Continuing Education Activity

Leucovorin is a medication used in the treatment of methotrexate toxicity and chemotherapy regimens. Leucovorin is a folate analog. This activity reviews the indications, action, and contraindications for leucovorin as a valuable agent in the reversal of methotrexate toxicity and as a part of chemotherapy regimens. This activity will highlight the mechanism of action, adverse event profile, and other key factors pertinent to members of the healthcare team in the management of patients on leucovorin therapy.

Objectives:

• Identify the mechanism of action of leucovorin.
• Describe the potential adverse effects of leucovorin.
• Review the appropriate monitoring necessary following administration of leucovorin.
• Outline interprofessional team strategies for improving care coordination and communication to improve outcomes for patients on leucovorin therapy.

Indications

Leucovorin is a 5-formyl derivative of folic acid, used in biochemical reactions without having to undergo reduction. Leucovorin is FDA indicated after high dose methotrexate therapy in osteosarcoma to decrease the toxic effects of methotrexate or counter the toxic effects of folate antagonists. Leucovorin is also occasionally an alternative agent used in the treatment of megaloblastic anemia when oral intake of folic acid is not possible. Leucovorin can prolong survival in patients when used in combination with 5-fluorouracil for the palliative treatment of colon cancer.[1]

Off-label uses include neoadjuvant treatment in bladder cancer, as a cofactor in methanol toxicity, in the treatment of advanced esophageal cancer, advanced gastric cancer, advanced pancreatic cancer, prevention of hematological toxicity of pyrimethamine in patients with AIDS, and the treatment of ectopic pregnancy (along with methotrexate).[2][3][4]

Leucovorin was initially known as the "citrovorum factor" when researchers discovered it in 1948; they found it to be an essential cofactor for the growth of Leuconostoc citrovorum, a lactic acid bacterium. The FDA approved leucovorin in 2002, and the levo isomer leucovorin received approval in the year 2008 during a shortage of leucovorin.[5] 

Clinical manifestations of methotrexate toxicity include nausea, vomiting, diarrhea, stomatitis, mucositis, esophagitis, elevated hepatic enzymes, rash, renal failure, myelosuppression, acute lung injury, hypotension, tachycardia, and neurologic dysfunction. Toxic effects may occur hours to days to weeks after methotrexate overdose or administration.

Mechanism of Action

Methotrexate is a folate antagonist that works by inhibiting the dihydrofolate reductase enzyme in cells. Leucovorin is a folate derivative that does not need to undergo reduction by the enzyme dihydrofolate reductase for utilization in various one-carbon transfer reactions in the body, such as DNA synthesis.[6]

In contrast, leucovorin can also enhance the therapeutic effect and toxicity of 5 fluoropyrimidines, such as 5-fluorouracil, by increasing the binding of the drug to thymidylate synthase.

The onset of action is less than 5 minutes for intravenous dosing and 10 to 20 minutes and 20 to 30 minutes for intramuscular and oral administration, respectively. Leucovorin rapidly absorbs after oral administration; however, the absorption remains saturated in the gut for doses of more than 25 mg.

Leucovorin is excreted by the kidneys mainly as 10-formyl tetrahydrofolate and 5,10-methenyl tetrahydrofolate.

Administration

Leucovorin administration is by oral, intramuscular, or intravenous routes. Intravenous dosing is preferable in the presence of vomiting or malabsorption.

In the setting of methotrexate toxicity, intravenous dosing is preferred and should start immediately. Methotrexate becomes increasingly polyglutamated; the longer it stays in the cell, the polyglutamated methotrexate stays in the nucleus and is less susceptible to reversal with leucovorin.[7] Monitoring the levels of methotrexate is recommended to determine the appropriate dosage and duration for leucovorin rescue therapy. Dosing may require alteration to account for renal insufficiency, dehydration, and third spacing. 

When used as a part of chemotherapeutic regimens, leucovorin is not administered along with methotrexate. It is usually administered 24 hours after a course of methotrexate. Tissue toxicity may be permanent if leucovorin therapy gets delayed beyond 40 hours. It is not uncommon for methotrexate to be administered intrathecally, for example, in the presence of leptomeningeal carcinomatosis. Leucovorin rescue must not be administered intrathecally and may be fatal if administered by this route.[8] Elimination of methotrexate from the cerebrospinal fluid (CSF) occurs by slow systemic diffusion and can be countered by intravenous methotrexate. Monitoring the level of methotrexate is recommended.

Leucovorin enhances the binding of 5-fluorouracil, and when administering both together, a lower dosage of 5-fluorouracil is necessary. Leucovorin administration usually takes place in the middle of or after the dose of the fluorouracil regimen.

