Levoleucovorin

What is Levoleucovorin?

11 DESCRIPTION Levoleucovorin is a folate analog and the pharmacologically active levo-isomer of d,l -leucovorin. The chemical name of levoleucovorin calcium is calcium (6 S )-N-{4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl] amino]benzoyl}- L -glutamate mixed hydrates. The molecular formula is C 20 H 21 CaN 7 O 7 ● nH 2 O (n = 3 to 6) and the molecular weight is 565.6 to 619.6. The molecular structure is: Levoleucovorin Injection, for intravenous use is supplied as a sterile colorless to yellow, clear solution of either 175 mg levoleucovorin in 17.5 mL or 250 mg levoleucovorin in 25 mL per single-dose vial. Each mL contains 10 mg levoleucovorin (equivalent to 10.8 mg levoleucovorin calcium, on anhydrous basis) and 8.3 mg sodium chloride. Sodium hydroxide is used for pH adjustment to pH 8.0 (6.5 to 8.5). molecular structure

Uses of Levoleucovorin

Established uses

1 INDICATIONS AND USAGE Levoleucovorin Injection is indicated for: rescue after high-dose methotrexate therapy in adult and pediatric patients with osteosarcoma.
diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination in adult and pediatric patients.
the treatment of adults with metastatic colorectal cancer in combination with fluorouracil.
Limitations of Use Levoleucovorin Injection is not indicated for pernicious anemia and megaloblastic anemia secondary to the lack of vitamin B 12 , because of the risk of progression of neurologic manifestations despite hematologic remission.
Levoleucovorin Injection is a folate analog indicated for: Rescue after high-dose methotrexate therapy in adult and pediatric patients with osteosarcoma.
( 1 ) Diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination in adult and pediatric patients.

How Levoleucovorin works

In more detail: 12.1 Mechanism of Action 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 counteracts the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. Combination with Fluorouracil in Colorectal Cancer Levoleucovorin enhances the therapeutic and toxic effects of fluorouracil. Fluorouracil is metabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase (an enzyme important in DNA repair and replication). Levoleucovorin is converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of FdUMP to thymidylate synthase and thereby enhancing the inhibition of thymidylate synthase.

How to take Levoleucovorin

2 DOSAGE AND ADMINISTRATION For intravenous administration only. Do not administer intrathecally. ( 2.1 ) Rescue After High-Dose Methotrexate Therapy Rescue recommendations are based on methotrexate dose of 12 grams/m 2 administered by intravenous infusion over 4 hours. Initiate rescue at a dose of 7.5 mg (approximately 5 mg/m 2 ) every 6 hours, 24 hours after the beginning of methotrexate infusion. ( 2.3 ) Continue until the methotrexate level is below 5 x 10 -8 M (0.05 micromolar). Adjust dose if necessary based on methotrexate elimination; refer to Full Prescribing Information. ( 2.3 ) Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination Start as soon as possible after methotrexate overdosage or within 24 hours of delayed methotrexate elimination. ( 2.4 ) Administer levoleucovorin injection 7.5 mg (approximately 5 mg/m 2 ) intravenously every 6 hours until methotrexate level is less than 5 x 10 -8 M (0.05 micromolar). ( 2.4 ) Metastatic Colorectal Cancer in Combination with Fluorouracil The following regimens have been used for the treatment of colorectal cancer: Levoleucovorin injection 100 mg/m 2 by intravenous injection over a minimum of 3 minutes, follow

Dosage

Follow the dose prescribed by your doctor or pharmacist. The ranges below are general information, not a personal prescription.

Adults: 2 DOSAGE AND ADMINISTRATION For intravenous administration only. Do not administer intrathecally. ( 2.1 ) Rescue After High-Dose Methotrexate Therapy Rescue recommendations are based on methotrexate dose of 12 grams/m 2 administered by intravenous infusion over 4 hours. Initiate rescue at a dose of 7.5 mg (approximately 5 mg/m 2 ) every 6 hours, 24 hours after the beginning of methotrexate infusion. ( 2.3 ) Continue until the methotrexate level is below 5 x 10 -8 M (0.05 micromolar). Adjust dose if necessary based on methotrexate elimination; refer to Full Prescribing Information. ( 2.3 ) Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination Start as soon as possible after methotrexate overdosage or within 24 hours of delayed methotrexate elimination. ( 2.4 ) Administer levoleucovorin injection 7.5 mg (approximately 5 mg/m 2 ) intravenously every 6 hours until methotrexate level is less than 5 x 10 -8 M (0.05 micromolar). ( 2.4 ) Metastatic Colorectal Cancer in Combination with Fluorouracil The following regimens have been used for the treatment of colorectal cancer: Levoleucovorin injection 100 mg/m 2 by intravenous injection over a minimum of 3 minutes, follow

