*Leucovorin calcium rescue is indicated after high-dose methotrexate therapy in osteosarcoma. Leucovorin calcium is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists.
====Megaloblastic anemias====
*Leucovorin calcium is indicated in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible.
Megaloblastic Anemia Due to Folic Acid Deficiency
Up to 1 mg daily. There is no evidence that doses greater than 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg.
Each 50, 100, and 200 mg vial of Leucovorin Calcium for Injection when reconstituted with 5, 10, and 20 mL, respectively, of sterile diluent yields a leucovorin concentration of 10 mg leucovorin per mL. Each 350 mg vial of Leucovorin Calcium for Injection when reconstituted with 17.5 mL of sterile diluent yields a leucovorin concentration of 20 mg leucovorin per mL. Leucovorin Calcium for Injection contains no preservative. Reconstitute the lyophilized vial products with Bacteriostatic Water for Injection, USP, which contains benzyl alcohol, or with Sterile Water for Injection, USP. When reconstituted with Bacteriostatic Water for Injection, USP, the resulting solution must be used within 7 days. If the product is reconstituted with Sterile Water for Injection, USP, use immediately and discard unused portion.
Because of the benzyl alcohol contained in Bacteriostatic Water for Injection, USP, when doses greater than 10 mg/m2 are administered Leucovorin Calcium for Injection should be reconstituted with Sterile Water for Injection, USP, and used immediately. (See WARNINGS.) Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin should be injected intravenously per minute (16 mL of a 10 mg/mL, or 8 mL of a 20 mg/mL solution per minute).
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Leucovorin should not be mixed in the same infusion as 5-fluorouracil, since this may lead to the formation of a precipitate.
=====Advanced colorectal cancer=====
*Leucovorin is also indicated for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer.
*Leucovorin should not be mixed in the same infusion as 5-fluorouracil because a precipitate may form.
* Dosing Information
* Dosing Information
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|mechAction=
*
*Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF). The biologically active compound of the mixture is the (-)-l-isomer, known as Citrovorum factor, or (-)-folinic acid. Leucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties.l-Leucovorin (l-5-formyltetrahydrofolate) is rapidly metabolized (via 5,10-methenyltetrahydrofolate then 5,10-methylenetetrahydrofolate) to l-5-methyltetrahydrofolate. l-5-Methyltetrahydrofolate can in turn be metabolized via other pathways back to 5,10-methylenetetrahydrofolate, which is converted to 5-methyltetrahydrofolate by an irreversible, enzyme catalyzed reduction using the cofactors FADH2 and NADPH.
*Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase.
*In contrast, leucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy, such as 5-fluorouracil. Concurrent administration of leucovorin does not appear to alter the plasma pharmacokinetics of 5-fluorouracil. 5-Fluorouracil is metabolized to fluorodeoxyuridylic acid, which binds to and inhibits the enzyme thymidylate synthase (an enzyme important in DNA repair and replication).
Leucovorin is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of fluorodeoxyuridylic acid to thymidylate synthase and thereby enhances the inhibition of this enzyme.
<!--Structure-->
<!--Structure-->
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|structure=
|structure=
*
*Leucovorin is one of several active, chemically reduced derivatives of folic acid. It is useful as an antidote to drugs which act as folic acid antagonists.
Also known as folinic acid, Citrovorum factor, or 5-formyl-5,6,7,8-tetrahydrofolic acid, this compound has the chemical designation of Calcium N-[p-[(6RS)-2-amino-5-formyl-5,6,7,8-tetrahydro-4-hydroxy-6-pteridinyl]methyl]amino]benzoyl]-L-glutamate (1:1). The structural formula of leucovorin calcium is:
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
*Leucovorin calcium for injection is a sterile product indicated for intramuscular (IM) or intravenous (IV) administration and is supplied in 50 mg, 100 mg, 200 mg, and 350 mg vials.
*Each 50 mg vial of leucovorin calcium for injection, when reconstituted with 5 mL of sterile diluent, contains leucovorin (as the calcium salt) 10 mg/mL.
*Each 100 mg vial of leucovorin calcium for injection, when reconstituted with 10 mL of sterile diluent, contains leucovorin (as the calcium salt) 10 mg/mL.
*Each 200 mg vial of leucovorin calcium for injection, when reconstituted with 20 mL of sterile diluent, contains leucovorin (as the calcium salt) 10 mg/mL.
*Each 350 mg vial of leucovorin calcium for injection, when reconstituted with 17.5 mL of sterile diluent, contains leucovorin (as the calcium salt) 20 mg/mL.
