Leucovorin Calcium
Generic: LEUCOVORIN CALCIUM
Basic Information
Manufacturer
Sagent Pharmaceuticals
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
INTRAMUSCULAR
FDA Set ID
c0cbcbf6-6fd2-4cf3-877a-bb0fe3df4e59
Indications & Usage
INDICATIONS AND USAGE Leucovorin calcium rescue is indicated after high-dose methotrexate therapy in osteosarcoma.
Leucovorin Calcium for Injection is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists.
Leucovorin Calcium for Injection is indicated in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible.
Leucovorin Calcium for Injection is also indicated for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer.
Leucovorin Calcium for Injection should not be mixed in the same infusion as 5-fluorouracil because a precipitate may form.
Leucovorin Calcium for Injection is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists.
Leucovorin Calcium for Injection is indicated in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible.
Leucovorin Calcium for Injection is also indicated for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer.
Leucovorin Calcium for Injection should not be mixed in the same infusion as 5-fluorouracil because a precipitate may form.
Warnings
WARNINGS In the treatment of accidental overdosages of folic acid antagonists, intravenous leucovorin should be administered as promptly as possible.
As the time interval between antifolate administration [e.g., methotrexate (MTX)] and leucovorin rescue increases, leucovorin's effectiveness in counteracting toxicity decreases.
In the treatment of accidental overdosages of intrathecally administered folic acid antagonists, do not administer leucovorin intrathecally.
LEUCOVORIN MAY BE HARMFUL OR FATAL IF GIVEN INTRATHECALLY.
Monitoring of the serum MTX concentration is essential in determining the optimal dose and duration of treatment with leucovorin.
Delayed MTX excretion may be caused by a third space fluid accumulation (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration.
Under such circumstances, higher doses of leucovorin or prolonged administration may be indicated.
Doses higher than those recommended for oral use must be given intravenously.
Because of the benzyl alcohol contained in certain diluents used for leucovorin, when doses greater than 10 mg/m 2 are administered, leucovorin should be reconstituted with Sterile Water for Injection, USP, and used immediately (see DOSAGE AND ADMINISTRATION ).
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 per mL, or 8 mL of a 20 mg per mL solution per minute).
Leucovorin enhances the toxicity of 5-fluorouracil.
When these drugs are administered concurrently in the palliative therapy of advanced colorectal cancer, the dosage of 5-fluorouracil must be lower than usually administered.
Although the toxicities observed in patients treated with the combination of leucovorin plus 5-fluorouracil are qualitatively similar to those observed in patients treated with 5-fluorouracil alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be more severe and of prolonged duration in patients treated with the combination.
In the first Mayo/NCCTG controlled trial, toxicity, primarily gastrointestinal, resulted in 7% of patients requiring hospitalization when treated with 5-fluorouracil alone or 5-fluorouracil in combination with 200 mg/m 2 of leucovorin and 20% when treated with 5-fluorouracil in combination with 20 mg/m 2 of leucovorin.
In the second Mayo/NCCTG trial, hospitalizations related to treatment toxicity also appeared to occur more often in patients treated with the low dose leucovorin/5-fluorouracil combination than in patients treated with the high dose combination — 11% versus 3%.
Therapy with leucovorin/5-fluorouracil must not be initiated or continued in patients who have symptoms of gastrointestinal toxicity of any severity, until those symptoms have completely resolved.
Patients with diarrhea must be monitored with particular care until the diarrhea has resolved, as rapid clinical deterioration leading to death can occur.
In an additional study utilizing higher weekly doses of 5-FU and leucovorin, elderly and/or debilitated patients were found to be at greater risk for severe gastrointestinal toxicity.
Seizures and/or syncope have been reported rarely in cancer patients receiving 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.
The concomitant use of 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.
As the time interval between antifolate administration [e.g., methotrexate (MTX)] and leucovorin rescue increases, leucovorin's effectiveness in counteracting toxicity decreases.
In the treatment of accidental overdosages of intrathecally administered folic acid antagonists, do not administer leucovorin intrathecally.
LEUCOVORIN MAY BE HARMFUL OR FATAL IF GIVEN INTRATHECALLY.
Monitoring of the serum MTX concentration is essential in determining the optimal dose and duration of treatment with leucovorin.
Delayed MTX excretion may be caused by a third space fluid accumulation (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration.
Under such circumstances, higher doses of leucovorin or prolonged administration may be indicated.
Doses higher than those recommended for oral use must be given intravenously.
Because of the benzyl alcohol contained in certain diluents used for leucovorin, when doses greater than 10 mg/m 2 are administered, leucovorin should be reconstituted with Sterile Water for Injection, USP, and used immediately (see DOSAGE AND ADMINISTRATION ).
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 per mL, or 8 mL of a 20 mg per mL solution per minute).
Leucovorin enhances the toxicity of 5-fluorouracil.
When these drugs are administered concurrently in the palliative therapy of advanced colorectal cancer, the dosage of 5-fluorouracil must be lower than usually administered.
Although the toxicities observed in patients treated with the combination of leucovorin plus 5-fluorouracil are qualitatively similar to those observed in patients treated with 5-fluorouracil alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be more severe and of prolonged duration in patients treated with the combination.
In the first Mayo/NCCTG controlled trial, toxicity, primarily gastrointestinal, resulted in 7% of patients requiring hospitalization when treated with 5-fluorouracil alone or 5-fluorouracil in combination with 200 mg/m 2 of leucovorin and 20% when treated with 5-fluorouracil in combination with 20 mg/m 2 of leucovorin.
