Why Leucovorin Drug Interactions Matter

Leucovorin (Folinic Acid) is a medication that works closely with other drugs — sometimes by design, and sometimes in ways that can cause serious problems. Whether you're taking it as part of chemotherapy, for Methotrexate rescue, or for another reason, knowing which medications interact with Leucovorin could be the difference between effective treatment and dangerous complications.

This guide covers the major and moderate drug interactions, supplements and over-the-counter products to watch, food considerations, and what to tell your doctor before starting Leucovorin.

How Drug Interactions Work With Leucovorin

Drug interactions happen when one medication changes how another works. With Leucovorin, interactions fall into two main categories:

1. Leucovorin enhances another drug's effects — This can be intentional (like boosting 5-Fluorouracil in cancer treatment) or harmful (like increasing toxicity beyond safe levels).
2. Leucovorin reduces another drug's effects — Because Leucovorin provides folate to cells, it can counteract medications that work by depleting folate, making those drugs less effective.

Understanding these patterns helps you see why your doctor chooses specific doses and timing for Leucovorin alongside your other medications.

Major Drug Interactions

These interactions are clinically significant and require careful management by your healthcare team:

5-Fluorouracil (5-FU)

This is Leucovorin's most important interaction — and it's intentional. Leucovorin enhances the cancer-killing effects of 5-FU by helping it bind more tightly to the enzyme thymidylate synthase. However, this also means all of 5-FU's side effects become more severe, including:

• Severe diarrhea (can be life-threatening)
• Severe mouth sores (stomatitis)
• Myelosuppression (dangerously low blood cell counts)

Your oncologist carefully adjusts doses to balance effectiveness against toxicity. If you experience severe side effects, report them immediately.

Methotrexate

Leucovorin is specifically designed to counteract Methotrexate's effects on healthy cells. This interaction is the entire basis of "Leucovorin rescue." However, the timing and dosing must be precise:

• Given too early, Leucovorin can reduce Methotrexate's effectiveness against cancer
• Given too late, it may not prevent serious toxicity to the gut, kidneys, and bone marrow
• Rescue typically starts 24 hours after Methotrexate and continues every 6 hours for 10 doses

For more on how this works, see our guide on Leucovorin's mechanism of action.

Trimethoprim-Sulfamethoxazole (TMP-SMX, Bactrim, Septra)

This is a critical interaction that many patients don't know about. TMP-SMX is a common antibiotic used to treat urinary tract infections, pneumonia, and other infections. When used with Leucovorin, treatment failure rates for Pneumocystis jirovecii pneumonia (PCP) increase significantly.

This is especially important for HIV/AIDS patients who may be taking both Leucovorin (for Pyrimethamine side effect prevention) and TMP-SMX (for PCP prophylaxis). Tell your doctor if you take either of these medications.

Anti-Seizure Medications (Phenytoin, Phenobarbital, Primidone)

Large doses of folates — including Leucovorin — can reduce the effectiveness of anti-seizure medications like:

• Phenytoin (Dilantin)
• Phenobarbital (Luminal)
• Primidone (Mysoline)

This can increase seizure frequency, which is particularly dangerous for patients already at risk. If you take any anti-epileptic medication, your doctor will monitor your drug levels closely and may adjust your seizure medication dose.

Glucarpidase (Voraxaze)

Both Glucarpidase and Leucovorin are used to manage Methotrexate toxicity, but they should not be given within 2 hours of each other. Glucarpidase breaks down Methotrexate enzymatically, while Leucovorin provides an alternate folate pathway. If given too close together, Glucarpidase may also break down Leucovorin, reducing its effectiveness.

Moderate Drug Interactions

Capecitabine (Xeloda)

Capecitabine is an oral chemotherapy drug that converts to 5-FU in the body. Because Leucovorin enhances 5-FU's effects, it can also enhance Capecitabine's toxicity. If you're taking both, your oncologist will closely monitor you for increased GI side effects and myelosuppression.

Sulfasalazine (Azulfidine)

Sulfasalazine, used for ulcerative colitis and rheumatoid arthritis, may reduce folate absorption. While this doesn't directly interact with Leucovorin, patients taking both should be aware that their folate status may be affected.

Supplements and Over-the-Counter Products to Watch

While Leucovorin doesn't have as many OTC interactions as some medications, there are a few things to be aware of:

Folic Acid Supplements

Taking additional Folic Acid supplements while on Leucovorin is generally unnecessary and could complicate your treatment. Leucovorin already provides reduced folate. Extra Folic Acid won't help and could theoretically interfere with the precise dosing your doctor has calculated, especially during Methotrexate rescue.

Multivitamins Containing Folic Acid

Many daily multivitamins contain 400-800 mcg of Folic Acid. While this small amount is unlikely to cause problems, tell your doctor about any vitamins you take so they can factor it into your treatment plan.

B-Complex Vitamins

B-complex supplements typically contain Folic Acid and vitamin B12. These are generally safe in normal doses but should be disclosed to your healthcare team.

Food and Drink Interactions

The good news: Leucovorin has no significant food interactions. Oral tablets can be taken with or without food.

There is one practical note: oral absorption of Leucovorin saturates at about 25 mg regardless of whether you take it with food. This means eating won't help you absorb a higher dose — which is why doses above 25 mg need to be given by injection.

There are no known interactions with alcohol, caffeine, grapefruit, or other common food-drug interaction culprits. However, if you're receiving Leucovorin as part of chemotherapy, your oncologist may have separate dietary recommendations related to your overall treatment regimen.

What to Tell Your Doctor Before Starting Leucovorin

Before you begin Leucovorin therapy, make sure your doctor knows about:

• All prescription medications — Especially anti-seizure drugs, antibiotics (particularly TMP-SMX), and any chemotherapy agents
• Over-the-counter medications — Including pain relievers, antacids, and cold medicines
• Vitamins and supplements — Particularly anything containing Folic Acid or B vitamins
• Herbal products — While no major herbal interactions are documented, full disclosure helps your doctor make safe decisions
• Allergies — Especially any previous reaction to Folic Acid or Leucovorin
• Kidney problems — Impaired kidney function can delay Methotrexate clearance, requiring higher Leucovorin doses
• Pregnancy or breastfeeding — Leucovorin is Pregnancy Category C and its safety during nursing is unknown

Bring a complete medication list to every appointment. Even medications that seem unrelated can matter.

Final Thoughts

Leucovorin's drug interactions range from intentional and therapeutic (enhancing 5-FU, rescuing from Methotrexate) to potentially dangerous (reducing seizure medication effectiveness, increasing PCP treatment failure). The key is open communication with your healthcare team about every medication, supplement, and vitamin you take.

For more about Leucovorin, explore our guides on what Leucovorin is, its side effects, and how to save money on your prescription. If you're having trouble finding Leucovorin, Medfinder can help you check pharmacy stock near you.