Levoleucovorin

Dosage Forms & Strengths

powder for injection

• 50mg

Methotrexate Inadvertent Overdose

7.5 mg (approximately 5 mg/m²) intravenously (IV) every 6 hours until the serum methotrexate level is less than 0.01 micromolar 

Measure methotrexate and creatinine levels at 24 hours interval; increase dose of levoleucovorin to 50 mg/m² IV every 3 hours until the methotrexate is less than 0.01 micromolar if methotrexate level is > 5 micromolar or serum creatinine has increased 50% over baseline after 24 hr of initiating treatment or if the 48 hr methotreaxate level is >0.9 micromolar

Aggressive hydration and urinary alkalinization (with sodium bicarbonate) should be maintained during the treatment period

High Dose Methotrexate Rescue

7.5 mg or 5 mg/m² IV q6hr for 10 doses starting 24 hr after initiating methotrexate infusion 

Renal failure may occur in patients with delayed early methotrexate elimination; such patients require continuing hydration and urinary alkalization (with sodium bicarbonate); fluid and electrolyte monitoring is necessary until serum methotrexate has fallen to below 0.05 micromolar and renal failure has resolved

Advanced Colorectal Cancer

Indicated in combination with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer

100 mg/m² by slow IV injection over a minimum of 3 minutes, followed by 5-FU at 370 mg/m² by IV injection, OR 

10 mg/m² by slow IV injection followed by 5-FU at 425 mg/m² by IV injection

Repeat daily for 5 days at 4-week intervals for 2 cycles, and then repeat at 4-5 week intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course

5-FU dose may need to be adjusted downward by 20-30% according to toxicities or upward by 10% if no toxicities experienced

Administer levoleucovorin separate from 5-FU to avoid precipitant

Dosage Forms & Strengths

powder for injection

• 50mg

Methotrexate Inadvertent Overdose

7.5 mg (approximately 5 mg/m²) intravenously (IV) every 6 hours until the serum methotrexate level is less than 0.01 micromolar 

Measure methotrexate and creatinine levels at 24 hours interval; increase dose of levoleucovorin to 50 mg/m² IV every 3 hours until the methotrexate is less than 0.01 micromolar if methotrexate level is > 5 micromolar or serum creatinine has increased 50% over baseline after 24 hr of initiating treatment or if the 48 hr methotreaxate level is >0.9 micromolar

Aggressive hydration and urinary alkalinization (with sodium bicarbonate) should be maintained during the treatment period

High Dose Methotrexate Rescue

7.5 mg or 5 mg/m² IV q6hr for 10 doses starting 24 hr after initiating methotrexate infusion 

Renal failure may occur in patients with delayed early methotrexate elimination; such patients require continuing hydration and urinary alkalization (with sodium bicarbonate); fluid and electrolyte monitoring is necessary until serum methotrexate has fallen to below 0.05 micromolar and renal failure has resolved

No data are available for overdosage with levoleucovorin.

• 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.

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.

Pharmacodynamics

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.

Pharmacokinetics

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]

Levoleucovorin may be found in some form under the following brand names:

• Fusilev

You should not receive this medication if you are allergic to levoleucovorin or to folic acid or folinic acid.

If possible, before you receive levoleucovorin, tell your doctor or caregivers if you have kidney or liver disease, or if you are dehydrated.

Tell your doctor if you are taking sulfa drugs, seizure medication, a cancer medication called fluorouracil (5FU), or a multivitamin or mineral supplement than contains folic acid.

In an emergency situation, it may not be possible before you are treated to tell your caregivers about all of your medical conditions or if you are pregnant or breast-feeding. However, make sure any doctor caring for you afterward knows that you have received this medication.

Tell your doctor or caregivers at once if you have fever, chills, white patches or sores inside your mouth or on your lips, severe or ongoing diarrhea, confusion, urination problems, or if you feel very thirsty or hot, if you are unable to urinate, and you have heavy sweating or hot and dry skin.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Use levoleucovorin as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as a shot into a vein.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

    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.

Gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be of greater severity and of prolonged duration.

Seizures and/or syncope have been reported rarely in cancer patients receiving d,l-leucovorin, usually in association with fluoropyrimidine administration, and most commonly in those with CNS metastases or other predisposing factors. However, a causal relationship has not been established.

    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.

Mechanism Of Action

12.1.1 Levoleucovorin effects during high-dose methotrexate therapy

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.

Pharmacodynamics

Levoleucovorin is actively and passively transported 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.

Pharmacokinetics

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.

A pharmacokinetic study was conducted in 40 healthy subjects who received a single intravenous dose of either Levoleucovorin (200 mg/m2) or racemic d,l-leucovorin (400 mg/m2), each administered as a 2-hour infusion in a crossover design. Results indicate that the 90% confidence interval for the geometric mean ratios for both AUC0-inf and Cmax were within the standard limit of 80% to 125% for both l-leucovorin and l-5-methyl-THF. Therefore, the exposure to l-leucovorin and 5-methyl-THF (AUC0-inf and Cmax) was comparable whether it was administered as Levoleucovorin or as d,l-leucovorin. The geometric mean AUC0-inf values for Levoleucovorin were 30719 ng.h/mL and 31296 ng.h/mL for Levoleucovorin and d,l-leucovorin, respectively. The geometric mean Cmax values for Levoleucovorin were 10895 ng/mL and 11301 ng/ mL for Levoleucovorin and d,l-leucovorin, respectively. The geometric mean AUC0-inf values for 5-methyl-THF were 52105 ng.h/mL and 50137 ng.h/mL for Levoleucovorin and d,l-leucovorin, respectively. The geometric mean Cmax values for 5-methyl-THF were 4930 ng/mL and 4658 ng/mL for Levoleucovorin and d,l-leucovorin, respectively.

• 6S-leucovorin
• Calcium Levoleucovorin
• L-leucovorin
• Levo-folinic Acid
• Levo-leucovorin
• Levoleucovorin Calcium Pentahydrate
• S-leucovorin

There are no initial dosage adjustments provided in the manufacturer’s labeling; in patients with impaired methotrexate elimination, adjust levoleucovorin dose based on methotrexate levels.

Lyophilized powder: Reconstitute the 50 mg vial with 5.3 mL NS (preservative free) to a concentration of 10 mg/mL. Reconstitute 175 mg vial with 17.7 mL NS (preservative free) to a concentration of 10 mg/mL. Do not use if solution appears cloudy or contains a precipitate. May further dilute for infusion in NS or D5W to a final concentration of 0.5 to 5 mg/mL.

Injection solution: May further dilute for infusion in NS or D5W to a concentration of 0.5 mg/mL.

Do not prepare with other products in the same admixture; may cause precipitation.

For IV administration only; do not administer intrathecally. Administer by slow IV push or infusion over at least 3 minutes, not to exceed 160 mg/minute (due to calcium content).

For colorectal cancer: Levoleucovorin has also been administered (off-label administration rate) as IV infusion over 2 hours (Comella 2000; Tournigand 2006).

Animal reproduction studies have not been conducted. Levoleucovorin is the levo isomeric form of racemic leucovorin, a biologically active form of folic acid. Adequate amounts of folic acid are recommended during pregnancy. Refer to Folic Acid monograph.

More frequently reported side effects include: diarrhea. See below for a comprehensive list of adverse effects.

Data not available