Drug Interactions between Cardizem CD and selumetinib

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of selumetinib, which undergoes metabolism primarily by CYP450 3A4 and to a lesser extent by CYP450 2C19, 1A2, 2C9, 2E1 and 3A5, as well as glucuronidation by UGT1A1 and UGT1A3. 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. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. When coadministered with itraconazole, a potent CYP450 3A4 inhibitor, selumetinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 19% and 49%, respectively. When coadministered with fluconazole, a potent CYP450 2C19 and moderate CYP450 3A4 inhibitor, selumetinib Cmax and AUC increased by 26% and 53%, respectively. Concomitant use of erythromycin, a moderate CYP450 3A4 inhibitor, is predicted to increase selumetinib Cmax and AUC by 23% and 41%, respectively. 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 exposure to selumetinib may increase the risk and/or severity of serious adverse effects such as cardiomyopathy (decrease in left ventricular ejection fraction by 10% or more below baseline), ocular toxicity (blurred vision, photophobia, cataracts, ocular hypertension, retinal pigment epithelial detachment, retinal vein occlusion), gastrointestinal toxicity (diarrhea, colitis), skin toxicity (dermatitis acneiform, maculopapular rash, eczema), and musculoskeletal toxicity (creatine phosphokinase elevations, myalgia, rhabdomyolysis).

ADJUST DOSING INTERVAL: Food may decrease the rate and extent of the oral absorption of selumetinib. When a single 75 mg dose of selumetinib (1.5 times the approved maximum recommended dose) was administered with a high-fat meal (1000 calories; 50% fat) in healthy adults, mean Cmax and AUC of selumetinib decreased by 50% and 16%, respectively, and time to reach peak concentration (Tmax) was delayed by approximately 1.5 hours compared to administration in the fasted state. When a single 50 mg dose of selumetinib was administered with a low-fat meal (400 calories; 25% fat) in healthy adults, selumetinib Cmax and AUC decreased by 60% and 38%, respectively, and Tmax was delayed by approximately 0.9 hours.

MANAGEMENT: Selumetinib should be administered on an empty stomach at least 1 hour before or 2 hours after a meal. Patients should avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with selumetinib.

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MONITOR: Like many CNS-active agents, alcohol can exhibit hypotensive effects. Coadministration with antihypertensive agents including diltiazem may result in additive effects on blood pressure and orthostasis.

MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered diltiazem in some patients. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In a study of ten healthy male volunteers, administration of a single 120 mg oral dose of immediate-release diltiazem in combination with 250 mL of grapefruit juice increased the diltiazem peak plasma concentration (Cmax) and systemic exposure (AUC) by an average of 22% and 20%, respectively, compared to administration with water. The time to reach Cmax (Tmax) and the terminal half-life were not affected, and no statistically significant differences in blood pressure and heart rate were observed during administration with grapefruit juice relative to water. In a different study, repeated administration of 200 mL of grapefruit juice at 0, 2, 4, 8 and 12 hours had no significant effect on the Cmax or AUC of a single 120 mg oral dose of diltiazem, but increased its half-life from 4.1 to 5.1 hours. The ratios for the N-demethyl and deacetyl metabolites to diltiazem were also not affected by grapefruit juice. However, because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients should be advised that alcohol may potentiate the hypotensive effects of diltiazem, especially during the initiation of therapy and following a dosage increase. Caution should be exercised when rising from a sitting or recumbent position, and patients should notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients who regularly consume grapefruit or grapefruit juice should be monitored for increased adverse effects of diltiazem such as such as headache, irregular heartbeat, edema, unexplained weight gain, and chest pain. Grapefruit and grapefruit juice should be avoided if an interaction is suspected.

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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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