Drug Interaction Report

Hydrochlorothiazide and Methotrexate Injection: Interaction Details

A pharmacist-reviewed analysis of the Hydrochlorothiazide and Methotrexate 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

Hydrochlorothiazide

Inzirqo
+

Methotrexate Injection

Abitrexate® Folex® Jylamvo Mexate® Otrexup Otrexup® Rasuvo Rasuvo®
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 89 documented Hydrochlorothiazide interactions, 55 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
unspecified
Evidence
probable
Severity
Major

What happens

Increased methotrexate exposure and enhanced myelosuppression

Interaction Deep Dive

Thiazide diuretics may increase methotrexate exposure and enhance the myelosuppressive effects of antineoplastic agents by reducing the renal excretion of methotrexate3. During clinical trials, coadministration of combination cyclophosphamide/ methotrexate/5-fluorouracil and a thiazide diuretic resulted in significantly higher levels of granulocytes in breast cancer patients 2. If concurrent therapy is required, monitoring for excessive myelosuppression.

Why it happens (mechanism)

Reduced renal excretion of methotrexate

Literature reports

1 report — tap to read

a) Thiazide diuretics may enhance the myelosuppressive effects of antineoplastic agents. Fourteen breast cancer patients treated with a cyclophosphamide, methotrexate, 5-fluorouracil combination and a thiazide diuretic experienced significantly higher levels of granulocytes during treatment cycles without the thiazides as compared with cycles that included thiazides 2.

Common questions

Can I take Hydrochlorothiazide and Methotrexate Injection together?

Increased methotrexate exposure and enhanced myelosuppression Always confirm with your pharmacist or prescriber before making any change.

How serious is the Hydrochlorothiazide and Methotrexate 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 "unspecified". The timing of this interaction is not well characterized.

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 Hydrochlorothiazide or Methotrexate 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: LIVALO(R) oral tablets, pitavastatin oral tablets. Kowa Pharmaceuticals America, Inc. and Lilly USA, LLC (per FDA), Montgomery, AL, 2012. DailyMed
  2. Orr LE: Potentiation of myelosuppression from cancer chemotherapy and thiazide diuretics. Drug Intell Clin Pharm 1981; 15:967-970. PubMed
  3. Product Information: Diovan HCT oral tablets, valsartan hydrochlorothiazide oral tablets. Novartis Pharmaceuticals Corporation (per FDA), East Hanover, NJ, 2012. DailyMed
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Hydrochlorothiazide

Keep reading about Hydrochlorothiazide

All Hydrochlorothiazide interactions (89)
Also serious with: Dofetilide Glipizide Nateglinide Fenoprofen
Methotrexate Injection

Keep reading about Methotrexate Injection

All Methotrexate Injection interactions (354) Methotrexate Injection drug information
Also serious with: Dengue Tetravalent Vaccine, Live Yellow Fever Vaccine Varicella Virus Vaccine, Live Typhoid Vaccine
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:

Hydrochlorothiazide + Activated Charcoal American Hellebore American Mistletoe Asarabacca Dolomite Lithium Oleander Siberian Cocklebur + 222 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.