Drug Interactions between Calcium 600 D and neratinib

GENERALLY AVOID: Grapefruit, grapefruit juice, grapefruit hybrids, pomelos, star-fruit, and Seville oranges may increase the plasma concentrations of neratinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits. Inhibition of hepatic CYP450 3A4 may also contribute. In a study consisting of 24 healthy subjects, neratinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 3.2- and 4.8-fold, respectively, when a single 240 mg oral dose of neratinib was administered with the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily for 5 days). Also, mean apparent oral clearance of neratinib decreased by approximately 75% and mean elimination half-life increased by 54%. The interaction has not been studied with these fruits. In general, for example, 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 neratinib may increase adverse effects such as diarrhea, nausea, vomiting, abdominal pain, stomatitis, anorexia, and hepatotoxicity.

Food with a high fat content enhances the oral bioavailability of neratinib. In healthy volunteers, administration of neratinib 240 mg with a high-fat meal (approximately 55% fat; 31% carbohydrate; 14% protein) increased neratinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.7- and 2.2-fold, respectively, compared to administration under fasting conditions. By contrast, a standard breakfast (approximately 50% carbohydrate; 35% fat; 15% protein) increased the Cmax and AUC of neratinib by 1.2- and 1.1-fold, respectively.

MANAGEMENT: The manufacturer recommends administering neratinib with food at approximately the same time every day. Patients should avoid consumption of grapefruit, grapefruit juice, grapefruit hybrids, pomelos, star-fruit, and Seville oranges during treatment with neratinib.

ADJUST DOSING INTERVAL: Administration with food may increase the absorption of calcium. However, foods high in oxalic acid (spinach or rhubarb), or phytic acid (bran and whole grains) may decrease calcium absorption.

MANAGEMENT: Calcium may be administered with food to increase absorption. Consider withholding calcium administration for at least 2 hours before or after consuming foods high in oxalic acid or phytic acid.

MONITOR: Additive effects and possible toxicity (e.g., hypercalcemia, hypercalciuria, and/or hyperphosphatemia) may occur when patients using vitamin D and/or vitamin D analogs ingest a diet high in vitamin D, calcium, and/or phosphorus. The biologically active forms of vitamin D stimulate intestinal absorption of calcium and phosphorus. This may be helpful in patients with hypocalcemia and/or hypophosphatemia. However, sudden increases in calcium or phosphorus consumption due to dietary changes could precipitate hypercalcemia and/or hyperphosphatemia. Patients with certain disease states, such as impaired renal function, may be more susceptible to toxic side effects like ectopic calcification. On the other hand, if dietary calcium is inadequate for the body's needs, the active form of vitamin D will stimulate osteoclasts to pull calcium from the bones. This may be detrimental in a patient with reduced bone density.

MANAGEMENT: Given the narrow therapeutic index of vitamin D and vitamin D analogs, the amounts of calcium, phosphorus, and vitamin D present in the patient's diet may need to be taken into consideration. Specific dietary guidance should be discussed with the patient and regular lab work should be monitored as indicated. Calcium, phosphorus, and vitamin D levels should be kept within the desired ranges, which may differ depending on the patient's condition. Patients should also be counseled on the signs and symptoms of hypervitaminosis D, hypercalcemia, and/or hyperphosphatemia.