Drug Interactions between cinacalcet and clomipramine

MONITOR: Limited data suggest that the administration of clomipramine with grapefruit juice or cranberry juice may significantly increase plasma drug concentrations of clomipramine. Clomipramine is initially demethylated by CYP450 1A2, 3A3 and 3A4 before undergoing further metabolism to 8-hydroxyclomipramine. The increase in clomipramine bioavailability may stem from inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The precise mechanism by which cranberry juice exerts its effects is unknown, but may involve inhibition of CYP450 isoenzymes. This interaction has occasionally been exploited in attempts to improve symptomatic control of obsessive compulsive disorder.

MANAGEMENT: Patients receiving clomipramine therapy who ingest cranberry juice, grapefruits, or grapefruit juice should be monitored for adverse effects and undue fluctuations in plasma drug levels.

ADJUST DOSING INTERVAL: Food enhances the oral absorption and bioavailability of cinacalcet. According to the product labeling for cinacalcet, administration with a high-fat meal increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of cinacalcet by 82% and 68%, respectively, compared to administration in the fasting state. The Cmax and AUC were increased 65% and 50%, respectively, when cinacalcet was administered with a low-fat meal compared to fasting.

MANAGEMENT: To ensure maximal oral absorption, cinacalcet should be administered with or immediately after a meal. The tablets should be taken whole and not divided or crushed.

GENERALLY AVOID: The combination of ethanol and a tricyclic antidepressant may result in additive impairment of motor skills, especially driving skills. Also, one study has suggested that clomipramine metabolism is significantly impaired for several weeks or more following discontinuation of chronic alcohol consumption.

MANAGEMENT: Patients should be warned of this interaction and advised to limit their ethanol intake while taking tricyclic antidepressants. Monitoring for TCA toxicity (CNS depression, excessive anticholinergic effects, hypotension, arrhythmias) is recommended during alcohol withdrawal.