Drug Interactions between diltiazem and vericiguat

MONITOR: Like many CNS-active agents, alcohol can exhibit hypotensive effects. Coadministration with antihypertensive agents including diltiazem may result in additive effects on blood pressure and orthostasis.

MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered diltiazem in some patients. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In a study of ten healthy male volunteers, administration of a single 120 mg oral dose of immediate-release diltiazem in combination with 250 mL of grapefruit juice increased the diltiazem peak plasma concentration (Cmax) and systemic exposure (AUC) by an average of 22% and 20%, respectively, compared to administration with water. The time to reach Cmax (Tmax) and the terminal half-life were not affected, and no statistically significant differences in blood pressure and heart rate were observed during administration with grapefruit juice relative to water. In a different study, repeated administration of 200 mL of grapefruit juice at 0, 2, 4, 8 and 12 hours had no significant effect on the Cmax or AUC of a single 120 mg oral dose of diltiazem, but increased its half-life from 4.1 to 5.1 hours. The ratios for the N-demethyl and deacetyl metabolites to diltiazem were also not affected by grapefruit juice. However, because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients should be advised that alcohol may potentiate the hypotensive effects of diltiazem, especially during the initiation of therapy and following a dosage increase. Caution should be exercised when rising from a sitting or recumbent position, and patients should notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients who regularly consume grapefruit or grapefruit juice should be monitored for increased adverse effects of diltiazem such as such as headache, irregular heartbeat, edema, unexplained weight gain, and chest pain. Grapefruit and grapefruit juice should be avoided if an interaction is suspected.

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.

MONITOR: Calcium-containing products may decrease the effectiveness of calcium channel blockers by saturating calcium channels with calcium. Calcium chloride has been used to manage acute severe verapamil toxicity.

MANAGEMENT: Management consists of monitoring the effectiveness of calcium channel blocker therapy during coadministration with calcium products.