Drug Interactions between methotrexate and mitotane

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.

ADJUST DOSING INTERVAL: Fat-rich food enhances the absorption of mitotane. One study evaluated blood levels of mitotane (o,p'-DDD) after subjects ingested a single dose of 2 g administered using various delivery vehicles (e.g., tablets, granules, milk, chocolate or oil emulsion). Mitotane plasma levels were significantly higher for milk, chocolate, and oil emulsion when compared to those who received tablets or granules alone. In the same study, mitotane levels were evaluated in subjects following long-term treatment (total dose of 200 g over 30 to 60 days) in tablet, oil emulsion, or milk formulations. Significantly higher mean plasma levels were recorded in subjects who received mitotane as an oil emulsion or mixed in milk, when compared to tablets alone. Additionally, the recovery of o,p'-DDD from the feces was about 5 times higher in subjects who received tablets alone, suggesting absorption was reduced when compared to subjects who received mitotane mixed with a fat-rich vehicle (e.g., oil emulsion or milk).

GENERALLY AVOID: Concomitant use of mitotane with central nervous system (CNS) depressants, including alcohol, may potentiate adverse effects such as somnolence and sedation.

MANAGEMENT: According to product labeling, mitotane tablets should be taken during meals containing fat-rich food (e.g., milk, chocolate, or oil) and with a full glass of water. Patients should be advised to avoid or limit consumption of alcohol and to avoid activities requiring mental alertness such as driving or operating hazardous machinery until they know how the medication affects them.

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.