Drug Interactions between metformin and Purinethol

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).

ADJUST DOSING INTERVAL: The oral bioavailability of mercaptopurine (6-MP) is highly variable and may be affected by administration with food or dairy products. The mechanism by which food may impact the absorption of 6-MP has not been fully established, but cow's milk specifically has been found to contain a high concentration of xanthine oxidase, the enzyme responsible for first-pass metabolism of 6-MP to the inactive metabolite 6-thiouric acid. Incubation with cow's milk at 37 C induced a 30% catabolism of 6-MP within 30 minutes in one investigation. However, food or dairy intake with 6-MP in study patients has yielded variable results. In a study conducted in 17 children with acute lymphoblastic leukemia (ALL), oral 6-MP 75 mg/m2 administered 15 minutes after a standardized breakfast including 250 mL of milk resulted in a prolonged Tmax and a lower Cmax and AUC compared with 6-MP administration in the fasting state (mean Tmax: 2.3 hours vs. 1.2 hours; mean Cmax: 0.63 uM vs. 0.98 uM; mean AUC: 105 uM vs. 143 uM, respectively). In a different study, oral 6-MP 31.2 to 81.1 mg/m2 administered to 7 subjects with ALL 15 minutes after a standard breakfast consisting of orange juice, cereal, and toast also trended towards longer Tmax and lower Cmax values compared to 6-MP administration after an overnight fast, although the differences were not statistically significant. Two subjects had blood samples that were all below the limit of detection (20 ng/mL) following administration in the fed state. Likewise, a study of 15 pediatric patients reported non-significant 20% to 22% decreases in the Cmax and AUC of 6-MP when administered after a standardized breakfast containing both milk and cheese compared to administration after fasting, but in contrast to the two earlier studies, Tmax was decreased from 1.8 to 1.1 hours. Another study of 10 children with ALL or non-Hodgkin's lymphoma given an average oral 6-MP dose of 63 mg/m2 revealed substantial interpatient variations in the effect of food intake on 6-MP plasma levels, with Cmax changes ranging from 67% decrease to 81% increase and AUC changes ranging from 53% decrease to 86% increase relative to administration following fasting. Collectively for the group, however, there was no statistically significant difference in mean Tmax, Cmax, or AUC between the fed and fasting states. In this study, patients were fed what they normally ate at home rather than a standardized breakfast, which may have contributed to the inconsistent results. The clinical significance of the data and observations from these studies has not been determined. An interaction with milk was suspected in a four-year-old male with ALL who experienced persistent elevations of peripheral blood counts during maintenance with 6-MP and methotrexate despite increasing doses of 6-MP up to 160% of the calculated dosage for his body surface area (75 mg/m2). Cessation of concomitant milk ingestion allowed for the 6-MP dosage to return to 75 mg/m2 and resulted in control of peripheral blood counts within a week. Other data do not support a clinically relevant interaction with food or dairy products. In a prospective study of 441 patients aged 2 to 20 years receiving 6-MP for ALL maintenance, investigators found no significant association between relapse risk and 6-MP ingestion habits including administration with food versus never with food and administration with milk/dairy versus never with milk/dairy. Among the 56.2% of patients who were considered adherent by the study, there was also no significant association between red cell thioguanine nucleotide (active metabolite) levels and taking 6-MP with food versus without or taking with milk/dairy versus without. However, taking 6-MP with milk/dairy was associated with a 1.9-fold increased risk for nonadherence. These results suggest that taking 6-MP with food or milk/dairy products may not influence clinical outcome but may hinder patient adherence. Poor 6-MP adherence has been associated with an increased risk of childhood ALL relapse.

MANAGEMENT: To minimize variability in absorption and systemic exposure, the timing of mercaptopurine administration should be standardized in relation to food intake (i.e., always with food or always on an empty stomach). Some authorities suggest avoiding concomitant administration with milk or dairy products, although the clinical relevance of their effects on mercaptopurine bioavailability has not been established. As a precaution, patients may consider taking mercaptopurine at least 1 hour before or 2 hours after milk or dairy ingestion if they are able to do so without compromising treatment adherence.