*In each dosage form, one milligram of leucovorin calcium contains 0.002 mmol of leucovorin and 0.002 mmol of calcium.
*These lyophilized products contain no preservative. The inactive ingredient is Sodium Chloride, USP, added to adjust tonicity. Sodium hydroxide and / or hydrochloric acid may be used to adjust the pH. The pH is between 6.5 and 8.5. Reconstitute with Bacteriostatic Water for Injection, USP, which contains benzyl alcohol (see WARNINGS section), or with Sterile Water for Injection, USP.
<!--Pharmacodynamics-->
<!--Pharmacodynamics-->
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|PK=
|PK=
There is limited information regarding <i>Pharmacokinetics</i> of {{PAGENAME}} in the drug label.
*The pharmacokinetics after intravenous, intramuscular and oral administration of a 25 mg dose of leucovorin were studied in male volunteers. After intravenous administration, serum total reduced folates (as measured by Lactobacillus casei assay) reached a mean peak of 1259 ng/mL (range 897 to 1625). The mean time to peak was 10 minutes. This initial rise in total reduced folates was primarily due to the parent compound 5-formyl-THF (measured by Streptococcus faecalis assay) which rose to 1206 ng/mL at 10 minutes. A sharp drop in parent compound followed and coincided with the appearance of the active metabolite 5-methyl-THF which became the predominant circulating form of the drug.
*The mean peak of 5-methyl-THF was 258 ng/mL and occurred at 1.3 hours. The terminal half-life for total reduced folates was 6.2 hours. The area under the concentration versus time curves (AUCs) for l-leucovorin, d-leucovorin and 5-methyltetrahydrofolate were 28.4 ± 3.5, 956 ± 97 and 129 ± 12 (mg/min/L ± S.E.). When a higher dose of d,l-leucovorin (200 mg/m2) was used, similar results were obtained. The d-isomer persisted in plasma at concentrations greatly exceeding those of the l-isomer.
*After intramuscular injection, the mean peak of serum total reduced folates was 436 ng/mL (range 240 to 725) and occurred at 52 minutes. Similar to IV administration, the initial sharp rise was due to the parent compound. The mean peak of 5-formyl-THF was 360 ng/mL and occurred at 28 minutes. The level of the metabolite 5-methyl-THF increased subsequently over time until at 1.5 hours it represented 50% of the circulating total folates. The mean peak of 5-methyl-THF was 226 ng/mL at 2.8 hours. The terminal half-life of total reduced folates was 6.2 hours. There was no difference of statistical significance between IM and IV administration in the AUC for total reduced folates, 5-formyl-THF, or 5-methyl-THF.
*After oral administration of leucovorin reconstituted with aromatic elixir, the mean peak concentration of serum total reduced folates was 393 ng/mL (range 160 to 550). The mean time to peak was 2.3 hours and the terminal half-life was 5.7 hours. The major component was the metabolite 5-methyltetrahydrofolate to which leucovorin is primarily converted in the intestinal mucosa. The mean peak of 5-methyl-THF was 367 ng/mL at 2.4 hours. The peak level of the parent compound was 51 ng/mL at 1.2 hours. The AUC of total reduced folates after oral administration of the 25 mg dose was 92% of the AUC after intravenous administration.
*Following oral administration, leucovorin is rapidly absorbed and expands the serum pool of reduced folates. At a dose of 25 mg, almost 100% of the l-isomer but only 20% of the d-isomer is absorbed. Oral absorption of leucovorin is saturable at doses above 25 mg. The apparent bioavailability of leucovorin was 97% for 25 mg, 75% for 50 mg, and 37% for 100 mg.
*In a randomized clinical study conducted by the Mayo Clinic and the North Central Cancer Treatment Group (Mayo/NCCTG) in patients with advanced metastatic colorectal cancer three treatment regimens were compared: Leucovorin (LV) 200 mg/m2 and 5-fluorouracil (5-FU) 370 mg/m2 versus LV 20 mg/m2 and 5-FU 425 mg/m2 versus 5-FU 500 mg/m2. All drugs were administered by slow intravenous infusion daily for 5 days repeated every 28 to 35 days. Response rates were 26% (p = 0.04 versus 5-FU alone), 43% (p = 0.001 versus 5-FU alone) and 10% for the high dose leucovorin, low dose leucovorin and 5-FU alone groups respectively. Respective median survival times were 12.2 months (p = 0.037), 12 months (p = 0.050), and 7.7 months. The low dose LV regimen gave a statistically significant improvement in weight gain of more than 5%, relief of symptoms, and improvement in performance status. The high dose LV regimen gave a statistically significant improvement in performance status and trended toward improvement in weight gain and in relief of symptoms but these were not statistically significant.
