Drug Interaction Report

MONITOR: Bowel cleansing as well as overuse of certain laxatives may cause electrolyte loss and increase the risk of torsade de pointes ventricular arrhythmia in patients treated with drugs that prolong the QT interval. Electrolyte disturbances including hypokalemia and hypomagnesemia have been reported with laxative abuse and are known risk factors for torsade de pointes associated with QT interval prolongation.

MANAGEMENT: Patients treated with drugs that prolong the QT interval should exercise caution when self-medicating with laxatives. The recommended dosage and duration of use should not be exceeded. Patients treated with lactulose for more than six months should be monitored periodically for electrolyte imbalance. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

CONTRAINDICATED: Coadministration with grapefruit juice may increase the plasma concentrations of cisapride. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In a study of 14 healthy volunteers, administration with 250 mL of grapefruit juice increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of cisapride (10 mg single dose) by 34% and 39%, respectively, compared to water. A second single-dose study involving 12 healthy volunteers demonstrated an increase of 68% and 51% in cisapride Cmax and AUC, respectively, compared to water. In another 10 healthy volunteers, repeated ingestion of double-strength grapefruit juice (200 mL three times a day for 2 days, then with a 10 mg dose of cisapride and at 0.5 and 1.5 hours afterwards) resulted in an 81% and 144% increase in mean cisapride Cmax and AUC, respectively, compared to water. A high degree of intersubject variability in the grapefruit juice effect was observed in all three studies, but no patient experienced any changes in heart rate, blood pressure, or QT interval. However, high plasma levels of cisapride have been associated with prolongation of the QT interval on the ECG; ventricular arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsade de pointes; cardiac arrest; and sudden death.

GENERALLY AVOID: Coadministration with red wine may increase the plasma concentrations of cisapride in susceptible individuals. The exact mechanism of interaction is unknown but is believed to involve inhibition of CYP450 3A4 in the gut wall similar to grapefruit juice. In 12 healthy volunteers, administration with 250 mL of red wine (cabernet sauvignon) produced only minor and statistically insignificant changes in cisapride pharmacokinetics compared to water. However, one subject had a doubling in cisapride AUC and Cmax with red wine. The same subject also had the largest interaction with grapefruit juice, which suggests that a significant interaction may occur in certain individuals, perhaps those with a preexisting high intestinal CYP450 3A4 content.

MANAGEMENT: Patients receiving cisapride therapy should avoid the consumption of grapefruits and grapefruit juice. Because a significant interaction may occur with red wine in the occasional patient, red wine should preferably be avoided also during cisapride therapy.

MONITOR: Oral caffeine may significantly increase the bioavailability of melatonin. The proposed mechanism is inhibition of CYP450 1A2 first-pass metabolism. After administration of melatonin 6 mg and caffeine 200 mg orally (approximately equivalent to 1 large cup of coffee) to 12 healthy subjects, the mean peak plasma concentration (Cmax) of melatonin increased by 137% and the area under the concentration-time curve (AUC) increased by 120%. The metabolic inhibition was greater in nonsmokers (n=6) than in smokers (n=6). The greatest effect was seen in subjects with the *1F/*1F genotype (n=7), whose melatonin Cmax increased by 202%. The half-life did not change significantly. The clinical significance of this interaction is unknown.

According to some authorities, alcohol may reduce the effect of melatonin on sleep. The mechanism of this interaction is not fully understood.

In addition, CYP450 1A2 inducers like cigarette smoking may reduce exogenous melatonin plasma levels. In a small clinical trial (n=8), habitual smokers had their melatonin plasma levels measured two times, each after a single oral dose of 25 mg of melatonin. They had smoked prior to the first measurement but had not smoked for 7 days prior to the second. Cigarette smoking significantly reduced melatonin plasma exposure (AUC) as compared to melatonin levels after 7 days of smoking abstinence (7.34 +/- 1.85 versus 21.07 +/- 7.28 nmol/L*h, respectively).

MANAGEMENT: Caution and monitoring are recommended if melatonin is used with inhibitors of CYP450 1A2 like caffeine or inducers of CYP450 1A2 like cigarette smoking. Consumption of alcohol should be avoided when taking melatonin.