Vericiguat

Addition of single doses of sildenafil (25, 50, or 100 mg) to multiple doses of vericiguat (10 mg) once daily in healthy subjects was associated with additional seated blood pressure (BP) reduction of less than or equal to 5.4 mmHg (systolic/diastolic BP, mean arterial pressure [MAP]) compared to administration of vericiguat alone. No dose-dependent trend was observed with the different sildenafil doses.

Co-administration was not associated with a clinically relevant effect on the exposure (AUC and C_max) of either medicinal product.

Concomitant use of vericiguat and PDE5 inhibitors, such as sildenafil, has not been studied in patients with heart failure and is therefore not recommended due to the potential increased risk for symptomatic hypotension.

Vericiguat is metabolised by UGT1A9 and UGT1A1. Inhibitors of these UGTs may result in increased exposure of vericiguat. No clinically meaningful effect on vericiguat exposure was observed when vericiguat was coadministered with mefenamic acid (weak to moderate UGT1A9 inhibitor). As strong inhibition of UGT1A9 or combined UGT1A9/1A1 has not been tested in clinical drug-drug interaction studies due to the lack of available inhibitors, the clinical consequences of coadministration with these medicinal products are currently unknown.

Treatment with vericiguat is not recommended in patients with eGFR <15 mL/min/1.73 m² at treatment initiation or on dialysis.

Treatment with vericiguat is not recommended in patients with severe hepatic impairment.

There are no data from the use of vericiguat in pregnant women. Studies in animals have shown reproductive toxicity in presence of maternal toxicity. As a precautionary measure, vericiguat should not be used during pregnancy and in women of childbearing potential not using contraception.

There is no information regarding the presence of vericiguat in human milk, the effects on the breastfed infant, or the effects on milk production. Vericiguat is present in the milk of lactating rats. A risk to the breastfed child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue or abstain from vericiguat therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data available on the effect of vericiguat on human fertility. In a study with male and female rats, vericiguat showed no impairment of fertility.

Vericiguat has minor influence on the ability to drive or use machines. When driving vehicles or operating machines it should be taken into account that dizziness may occur occasionally.

Summary of the safety profile

The most frequently reported adverse reaction under treatment with vericiguat was hypotension (16.4%).

Tabulated list of adverse reactions

The safety of vericiguat was evaluated in a phase III study (VICTORIA) which included a total of 2,519 patients treated with vericiguat (up to 10 mg once daily). The mean duration of vericiguat exposure was 1 year and the maximum duration was 2.6 years.

The adverse reactions reported with vericiguat obtained from clinical studies are listed in the table below by MedDRA system organ class and by frequency. Frequencies 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).

Adverse reactions:

Description of selected adverse reactions

Hypotension

Over the course of the VICTORIA study, the mean reduction in systolic blood pressure was approximately 1 to 2 mmHg greater in patients who received vericiguat compared with placebo. In VICTORIA, hypotension was reported in 16.4% of vericiguat-treated patients compared with 14.9% of placebo-treated patients. This includes also orthostatic hypotension that was reported in 1.3% of vericiguat-treated patients compared with 1.0% of placebo-treated patients. Symptomatic hypotension was reported in 9.1% of vericiguat-treated and 7.9% of placebo-treated patients, and was considered as a serious adverse event in 1.2% of vericiguat-treated patients and 1.5% of placebo-treated patients.