Drug Interaction Report

MONITOR CLOSELY: The use of droperidol has been associated with QT interval prolongation, torsade de pointes and other serious arrhythmias, and sudden death. The concurrent administration of agents that can produce bradycardia, a known risk factor for QT interval prolongation, such as benzodiazepines and opiates, particularly intravenous opiates, may increase the risk of QT interval prolongation. In addition, hypotensive effects and central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking droperidol with benzodiazepines or opiates, especially in elderly or debilitated patients.

MANAGEMENT: Extreme caution and close monitoring are recommended if droperidol must be administered concomitantly with other bradycardic drugs. The dosage of droperidol should be individualized and titrated to the desired effect. Routine vital sign and ECG monitoring is recommended. When droperidol is used in combination with benzodiazepines or opiates, patients should be monitored for potentially excessive or prolonged CNS or respiratory depression as well as severe hypotension. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their doctor if they experience excessive or prolonged CNS effects that interfere with their normal activities.

MONITOR: Plasma concentrations and effects of drugs that are CYP450 substrates may be altered following the initiation of interleukin (IL) inhibitors, tumor necrosis factor (TNF) blockers, or interferon (IFN) inhibitors in patients with chronic inflammatory diseases. The formation of hepatic CYP450 enzymes may be suppressed during infection and chronic inflammation by increased levels of certain cytokines (e.g., interleukins-1, -6, and -10; tumor necrosis factor alpha; interferons). Immunomodulating therapy that improves inflammation by targeting these cytokines may restore or normalize CYP450 enzyme levels resulting in increased or decreased metabolism of these substrates to active or inactive metabolites. The therapeutic target and disease state being treated may play a role in the significance of this interaction. The most evidence is currently for agents targeting the actions of IL-6 and in disease states with high levels of inflammation such as rheumatoid arthritis, rather than in patients with psoriasis and atopic dermatitis. In vitro studies showed that tocilizumab, an IL-6 inhibitor, has the potential to impact expression of various hepatic microsomal enzymes including CYP450 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4. Its effects on CYP450 2C8 or transporters is unknown. In vivo studies with omeprazole (a substrate of CYP450 2C19 and 3A4) and simvastatin (a substrate of CYP450 3A4 and OATP 1B1) showed decreases of up to 28% and 57% in systemic exposure, respectively, one week following a single dose of tocilizumab. Likewise, simvastatin and simvastatin acid exposures decreased by 45% and 36%, respectively, in 17 patients with rheumatoid arthritis one week following a single 200 mg subcutaneous dose of sarilumab, another IL-6 inhibitor. A role for other interleukins such as IL-12, IL-17A, or IL-23 in the regulation of CYP450 enzymes has not been clearly established, and it is not known whether antagonists of these interleukins would similarly affect CYP450 metabolism. For example, in drug interaction studies, the IL-23 antagonists risankizumab and tildrakizumab, and the IL-17A antagonist ixekizumab demonstrated no clinically significant effects on the activity of CYP450 isoenzymes 1A2, 3A, 2C19, 2D6, or 2C9. Similarly, data evaluating this interaction are not available for the TNF blockers certolizumab and etanercept.

MANAGEMENT: Caution is advised when treatments targeting cytokines such as interleukins, tumor necrosis factors, or interferons are prescribed to patients receiving concomitant drugs that are CYP450 substrates, particularly those with narrow therapeutic ranges (e.g., antiarrhythmics, anticonvulsants, immunosuppressants, theophylline) or sensitive substrates where decreases in plasma levels may be significant or undesirable (e.g., oral contraceptives, statins, benzodiazepines, opioids). Clinical and/or laboratory monitoring should be considered following the initiation or withdrawal of such treatments, and the dosage(s) of the CYP450 substrate(s) adjusted accordingly. Clinicians should note that the effects of IL inhibitors, TNF blockers, and IFN inhibitors on CYP450 activities may persist for several weeks after stopping therapy. Individual product labeling for these products should be consulted for specific recommendations.

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.

MONITOR CLOSELY: The use of droperidol has been associated with QT interval prolongation, torsade de pointes and other serious arrhythmias, and sudden death. The concurrent administration of agents that can produce hypokalemia and/or hypomagnesemia (e.g., potassium-wasting diuretics, amphotericin B, cation exchange resins), drugs known to increase the QT interval (e.g., phenothiazines, tricyclic antidepressants, antiarrhythmic agents, etc.), certain other drugs (benzodiazepines, volatile anesthetics, intravenous opiates), or alcohol abuse may increase the risk of prolonged QT syndrome. In addition, central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking droperidol with certain other drugs that cause these effects, especially in elderly or debilitated patients.

MANAGEMENT: The manufacturer recommends extreme caution if droperidol must be given concomitantly with these agents. The dosage of droperidol should be individualized and titrated to the desired effect. Routine vital sign and ECG monitoring is recommended. When droperidol is used in combination with other drugs that cause CNS and/or respiratory depression, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their doctor if they experience excessive or prolonged CNS effects that interfere with their normal activities.

MONITOR: Smoking cessation may lead to elevated plasma concentrations and enhanced pharmacologic effects of drugs that are substrates of CYP450 1A2 (and possibly CYP450 1A1) and/or certain drugs with a narrow therapeutic index (e.g., flecainide, pentazocine). One proposed mechanism is related to the loss of CYP450 1A2 and 1A1 induction by polycyclic aromatic hydrocarbons in tobacco smoke; when smoking cessation agents are initiated and smoking stops, the metabolism of certain drugs may decrease leading to increased plasma concentrations. The mechanism by which smoking cessation affects narrow therapeutic index drugs that are not known substrates of CYP450 1A2 or 1A1 is unknown. The clinical significance of this interaction is unknown as clinical data are lacking.

MANAGEMENT: Until more information is available, caution is advisable if smoking cessation agents are used concomitantly with drugs that are substrates of CYP450 1A2 or 1A1 and/or those with a narrow therapeutic range. Patients receiving smoking cessation agents may require periodic dose adjustments and closer clinical and laboratory monitoring of medications that are substrates of CYP450 1A2 or 1A1.