Drug Interactions between Fentanyl Transdermal System and metformin

GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of opioid analgesics including fentanyl. Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills. In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.

GENERALLY AVOID: Consumption of grapefruit juice during treatment with oral transmucosal formulations of fentanyl may result in increased plasma concentrations of fentanyl, which is primarily metabolized by CYP450 3A4 isoenzyme in the liver and intestine. Certain compounds present in grapefruit are known to inhibit CYP450 3A4 and may increase the bioavailability of swallowed fentanyl (reportedly up to 75% of a dose) and/or decrease its systemic clearance. The clinical significance is unknown. In 12 healthy volunteers, consumption of 250 mL regular-strength grapefruit juice the night before and 100 mL double-strength grapefruit juice one hour before administration of oral transmucosal fentanyl citrate (600 or 800 mcg lozenge) did not significantly affect fentanyl pharmacokinetics, overall extent of fentanyl-induced miosis (miosis AUC), or subjective self-assessment of various clinical effects compared to control. However, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability. The possibility of significant interaction in some patients should be considered.

MANAGEMENT: Patients should not consume alcoholic beverages or use drug products that contain alcohol during treatment with fentanyl. Any history of alcohol or illicit drug use should be considered when prescribing fentanyl, and therapy initiated at a lower dosage if necessary. Patients should be closely monitored for signs and symptoms of sedation, respiratory depression, and hypotension. Due to a high degree of interpatient variability with respect to grapefruit juice interactions, patients treated with fentanyl should preferably avoid the consumption of grapefruit and grapefruit juice. In addition, patients receiving transdermal formulations of fentanyl should be cautioned that drug interactions and drug effects may be observed for a prolonged period beyond removal of the patch, as significant amounts of fentanyl are absorbed from the skin for 17 hours or more after the patch is removed.

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).