*In a second Mayo/NCCTG randomized clinical study the 5-FU alone arm was replaced by a regimen of sequentially administered methotrexate (MTX), 5-FU, and LV. Response rates with LV 200 mg/m2and 5-FU 370 mg/m2 versus LV 20 mg/m2 and 5-FU 425 mg/m2 versus sequential MTX and 5-FU and LV were respectively 31% (p = < 0.01), 42% (p = < 0.01), and 14%. Respective median survival times were 12.7 months (p = < 0.04), 12.7 months (p = < 0.01), and 8.4 months. No statistically significant difference in weight gain of more than 5% or in improvement in performance status was seen between the treatment arms.
*The pharmacokinetics of 200 mg doses of Leucovorin administered intravenously and orally (reconstituted powder, not tablets) have been evaluated. The serum clearance corrected for bioavailability, terminal half-life, and apparent volume of distribution of total folate were not significantly different between the routes of administration. The oral bioavailability of the 200 mg dose was 31%. Eighty-three percent of the biologically active IV dose was recovered in the urine within 24 hours, 31% as 5-methyltetrahydrofolate. Twenty percent of the same oral dose was excreted in 24 hours, 16% as 5-methyltetrahydrofolate.1
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Black Box Warning
Title
See full prescribing information for complete Boxed Warning.
ConditionName:
Content
Overview
Leucovorin (injection) is a that is FDA approved for the {{{indicationType}}} of . There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Osteosarcoma
Leucovorin calcium rescue is indicated after high-dose methotrexate therapy in osteosarcoma. Leucovorin calcium is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists.
Megaloblastic anemias
Leucovorin calcium is indicated in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible.
Megaloblastic Anemia Due to Folic Acid Deficiency
Up to 1 mg daily. There is no evidence that doses greater than 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg.
Each 50, 100, and 200 mg vial of Leucovorin Calcium for Injection when reconstituted with 5, 10, and 20 mL, respectively, of sterile diluent yields a leucovorin concentration of 10 mg leucovorin per mL. Each 350 mg vial of Leucovorin Calcium for Injection when reconstituted with 17.5 mL of sterile diluent yields a leucovorin concentration of 20 mg leucovorin per mL. Leucovorin Calcium for Injection contains no preservative. Reconstitute the lyophilized vial products with Bacteriostatic Water for Injection, USP, which contains benzyl alcohol, or with Sterile Water for Injection, USP. When reconstituted with Bacteriostatic Water for Injection, USP, the resulting solution must be used within 7 days. If the product is reconstituted with Sterile Water for Injection, USP, use immediately and discard unused portion.
Because of the benzyl alcohol contained in Bacteriostatic Water for Injection, USP, when doses greater than 10 mg/m2 are administered Leucovorin Calcium for Injection should be reconstituted with Sterile Water for Injection, USP, and used immediately. (See WARNINGS.) Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin should be injected intravenously per minute (16 mL of a 10 mg/mL, or 8 mL of a 20 mg/mL solution per minute).
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Leucovorin should not be mixed in the same infusion as 5-fluorouracil, since this may lead to the formation of a precipitate.
Advanced colorectal cancer
Leucovorin is also indicated for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer.
Leucovorin should not be mixed in the same infusion as 5-fluorouracil because a precipitate may form.
Dosing Information
Dosage
Condition2
Dosing Information
Dosage
Condition3
Dosing Information
Dosage
Condition4
Dosing Information
Dosage
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Leucovorin (injection) in adult patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Leucovorin (injection) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding FDA-Labeled Use of Leucovorin (injection) in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Leucovorin (injection) in pediatric patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Leucovorin (injection) in pediatric patients.
Contraindications
Condition1
Warnings
Title
See full prescribing information for complete Boxed Warning.
ConditionName:
Content
Description
Precautions
Description
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Leucovorin (injection) in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Leucovorin (injection) in the drug label.
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Leucovorin (injection) in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Leucovorin (injection) during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Leucovorin (injection) with respect to nursing mothers.
Pediatric Use
There is no FDA guidance on the use of Leucovorin (injection) with respect to pediatric patients.
Geriatic Use
There is no FDA guidance on the use of Leucovorin (injection) with respect to geriatric patients.
Gender
There is no FDA guidance on the use of Leucovorin (injection) with respect to specific gender populations.
Race
There is no FDA guidance on the use of Leucovorin (injection) with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Leucovorin (injection) in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Leucovorin (injection) in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Leucovorin (injection) in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Leucovorin (injection) in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Intravenous
Monitoring
There is limited information regarding Monitoring of Leucovorin (injection) in the drug label.
