Interactions : אינטראקציות

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).



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.