Drug Interaction Report

MONITOR: The chronic use or abuse of laxatives may potentiate the pharmacologic effects of diuretics. Laxatives can cause significant losses of fluid and electrolytes, including sodium, potassium, magnesium and zinc, and these effects may be additive to those of diuretics.

MANAGEMENT: In general, laxatives should only be used on a short-term, intermittent basis in recommended dosages. During concomitant use with diuretics, patients should be advised to contact their physician if they experience signs and symptoms of fluid and electrolyte depletion such as dizziness, lightheadedness, dry mouth, thirst, fatigue, weakness, lethargy, muscle cramps, decreased urination, postural hypotension, and tachycardia. If maintenance of bowel regularity is required, patients should be advised to exercise and increase fiber in the diet and/or consider the use of bulk-forming laxatives.

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.