leucovorin

Leucovorin is a medication used to reduce the toxic effects of methotrexate and drugs that work by blocking the activity of vitamin B9 (folic acid antagonists). Leucovorin is used in combination with fluorouracil (5FU) in the treatment of metastatic colorectal cancer. Leucovorin is used off-label in methanol poisoning and occasionally, to treat megaloblastic anemia due to folate (vitamin B9) deficiency. Leucovorin may be administered as intravenous (IV) injections or as oral tablets.

Leucovorin is a structurally similar analog of vitamin B9 (folate), a water-soluble vitamin that is essential for DNA/RNA synthesis. Methotrexate and other folate antagonists work by blocking the synthesis of folate. Leucovorin supplements the folate deficiency caused by these drugs, however, leucovorin also reduces the therapeutic effect of methotrexate. When administered with fluorouracil, leucovorin enhances its toxic effects on the cancer cells, as well as on healthy cells. As an antidote to methanol poisoning, leucovorin eliminates formic acid, its toxic metabolite.

The uses of leucovorin include:

FDA-approved:

Adult and Pediatric:

• Rescue treatment after high-dose methotrexate in adults and children with osteosarcoma, a type of bone cancer
• To reduce the toxicity of overdose of folic acid antagonists or impaired methotrexate elimination in adults and children
• Treatment of metastatic cancer in adults, in combination with fluorouracil

Adult:

Off-label

• Megaloblastic anemia due to folate deficiency
• Methanol poisoning
• Neoadjuvant treatment of cancers such as:
  • Bladder cancer
  • Advanced esophageal cancer
  • Advanced pancreatic cancer
  • Advanced gastric cancer
•  Prevention of hematological toxicity of pyrimethamine in patients with acquired immunodeficiency syndrome (AIDS)
• Treatment of ectopic pregnancy, with methotrexate

• Do not use leucovorin in patients with a history of severe hypersensitivity to leucovorin products, folic or folinic acid. Leucovorin can cause hives (urticaria) and severe allergy-like (anaphylactoid) reactions. 
• Do not use leucovorin to treat pernicious anemia and megaloblastic anemia associated with vitamin B12 deficiency, because of the risk of progression of neurologic effects despite hematologic remission. There is a risk of neurologic complications in patients with undiagnosed anemia.
• Administer leucovorin as promptly as possible after an accidental overdose of folic acid antagonists such as methotrexate. Delay can reduce leucovorin’s efficacy in countering hematologic toxicity.
• Leucovorin has no effect on other established toxicities of methotrexate such as nephrotoxicity and/or metabolite precipitation in the kidney.
  • Monitor methotrexate concentration in the blood to determine the optimal dose and duration of treatment with leucovorin.
  • Methotrexate excretion may be delayed in patients with fluid accumulation conditions such as ascites or pleural effusion, insufficient kidney function or inadequate hydration. Such patients may require higher doses of leucovorin or longer duration of treatment. Dosages higher than recommended oral doses should be administered as IV infusion.
• Do not administer leucovorin into the spinal canal (intrathecal).
• Leucovorin injection contains calcium and can cause hypercalcemia. Inject no more than 16 mL (160 mg leucovorin) intravenously per minute.
• Administer leucovorin intravenously instead of oral dosing in patients who may vomit and fail to absorb leucovorin.
• Leucovorin may enhance the toxicity of fluorouracil, particularly in the elderly. There have been reports of death from enterocolitis, diarrhea and dehydration in elderly patients treated with weekly fluorouracil and leucovorin.
• Monitor patients for gastrointestinal toxicities and closely monitor patients with diarrhea, because it can rapidly lead to death.
• Do not initiate or continue treatment with leucovorin and fluorouracil in patients with gastrointestinal toxicity, until symptoms are resolved.
• Studies show concurrent use of leucovorin with trimethoprim-sulfamethoxazole for the treatment of Pneumocystis carinii pneumonia in patients with human immunodeficiency virus (HIV) infection may increase rates of treatment failure and mortality.
• Large doses of leucovorin may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible children.
• High doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate.

