Methotrexate with Trimethoprim Interaction Details

Brand Names Associated with Methotrexate

Brand Names Associated with Trimethoprim

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 17, 2023

Interaction Effect

Increased methotrexate exposure, an increased risk of methotrexate toxicity or methotrexate-related severe adverse reactions, reduced active metabolite formation and possibly reduced methotrexate efficacy

Interaction Summary

Coadministration of methotrexate with oral or sulfonamides antibiotics like sulfamethoxazole or trimethoprim may increase methotrexate plasma concentrations, which may increase the risk of methotrexate severe adverse reactions. In some cases, the coadministration of methotrexate with sulfamethoxazole or trimethoprim may also subsequently reduce active metabolite formation, which may decrease the clinical effectiveness of methotrexate. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions. Also, coadministered sulfamethoxazole/trimethoprim may increase methotrexate toxicity, often manifesting as myelotoxicity and pancytopenia. The mechanism of this interaction is thought to be additive inhibition of dihydrofolate reductase by methotrexate and trimethoprim. In addition, sulfamethoxazole may increase free serum levels of methotrexate by displacement of methotrexate from plasma protein binding sites or decreased renal tubular elimination .

Severity

Major

Onset

Delayed

Evidence

Established

How To Manage Interaction

Coadministration of methotrexate with oral or sulfonamides antibiotics like sulfamethoxazole or trimethoprim may increase methotrexate plasma concentrations, which may increase the risk of methotrexate severe adverse reactions. In some cases, the coadministration of methotrexate with sulfamethoxazole or trimethoprim may also subsequently reduce active metabolite formation, which may decrease the clinical effectiveness of methotrexate. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions. Also, coadministered sulfamethoxazole/trimethoprim may increase methotrexate toxicity, often manifesting as myelotoxicity and pancytopenia. The mechanism of this interaction is thought to be additive inhibition of dihydrofolate reductase by methotrexate and trimethoprim. In addition, sulfamethoxazole may increase free serum levels of methotrexate by displacement of methotrexate from plasma protein binding sites or decreased renal tubular elimination .

Mechanism Of Interaction

Synergistic anti-folate effects, protein binding displacement, decreased renal tubular elimination

Literature Reports

A) A 70-year-old woman was taking long-term, low-dose methotrexate for psoriasis . After diagnosing acute bronchitis, her general practitioner prescribed sulfamethoxazole/trimethoprim for her. She developed severe pancytopenia with concurrent use of methotrexate and sulfamethoxazole/trimethoprim.

B) A pharmacokinetic study found a 66% increase in systemic exposure to methotrexate when this agent was given concurrently with sulfamethoxazole/trimethoprim. Methotrexate concentrations were measured in nine children with acute lymphoblastic leukemia during methotrexate dosing alone and during coadministration with sulfamethoxazole/trimethoprim. The free methotrexate fraction increased from 37.4% to 52.2% when sulfamethoxazole/trimethoprim was added to methotrexate therapy, and free methotrexate renal clearance decreased from 12.1 to 5.6 mL/kg/min during multidrug administration. Serum concentrations of sulfamethoxazole/trimethoprim and the percentage decrease in renal clearance of free methotrexate were closely correlated .

C) An 81-year-old woman stabilized on methotrexate for rheumatoid arthritis was diagnosed with inoperable cancer of the bladder, and was placed on trimethoprim 100 mg daily with an indwelling catheter. Two months later, she was readmitted with severe pancytopenia after her general practitioner increased her trimethoprim dose to 200 mg daily for symptoms of a urinary tract infection. Despite aggressive treatment with granulocyte colony stimulating factor, the patient's bone marrow did not recover and she died of bronchopneumonia .

D) An 80-year-old female was started on intramuscular methotrexate therapy for deteriorating psoriasis. Blood counts were normal prior to the sixth injection of methotrexate, but five days later she presented with painful, ulcerated areas and contact bleeding over her thighs, buttocks, back, and upper chest. Blood work revealed severe neutropenia (white cell count 0.9 x 10(9)/L, neutrophils 0.3 x 10(9)/L). Five days prior to the sixth injection of methotrexate, the patient had been started on trimethoprim 200 mg twice daily for a urinary tract infection. Her skin ulcerations and leukopenia were attributed to an interaction between methotrexate and trimethoprim .

E) A case report describes a patient who developed megaloblastic pancytopenia secondary to methotrexate and sulfamethoxazole/trimethoprim. A 58-year-old male with a history of rheumatoid arthritis presented with symptoms of prostatitis. The patient was started on a 6-week regimen of sulfamethoxazole/trimethoprim. Four weeks later symptoms of prostatitis resolved, but the patient had hematuria, fatigue, decreased appetite, and orthostatic dizziness. A CBC demonstrated a hemoglobin of 72 g/L, a hematocrit of 0.21, a leukocyte count of 2,000,000/L, and a platelet count of 50,000/L with macrocytic red cells, absence of reticulocytes, and markedly hypersegmented neutrophils on a peripheral smear. All drugs were discontinued and the patient was hospitalized for transfusion of platelets and packed red blood cells. The bone marrow revealed hypocellularity with megaloblastic red-cell precursors and hypersegmented polyps. The patient was diagnosed with megaloblastic pancytopenia, secondary to methotrexate and sulfamethoxazole/trimethoprim. The patient received leucovorin 25 mg every 6 hours and within 96 hours the patients complete blood count showed a hemoglobin of 104 g/L, a hematocrit of 0.32, a leukocyte count of 7,100,000/L, and a platelet count of 218,000,000,000/L. Clinicians should be aware of the possibility of life-threatening pancytopenia when methotrexate is used concomitantly with trimethoprim .

Methotrexate Overview

• Methotrexate is used to treat severe psoriasis (a skin disease in which red, scaly patches form on some areas of the body) that cannot be controlled by other treatments. Methotrexate is also used along with rest, physical therapy, and sometimes other medications to treat severe active rheumatoid arthritis (RA; a condition in which the body attacks its own joints, causing pain, swelling, and loss of function) that cannot be controlled by certain other medications. Methotrexate is also used to treat certain types of cancer including cancers that begin in the tissues that form around a fertilized egg in the uterus, breast cancer, lung cancer, certain cancers of the head and neck, certain types of lymphoma, and leukemia (cancer that begins in the white blood cells). Methotrexate is in a class of medications called antimetabolites. Methotrexate treats cancer by slowing the growth of cancer cells. Methotrexate treats psoriasis by slowing the growth of skin cells to stop scales from forming. Methotrexate may treat rheumatoid arthritis by decreasing the activity of the immune system.

Trimethoprim Overview

• Trimethoprim eliminates bacteria that cause urinary tract infections. It is used in combination with other drugs to treat certain types of pneumonia. It also is used to treat traveler's diarrhea. Antibiotics will not work for colds, flu, or other viral infections.

• This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.