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.

CONTRAINDICATED: Coadministration of metoclopramide with phenothiazines, neuroleptics, or other antidopaminergic agents (e.g., tetrabenazine) may increase the frequency and severity of extrapyramidal reactions (i.e., acute dystonic reactions, tardive dyskinesia, akathisia, Parkinson-like symptoms) due to additive antidopaminergic effects. By itself, metoclopramide can cause acute dystonic reactions in approximately 0.2% of patients treated with the usual adult dosages of 30 to 40 mg/day. These reactions are typically seen during the first 24 to 48 hours of treatment, occur more frequently in pediatric and adult patients less than 30 years of age, and are increased with higher dosages. Symptoms may include involuntary movements of limbs, facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of tongue, bulbar type of speech, trismus, opisthotonus (tetanus-like reactions), and rarely, stridor and dyspnea due to laryngospasm. Dystonic reactions usually respond to treatment with anticholinergic agents such as diphenhydramine or benztropine. Tardive dyskinesia (TD) is a potentially irreversible and disfiguring disorder characterized most frequently by involuntary movements of the tongue, face, mouth, or jaw, and less frequently by involuntary movements of the trunk and/or extremities. Movements may be choreoathetotic in appearance. Although the risk of TD with metoclopramide has not been extensively studied, a prevalence of 20% has been reported in one study among patients treated for at least 12 weeks. The risk is increased in the elderly, women, and diabetic populations; however, it is not possible to predict which patients will develop TD. Both the risk of developing TD and the likelihood that TD will become irreversible increase with duration of treatment and total cumulative dose. There is no known effective treatment. In some patients, TD may remit, partially or completely, within several weeks to months after metoclopramide is withdrawn. Akathisia, or motor restlessness, consist of feelings of anxiety, agitation, jitteriness, and insomnia, as well as inability to sit still, pacing, and foot tapping. Symptoms may disappear spontaneously or respond to a reduction in dosage. Parkinsonian-like symptoms may include bradykinesia, tremor, cogwheel rigidity, and mask-like facies. These symptoms most commonly occur within the first 6 months of metoclopramide therapy and subside within 2 to 3 months following drug discontinuation.

MANAGEMENT: Due to the potential for increased risk of serious and potentially irreversible extrapyramidal reactions, metoclopramide should not be prescribed in combination with other antidopaminergic agents. In addition, metoclopramide should not be used for longer than 12 weeks except in rare cases where therapeutic benefit is anticipated to outweigh the risk of developing tardive dyskinesia.

MONITOR: By diminishing gastrointestinal motility, narcotic analgesics may antagonize the pharmacologic effects of gastrointestinal prokinetic agents. In addition, concomitant use may increase central nervous system effects such as sedation, dizziness, confusion, and mental depression.

MONITOR: Gastrointestinal prokinetic agents may alter the absorption characteristics of some controlled release narcotic analgesic preparations. In a study of 20 patients undergoing surgery, peak plasma concentration (Cmax) of morphine was reached more quickly in patients who received a 20 mg dose of sustained-release morphine with 20 mg metoclopramide compared to patients who received morphine alone, although the actual Cmax and systemic exposure (AUC) were not significantly altered. Both the degree and the rate of onset of sedation were also increased in the metoclopramide group, which may have been partially due to additive pharmacodynamic effects of the drugs. During chronic administration, however, the clinical relevance of this interaction may be diminished due to tolerance.

MANAGEMENT: The potential for reduced efficacy of gastrokinetic agents should be considered during coadministration with opioid analgesics. 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.

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.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician 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.

The recommended maximum number of medicines in the 'antidopaminergic-like antiemetics' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'antidopaminergic-like antiemetics' category:

• droperidol / fentanyl
• metoclopramide

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.