Drug Interactions between Cardizem CD and palbociclib

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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GENERALLY AVOID: Grapefruit and/or grapefruit juice may increase the systemic exposure to palbociclib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Increased exposure to palbociclib may increase the risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, asthenia, peripheral neuropathy, and epistaxis.

ADJUST DOSING INTERVAL: Food may enhance the oral bioavailability of palbociclib capsules and reduce the intersubject variability of palbociclib exposure. According to the product labeling, absorption and exposure of palbociclib from its oral capsule formulation were very low in approximately 13% of the population when taken in the fasted state. Food intake increased the palbociclib exposure in this small subset of the population but did not alter exposure in the rest of the population to a clinically relevant extent. Compared to palbociclib capsules given under overnight fasted conditions, the population average palbociclib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 38% and 21%, respectively, when given with high-fat, high-calorie food (approximately 800 to 1000 calories; 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively); by 27% and 12%, respectively, when given with low-fat, low-calorie food (approximately 400 to 500 calories; 120, 250, and 28 to 35 calories from protein, carbohydrate and fat, respectively); and by 24% and 13%, respectively, when given with moderate-fat, standard calorie food (approximately 500 to 700 calories; 75 to 105, 250 to 350 and 175 to 245 calories from protein, carbohydrate and fat, respectively) one hour before and two hours after palbociclib capsule dosing.

MANAGEMENT: Patients should avoid consumption of grapefruit or grapefruit juice while on treatment with palbociclib. To avoid variability in drug absorption between doses, palbociclib capsules should be taken with food. Palbociclib tablet formulations may be taken with or without food.

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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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