Drug Interactions between acalabrutinib and Glumetza

GENERALLY AVOID: Alcohol can potentiate the effect of metformin on lactate metabolism and increase the risk of lactic acidosis. In addition, alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes. Although hypoglycemia rarely occurs during treatment with metformin alone, the risk may increase with acute consumption of alcohol. Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise. The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia. Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion. By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia. Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes.

Food may have varying effects on the absorption of metformin from immediate-release versus extended-release formulations. When a single 850 mg dose of immediate-release metformin was administered with food, mean peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 40% and 25%, respectively, and time to peak plasma concentration (Tmax) increased by 35 minutes compared to administration under fasting conditions. By contrast, administration of extended-release metformin with food increased AUC by 50% without affecting Cmax or Tmax, and both high- and low-fat meals had the same effect. These data may not be applicable to formulations that contain metformin with other oral antidiabetic agents.

MANAGEMENT: Metformin should be taken with meals, and excessive alcohol intake should be avoided during treatment. Diabetes patients in general should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis. Alcohol should not be consumed on an empty stomach or following exercise, as it may increase the risk of hypoglycemia. Patients should contact their physician immediately if they experience potential signs and symptoms of lactic acidosis such as malaise, myalgia, respiratory distress, increasing somnolence, and nonspecific abdominal distress (especially after stabilization of metformin therapy, when gastrointestinal symptoms are uncommon). With more marked acidosis, there may also be associated hypothermia, hypotension, and resistant bradyarrhythmias. Metformin should be withdrawn promptly if lactic acidosis is suspected. Serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful in establishing a diagnosis. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

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GENERALLY AVOID: Consumption of grapefruit and/or grapefruit juice may increase the plasma concentrations of acalabrutinib. 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 specifically, but has been reported for other CYP450 3A4 inhibitors. When acalabrutinib was administered with the potent CYP450 3A4 inhibitor itraconazole (200 mg once daily for 5 days) in 17 healthy subjects, acalabrutinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 3.9- and 5.1-fold, respectively. Physiologically based pharmacokinetic (PBPK) simulations showed that moderate CYP450 3A4 inhibitors (erythromycin, fluconazole, diltiazem) increased acalabrutinib Cmax and AUC by 2- to nearly 3-fold. In healthy subjects, administration of acalabrutinib with the moderate CYP450 3A4 inhibitors fluconazole (400 mg as a single dose) or isavuconazole (200 mg as a repeated dose for 5 days) increased acalabrutinib Cmax and AUC by 1.4- to 2-fold, while the Cmax and AUC of the active metabolite, ACP-5862, was decreased by 0.65- to 0.88-fold. 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 acalabrutinib exposure may potentiate the risk of toxicities such as hemorrhage, infection, cytopenias, malignancies, and atrial fibrillation or flutter.

Food may delay the absorption of acalabrutinib, but does not appear to affect the overall extent of absorption. When a single 100 mg tablet or a 75 mg developmental formulation of acalabrutinib was administered with a high-fat, high-calorie meal (approximately 918 calories; 59 grams carbohydrate, 59 grams fat, 39 grams protein) in healthy study subjects, mean acalabrutinib Cmax was decreased by 54% and 73%, respectively, while time to reach Cmax was delayed by 1 to 2 hours compared to administration under fasted conditions. However, mean AUC was not affected.

MANAGEMENT: Acalabrutinib may be administered with or without food. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with acalabrutinib.

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