdrawal of therapy

Giapreza should be gradually decreased since patients may experience hypotension or worsening of the underlying diagnosis of shock on abrupt withdrawal or premature discontinuation (see section 4.2).

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per 2.5 mg/ml, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. No in vitro metabolism studies have been performed with Giapreza.

Patients who have recently received angiotensin converting enzyme (ACE) inhibitors may be more sensitive to Giapreza's action with an increased response. Patients who have recently received angiotensin II receptor blockers (ARBs) may be less sensitive to Giapreza's actions with a reduced response.

Concomitant administration of Giapreza and other vasopressors may have an additive effect on mean arterial pressure (MAP). The addition of Giapreza may require a reduction in doses of other vasopressors (e.g. adrenergic or dopaminergic agents).

4.6. Fertility, pregnancy and lactation

Pregnancy

There is a limited amount of data from the use of angiotensin II in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. Use during pregnancy should be avoided if possible and the potential benefit to the patient weighed against any possible risk to the foetus.

Breast-feeding

It is unknown whether angiotensin II or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with Giapreza.

Fertility

There are no data available on the potential effects on fertility in humans.

4.7. Effects on ability to drive and use machines

Not relevant.

4.8. Undesirable effects

Summary of the safety profile

The adverse reactions described in this section were identified in the pivotal clinical trial (N = 163 treated with Giapreza). The most frequent adverse reactions reported in the Giapreza versus placebo arm are thromboembolic events (12.9% vs 5.1%) and transient hypertension (22.7% vs 1.9%) respectively.

Tabulated list of adverse reactions

Table 1 lists the adverse reactions recorded in clinical trials in the total safety population treated with Giapreza by MedDRA system organ class and frequency. Frequency categories are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), and very rare (< 1/10 000).

Table 1: Frequency of adverse reactions

MedDRA System organ class

Very common

Common

Cardiac disorders

Tachycardia

Vascular disorders

Thromboembolic eventsa

Transient hypertensionb

Peripheral ischaemia

a Grouped term to include arterial and venous thrombotic events

b Defined as an increase in mean arterial pressure > 100 mmHg

Description of selected adverse reactions

Transient hypertension

A total of 37 patients (23%) experienced transient hypertension with the angiotensin II 20 ng/kg/min starting dose. Transient hypertension may be promptly mitigated by dose down-titration (see section 4.2).

Thromboembolic events

More patients experienced venous and arterial thromboembolic events in the Giapreza arm compared to placebo arm in the Phase 3 (ATHOS-3) study (21 [12.9%] vs 8 [5.1%]). The major imbalance corresponded to venous thromboembolism (10 [6.1%] vs 0 [0%] respectively). Of these, 7 cases corresponded to deep vein thrombosis. Two (1.2%) patients in the Giapreza arm experienced a fatal thromboembolic event compared with no patients in the placebo arm. Concurrent venous thromboembolism prophylaxis should be used unless contraindicated during treatment with Giapreza (see section 4.4).

Peripheral ischaemia

More patients experienced peripheral ischaemia in the Giapreza arm compared to the placebo arm (7 [4.3%] vs 4 [2.5%]). Of them, 5 cases (3.1%) in the Giapreza arm and 3 (1.9%) cases in the placebo arm were considered serious. One patient in each arm discontinued treatment as a result. Peripheral ischaemia may be a consequence of the mechanism of action of Giapreza. It is important to administer Giapreza at the lowest compatible dose to achieve or maintain adequate mean arterial pressure and tissue perfusion. In order to minimise adverse events derived from prolonged vasoconstriction, treatment should be withdrawn as soon as the underlying shock is sufficiently improved (see sections 4.2 and 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Overdose may result in severe hypertension. Down-titration of therapy, careful observation, and initiation of appropriate supportive measures are the indicated treatment of overdose of angiotensin II.

Hypertensive effects are expected to be brief because the half-life of angiotensin II is less than one minute.