Leucovorin

Leucovorin is a folate analog approved for several distinct uses across its oral and injectable forms.

• Reducing the toxic effects of methotrexate in adults (and in adults and children with injectable forms) who are slow to clear the drug
• Counteracting accidental overdoses of folic acid antagonists or drugs that block dihydrofolate reductase (DHFR inhibitors) in adults; injectable forms extend this to children as well
• Treating cerebral folate transport deficiency (FOLR1-CFTD) — a rare genetic condition — in adults and children with a confirmed FOLR1 gene variant (oral Leucovorin Calcium tablets)
• Vykoura (injection): rescue after high-dose methotrexate therapy in adults and children
• leucovorin calcium (injection): rescue after high-dose methotrexate therapy specifically in osteosarcoma
• Vykoura and leucovorin calcium injections: treatment of megaloblastic anemia due to folic acid deficiency in adults and children when oral therapy is not possible
• Vykoura and leucovorin calcium injections: used alongside fluorouracil (5-FU) in the treatment of metastatic colorectal cancer
• Not for use in pernicious anemia or megaloblastic anemia caused by vitamin B12 deficiency — this can mask dangerous nerve damage

Leucovorin is a ready-to-use form of folate — a B vitamin that the body needs to build and repair DNA. Drugs like methotrexate work by blocking an enzyme called dihydrofolate reductase (DHFR), which normally converts folate into a form cells can use. Leucovorin bypasses that block entirely, restoring the supply of active folate to healthy cells. When used alongside fluorouracil in cancer treatment, leucovorin has the opposite effect: it boosts fluorouracil's cancer-fighting power by helping it bind more tightly to an enzyme (thymidylate synthase) that cancer cells need to replicate.

How and how often leucovorin is given depends entirely on what it's being used for — there's no one-size-fits-all schedule. The oral tablet (Leucovorin Calcium) can be taken with or without food and may be crushed and mixed with food or liquid. Tablets are typically taken multiple times a day at set intervals. Injectable forms (leucovorin calcium and Vykoura) are given by a healthcare provider into a vein or muscle at scheduled intervals, often every few hours in acute settings, until blood levels of methotrexate fall to a safe level.

• Start leucovorin as soon as possible after a methotrexate overdose or within 24 hours when elimination is delayed — timing matters greatly
• Never inject leucovorin into the spinal canal (intrathecally)
• Follow your prescriber's exact dosing schedule and get blood tests as directed to guide treatment

When leucovorin is used on its own, the main reported side effect is allergic reactions. Most of the side effects below occur when leucovorin is combined with fluorouracil for colorectal cancer treatment.

• Nausea and vomiting
• Diarrhea (can be severe)
• Mouth sores (stomatitis)
• Low white blood cell count (leukopenia), increasing infection risk
• Skin rash or dermatitis
• Hair loss (alopecia)
• Fatigue or general feeling of illness
• Hives or allergic reactions, including rare anaphylaxis (a severe, whole-body allergic reaction)

Severe diarrhea or mouth sores should be reported to your doctor immediately — these can worsen quickly and, in older adults, have been fatal. Signs of a serious allergic reaction (throat tightening, difficulty breathing, swelling) need emergency care right away.

• Never inject into the spinal canal: Leucovorin given intrathecally (into the spinal fluid) can be harmful or fatal.
• Enhanced fluorouracil toxicity: Leucovorin makes fluorouracil more powerful — including more toxic. Gut side effects (diarrhea, mouth sores, bowel inflammation) are more common and more severe. Deaths have been reported, especially in elderly patients. Combination treatment must stop if gut symptoms appear and must not restart until they fully resolve.
• Act fast in overdose situations: When leucovorin is being used to reverse a methotrexate overdose, it must be started as quickly as possible. Every hour of delay makes it less effective.
• Trimethoprim-sulfamethoxazole interaction: Using leucovorin together with this antibiotic in HIV patients has been linked to higher rates of treatment failure and death — avoid this combination.
• Seizure risk with antiepileptic drugs: Leucovorin may reduce the effectiveness of drugs like phenytoin or phenobarbital, potentially increasing seizure frequency — particularly in children.

