Drug Interaction Report

Theophylline and Methotrexate Injection: Interaction Details

A pharmacist-reviewed analysis of the Theophylline 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

Theophylline

Accurbron® Aerolate® Aquaphyllin® Asbron® Bronkodyl® Duraphyl® Elixicon® Elixomin®
+

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
Moderate
Can be significant — usually manageable with 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 46 documented Theophylline interactions, 18 are rated moderate — including this one.
Onset
delayed
Evidence
probable
Severity
Moderate

What happens

Increased theophylline exposure

Interaction Deep Dive

Methotrexate may decrease the clearance of theophylline when administered concurrently, increasing the risk of theophylline toxicity1. A pharmacokinetic study in steroid-dependent asthma patients demonstrated that concurrent use of methotrexate IM and theophylline oral resulted in a 19% decrease in theophylline clearance 2. Monitor theophylline levels with methotrexate coadministration 1.

Why it happens (mechanism)

Decreased hepatic metabolism

Literature reports

1 report — tap to read

a) A double-blind, placebo-controlled, single-dose study in 15 adult steroid-dependent asthma patients was conducted to observe the effects of concurrent use of methotrexate and theophylline 2. Eight of the patients received methotrexate and 7 received placebo for 6 weeks. Patients received their usual dose of theophylline once before methotrexate or placebo was begun and once again after 6 weeks. After 6 weeks, theophylline clearance significantly decreased from 48 to 38.9 mL/hr/kg in the methotrexate-treated patients.

Common questions

Can I take Theophylline and Methotrexate Injection together?

Increased theophylline exposure Always confirm with your pharmacist or prescriber before making any change.

How serious is the Theophylline and Methotrexate Injection interaction?

It is rated moderate. Can be significant — usually manageable with 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.

Questions for your pharmacist

  • Does my dose of Theophylline 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 anything you'd monitor while I'm on both?

References (2)

  1. Product Information: OTREXUP(TM) subcutaneous injection solution, methotrexate subcutaneous injection solution. Antares Pharma, Inc. (per manufacturer), Ewing, NJ, 2013. DailyMed
  2. Glynn-Barnhart AM, Erzurum SC, Leff JA, et al: Effect of low-dose methotrexate on the disposition of glucocorticoids and theophylline. J Allergy Clin Immunol 1991; 88:180-186. PubMed
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Theophylline

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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:

Theophylline + Activated Charcoal Ephedra Sida Cordifolia Adrafinil African Wild Potato Ashitaba Bacopa Baikal Skullcap + 118 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.