Drug Interaction Report

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.

MONITOR: Limited data suggest that consumption of greater than 180 mg/day of caffeine may interfere with the efficacy of methotrexate (MTX) in patients with rheumatoid arthritis. The exact mechanism of interaction is unknown but may be related to the antagonistic effect of caffeine on adenosine receptors, as anti-inflammatory properties of MTX is thought to result from the accumulation of adenosine. In a study of 39 patients treated with MTX 7.5 mg/week (without folate supplementation) for 3 months, patients with high caffeine intake (more than 180 mg/day) experienced significantly less improvement in morning stiffness and joint pain from baseline than patients with low caffeine intake (less than 120 mg/day). There were no significant differences between the responses of patients with moderate caffeine intake (120 to 180 mg/day) and those of the other 2 groups. In an interview of 91 patients treated with MTX, 26% of patients who discontinued the drug were regular coffee drinkers compared to only 2% of those still receiving the drug. Because treatment failure was the reason for MTX discontinuation in 80% of patients who discontinued, the investigators suggested that caffeine may have interfered with MTX efficacy.

MANAGEMENT: Until further information is available, the potential for interaction should be considered in patients who consume substantial amounts of caffeine and caffeine-containing foods and are prescribed methotrexate for rheumatoid arthritis. It may be appropriate to limit caffeine intake if an interaction is suspected in cases of treatment failure.

GENERALLY AVOID: Coadministration of methotrexate with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Methotrexate, especially at higher dosages or during prolonged treatment, has been associated with severe hepatotoxicity including acute hepatitis, chronic fibrosis, cirrhosis, and fatal liver failure.

MANAGEMENT: The risk of hepatic injury should be considered when methotrexate is used with other potentially hepatotoxic agents (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; nucleoside reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Baseline and periodic monitoring of hepatic function is recommended, while liver biopsy may be warranted during long-term use of methotrexate. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, pale stools, and jaundice.

MONITOR: Limited data suggest that consumption of greater than 180 mg/day of caffeine may interfere with the efficacy of methotrexate (MTX) in patients with rheumatoid arthritis. The exact mechanism of interaction is unknown but may be related to the antagonistic effect of caffeine on adenosine receptors, as anti-inflammatory properties of MTX is thought to result from the accumulation of adenosine. In a study of 39 patients treated with MTX 7.5 mg/week (without folate supplementation) for 3 months, patients with high caffeine intake (more than 180 mg/day) experienced significantly less improvement in morning stiffness and joint pain from baseline than patients with low caffeine intake (less than 120 mg/day). There were no significant differences between the responses of patients with moderate caffeine intake (120 to 180 mg/day) and those of the other 2 groups. In an interview of 91 patients treated with MTX, 26% of patients who discontinued the drug were regular coffee drinkers compared to only 2% of those still receiving the drug. Because treatment failure was the reason for MTX discontinuation in 80% of patients who discontinued, the investigators suggested that caffeine may have interfered with MTX efficacy.

MANAGEMENT: Until further information is available, the potential for interaction should be considered in patients who consume substantial amounts of caffeine and caffeine-containing foods and are prescribed methotrexate for rheumatoid arthritis. It may be appropriate to limit caffeine intake if an interaction is suspected in cases of treatment failure.