Drug Interactions between atorvastatin and sodium zirconium cyclosilicate

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.

ADJUST DOSING INTERVAL: Because sodium zirconium cyclosilicate can transiently increase gastric pH, it may affect the absorption of coadministered medications that exhibit pH-dependent solubility. Altered efficacy or safety of these medications may occur when they are administered too close to the dosing of sodium zirconium cyclosilicate. According to the product labeling, 39 drugs were tested to determine potential interactions with sodium zirconium cyclosilicate. Drugs that did not show an in vitro interaction with sodium zirconium cyclosilicate were allopurinol, apixaban, aspirin, captopril, cyclosporine, digoxin, ethyl estradiol, lisinopril, magnesium, metformin, phenytoin, prednisone, propranolol, quinapril, spironolactone, and ticagrelor. Of the 23 drugs that showed an in vitro interaction, nine were subsequently tested in healthy volunteers. Losartan, glipizide, and levothyroxine did not demonstrate an in vivo interaction with sodium zirconium cyclosilicate. However, an increase in systemic exposure was observed for weak acids such as furosemide and atorvastatin when coadministered with sodium zirconium cyclosilicate, while a decrease in systemic exposure was observed for weak bases such as dabigatran.

MANAGEMENT: In general, concomitant oral medications should be administered at least 2 hours before or 2 hours after sodium zirconium cyclosilicate. Separation of dosing times is not needed if it has been determined that the concomitant medication does not exhibit pH-dependent solubility.