Adverse Effects

Allergic reactions such as anaphylactoid reactions and urticaria have occurred in patients receiving both oral and parenteral leucovorin.[9][10]

Leucovorin enhances the effects of 5-fluorouracil and may cause toxicity.

Folic acid in large quantities has been shown to counteract the pharmacological actions of antiepileptics such as primidone, phenobarbital, and phenytoin. 

When leucovorin has been used concomitantly during the treatment of Pneumocystis jirovecii with trimethoprim-sulfamethoxazole (TMP-SMX), higher rates of treatment failure and morbidity have been reported.

The effects of leucovorin in pregnancy have not been the object of study. Leucovorin was a category C drug under the prior FDA system for categorizing medications in pregnancy. It is not known whether leucovorin gets excreted in breast milk. Caution is necessary when treating patients that are nursing with leucovorin as it may get excreted in breast milk.

Contraindications

If the clinician is using leucovorin alone to treat megaloblastic anemia, they must rule out B12 deficiency. Treating vitamin B12 deficient patients with leucovorin may reverse the megaloblastic anemia; however, it will worsen the neurological manifestations of B12 deficiency.

Monitoring

In the setting of inadvertent methotrexate overdose, leucovorin must start as soon as possible; 10 mg/m^2 must be administered every 6 hours till the concentration of serum methotrexate falls below 10^-8 M on the methotrexate assay. The levels of serum methotrexate require monitoring once every 24 hours until the level falls below the threshold, and renal function must be monitored with daily checks of the serum creatinine levels. If the serum creatinine rises by more than 50% over the previous day's baseline or if the methotrexate one day after admission level is measured to be greater than 5 x 10^-6 M or serum methotrexate value at two days is greater than 9 x 10^-7 M, the dose of leucovorin should get increased to 100 mg/m2 administered intravenously till the serum methotrexate value falls below 10^-8 moles. Hydration is essential, and the team should start a sodium bicarbonate drip; the sodium bicarbonate dose gets titrated to maintain a urinary pH above 7.0.

For patients receiving leucovorin rescue after high dose methotrexate therapy, methotrexate and serum creatinine levels require monitoring at least once a day. Hydration and urinary alkalinization are essential. Leucovorin must continue till the methotrexate level falls below 0.05 micromolar. If delayed excretion is suspected or if raised creatinine levels appear, the dose of leucovorin must increase.

Patients receiving leucovorin along with 5-fluorouracil should have monitoring of serial complete blood counts with differential counts. The CBC and differential must be obtained after the first two rounds of chemotherapy and repeated once a week. Counts should get repeated after courses until reaching the lowest anticipated WBC count. Routine monitoring of liver function tests (LFTs) and serum electrolytes should take place before each course. In the presence of severe stomatitis, gastrointestinal toxicity, a WBC nadir of 1000 to 1900/ mm^3, or a platelet nadir 25000 to 75000/mm^3, the dose is decreased by 20%. In the presence of severe gastrointestinal toxicity, a WBC count below 1000/mm^3, or a platelet count less than 25000/mm^3, the dose must decrease by 30%. If none occurs during a course, the dose of leucovorin and fluorouracil may increase by ten percent.

When administered for folic acid deficiency, up to 1 mg per day can be administered intramuscularly. Serum levels of leucovorin do not require checking. Reticulocyte counts measure the response to treatment, and serial hemoglobin measurements, measuring indirect bilirubin, LDH, serum iron, and potassium levels can be considered.

Toxicity

When administered along with fluorouracil, the following side effects can occur.

• Dermatologic: alopecia, dermatitis
• Gastrointestinal: stomatitis, nausea, diarrhea, vomiting, anorexia
• Central nervous system: fatigue, malaise

Enhancing Healthcare Team Outcomes

Leucovorin is a useful drug used in the setting of chemotherapy and methotrexate overdose/toxicity. 

Care of patients undergoing combination chemotherapy with leucovorin can be challenging and requires an interprofessional team of clinicians from different specialties, nurses, and pharmacists. It is useful to know the symptoms of the toxicity of methotrexate. Early recognition of toxicity and early institution of treatment can reduce adverse outcomes.

When the clinician initiates leucovorin, they will do well to consult with the pharmacist to ensure proper dosing, the absence of potential interactions, and review the adverse events and corrective actions. Dosing and administration will fall to nursing; they must also be well-informed regarding early signs of adverse reactions and keep the team informed on patient tolerance and therapeutic progress. If any issues become apparent, the nursing staff should promptly involve the pharmacy and the clinicians for corrective action. These interprofessional actions will optimize leucovorin therapy results while minimizing adverse effects. [Level 5]