In the second Mayo/NCCTG trial, hospitalizations related to treatment toxicity also appeared to occur more often in patients treated with the low dose leucovorin/5-fluorouracil combination than in patients treated with the high dose combination — 11% versus 3%.
Therapy with leucovorin/5-fluorouracil must not be initiated or continued in patients who have symptoms of gastrointestinal toxicity of any severity, until those symptoms have completely resolved.
Patients with diarrhea must be monitored with particular care until the diarrhea has resolved, as rapid clinical deterioration leading to death can occur.
In an additional study utilizing higher weekly doses of 5-FU and leucovorin, elderly and/or debilitated patients were found to be at greater risk for severe gastrointestinal toxicity.
Seizures and/or syncope have been reported rarely in cancer patients receiving 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.
The concomitant use of 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.
Adverse Reactions
ADVERSE REACTIONS Allergic sensitization, including anaphylactoid reactions and urticaria, has been reported following administration of both oral and parenteral leucovorin.
No other adverse reactions have been attributed to the use of leucovorin per se .
Table 1 summarizes significant adverse events occurring in 316 patients treated with the leucovorin-5-fluorouracil combinations compared against 70 patients treated with 5-fluorouracil alone for advanced colorectal carcinoma.
These data are taken from the Mayo/NCCTG large multicenter prospective trial evaluating the efficacy and safety of the combination regimen.
TABLE 1 PERCENTAGE OF PATIENTS TREATED WITH LEUCOVORIN/FLUOROURACIL FOR ADVANCED COLORECTAL CARCINOMA REPORTING ADVERSE EXPERIENCES OR HOSPITALIZED FOR TOXICITY High LV = Leucovorin 200 mg/m 2 , Low LV = Leucovorin 20 mg/m 2 Any = percentage of patients reporting toxicity of any severity Grade 3+ = percentage of patients reporting toxicity of grade 3 or higher (High LV)/5-FU (N=155) (Low LV)/5-FU (N=161) 5-FU Alone (N=70) Any (%) Grade 3+ (%) Any (%) Grade 3+ (%) Any (%) Grade 3+ (%) Leukopenia 69 14 83 23 93 48 Thrombocytopenia 8 2 8 1 18 3 Infection 8 1 3 1 7 2 Nausea 74 10 80 9 60 6 Vomiting 46 8 44 9 40 7 Diarrhea 66 18 67 14 43 11 Stomatitis 75 27 84 29 59 16 Constipation 3 0 4 0 1 - Lethargy/Malaise/Fatigue 13 3 12 2 6 3 Alopecia 42 5 43 6 37 7 Dermatitis 21 2 25 1 13 - Anorexia 14 1 22 4 14 - Hospitalization for Toxicity 5% 15% 7% TABLE 2 GUIDELINES FOR LEUCOVORIN CALCIUM DOSAGE AND ADMINISTRATION DO NOT ADMINISTER LEUCOVORIN CALCIUM INTRATHECALLY Clinical Situation Laboratory Findings Leucovorin Calcium 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.
15 mg PO, IM, or 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 15 mg PO, IM, or 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).
150 mg IV q 3 hours, until methotrexate level is less than 1 micromolar; then 15 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar.
To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals, Inc.
at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
No other adverse reactions have been attributed to the use of leucovorin per se .
Table 1 summarizes significant adverse events occurring in 316 patients treated with the leucovorin-5-fluorouracil combinations compared against 70 patients treated with 5-fluorouracil alone for advanced colorectal carcinoma.
These data are taken from the Mayo/NCCTG large multicenter prospective trial evaluating the efficacy and safety of the combination regimen.
TABLE 1 PERCENTAGE OF PATIENTS TREATED WITH LEUCOVORIN/FLUOROURACIL FOR ADVANCED COLORECTAL CARCINOMA REPORTING ADVERSE EXPERIENCES OR HOSPITALIZED FOR TOXICITY High LV = Leucovorin 200 mg/m 2 , Low LV = Leucovorin 20 mg/m 2 Any = percentage of patients reporting toxicity of any severity Grade 3+ = percentage of patients reporting toxicity of grade 3 or higher (High LV)/5-FU (N=155) (Low LV)/5-FU (N=161) 5-FU Alone (N=70) Any (%) Grade 3+ (%) Any (%) Grade 3+ (%) Any (%) Grade 3+ (%) Leukopenia 69 14 83 23 93 48 Thrombocytopenia 8 2 8 1 18 3 Infection 8 1 3 1 7 2 Nausea 74 10 80 9 60 6 Vomiting 46 8 44 9 40 7 Diarrhea 66 18 67 14 43 11 Stomatitis 75 27 84 29 59 16 Constipation 3 0 4 0 1 - Lethargy/Malaise/Fatigue 13 3 12 2 6 3 Alopecia 42 5 43 6 37 7 Dermatitis 21 2 25 1 13 - Anorexia 14 1 22 4 14 - Hospitalization for Toxicity 5% 15% 7% TABLE 2 GUIDELINES FOR LEUCOVORIN CALCIUM DOSAGE AND ADMINISTRATION DO NOT ADMINISTER LEUCOVORIN CALCIUM INTRATHECALLY Clinical Situation Laboratory Findings Leucovorin Calcium 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.
15 mg PO, IM, or 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 15 mg PO, IM, or 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).
150 mg IV q 3 hours, until methotrexate level is less than 1 micromolar; then 15 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar.
To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals, Inc.
at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .