Drug Interactions between Proben-C and Verelan

GENERALLY AVOID: Coadministration with grapefruit juice may increase the serum concentrations of colchicine. Clinical toxicity including myopathy, neuropathy, multiorgan failure, and pancytopenia may occur. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism and P-glycoprotein efflux in the gut wall by certain compounds present in grapefruits. A published case report describes an eight-year-old patient with familial Mediterranean fever who developed acute clinical colchicine intoxication after ingesting approximately one liter of grapefruit juice per day for two months prior to hospital admission while being treated with colchicine 2 mg/day. Her condition progressed to circulatory shock and multiorgan failure, but she recovered with supportive therapy after 24 days in the hospital. In a study of 21 healthy volunteers, administration of 240 mL grapefruit juice twice a day for 4 days was found to have no significant effect on the pharmacokinetics of a single 0.6 mg dose of colchicine. However, significant interactions have been reported with other CYP450 3A4 inhibitors such as clarithromycin, diltiazem, erythromycin, ketoconazole, ritonavir, and verapamil.

MANAGEMENT: Patients treated with colchicine should be advised to avoid the consumption of grapefruit and grapefruit juice, and to contact their physician if they experience symptoms of colchicine toxicity such as abdominal pain, nausea, vomiting, diarrhea, fatigue, myalgia, asthenia, hyporeflexia, paresthesia, and numbness.

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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: 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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