Drug Interactions between atorvastatin and posaconazole

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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ADJUST DOSING INTERVAL: Food significantly increases the absorption of posaconazole from the oral suspension but only modestly from the delayed-release tablet. Following single-dose administration, posaconazole mean peak plasma concentration (Cmax) and systemic exposure (AUC) are approximately 2.5 to 3 times higher when the oral suspension is given with a nonfat meal or a nutritional supplement (14 grams of fat) than when given under fasting conditions, and approximately 3.5 to 4 times higher when given during or 20 minutes after a high-fat meal (50 grams of fat) than under fasting conditions. Acidic beverages may also increase posaconazole absorption. In 12 healthy volunteers, administration of a single 400 mg dose of posaconazole suspension with 12 ounces of ginger ale increased posaconazole Cmax by 92% and AUC by 70% compared to administration after fasting. In contrast, the Cmax and AUC of posaconazole increased by just 16% and 51%, respectively, when posaconazole tablets were given as a single 300 mg dose to healthy volunteers after a high-fat meal relative to a fasted state.

GENERALLY AVOID Concomitant use of alcohol and posaconazole administered in the form of delayed-release oral suspension may lead to a faster release of posaconazole. An in vitro dissolution study determined a potential for alcohol-induced dose-dumping with the delayed-release oral suspension of posaconazole.

MONITOR: In 5 study subjects, posaconazole Cmax decreased by 27% to 53% and AUC decreased by 33% to 51% when the oral suspension was administered via a nasogastric tube as opposed to orally.

MANAGEMENT: Posaconazole tablets should be taken with food, whereas posaconazole oral suspension should be administered during or immediately (i.e., within 20 minutes) following a full meal to enhance bioavailability. Patients who cannot eat a full meal should take the suspension with a liquid nutritional supplement or an acidic carbonated beverage such as ginger ale. In patients who cannot eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage and who do not have the option of taking another formulation of posaconazole, alternative antifungal therapy should be considered; otherwise, monitor patients closely for breakthrough fungal infections. Patients receiving posaconazole via a nasogastric tube should also be closely monitored due to increased risk of treatment failure associated with lower plasma exposure. Administration of alcohol with posaconazole from the delayed-release oral suspension formulation is not recommended.

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