Side effects of Levoleucovorin

Common

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypercalcemia [see Warnings and Precautions ( 5.1 )] Increased gastrointestinal toxicities with fluorouracil [see Warnings and Precautions ( 5.2 )] The most common adverse reactions (≥20%) in patients receiving high-dose methotrexate therapy with levoleucovorin rescue are stomatitis and vomiting.
( 6.1 ) The most common adverse reactions (>50%) in patients receiving levoleucovorin in combination with fluorouracil for metastatic colorectal cancer are stomatitis, diarrhea, and nausea.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc.
at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Trials Experience Because 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.
High-Dose Methotrexate Therapy Table 2 presents the frequency of adverse reactions which occurred during the administration of 58 courses of high-d

Warnings and who should not take it

Who should NOT take Levoleucovorin?

4 CONTRAINDICATIONS Levoleucovorin is contraindicated in patients who have had severe hypersensitivity to leucovorin products, folic acid or folinic acid [see Adverse Reactions ( 6.2 )] .
Patients who have had severe hypersensitivity reactions to leucovorin products, folic acid or folinic acid.
( 4 )

Overdose

2.4 Recommended Dosage for Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination Start levoleucovorin injection as soon as possible after an overdosage of methotrexate or within 24 hours of methotrexate administration when methotrexate elimination is impaired. As the time interval between methotrexate administration and levoleucovorin injection increases, the effectiveness of levoleucovorin injection to diminish methotrexate toxicity may decrease. Administer levoleucovorin injection 7.5 mg (approximately 5 mg/m 2 ) by intravenous infusion every 6 hours until the serum methotrexate level is less than 5 x 10 -8 M (0.05 micromolar). Monitor serum creatinine and methotrexate levels at least every 24 hours. Increase the dosage of levoleucovorin injection to 50 mg/m 2 intravenously every 3 hours and continue levoleucovorin injection at this dosage until the methotrexate level is less than 5 x 10 -8 M for the following: if serum creatinine at 24-hours increases 50% or more compared to baseline if the methotrexate level at 24-hours is greater than 5 x 10 -6 M if the methotrexate level at 48-hours is greater than 9 x 10 -7 M, Continue concomitant hydration (3 L per day)

Safety at a glance

PregnancyCaution

8.1 Pregnancy Risk Summary There are limited data with levoleucovorin use in pregnant women. Animal reproduction studies have not been conducted with levoleucovorin. Levoleucovorin is administered in combination with methotrexate or fluorouracil, which can cause embryo-fetal harm. Refer to methotrexate and fluorouracil prescribing information for additional information. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Children and elderly

Children

8.4 Pediatric Use The safety and effectiveness of levoleucovorin have been established in pediatric patients for rescue after high-dose methotrexate therapy in osteosarcoma and diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination. Use of levoleucovorin in pediatric patients is supported by open-label clinical trial data in 16 pediatric patients 6 years of age and older, with additional supporting evidence from literature [see Clinical Studies ( 14.1 )]. The safety and effectiveness of levoleucovorin have not been established for the treatment of pediatric patients with advanced metastatic colorectal cancer.

Elderly

8.5 Geriatric Use Clinical studies of levoleucovorin in the treatment of osteosarcoma did not include patients aged 65 and over to determine whether they respond differently from younger patients. In the NCCTG clinical trial of levoleucovorin in combination with fluorouracil for the treatment of metastatic colorectal cancer, no overall differences in safety or effectiveness were observed between patients age 65 years and older and younger patients.

Interactions

Medicine and medicine

7 DRUG INTERACTIONS 7.1 Effects of Leucovorin Products on Other Drugs Antiepileptic Drugs 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.
Monitor patients taking folinic acid in combination with antiepileptic drugs.
Fluorouracil Leucovorin products increase the toxicity of fluorouracil.
Do not initiate or continue therapy with levoleucovorin and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved.

Frequently asked questions

What is Levoleucovorin used for?

