Angiotensin II

Patients who have recently received angiotensin converting enzyme (ACE) inhibitors may be more sensitive to angiotensin II’s action with an increased response.

Patients who have recently received angiotensin II receptor blockers (ARBs) may be less sensitive to angiotensin II’s actions with a reduced response.

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.

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 angiotensin II.

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 angiotensin II). The most frequent adverse reactions reported more often in the angiotensin II arm are thromboembolic events (12.9% vs 5.1%) and transient hypertension.

Tabulated list of adverse reactions

The table below lists the adverse reactions recorded in clinical studies in the total safety population treated with angiotensin II 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).

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.

Thromboembolic events

More patients experienced venous and arterial thromboembolic events in the angiotensin II 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 angiotensin II 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 angiotensin II.

Peripheral ischaemia

More patients experienced peripheral ischaemia in the angiotensin II arm compared to the placebo arm (7 [4.3%] vs 4 [2.5%]). Of them, 5 cases (3.1%) in the angiotensin II 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 angiotensin II. It is important to administer angiotensin II 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.