4.1. Therapeutic indications

Verquvo is indicated for the treatment of symptomatic chronic heart failure in adult patients with reduced ejection fraction who are stabilised after a recent decompensation event requiring IV therapy (see section 5.1).

4.2. Posology and method of administration

Posology

Vericiguat is administered in conjunction with other heart failure therapies.

Before starting vericiguat, care should be taken to optimise volume status and diuretic therapy to stabilise patients after the decompensation event, particularly in patients with very high NT-proBNP levels (see section 5.1).

The recommended starting dose is 5 mg vericiguat once daily. The dose should be doubled after approximately 2 weeks to reach the target maintenance dose of 10 mg once daily, as tolerated by the patient.

For patients with symptomatic hypotension within the past 4 weeks, the recommended starting dose is 2.5 mg vericiguat once daily. The dose should be doubled approximately every 2 weeks to reach the target maintenance dose of 10 mg once daily, as tolerated by the patient.

If patients experience tolerability issues (symptomatic hypotension or systolic blood pressure [SBP] less than 90 mmHg), temporary down-titration or discontinuation of vericiguat is recommended (see section 4.4).

Treatment should not be initiated in patients with SBP <100 mmHg (see section 4.4).

Missed dose

If a dose is missed, it should be taken as soon as the patient remembers on the same day of the missed dose. Patients should not take two doses of vericiguat on the same day.

Special populations

Elderly

No dose adjustment is required for elderly patients (see sections 5.1 and 5.2).

Renal impairment

No dose adjustment is required in patients with estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m2 (without dialysis). Treatment with vericiguat is not recommended in patients with eGFR <15 mL/min/1.73 m2 at treatment initiation or on dialysis (see sections 4.4 and 5.2).

Hepatic impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment. Treatment with vericiguat is not recommended in patients with severe hepatic impairment (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of vericiguat in children and adolescents aged below 18 years have not yet been established. No clinical data are available. Undesirable effects were observed on growing bone in non-clinical studies (see section 5.3).

Method of administration

For oral use. Verquvo should be taken with food (see section 5.2).

Crushed tablets

For patients who are unable to swallow whole tablets, Verquvo may be crushed and mixed with water immediately before administration (see section 5.2).

4.3. Contraindications

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

- Concomitant use of other soluble guanylate cyclase (sGC) stimulators, such as riociguat (see section 4.5).

4.4. Special warnings and precautions for use

Symptomatic hypotension

Vericiguat may cause symptomatic hypotension (see section 4.8). Patients with SBP less than 100 mmHg or symptomatic hypotension at treatment initiation were not studied.

The potential for symptomatic hypotension should be considered in patients with hypovolaemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, history of hypotension, or concomitant treatment with antihypertensives or organic nitrates (see section 4.5). If patients experience tolerability issues (symptomatic hypotension or SBP less than 90 mmHg), temporary down-titration or discontinuation of vericiguat is recommended (see section 4.2).

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 (see section 4.5).

Renal impairment

Patients with eGFR <15 mL/min/1.73 m2 at treatment initiation or on dialysis have not been studied, therefore treatment with vericiguat is not recommended in these patients (see sections 4.2 and 5.2).

Hepatic impairment

Patients with severe hepatic impairment have not been studied, therefore treatment with vericiguat is not recommended in these patients (see sections 4.2 and 5.2).

Excipients

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”.

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

Pharmacodynamic interactions

Vericiguat co-administration with haemodynamic active substances did not result in a more than additive effect (see sections 4.4 and 5.1). In addition, vericiguat reduced systolic blood pressure by approximately 1 to 2 mmHg when co-administered with other medicinal products used in patients with heart failure (see section 4.8).

Other soluble guanylate cyclase (sGC) stimulators

Verquvo is contraindicated in patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators, such as riociguat (see section 4.3).

PDE5 inhibitors

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 Cmax) 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 (see section 4.4).

Acetylsalicylic acid

Administration of a single dose of vericiguat (15 mg) in healthy subjects did not alter the effect of acetylsalicylic acid (500 mg) on bleeding time or platelet aggregation. Bleeding time or platelet aggregation did not change under treatment with vericiguat (15 mg) alone.

Co‑administration of acetylsalicylic acid was not associated with a clinically relevant effect on the exposure (AUC and Cmax) of vericiguat.

Warfarin

Administration of multiple doses of vericiguat (10 mg) once daily in healthy subjects did not alter the effect of a single dose of warfarin (25 mg) on prothrombin time and the activities of Factors II, VII, and X.

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

Combination of sacubitril/valsartan

Addition of multiple doses of vericiguat (2.5 mg) to multiple doses of sacubitril/valsartan (97/103 mg) in healthy subjects had no additional effect on seated blood pressure compared to administration of sacubitril/valsartan alone.

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

Organic nitrates

Co‑administration of multiple doses of vericiguat increased to 10 mg once daily did not significantly alter the seated blood pressure effects of short‑ and long-acting nitrates (nitroglycerin spray and isosorbide mononitrate [ISMN]) in patients with coronary artery disease. In patients with heart failure, concomitant use of short-acting nitrates was well tolerated. There is limited experience with concomitant use of vericiguat and long-acting nitrates in patients with heart failure (see section 4.4).

Pharmacokinetic interactions

Vericiguat is eliminated via multiple routes in humans. The dominant route is glucuronidation via UGT1A9 and UGT1A1, and vericiguat does not affect the pharmacokinetics of other medicinal products (see section 5.2).

UGT1A9/1A1 inhibitors

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 co-administered 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 co-administration with these medicinal products are currently unknown.

Concomitant use with medicinal products that increase gastric pH

Co‑treatment with medicinal products that increase gastric pH, such as proton pump inhibitors (omeprazole), H2‑receptor antagonists or antacids (aluminium hydroxide/magnesium hydroxide) did not affect vericiguat exposure when vericiguat was taken as directed with food in heart failure patients (see section 4.2).

No significant interactions

Concomitant administration of medicinal products affecting one or more of vericiguat´s elimination pathways does not have a clinically relevant effect on the pharmacokinetics of vericiguat.

No clinically meaningful effect on vericiguat exposure was observed when vericiguat was co‑administered with ketoconazole (multi‑pathway CYP and transporter inhibitor), or rifampicin (multi‑pathway UGT, CYP and transporter inducer).

No clinically meaningful effect on midazolam (CYP3A substrate) or digoxin (P‑gp substrate) exposure was observed when vericiguat was co‑administered with these medicinal products.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of vericiguat in pregnant women. Studies in animals have shown reproductive toxicity in the presence of maternal toxicity (see section 5.3). As a precautionary measure, vericiguat should not be used during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

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 (see section 5.3).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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) (see section 5.1). 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).

Table 1: Adverse reactions

MedDRA system organ class

Very common

Common

Blood and lymphatic system disorders

Anaemia

Nervous system disorders

Dizziness

Headache

Vascular disorders

Hypotension

Gastrointestinal disorders

Nausea

Dyspepsia

Vomiting

Gastro-oesophageal reflux disease

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 (see section 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.yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Overdose of vericiguat may lead to hypotension. If necessary, symptomatic treatment should be provided. The medicinal product is unlikely to be removed by haemodialysis due to high protein binding.