Drug Interaction Report

MONITOR: Vericiguat may cause hypotension and coadministration with antihypertensives, organic nitrates, or agents with hypotensive properties may increase the potential for symptomatic hypotension, especially in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or patients with a history of hypotension. Patients with heart failure receiving hemodynamically active substances have reported systolic blood pressure (SBP) reductions of approximately 1 to 2 mmHg with concomitant use. Co-administration of multiple doses of vericiguat up to 10 mg once daily did not significantly alter the seated blood pressure effects of short- and long-acting nitrates in patients with coronary artery disease and concomitant use of short-acting nitrates was well tolerated in patients with heart failure. However, there is limited experience with concomitant use of vericiguat and long-acting nitrates in patients with heart failure and no data on initiation of vericiguat in patients with systolic blood pressure (SBP) less than 100 mmHg or symptomatic hypotension at treatment initiation.

MANAGEMENT: If patients experience tolerability issues (symptomatic hypotension or SBP less than 90 mmHg), temporary down-titration or discontinuation of vericiguat is recommended.

GENERALLY AVOID: The consumption of grapefruit juice may be associated with significantly increased plasma concentrations of some calcium channel blockers (CCBs) when they are administered orally. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. The interaction has been reported with the dihydropyridine CCBs (in roughly decreasing order of magnitude) felodipine, nisoldipine, nifedipine, and nimodipine, often with a high degree of interindividual variability. Grapefruit juice caused more than twofold increases in felodipine, nifedipine, and nisoldipine AUCs.

MANAGEMENT: The manufacturers of nifedipine and nisoldipine recommend avoiding grapefruit juice. Patients treated orally with other calcium channel blockers should be advised to avoid consumption of large amounts of grapefruits and grapefruit juice to prevent any undue fluctuations in serum drug levels. Increased effects on blood pressure may persist for up to 4 days after the consumption of grapefruit juice. Monitoring for calcium channel blocker adverse effects (e.g., headache, hypotension, syncope, tachycardia, edema) is recommended.

ADJUST DOSING INTERVAL: Administration of vericiguat with food reduces its pharmacokinetic variability and increases its exposure. Vericiguat is less soluble at neutral pH than at acidic pH. Administration of vericiguat with a high-fat, high-calorie meal or low-fat, high-carbohydrate meal increased time to reach peak plasma concentration (Tmax) from about 1 hour (fasted) to about 4 hours (fed) and increased vericiguat systemic exposure (AUC) by 19% and peak plasma concentration (Cmax) by 9% for the 5 mg tablet and by 44% (AUC) and 41% (Cmax) for the 10 mg tablet as compared with the fasted state. Concurrent treatment with drugs that increase gastric pH, such as proton pump inhibitors or antacids, decrease vericiguat AUC by about 30%. Co-treatment with drugs that increase gastric pH did not affect vericiguat exposure in patients with heart failure when vericiguat was taken as directed with food.

MANAGEMENT: Administer vericiguat with food to ensure maximal exposure and decrease pharmacokinetic variability.