Description
IV Compatibility
There is limited information regarding IV Compatibility of Leucovorin (injection) in the drug label.
Overdosage
Acute Overdose
Signs and Symptoms
Description
Management
Description
Chronic Overdose
There is limited information regarding Chronic Overdose of Leucovorin (injection) in the drug label.
Pharmacology
There is limited information regarding Leucovorin (injection) Pharmacology in the drug label.
Mechanism of Action
Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF). The biologically active compound of the mixture is the (-)-l-isomer, known as Citrovorum factor, or (-)-folinic acid. Leucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties.l-Leucovorin (l-5-formyltetrahydrofolate) is rapidly metabolized (via 5,10-methenyltetrahydrofolate then 5,10-methylenetetrahydrofolate) to l-5-methyltetrahydrofolate. l-5-Methyltetrahydrofolate can in turn be metabolized via other pathways back to 5,10-methylenetetrahydrofolate, which is converted to 5-methyltetrahydrofolate by an irreversible, enzyme catalyzed reduction using the cofactors FADH2 and NADPH.
Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase.
In contrast, leucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy, such as 5-fluorouracil. Concurrent administration of leucovorin does not appear to alter the plasma pharmacokinetics of 5-fluorouracil. 5-Fluorouracil is metabolized to fluorodeoxyuridylic acid, which binds to and inhibits the enzyme thymidylate synthase (an enzyme important in DNA repair and replication).
Leucovorin is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of fluorodeoxyuridylic acid to thymidylate synthase and thereby enhances the inhibition of this enzyme.
Structure
Leucovorin is one of several active, chemically reduced derivatives of folic acid. It is useful as an antidote to drugs which act as folic acid antagonists.
Also known as folinic acid, Citrovorum factor, or 5-formyl-5,6,7,8-tetrahydrofolic acid, this compound has the chemical designation of Calcium N-[p-[(6RS)-2-amino-5-formyl-5,6,7,8-tetrahydro-4-hydroxy-6-pteridinyl]methyl]amino]benzoyl]-L-glutamate (1:1). The structural formula of leucovorin calcium is:
Leucovorin calcium for injection is a sterile product indicated for intramuscular (IM) or intravenous (IV) administration and is supplied in 50 mg, 100 mg, 200 mg, and 350 mg vials.
Each 50 mg vial of leucovorin calcium for injection, when reconstituted with 5 mL of sterile diluent, contains leucovorin (as the calcium salt) 10 mg/mL.
Each 100 mg vial of leucovorin calcium for injection, when reconstituted with 10 mL of sterile diluent, contains leucovorin (as the calcium salt) 10 mg/mL.
Each 200 mg vial of leucovorin calcium for injection, when reconstituted with 20 mL of sterile diluent, contains leucovorin (as the calcium salt) 10 mg/mL.
Each 350 mg vial of leucovorin calcium for injection, when reconstituted with 17.5 mL of sterile diluent, contains leucovorin (as the calcium salt) 20 mg/mL.
In each dosage form, one milligram of leucovorin calcium contains 0.002 mmol of leucovorin and 0.002 mmol of calcium.
These lyophilized products contain no preservative. The inactive ingredient is Sodium Chloride, USP, added to adjust tonicity. Sodium hydroxide and / or hydrochloric acid may be used to adjust the pH. The pH is between 6.5 and 8.5. Reconstitute with Bacteriostatic Water for Injection, USP, which contains benzyl alcohol (see WARNINGS section), or with Sterile Water for Injection, USP.
Pharmacodynamics
There is limited information regarding Pharmacodynamics of Leucovorin (injection) in the drug label.
Pharmacokinetics
The pharmacokinetics after intravenous, intramuscular and oral administration of a 25 mg dose of leucovorin were studied in male volunteers. After intravenous administration, serum total reduced folates (as measured by Lactobacillus casei assay) reached a mean peak of 1259 ng/mL (range 897 to 1625). The mean time to peak was 10 minutes. This initial rise in total reduced folates was primarily due to the parent compound 5-formyl-THF (measured by Streptococcus faecalis assay) which rose to 1206 ng/mL at 10 minutes. A sharp drop in parent compound followed and coincided with the appearance of the active metabolite 5-methyl-THF which became the predominant circulating form of the drug.