Common side effects of leucovorin include:

• Nausea
• Vomiting
• Oral inflammation (stomatitis)
• Indigestion (dyspepsia)
• Diarrhea
• Abdominal pain
• Inflammation of cecum, the beginning portion of the colon (typhlitis)
• Decrease in appetite
• Loss of appetite (anorexia)
• Fatigue
• Feeling unwell (malaise)
• Weakness (asthenia)
• Abnormal kidney function
• Nerve damage (neuropathy)
• Confusion
• Taste perversion
• Shortness of breath (dyspnea)
• Dermatitis
• Hair loss (alopecia)

Less common side effects of leucovorin include:

• Rash
• Itching (pruritus)
• Hives (urticaria)
• Severe allergy-like (anaphylactoid) reactions
• Rigors
• Temperature change

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Tablets

• 5 mg
• 10 mg
• 15 mg
• 25 mg

Injection, powder for reconstitution

• 50 mg
• 100 mg
• 200 mg
• 350 mg
• 500 mg

Injectable solution

• 10 mg/mL

Adult and Pediatric:

Methotrexate Overdose

• Administer as soon as possible and within 24 hours; if the methotrexate level is above 10-6 M or 48-hour level is above 9 x 10-7 M, the dose of leucovorin should be increased to 100 mg/m2 intravenous (IV) every 3 hours until methotrexate level is below 10-8 M

Dosing considerations

• Hydration (3 L/day) and urinary alkalinization with sodium bicarbonate solution should be employed concomitantly; bicarbonate dose should be adjusted to maintain urine pH at 7.0 or greater

High Dose Methotrexate Rescue

• 10 mg/m² IV once every 6 hours for 10 doses; starts 24 hours after beginning of methotrexate infusion  
• May give orally after 1st IV dose

Adjust dose as follows:

Normal methotrexate elimination

• Serum methotrexate level approximately 10 micromolar, 24 hours after administration, 1 micromolar at 48 hours, below 0.2 micromolar at 72 hours
  • Administer 15 mg orally or IV once every 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion)

Delayed late methotrexate elimination

• Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration
  • Continue 15 mg oral or IV once every 6 hours, until methotrexate level is below 0.05 micromolar

Delayed early methotrexate elimination and/or evidence of acute renal injury

• Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, or a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., increase from 0.5 mg/dL to a level of 1 mg/dL or more)
  • Administer 150 mg IV once every 3 hours until methotrexate level is below 1 micromolar; then 15 mg IV once every 3 hours until methotrexate level is below 0.05 micromolar

Dosing considerations

• In presence of gastrointestinal toxicity, nausea or vomiting, administer leucovorin parenterally; do not administer leucovorin intrathecally; serum creatinine and methotrexate levels should be determined at least once daily
• Administration, hydration, and urinary alkalization (pH of 7.0 or greater) should be continued until methotrexate level is below 5 x 10-8 M (0.05 micromolar)

Megaloblastic Anemia Due to Folate Deficiency

• Up to 1 mg daily; there is no evidence that doses above 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg

Trimethoprim Toxicity

• 10 mg/m² orally once every 6 hours

Adult:

Coadministration with Trimetrexate (Discontinued)

• 20 mg/m² IV/oral once every 6 hours (for oral, round dose up to next 25 mg increment)  
• Dose adjustment for both trimetrexate & leucovorin may be necessary if hematologic toxicity occurs

Advanced Colorectal Carcinoma (with fluorouracil [5FU])

• Recommended 20 mg/m² IV followed by 425 mg/m² fluorouracil  
• Dose reduction treatment pause may be necessary based on hematologic toxicity

Methanol Poisoning (Off-label)

• 1 mg/kg (50-70 mg adults) IV once every 4-6 hours

Other Indications and Uses

• Bone marrow suppression due to folic acid antagonism

Overdose

Excessive amounts of leucovorin may nullify the chemotherapeutic effect of folic acid antagonists.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Leucovorin has no known severe interactions with other drugs.
• Serious interactions of leucovorin include:
  • trimethoprim
• Moderate interactions of leucovorin include:
  • capecitabine
  • fluorouracil
  • glucarpidase
• Leucovorin has no known mild interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There are no animal reproductive studies or well-controlled studies of leucovorin use in pregnant women. It is not known if leucovorin can cause fetal harm. Use during pregnancy should be restricted to only when clearly needed and potential benefits outweigh potential risks to the fetus.
• Leucovorin is administered in combination with methotrexate or fluorouracil, which can cause fetal harm. Refer to methotrexate and fluorouracil prescribing information for additional information.
• There is no information on the presence of leucovorin in breastmilk or its effects on milk production or the breastfed infant. Use with caution in nursing mothers, because many drugs are excreted in breastmilk.

• Take oral leucovorin exactly as prescribed.
• Report to your physician immediately if you develop hypersensitivity reactions.
• Store leucovorin tablets safely out of reach of children.
• In case of overdose, seek medical care or call Poison Control.