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Drug Interactions between methotrexate and trimethoprim

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Major

methotrexate trimethoprim

Applies to: methotrexate and trimethoprim

GENERALLY AVOID: Coadministration of methotrexate with trimethoprim may increase the risk of severe myelosuppression and megaloblastic anemia due to potential additive effects resulting from inhibition of dihydrofolate reductase by both drugs. The interaction has been reported primarily with sulfamethoxazole-trimethoprim, but has also occurred with trimethoprim alone. Most cases involved the elderly, often in association with renal impairment. Some were fatal. In one report, an 81-year-old woman receiving low-dose methotrexate (7.5 mg/week) for rheumatoid arthritis developed fatal pancytopenia following the addition of trimethoprim. The dosage of trimethoprim had been 100 mg/day for nearly two months, but was increased to 200 mg/day due to suspected urinary tract infection one week before admission to hospital. The patient's bone marrow failed to recover despite treatment with calcium folinate and granulocyte colony stimulating factor, and she died of bronchopneumonia one week after admission. Likewise, concomitant use of sulfamethoxazole-trimethoprim was identified as a risk factor for pancytopenia associated with low-dose methotrexate use over a 10-year period in a regional survey conducted by a group of investigators in Ottawa.

MANAGEMENT: Concomitant use of methotrexate with trimethoprim should be avoided if possible. Some clinicians consider the use of methotrexate with low-dose sulfamethoxazole-trimethoprim (e.g., for the prophylaxis of Pneumocystis jiroveci pneumonia) to be acceptable; however, close monitoring for hematologic toxicity is recommended, particularly in the elderly. Complete blood counts, liver enzymes, and serum creatinine levels should be performed at baseline and periodically during treatment. Folate supplementation may be required in some cases. Patients should be advised to notify their doctor if they experience signs and symptoms of bone marrow depression or anemia such as fever, chills, sore throat, easy bruising or bleeding, pallor, dizziness, fatigue, lethargy, sore mouth or tongue, and tingling in hands or feet.

References

  1. Thomas MH, Gutterman LA (1986) "Methotrexate toxicity in a patient receiving trimethoprim-sulfamethoxazole." J Rheumatol, 13, p. 440-1
  2. Frain JB (1987) "Methotrexate toxicity in a patient receiving trimethoprim-sulfamethoxazole." J Rheumatol, 14, p. 176-7
  3. Ng HW, Macfarlane AW, Graham RM, Verbov JL (1987) "Near fatal drug interactions with methotrexate given for psoriasis." Br Med J (Clin Res Ed), 295, p. 752-3
  4. Thomas DR, Dover JS, Camp RD (1987) "Pancytopenia induced by the interaction between methotrexate and trimethoprim-sulfamethoxazole." J Am Acad Dermatol, 17, p. 1055-6
  5. Jeurissen ME, Boerbooms AM, van de Putte LB (1989) "Pancytopenia and methotrexate with trimethoprim-sulfamethoxazole." Ann Intern Med, 111, p. 261
  6. Kobrinsky NL, Ramsay NK (1981) "Acute megaloblastic anemia induced by high-dose trimethoprim-sulfamethoxazole." Ann Intern Med, 94, p. 780-1
  7. Maricic M, Davis M, Gall EP (1986) "Megaloblastic pancytopenia in a patient receiving concurrent methotrexate and trimethoprim-sulfamethoxazole treatment." Arthritis Rheum, 29, p. 133-5
  8. Verbov JL (1991) "Methotrexate and trimethoprim-sulfamethoxazole." Clin Exp Dermatol, 16, p. 231
  9. Govert JA, Patton S, Fine RL (1992) "Pancytopenia from using trimethoprim and methotrexate." Ann Intern Med, 117, p. 877-8
  10. (2002) "Product Information. Methotrexate (methotrexate)." Lederle Laboratories
  11. al-Awadhi A, Dale P, McKendry RJ (1993) "Pancytopenia associated with low dose methotrexate therapy. A regional survey." J Rheumatol, 20, p. 1121-5
  12. Graham LD, Myones BL, Rivas-Chacon RF, Pachman LM (1992) "Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis." J Pediatr, 120, p. 468-73
  13. Furst DE (1995) "Practical clinical pharmacology and drug interactions of low-dose methotrexate therapy in rheumatoid arthritis." Br J Rheumatol, 34 Suppl, p. 20-5
  14. Yang CH, Yang LJ, Jaing TH, Chan HL (2000) "Toxic epidermal necrolysis following combination of methotrexate and trimethoprim-sulfamethoxazole." Int J Dermatol, 39, p. 621-3
  15. Steuer A, Gumpel JM (1998) "Methotrexate and trimethoprim: a fatal interaction." Br J Rheumatol, 37, p. 105-6
  16. Saravana S, Lalukotta K (2003) "Myelotoxicity due to methotrexate - an iatrogenic cause." Eur J Haematol, 71, p. 315-6
  17. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  18. Bourre-Tessier J, Haraoui B (2010) "Methotrexate drug interactions in the treatment of rheumatoid arthritis: a systematic review." J Rheumatol, 37, p. 1416-21
  19. Yamazaki H, Nanki T, Miyasaka N, Harigai M (2011) "Methotrexate and trimethoprim-sulfamethoxazole for pneumocystis pneumonia prophylaxis." J Rheumatol, 38, p. 777
  20. Al-Quteimat OM, Al-Badaineh MA (2013) "Methotrexate and trimethoprim-sulphamethoxazole: extremely serious and life-threatening combination." J Clin Pharm Ther, 38, p. 203-5
  21. Cudmore J, Seftel M, Sisler J, Zarychanski R (2014) "Methotrexate and trimethoprim-sulfamethoxazole: toxicity from this combination continues to occur." Can Fam Physician, 60, p. 53-6
  22. Chevrel G, Brantus JF, Sainte-Laudy J, Miossec P (1999) "Allergic pancytopenia to trimethoprim-sulphamethoxazole for Pneumocystis carinii pneumonia following methotrexate treatment for rheumatoid arthritis." Rheumatology(Oxford), 38, p. 475-6
View all 22 references

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Drug and food interactions

Moderate

methotrexate food

Applies to: methotrexate

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.

References

  1. Nesher G, Mates M, Zevin S (2003) "Effect of caffeine consumption on efficacy of methotrexate in rheumatoid arthritis." Arthritis Rheum, 48, p. 571-572

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Moderate

methotrexate food

Applies to: methotrexate

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.

References

  1. (2002) "Product Information. Methotrexate (methotrexate)." Lederle Laboratories
  2. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  3. (2023) "Product Information. Methotrexate (methotrexate)." Hospira Inc

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Moderate

methotrexate food

Applies to: methotrexate

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.

References

  1. Nesher G, Mates M, Zevin S (2003) "Effect of caffeine consumption on efficacy of methotrexate in rheumatoid arthritis." Arthritis Rheum, 48, p. 571-572

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.


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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.