Medical Editor: John P. Cunha, DO, FACOEP Last updated on RxList: 3/10/2022

Drug Summary

What Is Levoleucovorin?

Levoleucovorin Injection, Powder, Lyophilized, for Solution for Intravenous use is used to treat or prevent toxic effects of methotrexate in people who have received methotrexate to treat bone cancer, or in people whose bodies do not eliminate methotrexate properly after the drug is metabolized, or to treat toxic effects of an accidental overdose of methotrexate. Levoleucovorin Injection is also used in combination chemotherapy with fluorouracil to treat colorectal cancer that has spread to other parts of the body.

What Are Side Effects of Levoleucovorin?

Common side effects of Levoleucovorin Injection include:

  • nausea
  • vomiting
  • diarrhea
  • stomach pain or upset
  • numbness or tingling
  • loss of appetite
  • unusual or unpleasant taste in your mouth
  • weakness
  • tired feeling
  • hair loss
  • mild skin rash
  • swelling of the mouth and lips
  • indigestion
  • shortness of breath, or
  • confusion

Dosage for Levoleucovorin/h4>

The dose of Levoleucovorin is determined based on the dose of methotrexate.

What Drugs, Substances, or Supplements Interact with Levoleucovorin?

Levoleucovorin may interact with sulfa drugs, seizure medications, or multivitamin or mineral supplements containing folic acid. Tell your doctor all medications and supplements you use.

Levoleucovorin During Pregnancy or Breastfeeding

During pregnancy, Levoleucovorin should be used only if prescribed. It is unknown if this drug is excreted in human milk. Consult your doctor before breastfeeding.

Additional Information

Our Levoleucovorin Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

Drug Description


levoleucovorin is the levo isomeric form of racemic d,l-leucovorin, present as the calcium salt. levoleucovorin is the pharmacologically active isomer of leucovorin [(6-S)-leucovorin].

levoleucovorin for injection contains levoleucovorin calcium, which is one of several active, chemically reduced derivatives of folic acid. It is useful as antidote to the inhibition of dihydrofolate reductase by methotrexate. This compound has the chemical designation calcium (6S)-N-{4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl] amino]benzoyl-L-glutamate pentahydrate. The molecular weight is 601.6 and the structural formula is:

levoleucovorin (injection) Structural Formula Illustration

Its molecular formula is: C20H21CaN7O7 5 H2O.

levoleucovorin for injection is supplied as a sterile lyophilized powder consisting of 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin) and 50 mg mannitol per 50 mg vial.

Sodium hydroxide and/or hydrocholoric acid are used to adjust the pH during manufacture. It is intended for intravenous administration after reconstitution with 5.3 mL of sterile 0.9% Sodium Chloride Injection, USP [See DOSAGE AND ADMINISTRATION]



  • levoleucovorin is a folate analog.
  • levoleucovorin rescue is indicated after high-dose methotrexate therapy in osteosarcoma.
  • levoleucovorin is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists.

Limitations of Use

levoleucovorin is not approved for pernicious anemia and megaloblastic anemias secondary to the lack of vitamin B12. Improper use may cause a hematologic remission while neurologic manifestations continue to progress.



Administration Guidelines

levoleucovorin is dosed at one-half the usual dose of the racemic form.

levoleucovorin is indicated for intravenous administration only. Do not administer intrathecally.

Co-administration of levoleucovorin with other agents

Due to the risk of precipitation, do not co-administer levoleucovorin with other agents in the same admixture.

levoleucovorin Rescue After High-Dose Methotrexate Therapy

The recommendations for levoleucovorin rescue are based on a methotrexate dose of 12 grams/m² administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information). levoleucovorin rescue at a dose of 7.5 mg (approximately 5 mg/m²) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion.

Serum creatinine and methotrexate levels should be determined at least once daily. levoleucovorin administration, hydration, and urinary alkalinization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). The levoleucovorin dose should be adjusted or rescue extended based on the following guidelines.

Table 1 Guidelines for levoleucovorin Dosage and Administration

Clinical Situation Laboratory Findings levoleucovorin Dosage and Duration
Normal Methotrexate Elimination Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours 7.5 mg IV q 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 7.5 mg IV q 6 hours, until methotrexate level is less than 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., an increase from 0.5 mg/dL to a level of 1 mg/dL or more). 75 mg IV q 3 hours until methotrexate level is less than 1 micromolar; then 7.5 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar.

Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure. In addition to appropriate levoleucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.

Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table above. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, levoleucovorin rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

Delayed methotrexate excretion may be caused by accumulation in a third space fluid collection (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration. Under such circumstances, higher doses of levoleucovorin or prolonged administration may be indicated.

