Drug Interaction Report

Trimethoprim and Leucovorin Injection: Interaction Details

A pharmacist-reviewed analysis of the Trimethoprim and Leucovorin Injection interaction: the documented clinical effects, severity rating, onset, mechanism, and management considerations, with cited references throughout.

AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature

Leucovorin Injection

Vykoura Wellcovorin® I.V.
+

Trimethoprim

Primsol Primsol® Proloprim® Trimpex®
Dr. Brian Staiger, PharmD, BCPS
Medically reviewed by
Dr. Brian Staiger, PharmD, BCPS
Updated Aug 8, 2026
Editorial policy · Data sources
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Interaction severity
Major
Potentially serious — often needs a change or close monitoring.
How we grade severity & evidence

Severity levels

  • Contraindicated: These should generally not be used together.
  • Major: Potentially serious — often needs a change or close monitoring.
  • Moderate: Can be significant — usually manageable with monitoring.
  • Minor: Usually limited clinical impact.

Evidence grades

  • Established: Well documented — supported by controlled studies or strong clinical data.
  • Probable: Good supporting evidence, though not definitively proven.
  • Suspected: Some evidence suggests this interaction, but it is not well established.
  • Possible: Limited or conflicting evidence; the interaction may occur.
  • Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.

Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.

Of 48 documented Trimethoprim interactions, 40 are rated major — including this one.
Worried about symptoms right now? Contact your pharmacist or prescriber, or call Poison Control at 1-800-222-1222 (US). Call 911 for an emergency.
Onset
delayed
Evidence
probable
Severity
Major

What happens

Reduced efficacy of trimethoprim/sulfamethoxazole

Interaction Deep Dive

Avoid concomitant use of leucovorin and sulfamethoxazole/trimethoprim21, as it may reduce efficacy of sulfamethoxazole/trimethoprim which was associated with increased rates of treatment failure 1. In a placebo-controlled study, the concurrent administration of leucovorin and trimethoprim-sulfamethoxazole in HIV-infected patients with Pneumocystis carinii pneumonia resulted in increased rates of treatment failure and morbidity 3.

Why it happens (mechanism)

Unknown

Literature reports

1 report — tap to read

a) In a placebo-controlled study, the concurrent administration of leucovorin and trimethoprim-sulfamethoxazole in HIV-infected patients with Pneumocystis carinii pneumonia resulted in increased rates of treatment failure and morbidity 3.

Common questions

Can I take Trimethoprim and Leucovorin Injection together?

Reduced efficacy of trimethoprim/sulfamethoxazole Always confirm with your pharmacist or prescriber before making any change.

How serious is the Trimethoprim and Leucovorin Injection interaction?

It is rated major. Potentially serious — often needs a change or close monitoring.

How quickly could this interaction happen?

The documented onset is "delayed". Effects tend to build up gradually over days to weeks.

How strong is the evidence for this interaction?

The evidence is graded "probable". Good supporting evidence, though not definitively proven.

From our Q&A

Real reader questions about these medications, each personally answered by our pharmacist:

Questions for your pharmacist

  • Does my dose of Trimethoprim or Leucovorin Injection need adjusting while I take them together?
  • What symptoms should prompt me to call you or my prescriber right away?
  • Does the timing of my doses matter for this combination?
  • Is there a safer alternative to one of these medications for me?

References (3)

  1. Product Information: VYKOURA™ intramuscular, intravenous injection, leucovorin calcium intramuscular, intravenous injection. Avyxa Pharma LLC (per FDA), Denville, NJ, 2026.
  2. Product Information: BACTRIM(TM) double strength oral tablets, oral tablets, sulfamethoxazole and trimethoprim DS double strength oral tablets, oral tablets. AR Scientific, Inc. (per FDA), Philadelphia, PA, 2012.
  3. Product Information: Leucovorin calcium for injection. Immunex, US, 97. DailyMed
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Leucovorin Injection

Keep reading about Leucovorin Injection

All Leucovorin Injection interactions (11) Leucovorin Injection drug information
Also serious with: Capecitabine Doxifluridine Fluorouracil Glucarpidase
Trimethoprim

Keep reading about Trimethoprim

All Trimethoprim interactions (48) Trimethoprim drug information
Also serious with: Dofetilide Moexipril Arsenic Trioxide Perindopril
Beyond drug–drug

These medications also interact with supplements

Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:

Trimethoprim + Activated Charcoal American Hellebore Arsenic Cesium Ephedra Grapefruit Sida Cordifolia Bacillus Coagulans + 51 more

major · moderate · minor — check everything you take with our drug–supplement interaction checker.

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This information is for education, not a substitute for professional medical advice. Do not start, stop, or change any medication without talking to your pharmacist or prescriber.