Drug Interaction Report

ADJUST DOSE: Coadministration with moderate inhibitors of CYP450 3A4 may increase the plasma concentrations of eplerenone, which is primarily metabolized by the isoenzyme. In pharmacokinetic studies, administration of a single 100 mg dose of eplerenone in combination with the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice a day) resulted in a 1.7-fold increase in eplerenone peak plasma concentration (Cmax) and a 5.4-fold increase in systemic exposure (AUC), while administration with moderate inhibitors (erythromycin 500 mg twice daily; verapamil 240 mg once daily; saquinavir 1200 mg three times daily; fluconazole 200 mg once daily) resulted in increases in eplerenone Cmax ranging from 1.4- to 1.6-fold and AUC from 2.0- to 2.9-fold.

MANAGEMENT: For the treatment of heart failure with reduced ejection fraction (HFrEF) after an acute myocardial infarction, the dosage of eplerenone should not exceed 25 mg once daily when used with moderate CYP450 3A4 inhibitors. For the treatment of hypertension in combination with moderate CYP450 3A4 inhibitors, eplerenone should be started at 25 mg once daily. If the blood pressure response is inadequate, eplerenone may be increased to a maximum of 25 mg twice daily. Patients already on eplerenone who start treatment with a moderate CYP450 3A4 inhibitor should have serum potassium and creatinine checked in 3 to 7 days.

MONITOR: Coadministration of eplerenone with ACE inhibitors or angiotensin II receptor antagonists may increase the risk of hyperkalemia due to additive pharmacodynamic effects. In clinical studies of patients with hypertension, the addition of eplerenone 50 to 100 mg to ACE inhibitors and angiotensin II receptor antagonists increased mean serum potassium slightly, by about 0.09 to 0.13 mEq/L. However, the concomitant use of another mineralocorticoid receptor blocker with these agents has led to clinically relevant hyperkalemia. In a study of diabetics with microalbuminuria, the combination of eplerenone 200 mg and enalapril 10 mg resulted in increased frequency of hyperkalemia (i.e., serum potassium greater than 5.5 mEq/L) compared to enalapril alone (38% vs. 17%). In a study of eplerenone 25 to 50 mg for the treatment of congestive heart failure postmyocardial infarction, maximum potassium levels exceeding 5.5 mEq/L were observed at a similar rate in the 90% of patients who also received ACE inhibitors or angiotensin II receptor antagonists compared to the patients who didn't.

MANAGEMENT: Given the potential for serious, sometimes fatal cardiac arrhythmias associated with hyperkalemia, caution is advised if eplerenone is administered with ACE inhibitors or angiotensin II receptor antagonists. Periodic monitoring of serum potassium levels is recommended until the effect of eplerenone is established. In clinical trials, monitoring occurred every 2 weeks for the first 1 to 2 months, then monthly thereafter. Particular caution is warranted in patients with renal impairment, diabetes, old age, or dehydration. Patients should be advised to seek medical attention if they experience signs and symptoms of hyperkalemia such as nausea, vomiting, weakness, listlessness, tingling of the extremities, paralysis, confusion, weak pulse, and a slow or irregular heartbeat.

Calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors may have additive hypotensive effects. While these drugs are often safely used together, careful monitoring of the systemic blood pressure is recommended during coadministration, especially during the first one to three weeks of therapy.

GENERALLY AVOID: Moderate-to-high dietary intake of potassium can cause hyperkalemia in some patients who are using angiotensin converting enzyme (ACE) inhibitors. In some cases, affected patients were using a potassium-rich salt substitute. ACE inhibitors can promote hyperkalemia through inhibition of the renin-aldosterone-angiotensin (RAA) system.

MANAGEMENT: It is recommended that patients who are taking ACE inhibitors be advised to avoid moderately high or high potassium dietary intake. Particular attention should be paid to the potassium content of salt substitutes.

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.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of eplerenone. The primary mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Inhibition of hepatic CYP450 3A4 may also contribute. In drug interaction studies, administration of a single 100 mg dose of eplerenone in combination with grapefruit juice resulted in a 25% increase in eplerenone systemic exposure (AUC). High blood levels of eplerenone can increase the risk of side effects including hyperkalemia. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

MANAGEMENT: It may be advisable for patients to avoid the consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with eplerenone.

MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients should also avoid driving or operating hazardous machinery until they know how the medications affect them.

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.