Drug Interaction Report

MONITOR CLOSELY: Coadministration with P-glycoprotein (P-gp) inhibitors may increase the plasma concentrations of morphine and its risk of adverse effects, including hypotension, respiratory and CNS depression, profound sedation, coma, and death. The proposed mechanism may involve inhibition of the intestinal P-gp efflux transporter, resulting in enhanced oral bioavailability of morphine, a P-gp substrate. The interaction may be more significant for orally administered morphine. According to some authorities, the concomitant use of a P-gp inhibitor with oral morphine may increase the systemic exposure of morphine by approximately 2-fold. However, in a pharmacokinetic study involving 12 healthy subjects, itraconazole (200 mg daily for 4 days), a strong P-gp inhibitor, increased the morphine (0.3 mg/kg as a single oral dose) peak plasma concentration (Cmax) and systemic exposure (AUC) by 28% and 22%, respectively. Plasma concentrations of intravenously administered morphine appear less affected. In a crossover study involving 14 healthy volunteers, intravenous administration of P-gp inhibitor cyclosporine followed by an intravenous infusion of morphine 0.1 mg/kg led to a minimal increase of morphine AUC to 100 ng/mL*h compared to 85 ng/mL*h when administered after control (no infusion). In the same study, cyclosporine appeared to prolong morphine-induced miosis.

MANAGEMENT: Caution is recommended whenever morphine, particularly orally administered morphine, is used concomitantly with a P-gp inhibitor. Close clinical and laboratory monitoring should be considered whenever a P-gp inhibitor is added to or withdrawn from therapy, and the morphine dosage adjusted as necessary. Patients should be monitored closely for signs and symptoms of respiratory depression and sedation that may be greater than otherwise expected. In addition, patients should be advised to avoid driving or operating hazardous machinery until they know how these medications affect them.

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. 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 physician 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 morphine and diamorphine. 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 alcohol while taking some sustained-release formulations of morphine may cause rapid release of the drug, resulting in high systemic levels of morphine that may be potentially lethal. Alcohol apparently can disrupt the release mechanism of some sustained-release formulations. The interaction was observed in in vitro studies using a 24-hour morphine formulation (Avinza 30 mg capsule, available in the U.S. from Ligand Pharmaceuticals). When the capsule was mixed with 900 mL of buffer solutions containing ethanol 20% and 40%, the dose of morphine that was released was alcohol concentration-dependent, leading to a more rapid release of morphine. Although the clinical relevance of this finding is unknown, 'dose-dumping' into the bloodstream is conceivable.

MANAGEMENT: Until more information is available, patients taking sustained-release formulations of morphine should not consume alcohol or use medications that contain alcohol. In general, potent narcotics such as morphine or diamorphine should not be combined with alcohol.

GENERALLY AVOID: The concurrent use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol may lead to gastrointestinal (GI) blood loss. The mechanism may be due to a combined local effect as well as inhibition of prostaglandins leading to decreased integrity of the GI lining.

MANAGEMENT: Patients should be counseled on this potential interaction and advised to refrain from alcohol consumption while taking aspirin or NSAIDs.

GENERALLY AVOID: Use of anticholinergic agents with alcohol may result in sufficient impairment of attention so as to render driving and operating machinery more hazardous. In addition, the potential for abuse may be increased with the combination. The mechanism of interaction is not established but may involve additive depressant effects on the central nervous system. No effect of oral propantheline or atropine on blood alcohol levels was observed in healthy volunteers when administered before ingestion of a standard ethanol load. However, one study found impairment of attention in subjects given atropine 0.5 mg or glycopyrrolate 1 mg in combination with alcohol.

MANAGEMENT: Alcohol should generally be avoided during therapy with anticholinergic agents. Patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them.

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.