GIAPREZA Concentrate for solution for infusion Ref.[51552] Active ingredients: Angiotensin II

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 prophylaxis (VTE) 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.

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’.

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

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.

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.

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.

Not relevant.

Summary of the safety profile

The adverse reactions described in this section were identified in the pivotal clinical study (N=163 treated with GIAPREZA). The most frequent adverse reactions reported more often in the GIAPREZA arm are thromboembolic events (12.9% vs 5.1%) and transient hypertension.

Tabulated list of adverse reactions

Table 2 lists the adverse reactions recorded in clinical studies 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 2. Frequency of adverse reactions:

^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 national reporting system listed in Appendix V.

GIAPREZA may be co-administered with norepinephrine, epinephrine, vasopressin, terlipressin, dopamine, and/or phenylephrine.