The mean peak of 5-methyl-THF was 258 ng/mL and occurred at 1.3 hours. The terminal half-life for total reduced folates was 6.2 hours. The area under the concentration versus time curves (AUCs) for l-leucovorin, d-leucovorin and 5-methyltetrahydrofolate were 28.4 ± 3.5, 956 ± 97 and 129 ± 12 (mg/min/L ± S.E.). When a higher dose of d,l-leucovorin (200 mg/m2) was used, similar results were obtained. The d-isomer persisted in plasma at concentrations greatly exceeding those of the l-isomer.
After intramuscular injection, the mean peak of serum total reduced folates was 436 ng/mL (range 240 to 725) and occurred at 52 minutes. Similar to IV administration, the initial sharp rise was due to the parent compound. The mean peak of 5-formyl-THF was 360 ng/mL and occurred at 28 minutes. The level of the metabolite 5-methyl-THF increased subsequently over time until at 1.5 hours it represented 50% of the circulating total folates. The mean peak of 5-methyl-THF was 226 ng/mL at 2.8 hours. The terminal half-life of total reduced folates was 6.2 hours. There was no difference of statistical significance between IM and IV administration in the AUC for total reduced folates, 5-formyl-THF, or 5-methyl-THF.
After oral administration of leucovorin reconstituted with aromatic elixir, the mean peak concentration of serum total reduced folates was 393 ng/mL (range 160 to 550). The mean time to peak was 2.3 hours and the terminal half-life was 5.7 hours. The major component was the metabolite 5-methyltetrahydrofolate to which leucovorin is primarily converted in the intestinal mucosa. The mean peak of 5-methyl-THF was 367 ng/mL at 2.4 hours. The peak level of the parent compound was 51 ng/mL at 1.2 hours. The AUC of total reduced folates after oral administration of the 25 mg dose was 92% of the AUC after intravenous administration.
Following oral administration, leucovorin is rapidly absorbed and expands the serum pool of reduced folates. At a dose of 25 mg, almost 100% of the l-isomer but only 20% of the d-isomer is absorbed. Oral absorption of leucovorin is saturable at doses above 25 mg. The apparent bioavailability of leucovorin was 97% for 25 mg, 75% for 50 mg, and 37% for 100 mg.
In a randomized clinical study conducted by the Mayo Clinic and the North Central Cancer Treatment Group (Mayo/NCCTG) in patients with advanced metastatic colorectal cancer three treatment regimens were compared: Leucovorin (LV) 200 mg/m2 and 5-fluorouracil (5-FU) 370 mg/m2 versus LV 20 mg/m2 and 5-FU 425 mg/m2 versus 5-FU 500 mg/m2. All drugs were administered by slow intravenous infusion daily for 5 days repeated every 28 to 35 days. Response rates were 26% (p = 0.04 versus 5-FU alone), 43% (p = 0.001 versus 5-FU alone) and 10% for the high dose leucovorin, low dose leucovorin and 5-FU alone groups respectively. Respective median survival times were 12.2 months (p = 0.037), 12 months (p = 0.050), and 7.7 months. The low dose LV regimen gave a statistically significant improvement in weight gain of more than 5%, relief of symptoms, and improvement in performance status. The high dose LV regimen gave a statistically significant improvement in performance status and trended toward improvement in weight gain and in relief of symptoms but these were not statistically significant.
In a second Mayo/NCCTG randomized clinical study the 5-FU alone arm was replaced by a regimen of sequentially administered methotrexate (MTX), 5-FU, and LV. Response rates with LV 200 mg/m2and 5-FU 370 mg/m2 versus LV 20 mg/m2 and 5-FU 425 mg/m2 versus sequential MTX and 5-FU and LV were respectively 31% (p = < 0.01), 42% (p = < 0.01), and 14%. Respective median survival times were 12.7 months (p = < 0.04), 12.7 months (p = < 0.01), and 8.4 months. No statistically significant difference in weight gain of more than 5% or in improvement in performance status was seen between the treatment arms.
The pharmacokinetics of 200 mg doses of Leucovorin administered intravenously and orally (reconstituted powder, not tablets) have been evaluated. The serum clearance corrected for bioavailability, terminal half-life, and apparent volume of distribution of total folate were not significantly different between the routes of administration. The oral bioavailability of the 200 mg dose was 31%. Eighty-three percent of the biologically active IV dose was recovered in the urine within 24 hours, 31% as 5-methyltetrahydrofolate. Twenty percent of the same oral dose was excreted in 24 hours, 16% as 5-methyltetrahydrofolate.1
Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Leucovorin (injection) in the drug label.
Clinical Studies
There is limited information regarding Clinical Studies of Leucovorin (injection) in the drug label.
How Supplied
Storage
There is limited information regarding Leucovorin (injection) Storage in the drug label.
Images
Drug Images
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