When You Can't Find Leucovorin, Alternatives May Be Available

If your pharmacy can't fill your Leucovorin prescription, the situation can feel urgent — especially if you're in the middle of a cancer treatment regimen or need methotrexate rescue therapy. The good news is that alternatives do exist, and your doctor may be able to switch you to one without interrupting your care.

In this post, we'll explain what Leucovorin is, how it works, and walk you through the most common alternatives your healthcare team may consider.

What Is Leucovorin?

Leucovorin Calcium (also called Folinic Acid) is a folic acid analog. Unlike regular folic acid, Leucovorin doesn't need to be converted by the enzyme dihydrofolate reductase before your body can use it. This makes it essential in two key medical situations:

• Methotrexate rescue: High-dose methotrexate, used to treat cancers like osteosarcoma and certain lymphomas, can damage healthy cells. Leucovorin is given after methotrexate to "rescue" normal tissues by providing them with usable folate.
• Enhancing chemotherapy: When combined with 5-Fluorouracil (5-FU), Leucovorin increases 5-FU's ability to kill cancer cells. This combination is a cornerstone of colorectal cancer treatment in regimens like FOLFOX and FOLFIRI.

For a full overview, see our guide on what Leucovorin is and how it's used.

How Does Leucovorin Work?

Leucovorin is a reduced form of folate (specifically, the 5-formyl derivative of tetrahydrofolic acid). It enters cells and participates directly in DNA synthesis pathways without needing the enzyme that methotrexate blocks.

In cancer treatment with 5-FU, Leucovorin increases the binding of 5-FU's active metabolite to an enzyme called thymidylate synthase, making the chemotherapy more effective at stopping cancer cell growth. For more detail, read how Leucovorin works.

Alternatives to Leucovorin

1. Levoleucovorin (Fusilev, Khapzory)

Levoleucovorin is the most direct alternative to Leucovorin and the one your doctor is most likely to consider first. Here's what you need to know:

• What it is: Levoleucovorin is the active L-isomer of Leucovorin. Standard Leucovorin is a racemic mixture (a 50/50 mix of active and inactive forms). Levoleucovorin contains only the active half.
• How it's used: It can be used interchangeably with Leucovorin for both methotrexate rescue and in combination with 5-FU for colorectal cancer treatment.
• Dosing: Because it contains only the active isomer, Levoleucovorin is given at half the dose of Leucovorin. For example, if your Leucovorin dose is 200 mg/m², the equivalent Levoleucovorin dose would be 100 mg/m².
• Availability: Levoleucovorin was FDA-approved in 2008 specifically during a Leucovorin shortage. It's available as both a branded product (Fusilev, Khapzory) and in generic form.
• Cost: Levoleucovorin tends to be more expensive than generic Leucovorin, but it may be more readily available during shortages.

2. Folic Acid

Folic acid is not a substitute for Leucovorin in chemotherapy or methotrexate rescue therapy. However, if you take Leucovorin for megaloblastic anemia due to folate deficiency, regular folic acid may be an alternative — as long as your doctor has ruled out vitamin B12 deficiency.

• Important note: Folic acid must be converted to its active form by dihydrofolate reductase. Since methotrexate blocks this enzyme, folic acid cannot rescue cells from methotrexate toxicity. Only Leucovorin or Levoleucovorin can do that.
• Cost: Folic acid is very inexpensive and widely available over the counter.

3. Glucarpidase (Voraxaze)

Glucarpidase is not a direct substitute for Leucovorin, but it serves a related purpose in methotrexate toxicity:

• What it does: Glucarpidase is an enzyme that breaks down methotrexate directly in the bloodstream, rapidly lowering toxic methotrexate levels.
• When it's used: It's typically reserved for patients with delayed methotrexate clearance due to kidney problems — situations where Leucovorin rescue alone may not be enough.
• Important: Glucarpidase and Leucovorin should not be given within 2 hours of each other, as Glucarpidase can also break down Leucovorin.

What to Ask Your Doctor

If you can't find Leucovorin, here are questions to bring to your next appointment:

1. Can I switch to Levoleucovorin (Fusilev) for my current treatment regimen?
2. Will the dosing change if I switch to an alternative?
3. Is there a risk to delaying my next treatment while we look for supply?
4. Can your office or infusion center source Leucovorin through hospital channels?

For tips on locating Leucovorin in your area, visit our guide on how to find Leucovorin in stock near you, or search Medfinder directly.

Final Thoughts

Not being able to fill a Leucovorin prescription is stressful, especially when it's part of your cancer treatment. But alternatives like Levoleucovorin are clinically proven, FDA-approved, and designed for exactly this situation. Talk to your oncologist about your options and check Medfinder to see what's available near you.

For more on the current supply situation, read our Leucovorin shortage update for 2026.