Drug Interactions between Fentanyl Transdermal System and Viokase 16

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.

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MONITOR: Exogenous pancreatic enzymes may interfere with the gastrointestinal absorption of folic acid and iron. The exact mechanism of interaction is unknown. In one study, investigators compared oral iron absorption over a 3-hour period in the presence and absence of exogenous pancreatic enzymes in 13 stable young adults with cystic fibrosis and 9 age-matched controls. There was no difference between patients and controls in iron absorption in the absence of exogenous pancreatic enzymes. However, significant impairment of iron absorption was observed in both groups after administration of pancrelipase one hour prior to iron administration. In the patient group, one hour after iron administration, there was a 188% increase in serum iron level above baseline in the absence of pancrelipase but only a 62% increase in the presence of pancrelipase. In the controls, percentage increases as well as peak serum iron levels were significantly higher in the absence of pancrelipase during all 3 hours after iron administration. Clinically, at least one-third of cystic fibrosis patients reportedly have iron deficiency. In the study, mean serum iron concentration was significantly lower in patients than in controls (11.9 versus 18.9 micromoles/L), and 5 of the patients but none of the controls had a serum iron concentration lower than 9 micromoles/L at baseline, presumably due to long-term treatment with pancreatic enzyme supplements.

MANAGEMENT: Patients receiving therapeutic iron or folate therapy should be monitored for potentially reduced hematologic response if pancreatic enzymes are administered concomitantly. Separating the times of administration may be helpful.

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