Drug Interactions between Dilt-XR and trandolapril / verapamil

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.

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GENERALLY AVOID: Consumption of large quantities of grapefruit juice may be associated with significantly increased plasma concentrations of oral verapamil. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. One study reported no significant effect of a single administration of grapefruit juice on the pharmacokinetics of verapamil in ten hypertensive patients receiving chronic therapy. In another study conducted in nine healthy male volunteers, administration of 120 mg oral verapamil twice daily for 3 days following pretreatment with 200 mL grapefruit juice twice daily for 5 days resulted in a 57% increase in S-verapamil peak plasma concentration (Cmax), a 36% increase in S-verapamil systemic exposure (AUC), a 40% increase in R-verapamil Cmax, and a 28% increase in R-verapamil AUC compared to administration following orange juice. Elimination half-life and renal clearance of both S- and R-verapamil were not affected by grapefruit juice, and there were no significant effects on blood pressure, heart rate, or PR interval. A third study reported a 1.63-fold increase in Cmax and a 1.45-fold increase in AUC of (R,S)-verapamil in 24 young, healthy volunteers given verapamil sustained-release 120 mg twice daily for 7 days with 250 mL grapefruit juice four times daily on days 5 through 7. Two subjects developed PR interval prolongation of more than 350 ms during grapefruit juice coadministration. A high degree of interindividual variability has been observed in these studies. The interaction was also suspected in a case report of a 42-year-old woman who developed complete heart block, hypotension, hypoxic respiratory failure, severe anion gap metabolic acidosis, and hyperglycemia following accidental ingestion of three verapamil sustained-release 120 mg tablets over a span of six hours. The patient's past medical history was remarkable only for migraine headaches, for which she was receiving several medications including verapamil. Prior to admission, the patient had a 2-week history of poorly controlled migraine, and the six hours preceding hospitalization she suffered from worsening headache and palpitations progressing to altered sensorium. An extensive workup revealed elevated verapamil and norverapamil levels more than 4.5 times above the upper therapeutic limits. These levels also far exceeded those reported in the medical literature for patients taking verapamil 120 mg every 6 hours, or 480 mg in a 24-hour period. The patient recovered after receiving ventilator and vasopressor support. Upon questioning, it was discovered that the patient had been drinking large amounts of grapefruit juice (3 to 4 liters total) the week preceding her admission due to nausea. No other sources or contributing factors could be found for the verapamil toxicity.

MANAGEMENT: Patients treated with oral verapamil should avoid the consumption of large amounts of grapefruit or grapefruit juice to prevent any undue fluctuations in serum drug levels. Patients should be advised to seek medical attention if they experience edema or swelling of the lower extremities; sudden, unexplained weight gain; difficulty breathing; chest pain or tightness; or hypotension as indicated by dizziness, fainting, or orthostasis.

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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.

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GENERALLY AVOID: Verapamil may increase the blood concentrations and intoxicating effects of ethanol. The exact mechanism of interaction is unknown but may involve verapamil inhibition of ethanol metabolism. In 10 healthy, young volunteers, verapamil (80 mg orally every 8 hours for 6 days) increased the mean peak blood concentration (Cmax) and the 12-hour area under the concentration-time curve (AUC) of ethanol (0.8 g/kg single oral dose) by 17% and 30%, respectively, compared to placebo. Verapamil AUCs were positively correlated to increased ethanol blood AUC values. Subjectively (i.e. each subject's perception of intoxication as measured on a visual analog scale), verapamil also significantly increased the area under the ethanol effect versus time curve but did not change the peak effect or time to peak effect.

MANAGEMENT: Patients treated with verapamil should be counseled to avoid alcohol consumption.

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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.

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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.

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The recommended maximum number of medicines in the 'antiarrhythmics' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'antiarrhythmics' category:

• Dilt-XR (diltiazem)
• trandolapril/verapamil

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'calcium channel blockers' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'calcium channel blockers' category:

• Dilt-XR (diltiazem)
• trandolapril/verapamil

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'group IV antiarrhythmics' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'group IV antiarrhythmics' category:

• Dilt-XR (diltiazem)
• trandolapril/verapamil

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.