Drug Interaction Report

ADJUST DOSING INTERVAL: Colesevelam may decrease the gastrointestinal absorption of coadministered drugs. Approximately 20% to 40% reductions in systemic exposure (AUC) and 10% to 45% reductions in peak plasma concentration (Cmax) have been reported for cyclosporine, ethinyl estradiol, glimepiride, glyburide, levothyroxine, olmesartan, and sustained-release verapamil during coadministration with colesevelam. Significant pharmacokinetic changes were not observed when the drugs were administered 4 hours prior to colesevelam. During postmarketing use of colesevelam, there have been rare reports of suspected interaction with phenytoin, as evidenced by increased seizure activity or decreased phenytoin levels. Elevated thyroid-stimulating hormone (TSH) levels have also been observed in patients receiving thyroid hormone replacement therapy.

MANAGEMENT: In general, drugs with a narrow therapeutic index as well as those that have been shown to interact with colesevelam should be administered at least 4 hours before the colesevelam dose. Clinical and laboratory monitoring of drug levels and effects should be considered.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of propafenone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. In over 90% of patients, propafenone is rapidly and extensively converted to 2 active metabolites: 5-hydroxypropafenone via CYP450 2D6 and N-depropylpropafenone (norpropafenone) via CYP450 3A4 and 1A2. In less than 10% of patients (approximately 6% of Caucasians in the U.S. population), however, metabolism of propafenone is slower because the 5-hydroxy metabolite is not formed, or minimally formed, due to a genetic deficiency in CYP450 2D6. In these poor metabolizers of CYP450 2D6, clearance of propafenone via the CYP450 3A4 and 1A2 metabolic pathways becomes more important, and inhibition of these pathways may substantially increase systemic exposure to propafenone. Likewise, patients taking concomitant inhibitors of CYP450 2D6 and 3A4 may experience similar pharmacokinetic effects. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased systemic exposure to propafenone may result in proarrhythmic events and exaggerated beta-adrenergic blocking activity.

MANAGEMENT: It may be advisable for patients to avoid the consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with propafenone.