Leucovorin has several important drug interactions to know about before starting treatment.

• Fluorouracil (5-FU): Leucovorin intentionally boosts fluorouracil's effect — but this also increases its toxicity. Doses must be carefully managed, and severe or fatal gut complications have occurred, especially in elderly patients.
• Trimethoprim-sulfamethoxazole (Bactrim): Leucovorin can reduce this antibiotic's effectiveness. In HIV patients treated for Pneumocystis pneumonia, this combination was linked to treatment failure and increased death — avoid combining them.
• Phenobarbital, phenytoin, primidone (antiepileptic drugs): Leucovorin may lower the seizure-control effectiveness of these medications. Conversely, these drugs may reduce how well leucovorin works. Extra monitoring for seizure activity is needed.

This is not a complete list of interactions. Always talk with your doctor or pharmacist before starting, stopping, or changing any medication.

• Tell your doctor if you have ever had any allergic reaction to leucovorin, levoleucovorin, or folic acid — depending on your condition, even a prior mild reaction may be a contraindication
• Tell your doctor if you have pernicious anemia or vitamin B12-deficiency anemia — leucovorin is not appropriate and could allow serious neurological damage to progress undetected
• Tell your doctor if you have kidney impairment — the kidneys help clear leucovorin, and reduced kidney function may increase drug levels
• Tell your doctor if you have liver impairment — the liver helps process leucovorin, and reduced liver function may increase drug levels
• Tell your doctor if you have a deficiency of the enzyme MTHFS — the oral tablet form is not recommended in this case because MTHFS is needed to metabolize leucovorin properly
• Pregnancy: Limited data suggest leucovorin alone does not cause birth defects, but chemotherapy drugs used alongside it may harm a fetus — discuss all risks with your doctor
• Breastfeeding: It is not known whether leucovorin passes into breast milk — consult your doctor before breastfeeding while taking this medicine
• Children: The oral tablet is approved for FOLR1-CFTD in children; injectable Vykoura is approved in children for methotrexate rescue and toxicity reduction; seizure risk from antiepileptic drug interactions is a particular concern in children
• Older adults: Elderly patients are at significantly higher risk of severe and life-threatening gastrointestinal toxicity when leucovorin is combined with fluorouracil

Taking too much leucovorin can cancel out the intended cancer-fighting effect of methotrexate or other folic acid antagonists, so it's important to take exactly what is prescribed. If a methotrexate overdose occurs and leucovorin is being used to counter it, treatment should begin as soon as possible — the longer the delay, the less effective leucovorin becomes. Blood levels of methotrexate and kidney function (creatinine) should be checked at regular intervals to guide how much leucovorin to give and for how long.

Leucovorin and its active metabolites act as cofactors in the body's "one-carbon" metabolism — a set of chemical reactions essential for building DNA and regulating how genes are expressed. By restoring these folate-dependent reactions, leucovorin allows healthy cells to continue normal growth and repair when folic acid pathways have been disrupted by certain drugs. When used with fluorouracil, leucovorin helps that drug bind more tightly to its target enzyme (thymidylate synthase), increasing its ability to stop cancer cells from dividing.

When taken by mouth, leucovorin is rapidly absorbed — the oral tablet delivers over 95% of the available folate into the bloodstream at lower doses, though absorption becomes less complete at higher doses. The active form of leucovorin (levoleucovorin) is converted in the gut and liver to its main working metabolite, 5-MTHF (5-methyltetrahydrofolate), which circulates in the blood and does most of the work. After intravenous dosing, the drug peaks in minutes; after oral dosing, peak levels occur within about 1.5–2.5 hours. Leucovorin and its metabolites are cleared primarily by the kidneys, and patients with kidney or liver problems may have higher drug levels in their bodies.

Store dry product and reconstituted solution at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). Protect from light.