Although levoleucovorin may ameliorate the hematologic toxicity associated with high dose methotrexate, levoleucovorin has no effect on other established toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney.

Dosing Recommendations for Inadvertent Methotrexate Overdosage

levoleucovorin rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion. As the time interval between antifolate administration [e.g., methotrexate] and levoleucovorin rescue increases, levoleucovorin's effectiveness in counteracting toxicity may decrease. levoleucovorin 7.5 mg (approximately 5 mg/m²) should be administered IV every 6 hours until the serum methotrexate level is less than 10-8 M.

Serum creatinine and methotrexate levels should be determined at 24 hour intervals. If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 x 10-6 M or the 48 hour level is greater than 9 x 10-7 M, the dose of levoleucovorin should be increased to 50 mg/m² IV every 3 hours until the methotrexate level is less than 10-8 M. Hydration (3 L/day) and urinary alkalinization with NaHCO3 should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

Reconstitution and Infusion Instructions

  • Prior to intravenous injection, the 50 mg vial of levoleucovorin for Injection is reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP to yield a levoleucovorin concentration of 10 mg per mL. Reconstitution with Sodium Chloride solutions with preservatives (e.g. benzyl alcohol) has not been studied. The use of solutions other than 0.9% Sodium Chloride Injection, USP is not recommended.
  • The reconstituted 10 mg per mL levoleucovorin contains no preservative. Observe strict aseptic technique during reconstitution of the drug product.
  • Saline reconstituted levoleucovorin solutions may be further diluted, immediately, to concentrations of 0.5 mg/mL to 5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Initial reconstitution or further dilution using 0.9% Sodium Chloride Injection, USP may be held at room temperature for not more than a total of 12 hours. Dilutions in 5% Dextrose Injection, USP may be held at room temperature for not more than 4 hours.
  • Visually inspect the reconstituted solution for particulate matter and discoloration, prior to administration. CAUTION: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if cloudiness or precipitate is observed.
  • No more than 16 mL of reconstituted solutions (160 mg of levoleucovorin ) should be injected intravenously per minute, because of the calcium content of the levoleucovorin solution.


Dosage Forms And Strengths

levoleucovorin for Injection is supplied in sterile, single-use vials containing 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin ) and 50 mg mannitol.

Each 50 mg single-use vial of levoleucovorin for Injection contains a sterile lyophilized powder consisting of 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin) and 50 mg mannitol.

50 mg vial of freeze-dried powder - NDC 68152-101-00.

Store at 25°C (77 °F) in carton until contents are used. Excursions permitted from 15-30°C (59-86 °F). [See USP Controlled Room Temperature]. Protect from light.

Manufactured for Spectrum Pharmaceuticals, Inc. Irvine, CA 92618. Manufactured by Chesapeake Biological Laboratories, Inc. Baltimore, MD 21230, Spectrum Pharmaceuticals, Inc. FDA revision date: 3/7/2008

Side Effects


Clinical Studies Experience

Since clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following table presents the frequency of adverse reactions which occurred during the administration of 58 courses of high dose methotrexate 12 grams/m²followed by levoleucovorin rescue for osteosarcoma in 16 patients age 6-21. Most patients received levoleucovorin 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate.

Table 2: Adverse Reactions

Body System/Adverse Reactions Number (%) of Patients with Adverse Reactions
(N =16)
Number (%) of Courses with Adverse Reactions
(N = 58)
All Grade 3+ All Grade 3+
Stomatitis 6 (37.5) 1 (6.3) 10 (17.2) 1 (1.7)
Vomiting 6 (37.5) 0 14 (24.1) 0
Nausea 3 (18.8) 0 3 (5.2) 0
Diarrhea 1 (6.3) 0 1 (1.7) 0
Dyspepsia 1 (6.3) 0 1 (1.7) 0
Typhlitis 1 (6.3) 1 (6.3) 1 (1.7) 1 (1.7)
Dyspnea 1 (6.3) 0 1 (1.7) 0
Skin and Appendages
Dermatitis 1 (6.3) 0 1 (1.7) 0
Confusion 1 (6.3) 0 1 (1.7) 0
Neuropathy 1 (6.3) 0 1 (1.7) 0
Renal function abnormal 1 (6.3) 0 3 (5.2) 0
Taste perversion 1 (6.3) 0 1 (1.7) 0
Total number of patients 9 (56.3) 2 (12.5)
Total number of courses 25 (43.1) 2 (3.4)

The incidence of adverse reactions may be underestimated because not all patients were fully evaluable for toxicity for all cycles in the clinical trials. Leukopenia and thrombocytopenia were observed, but could not be attributed to high dose methotrexate with levoleucovorin rescue because patients were receiving other myelosuppressive chemotherapy.

