Interaction between
Methotrexate
and
Ibuprofen
Major
Excretion
Basic Information
| ID | DDInter1174 and DDInter900 |
| Interaction | 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. |
| 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. |
| References | [1] Tracy TS, Worster T, Bradley JD, Greene PK, Brater DC "Methotrexate disposition following concomitant administration of ketoprofen, piroxicam and flurbiprofen in patients with rheumatoid arthritis." Br J Clin Pharmacol 37 (1994): 453-6 [2] Vakily M, Amer F, Kukulka MJ, Andhivarothai N "Coadministration of lansoprazole and naproxen does not affect the pharmacokinetic profile of methotrexate in adult patients with rheumatoid arthritis." J Clin Pharmacol 45 (2005): 1179-86 [3] Schwartz JI, Agrawal NG, Wong PH, et al. "Lack of pharmacokinetic interaction between rofecoxib and methotrexate in rheumatoid arthritis patients." J Clin Pharmacol 41 (2001): 1120-30 [4] Kraus A, Alarcon-Segovia D "Low dose MTX and NSAID induced "mild" renal insufficiency and severe neutropenia." J Rheumatol 18 (1991): 1274 [5] Tracy TS, Krohn K, Jones DR, Bradley JD, Hall SD, Brater DC "The effects of a salicylate, ibuprofen, and naproxen on the disposition of methotrexate in patients with rheumatoid arthritis." Eur J Clin Pharmacol 42 (1992): 121-5 [6] Franck H, Rau R, Herborn G "Thrombocytopenia in patients with rheumatoid arthritis on long-term treatment with low dose methotrexate." Clin Rheumatol 15 (1996): 163-7 [7] Stewart CF, Fleming RA, Germain BF, Seleznick MJ, Evans WE "Aspirin alters methotrexate disposition in rheumatoid arthritis patients." Arthritis Rheum 34 (1991): 1514-20 [8] Matheson AJ, Figgitt DP "Rofecoxib - A review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis." Drugs 61 (2001): 833-65 [9] Brouwers JRBJ, Desmet PAGM "Pharmacokinetic-pharmacodynamic drug interactions with nonsteroidal anti-inflammatory drugs." Clin Pharmacokinet 27 (1994): 462-85 [10] Dupuis LL, Koren G, Shore A, Silverman ED, Laxer RM "Methotrexate-nonsteroidal antiinflammatory drug interaction in children with arthritis." J Rheumatol 17 (1990): 1469-73 [11] Maiche AG "Acute renal failure due to concomitant action of methotrexate and indomethacin." Lancet 1 (1986): 1390 [12] Baker H "Intermittent high dose oral methotrexate therapy in psoriasis." Br J Dermatol 82 (1970): 65-9 [13] EMEA. European Medicines Agency "EPARs. European Union Public Assessment Reports. Available from: URL: http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/medicines/medicines_landingpage.jsp&mid." [14] Ng HW, Macfarlane AW, Graham RM, Verbov JL "Near fatal drug interactions with methotrexate given for psoriasis." Br Med J (Clin Res Ed) 295 (1987): 752-3 [15] Combe B, Edno L, Lafforgue P, Bologna C, Bernard JC, Acquaviva P, Sany J "Total and free methotrexate pharmacokinetics, with and without piroxicam, in rheumatoid arthritis patients." Br J Rheumatol 34 (1995): 421-8 [16] Adams JD, Hunter GA "Drug interaction in psoriasis." Australas J Dermatol 17 (1976): 39-40 [17] Mayall B, Poggi G, Parkin JD "Neutropenia due to low-dose methotrexate therapy for psoriasis and rheumatoid arthritis may be fatal." Med J Aust 155 (1991): 480-4 [18] Stewart CF, Fleming RA, Arkin CR, Evans WE "Coadministration of naproxen and low-dose methotrexate in patients with rheumatoid arthritis." Clin Pharmacol Ther 47 (1990): 540-6 [19] Anaya JM, Fabre D, Bressolle F, Bologna C, Alric R, Cocciglio M, Dropsy R, Sany J "Effect of etodolac on methotrexate pharmacokinetics in patients with rheumatoid arthritis." J Rheumatol 21 (1994): 203-8 [20] Wallace CA, Smith AL, Sherry DD "Pilot investigation of naproxen/methotrexate interaction in patients with juvenile rheumatoid arthritis." J Rheumatol 20 (1993): 1764-8 [21] Hartmann SN, Rordorf CM, Milosavljev S, et al. "Lumiracoxib does not affect methotrexate pharmacokinetics in rheumatoid arthritis patients." Ann Pharmacother 38 (2004): 1582-7 [22] Thyss A, Milano G, Kubar J, Namer M, Schneider M "Clinical and pharmacokinetic evidence of a life-threatening interaction between methotrexate and ketoprofen." Lancet 1 (1986): 256-8 [23] Skeith KJ, Russell AS, Jamali F, Coates J, Friedman H "Lack of significant interaction between low dose methotrexate and ibuprofen or flurbiprofen in patients with arthritis." J Rheumatol 17 (1990): 1008-10 [24] "Product Information. Arthrotec (diclofenac-misoprostol)." Searle, Skokie, IL. [25] Bloom EJ, Ignoffo RJ, Reis CA, Cadman E "Delayed clearance (CL) of methotrexate (MTX) associated with antibiotics and antiinflammatory agents." Clin Res 34 (1986): a560 [26] Frenia ML, Long KS "Methotrexate and nonsteroidal antiinflammatory drug interactions." Ann Pharmacother 26 (1992): 234-7 [27] Karim A, Tolbert DS, Hunt TL, Hubbard RC, Harper KM, Geis GS "Celecoxib, a specific COX-2 inhibitor, has no significant effect on methotrexate pharmacokinetics in patients with rheumatoid arthritis." J Rheumatol 26 (1999): 2539-43 [28] Singh RR, Malaviya AN, Pandey JN, Guleria JS "Fatal interaction between methotrexate and naproxen." Lancet 1 (1986): 1390 [29] Ellison NM, Servi RJ "Acute renal failure and death following sequential intermediate-dose methotrexate and 5-FU: a possible adverse effect due to concomitant indomethacin administration." Cancer Treat Rep 69 (1985): 342-3 [30] Nesher G, Mates M, Zevin S "Effect of caffeine consumption on efficacy of methotrexate in rheumatoid arthritis." Arthritis Rheum 48 (2003): 571-572 |
| Alternative for Methotrexate |
L04A
|
| Alternative for Ibuprofen |
G02C
C01E M01A |
Potential Metabolism Interactions
Substrate-Substrate Interaction：If more than one drug is metabolized by the same CYP, it is possible that its metabolism is inhibited because of the competition between the drugs. That means, it can be useful to lower the dosage of the drugs in the drug-cocktail because they remain longer in the organism than in monotherapy.
Inhibitor-Inhibitor Interaction：Combining two or more inhibitors of one CYP, should be compensated by lowering the dosage of these drugs because the metabolism is reduced and the drugs remain longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.
Inhibitor-Substrate Interaction：Combining drugs that have inhibitory effect and are substrates of one particular CYP, should be compensated by lowering the dosage. They rest longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.