Drug Interactions between atorvastatin and pemigatinib

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of pemigatinib, which is primarily metabolized by CYP450 3A4 in vitro. 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 itraconazole, a potent CYP450 3A4 inhibitor, was administered following a single oral pemigatinib dose of 4.5 mg, pemigatinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 17% and 88%, respectively. Concomitant use of moderate CYP450 3A4 inhibitors is predicted to increase pemigatinib exposure by approximately 50% to 80%. 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 pemigatinib may increase the incidence and severity of serious adverse reactions such as hyperphosphatemia (which can cause precipitation of calcium-phosphate crystals over time that can lead to hypocalcemia, soft tissue mineralization such as cutaneous calcification and calcinosis, secondary hyperparathyroidism, anemia, muscle cramps, seizures, QT prolongation, and arrhythmias), serous retinal detachment (which may cause symptoms such as blurred vision, visual floaters, or photopsia), palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), arthralgia, stomatitis, diarrhea, nausea, vomiting, and constipation.

Pemigatinib pharmacokinetics were not significantly affected by coadministration of a high-fat, high-calorie meal (approximately 1000 calories; 500 to 600 calories from fat).

MANAGEMENT: Pemigatinib may be administered with or without food. Patients should avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit extract during treatment with pemigatinib.

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GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of atorvastatin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. When a single 40 mg dose of atorvastatin was coadministered with 240 mL of grapefruit juice, atorvastatin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 16% and 37%, respectively. Greater increases in Cmax (up to 71%) and/or AUC (up to 2.5 fold) have been reported with excessive consumption of grapefruit juice (>=750 mL to 1.2 liters per day). Clinically, high levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death.

ADJUST DOSING INTERVAL: Fibres such as oat bran and pectin may diminish the pharmacologic effects of HMG-CoA reductase inhibitors by interfering with their absorption from the gastrointestinal tract.

MANAGEMENT: Patients receiving therapy with atorvastatin should limit their consumption of grapefruit juice to no more than 1 liter per day. Patients should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed. In addition, patients should either refrain from the use of oat bran and pectin or, if concurrent use cannot be avoided, to separate the administration times by at least 2 to 4 hours.

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