Postmarketing Experience

Since adverse reactions from spontaneous reports are provided voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Spontaneously reported adverse reactions collected by the WHO Collaborating Center for International Drug Monitoring in Uppsala Sweden have yielded seven cases where levoleucovorin was administered with a regimen of methotrexate. The events were dyspnea, pruritus, rash, temperature change and rigors. For 217 adverse reactions (108 reports) where levoleucovorin was a suspected or interacting medication, there were 40 occurrences of “possible allergic reaction.”

Drug Interactions


Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible children. It is not known whether folinic acid has the same effects. However, both folic and folinic acids share some common metabolic pathways. Caution should be taken when taking folinic acid in combination with anticonvulsant drugs.

Preliminary human studieshave shown that small quantities of systemically administered leucovorin enter the CSF, primarily as its major metabolite, 5-methyltetrahydrofolate (5-MTHFA). In humans, the CSF levels of 5-MTHFA remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration.

levoleucovorin increases the toxicity of 5-fluorouracil [see WARNINGS and PRECAUTIONS].

Warnings & Precautions


Included as part of the PRECAUTIONS section.


Rate of Administration

Because of the Ca++ content of the levoleucovorin solution, no more than 16 mL (160 mg of levoleucovorin ) should be injected intravenously per minute.

Potential for Enhanced Toxicity with 5-Fluorouracil

levoleucovorin enhances the toxicity of 5-fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly d,l-leucovorin and 5-fluorouracil.

Potential for interaction with trimethoprim-sulfamethoxazole

The concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity in a placebo-controlled study.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No studies have been conducted to evaluate the potential of levoleucovorin for carcinogenesis, mutagenesis and impairment of fertility.

Use In Specific Populations


Pregnancy Category C. It is not known whether levoleucovorin can cause fetal harm when administered to a pregnant woman or if it can affect reproduction capacity. Animal reproduction studies have not been conducted with levoleucovorin. levoleucovorin should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when levoleucovorin is administered to a nursing mother.

Pediatric Use

[See Clinical Studies]

Geriatric Use

Clinical studies of levoleucovorin in the treatment of osteosarcoma did not include subjects aged 65 and over to determine whether they respond differently from younger subjects.

Overdose & Contraindications


No data are available for overdosage with levoleucovorin.


levoleucovorin is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid.

Clinical Pharmacology


Mechanism Of Action

levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid. levoleucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties. Administration of levoleucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase.


levoleucovorin is activelyand passivelytransported across cell membranes. In vivo, levoleucovorin is converted to 5-methyltetrahydrofolic acid (5-methyl-THF), the primary circulating form of active reduced folate.levoleucovorin and 5-methyl-THF are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase.Folylpolyglutamates are active and participate in biochemical pathways that require reduced folate.


The pharmacokinetics of levoleucovorin after intravenous administration of a 15 mg dose was studied in healthy male volunteers. After rapid intravenous administration, serum total tetrahydrofolate (total-THF) concentrations reached a mean peak of 1722 ng/mL. Serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations reached a mean peak of 275 ng/mL and the mean time to peak was 0.9 hours. The mean terminal half-life for total-THF and (6S)-5-methyl-5,6,7,8-tetrahydrofolate was 5.1 and 6.8 hours, respectively.

Animal Toxicology And/Or Pharmacology

The acute intravenous LD50 values in adult mice and rats were 575 mg/kg (1725 mg/m²) and 378 mg/kg ( 2268 mg/m²), respectively. Signs of sedation, tremors, reduced motor activity, prostration, labored breathing, and/or convulsion were observed in these studies. Anticipated human dose for each administration is approximately 5 mg/m², which represents a 3-log safety margin.

Clinical Studies

The safety and efficacy of levoleucovorin rescue following high-dose methotrexate were evaluated in 16 patients age 6-21 who received 58 courses of therapy for osteogenic sarcoma. High-dose methotrexate was one component of several different combination chemotherapy regimens evaluated across several trials. Methotrexate 12 g/m² IV over 4 hours was administered to 13 patients, who received levoleucovorin 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Three patients received methotrexate 12.5 g/m² IV over 6 hours, followed by levoleucovorin 7.5 mg every 3 hours for 18 doses beginning 12 hours after completion of methotrexate. The mean number of levoleucovorin doses per course was 18.2 and the mean total dose per course was 350 mg. The efficacy of levoleucovorin rescue following high-dose methotrexate was based on the adverse reaction profile. [See ADVERSE REACTIONS]

Medication Guide


No information provided. Please refer to the PRECAUTIONS section.

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