1 INDICATIONS AND USAGE Levoleucovorin Injection is indicated for: rescue after high-dose methotrexate therapy in adult and pediatric patients with osteosarcoma., diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination in adult and pediatric patients., the treatment of adults with metastatic colorectal cancer in combination with fluorouracil., Limitations of Use Levoleucovorin Injection is not indicated for pernicious anemia and megaloblastic anemia secondary to the lack of vitamin B 12 , because of the risk of progression of neurologic manifestations despite hematologic remission., Levoleucovorin Injection is a folate analog indicated for: Rescue after high-dose methotrexate therapy in adult and pediatric patients with osteosarcoma., ( 1 ) Diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination in adult and pediatric patients..

How should I take Levoleucovorin?

2 DOSAGE AND ADMINISTRATION For intravenous administration only. Do not administer intrathecally. ( 2.1 ) Rescue After High-Dose Methotrexate Therapy Rescue recommendations are based on methotrexate dose of 12 grams/m 2 administered by intravenous infusion over 4 hours. Initiate rescue at a dose of 7.5 mg (approximately 5 mg/m 2 ) every 6 hours, 24 hours after the beginning of methotrexate infusion. ( 2.3 ) Continue until the methotrexate level is below 5 x 10 -8 M (0.05 micromolar). Adjust dose if necessary based on methotrexate elimination; refer to Full Prescribing Information. ( 2.3 ) Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination Start as soon as possible after methotrexate overdosage or within 24 hours of delayed methotrexate elimination. ( 2.4 ) Administer levoleucovorin injection 7.5 mg (approximately 5 mg/m 2 ) intravenously every 6 hours until methotrexate level is less than 5 x 10 -8 M (0.05 micromolar). ( 2.4 ) Metastatic Colorectal Cancer in Combination with Fluorouracil The following regimens have been used for the treatment of colorectal cancer: Levoleucovorin injection 100 mg/m 2 by intravenous injection over a minimum of 3 minutes, follow

What are the common side effects?

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypercalcemia [see Warnings and Precautions ( 5.1 )] Increased gastrointestinal toxicities with fluorouracil [see Warnings and Precautions ( 5.2 )] The most common adverse reactions (≥20%) in patients receiving high-dose methotrexate therapy with levoleucovorin rescue are stomatitis and vomiting., ( 6.1 ) The most common adverse reactions (>50%) in patients receiving levoleucovorin in combination with fluorouracil for metastatic colorectal cancer are stomatitis, diarrhea, and nausea., ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc., at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ., 6.1 Clinical Trials Experience Because 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., High-Dose Methotrexate Therapy Table 2 presents the frequency of adverse reactions which occurred during the administration of 58 courses of high-d.

Who should not take Levoleucovorin?

4 CONTRAINDICATIONS Levoleucovorin is contraindicated in patients who have had severe hypersensitivity to leucovorin products, folic acid or folinic acid [see Adverse Reactions ( 6.2 )] .; Patients who have had severe hypersensitivity reactions to leucovorin products, folic acid or folinic acid.; ( 4 ).

Can I take Levoleucovorin during pregnancy?

8.1 Pregnancy Risk Summary There are limited data with levoleucovorin use in pregnant women. Animal reproduction studies have not been conducted with levoleucovorin. Levoleucovorin is administered in combination with methotrexate or fluorouracil, which can cause embryo-fetal harm. Refer to methotrexate and fluorouracil prescribing information for additional information. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Can children take Levoleucovorin?

8.4 Pediatric Use The safety and effectiveness of levoleucovorin have been established in pediatric patients for rescue after high-dose methotrexate therapy in osteosarcoma and diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination. Use of levoleucovorin in pediatric patients is supported by open-label clinical trial data in 16 pediatric patients 6 years of age and older, with additional supporting evidence from literature [see Clinical Studies ( 14.1 )]. The safety and effectiveness of levoleucovorin have not been established for the treatment of pediatric patients with advanced metastatic colorectal cancer.

Does Levoleucovorin interact with other medicines?

7 DRUG INTERACTIONS 7.1 Effects of Leucovorin Products on Other Drugs Antiepileptic Drugs 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.; Monitor patients taking folinic acid in combination with antiepileptic drugs.; Fluorouracil Leucovorin products increase the toxicity of fluorouracil.; Do not initiate or continue therapy with levoleucovorin and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved..