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Levoleucovorin Calcium

Pronunciation: LEE-voe-LOO-koe-VOR-in KAL-see-um
Class: Cytoprotective agent

Trade Names

- Injection, lyophilized powder for solution 50 mg
- Injection, solution 10 mg/mL


Counteracts the therapeutic and toxic effects of folic acid antagonists, such as methotrexate.



After rapid IV administration, C max of total tetrahydrofolate (THF) is 1,722 ng/mL. Serum (6S)-5-methyl-5,6,7,8-THF reached a C max of 275 ng/mL in 0.9 hours.


Mean terminal half-life of total-THF and (6S)-5-methyl-5,6,7,8-THF is 5.1 and 6.8 h, respectively.

Indications and Usage

For rescue after high-dose methotrexate therapy in osteosarcoma; to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists; in combination chemotherapy with 5-fluorouracil in the palliative treatment of advanced metastatic colorectal cancer.


Previous allergic reactions to folic acid or folinic acid.

Dosage and Administration

Rescue After High-Dose Methotrexate Therapy

IV Recommendations for levoleucovorin rescue are based on a dose of methotrexate 12 g/m 2 infused over 4 h. Administer levoleucovorin 7.5 mg (approximately 5 mg/m 2 ) every 6 h for 10 doses starting 24 h after beginning of methotrexate infusion. Determine serum creatinine and methotrexate levels at least once daily. Continue levoleucovorin administration, hydration, and urinary alkalinization (pH of 7 or more) until the methotrexate level is below 5 × 10 −8 M (0.05 micromolar).

Dosage adjustment Normal methotrexate elimination

If serum methotrexate level is approximately 10 micromolar at 24 h after administration, 1 micromolar at 48 h, and less than 0.2 micromolar at 72 h, administer levoleucovorin 7.5 mg every 6 h for 60 h (10 doses starting 24 h after the start of methotrexate infusion).

Delayed late methotrexate elimination

If serum methotrexate level remains above 0.2 micromolar at 72 h and more than 0.05 micromolar at 96 h after administration, continue levoleucovorin 7.5 mg every 6 h until the methotrexate level is less than 0.05 micromolar.

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

If serum methotrexate level is 50 micromolar or more at 24 h or 5 micromolar or more at 48 h after administration, or if there is a 100% or greater increase in serum creatinine level at 24 h after methotrexate administration (eg, an increase from 0.5 mg/dL to a level of 1 mg/dL or more), give levoleucovorin 75 mg every 3 h until methotrexate level is less than 1 micromolar, then administer levoleucovorin 7.5 mg every 3 h until methotrexate level is less than 0.05 micromolar.

Concomitant therapy

Patients experiencing 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 falls below 0.05 micromolar and renal failure resolves.

Impaired Methotrexate Elimination or Inadvertent Overdosage

IV Start levoleucovorin rescue as soon as possible after an inadvertent overdosage and within 24 h of methotrexate administration when there is delayed excretion. Administer levoleucovorin 7.5 mg (approximately 5 mg/m 2 ) every 6 h until the serum methotrexate level is less than 10 −8 M. Determine serum creatinine and methotrexate levels at 24-h intervals. If the 24-h serum creatinine increases 50% over baseline, or if the 24-h methotrexate level is greater than 5 × 10 −6 M, or the 48-h level is greater than 9 × 10 −7 M, increase the levoleucovorin dose to 50 mg/m 2 every 3 h until the methotrexate level is less than 10 −8 M. Concomitantly employ hydration (3 L/day) and urinary alkalinization with sodium bicarbonate. Adjust the bicarbonate dose to maintain the urine pH at 7 or more.

Metastatic Colorectal Cancer

IV Levoleucovorin 100 mg /m 2 over at least 3 min followed by 5-fluorouracil 370 mg/m 2 , or levoleucovorin 10 mg/m 2 followed by 5-fluorouracil 425 mg/m 2 . Administer daily for 5 days. The 5-day treatment course may be repeated at 4-wk (28-day) intervals for 2 courses, and then repeated at 4- to 5-wk (28- to 35-day) intervals provided that the patient has recovered from any toxicity experienced in a prior treatment course.

General Advice

  • For IV administration only; do not administer intrathecally.
  • If clinically important methotrexate toxicity is observed, extend levoleucovorin rescue for an additional 24 h (total of 14 doses over 84 h) in subsequent courses of therapy.
  • Delayed methotrexate excretion may be caused by accumulation in a third-space fluid collection (eg, ascites), renal impairment, or inadequate hydration. Under such circumstances, higher doses of levoleucovorin or prolonged administration may be indicated.
  • Do not coadminister with other agents in the same admixture.
  • When used in combination, administer 5-fluorouracil and levoleucovorin separately to avoid formation of precipitate.
  • Do not inject more than 16 mL of reconstituted solution or solution for injection (levoleucovorin 160 mg) IV per min because of the calcium content of the solution.
Powder for injection
  • The 50 mg vial of levoleucovorin powder for solution is reconstituted with 5.3 mL of sodium chloride 0.9% injection to yield a levoleucovorin concentration of 10 mg/mL.
  • The saline reconstituted solution may be further diluted to concentrations of 0.5 mL to 5 mg/mL in sodium chloride 0.9% injection or dextrose 5% injection.
Solution for injection
  • Solution for injection may be further diluted to concentrations of 0.5 mg/mL in sodium chloride 0.9% injection or dextrose 5% injection.


Powder for solution

Store single-use vials between 59° and 86°F. Protect from light. Initial reconstitution of powder for injection or additional dilution using sodium chloride 0.9% injection may be stored at room temperature for not more than 12 h. Dilutions with dextrose injection 5% may be stored at room temperature for not more than 4 h.

Solution for injection

Store single-use vials in refrigerator between 36° and 46°F in carton until contents are used. Protect from light. The solution for injection that is further diluted may be stored at room temperature for no more than 4 h.

Drug Interactions

Anticonvulsants (eg, phenobarbital, phenytoin, primidone)

Use with caution because of possible decreased anticonvulsant activity.


Risk of 5-fluorouracil toxicity (eg, dehydration, diarrhea, enterocolitis) may be increased. When coadministered, the dosage of 5-fluorouracil must be lower than usually administered. Close clinical and laboratory monitoring is warranted.


Efficacy of intrathecal methotrexate may be decreased. Close clinical monitoring is warranted.


In HIV-infected patients with acute Pneumocystis carinii pneumonia, the risk of trimethoprim-sulfamethoxazole treatment failure and morbidity may be increased. Close clinical monitoring is warranted.

Adverse Reactions

The following adverse reactions were reported in patients receiving high-dose methotrexate followed by levoleucovorin rescue.


Confusion, neuropathy (6%).


Dermatitis (6%); pruritus, rash (postmarketing).


Stomatitis, vomiting (38%); nausea (19%); diarrhea, dyspepsia, taste perversion, typhlitis (6%).


Abnormal renal function (6%).


Dyspnea (6%).


Allergic reaction, rigors, temperature changes (postmarketing).



For high-dose methotrexate therapy or inadvertent methotrexate overdose, monitor serum creatine and methotrexate levels once daily. Patients who develop diarrhea during combination therapy with 5-fluorouracil must be monitored with particular care until diarrhea resolves.


Category C .




Safety and efficacy of levoleucovorin rescue following high-dose methotrexate have been evaluated in a limited number of patients 6 to 21 years of age.


Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving d,l -leucovorin and 5-fluorouracil.

GI toxicity

GI toxicities (eg, diarrhea, stomatitis) may be of greater severity or longer duration when levoleucovorin and 5-fluorouracil are used in combination.


Have been reported, generally in patients with CNS metastases or other underlying risk factors.



No data are available.

Patient Information

  • Advise patients that they may experience adverse reactions, such as nausea, vomiting, changes in taste, or sores in mouth.
  • Advise patients to immediately report any signs and symptoms of severe enterocolitis, diarrhea, and dehydration, especially if the patient is elderly and receiving treatment with 5-fluorouracil.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.