Drug Interactions between Exaprin and methotrexate

GENERALLY AVOID: Coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) including salicylates may increase the plasma concentrations and toxicities of methotrexate. The proposed mechanism is NSAID inhibition of the renal elimination of methotrexate and its metabolite, 7-hydroxymethotrexate, although data from pharmacokinetic studies are inconsistent and conflicting. Displacement of methotrexate binding to serum albumin by salicylates and various other NSAIDs may also play a secondary role. Unexpectedly severe and sometimes fatal bone marrow suppression, aplastic anemia, gastrointestinal toxicity, and nephrotoxicity have been reported during concomitant administration of methotrexate with NSAIDs. The risk is greatest in patients receiving high dosages of methotrexate and those with renal impairment. In clinical studies, methotrexate at dosages of 7.5 to 15 mg/week has been used without apparent problems in patients with rheumatoid arthritis who also received constant dosage regimens of NSAIDs. However, there have been occasional reports of stomatitis, pneumonitis, bone marrow toxicity, and fatality in patients receiving low-dose weekly methotrexate with daily NSAIDs.

MANAGEMENT: NSAIDs including salicylates should generally not be administered prior to or concomitantly with high dosages of methotrexate, such as those used to treat osteosarcoma. Caution should be exercised when NSAIDs are administered concomitantly with lower dosages of methotrexate. Close monitoring for signs and symptoms of bone marrow suppression, nephrotoxicity, and hepatotoxicity is recommended during treatment. Patients should be advised to contact their physician if they develop stomatitis, nausea, vomiting, diarrhea, rash, anorexia, jaundice, dark urine, dry cough, shortness of breath, and/or signs and symptoms of myelosuppression such as pallor, dizziness, fatigue, lethargy, fainting, easy bruising or bleeding, fever, chills, sore throat, body aches, and other influenza-like symptoms. Patients should also be counseled to avoid any other over-the-counter NSAID products.

MONITOR CLOSELY: Coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the plasma concentrations and toxicities of methotrexate. The proposed mechanism is NSAID inhibition of the renal elimination of methotrexate and its metabolite, 7-hydroxymethotrexate, although data from pharmacokinetic studies are inconsistent and conflicting. Displacement of methotrexate binding to serum albumin by certain NSAIDs may also play a secondary role. Unexpectedly severe and sometimes fatal bone marrow suppression, aplastic anemia, gastrointestinal toxicity, and nephrotoxicity have been reported during concomitant administration of methotrexate with NSAIDs. The risk is greatest in patients receiving high dosages of methotrexate and those with renal impairment. In clinical studies, methotrexate at dosages of 7.5 to 15 mg/week has been used without apparent problems in patients with rheumatoid arthritis who also received constant dosage regimens of NSAIDs. However, there have been occasional reports of stomatitis, pneumonitis, bone marrow toxicity, and fatality in patients receiving low-dose weekly methotrexate with daily NSAIDs.

MANAGEMENT: NSAIDs should generally not be administered prior to or concomitantly with high dosages of methotrexate, such as those used to treat osteosarcoma. Caution should be exercised when NSAIDs are administered concomitantly with lower dosages of methotrexate. Close monitoring for signs and symptoms of bone marrow suppression, nephrotoxicity, and hepatotoxicity is recommended during treatment. Patients should be advised to contact their physician if they develop stomatitis, nausea, vomiting, diarrhea, rash, anorexia, jaundice, dark urine, dry cough, shortness of breath, and/or signs and symptoms of myelosuppression such as pallor, dizziness, fatigue, lethargy, fainting, easy bruising or bleeding, fever, chills, sore throat, body aches, and other influenza-like symptoms. Patients should also be counseled to avoid any other over-the-counter NSAID products.

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.

MONITOR: The combined use of low-dose or high-dose aspirin with other nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the potential for serious gastrointestinal (GI) toxicity, including inflammation, bleeding, ulceration, and perforation. Aspirin at anti-inflammatory dosages or higher may also decrease the plasma concentrations of many NSAIDs. The decreases have ranged from none or small (piroxicam, meloxicam, naproxen, tolmetin) to substantial (flurbiprofen, ibuprofen). However, the therapeutic response does not appear to be affected. Investigators theorize that aspirin may displace NSAIDs from plasma protein binding sites, resulting in increased concentration of unbound, or free, drug available for clearance. The increase in NSAID free fraction, and possibly some contributory anti-inflammatory effect from aspirin, may account for the lack of overall effect on therapeutic response.

MANAGEMENT: Caution is advised if aspirin, particularly at anti-inflammatory dosages, is used with other NSAIDs. Concomitant administration of NSAIDs is considered contraindicated or not recommended with aspirin at analgesic/anti-inflammatory dosages by many NSAID manufacturers. During concomitant therapy, patients should be advised to take the medications with food and to immediately report signs and symptoms of GI ulceration and bleeding such as abdominal pain, bloating, sudden dizziness or lightheadedness, nausea, vomiting, hematemesis, anorexia, and melena.

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.