What Is Leucovorin?

Leucovorin (also known as Leucovorin Calcium or Folinic Acid) is a reduced form of folic acid used in several critical medical situations. It is most commonly used as a "rescue" agent after high-dose Methotrexate therapy to protect healthy cells from Methotrexate toxicity. It is also used alongside 5-Fluorouracil (5-FU) in the treatment of advanced colorectal cancer, where it enhances the cancer-fighting effects of 5-FU. Additionally, Leucovorin can treat megaloblastic anemia caused by folic acid deficiency when oral folic acid is not an option.

How does Leucovorin work?

Leucovorin is a reduced folate — specifically the 5-formyl derivative of tetrahydrofolic acid. It works by bypassing the enzyme dihydrofolate reductase, which is blocked by drugs like Methotrexate. By providing cells with a ready-to-use source of reduced folates, Leucovorin allows healthy cells to continue DNA synthesis even when Methotrexate has shut down the normal folate pathway. When combined with 5-Fluorouracil (5-FU) for cancer treatment, Leucovorin enhances the binding of 5-FU to thymidylate synthase, making the chemotherapy drug more effective at killing cancer cells.

What doses are available for Leucovorin?

• Oral Tablets: 5 mg, 10 mg, 15 mg, 25 mg
• Powder for Injection: 50 mg, 100 mg, 200 mg, 350 mg, 500 mg vials
• Solution for Injection: 10 mg/mL

Doses above 25 mg should be given intravenously because oral absorption saturates at that level.

How hard is it to find Leucovorin in stock?

Leucovorin scores a 35 out of 100 on our findability scale, meaning it is frequently difficult to find in stock. Leucovorin Calcium injection (especially 500 mg vials) is currently on back order from multiple manufacturers, and oral tablets are intermittently in shortage as well. The FDA has authorized temporary importation from Canada to help address supply gaps. If your pharmacy is out of stock, Medfinder can help you locate pharmacies that currently have Leucovorin available near you.

Who Can Prescribe Leucovorin?

Leucovorin is most commonly prescribed by the following specialists:

• Oncologists and Hematologists — for chemotherapy regimens and Methotrexate rescue
• Rheumatologists — for Methotrexate rescue in autoimmune disease treatment
• Infectious Disease Specialists — for toxoplasmosis treatment alongside Pyrimethamine
• OB/GYN Physicians — for ectopic pregnancy management with Methotrexate
• Emergency Medicine Physicians — for Methotrexate overdose or methanol poisoning

Because Leucovorin is primarily used in hospital and clinic settings, most patients receive it through their treating specialist rather than a retail pharmacy.

Is Leucovorin a controlled substance?

No, Leucovorin is not a controlled substance. It has no potential for abuse or dependence and is not scheduled by the DEA. It can be prescribed by any licensed healthcare provider and dispensed without the additional restrictions that apply to controlled substances.

Common Side Effects of Leucovorin

• Nausea
• Vomiting
• Diarrhea
• Stomatitis (mouth sores)
• Allergic sensitization including rash, hives, and itching

Serious side effects can include anaphylactoid reactions, seizures (with high-dose Methotrexate), and enhanced gastrointestinal toxicity or bone marrow suppression when used with 5-FU. Leucovorin must never be administered intrathecally (into the spinal canal), as this can be fatal.

Alternative Medications to Leucovorin

• Levoleucovorin (Fusilev, Khapzory) — The active L-isomer of Leucovorin, approved for the same indications. Can be used at half the dose of racemic Leucovorin. Often more expensive but may be available during Leucovorin shortages.
• Folic Acid — Suitable only for megaloblastic anemia (not a substitute in chemotherapy or Methotrexate rescue). Much cheaper and widely available.
• Glucarpidase (Voraxaze) — Used specifically for toxic Methotrexate levels by enzymatically breaking down Methotrexate. Not a direct substitute but an alternative rescue agent.

Drug Interactions with Leucovorin

• 5-Fluorouracil (5-FU): Leucovorin enhances both the efficacy and toxicity of 5-FU — dose adjustments are required and patients must be closely monitored.
• Methotrexate: Leucovorin counteracts Methotrexate's effects — precise timing and dosing are critical for effective rescue.
• Trimethoprim-Sulfamethoxazole (TMP-SMX): Concurrent use may lead to higher treatment failure rates for Pneumocystis infections.
• Antiepileptics (Phenytoin, Phenobarbital, Primidone): Large doses of folates can reduce anticonvulsant effectiveness and increase seizure risk.
• Glucarpidase (Voraxaze): Should not be given within 2 hours of Leucovorin when both are used for Methotrexate rescue.
• Capecitabine: Enhanced toxicity similar to the 5-FU interaction.

Final Thoughts on Leucovorin

Leucovorin is a critical medication for cancer treatment and Methotrexate rescue, but ongoing shortages — particularly of the injectable form — have made it challenging to find in 2026. With a findability score of just 35 out of 100, patients and providers may need to explore alternatives like Levoleucovorin or work with specialty pharmacies. If you're having trouble locating Leucovorin, Medfinder can help you search pharmacies in your area that currently have it in stock. Always coordinate closely with your healthcare team, as timing and dosing of Leucovorin are often critical to treatment outcomes.