Drug General Information (ID: DDIQ597M10)
Drug Name			Tolmetin		Drug Info		Methotrexate		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antiinflammatory Agents				Antimetabolites
Structure

Mechanism of Tolmetin-Methotrexate Interaction (Severity Level: Major)
Increased risk of nephrotoxicity Click to Show/Hide Mechanism Graph
Drug Name		Tolmetin				Methotrexate
Mechanism		Nephrotoxicity				Nephrotoxicity
Key Mechanism Factor 1
		Factor Name		Nephrotoxicity
		Factor Description		The combination of drugs that can induce nephrotoxicity may increase the risk of kidney injury. When kidney injury occurs, the inability to remove excess urine and waste from the body can lead to high levels of urea nitrogen, creatinine, and electrolytes (such as potassium and magnesium) in the blood.
Mechanism Description		Increased risk of nephrotoxicity by the combination of Tolmetin and Methotrexate

Recommended Action
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	Adams JD, Hunter GA "Drug interaction in psoriasis." Australas J Dermatol 17 (1976): 39-40. [PMID: 1022213]
2	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. [PMID: 8182625]
3	Baker H "Intermittent high dose oral methotrexate therapy in psoriasis." Br J Dermatol 82 (1970): 65-9. [PMID: 5410994]
4	Kwon OC, Lee JS, Kim YG, Lee CK, Yoo B, Hong S. Safety of the concomitant use of methotrexate and a prophylactic dose of trimethoprim-sulfamethoxazole.?Clin Rheumatol. 2018;37(12):3215-3220. [PMID: 29383453]
5	Brouwers JRBJ, Desmet PAGM "Pharmacokinetic-pharmacodynamic drug interactions with nonsteroidal anti-inflammatory drugs." Clin Pharmacokinet 27 (1994): 462-85. [PMID: 7882636]
6	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. [PMID: 7788170]
7	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. [PMID: 2273487]
8	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. [PMID: 3978662]
9	EMEA. European Medicines Agency "EPARs. European Union Public Assessment Reports.".
10	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. [PMID: 8777850]
11	Frenia ML, Long KS "Methotrexate and nonsteroidal antiinflammatory drug interactions." Ann Pharmacother 26 (1992): 234-7. [PMID: 1554938]
12	Hartmann SN, Rordorf CM, Milosavljev S, et al. "Lumiracoxib does not affect methotrexate pharmacokinetics in rheumatoid arthritis patients." Ann Pharmacother 38 (2004): 1582-7. [PMID: 15340127]
13	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. [PMID: 10606360]
14	Kraus A, Alarcon-Segovia D "Low dose MTX and NSAID induced "mild" renal insufficiency and severe neutropenia." J Rheumatol 18 (1991): 1274. [PMID: 1796967]
15	Maiche AG "Acute renal failure due to concomitant action of methotrexate and indomethacin." Lancet 1 (1986): 1390. [PMID: 2872506]
16	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. [PMID: 11398914]
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. [PMID: 1921820]
18	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. [PMID: 3119023]
19	Product Information. Arthrotec (diclofenac-misoprostol). Searle, Skokie, IL.
20	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. [PMID: 11583481]
21	Singh RR, Malaviya AN, Pandey JN, Guleria JS "Fatal interaction between methotrexate and naproxen." Lancet 1 (1986): 1390. [PMID: 2872507]
22	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. [PMID: 2213774]
23	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. [PMID: 2328562]
24	Stewart CF, Fleming RA, Germain BF, Seleznick MJ, Evans WE "Aspirin alters methotrexate disposition in rheumatoid arthritis patients." Arthritis Rheum 34 (1991): 1514-20. [PMID: 1747136]
25	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. [PMID: 2868265]
26	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. [PMID: 1618240]
27	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. [PMID: 8054251]
28	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. [PMID: 16172183]
29	Wallace CA, Smith AL, Sherry DD "Pilot investigation of naproxen/methotrexate interaction in patients with juvenile rheumatoid arthritis." J Rheumatol 20 (1993): 1764-8. [PMID: 8295192]