Label: LEUCOVORIN CALCIUM tablet

Leucovorin calcium tablets, USP contain either 5 mg, 10 mg, 15 mg or 25 mg leucovorin as the calcium salt of N-[4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl] amino]benzoyl]-L-glutamic acid. This is equivalent to either 5.4 mg, 10.8 mg, 16.21 mg or 27.01 mg of anhydrous leucovorin calcium, USP, respectively. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, D&C yellow #10 (15 mg and 25 mg), magnesium stearate, microcrystalline cellulose, povidone and pregelatinized starch.

Leucovorin is a water soluble form of reduced folate in the folate group; it is useful as an antidote to drugs which act as folic acid antagonists. These tablets are intended for oral administration only.

The structural formula of leucovorin calcium is:

C20H21CaN7O7 M.W. 511.51

Leucovorin is a racemic mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid. 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. Following oral administration, leucovorin is rapidly absorbed and enters the general body pool of reduced folates. The increase in plasma and serum folate activity (determined microbiologically with Lactobacillus casei) seen after oral administration of leucovorin is predominantly due to 5-methyltetrahydrofolate.

Twenty normal men were given a single, oral 15 mg dose (7.5 mg/m2) of leucovorin calcium and serum folate concentrations were assayed with L. casei. Mean values observed (± one standard error) were:

a) Time to peak serum folate concentration: 1.72 ± 0.08 hours,

b) Peak serum folate concentration achieved: 268 ± 18 ng/mL,

c) Serum folate half-disappearance time: 3.5 hours.

Oral tablets yielded areas under the serum folate concentration-time curves (AUCs) that were 12% greater than equal amounts of leucovorin given intramuscularly and equal to the same amounts given intravenously.

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.

Leucovorin is indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists.

Leucovorin is improper therapy for pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B12. A hematologic remission may occur while neurologic manifestations continue to progress.

In the treatment of accidental overdosage of folic acid antagonists, leucovorin should be administered as promptly as possible. As the time interval between antifolate administration (e.g., methotrexate) and leucovorin rescue increases, leucovorin’s effectiveness in counteracting hematologic toxicity decreases.

Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin.

Delayed methotrexate 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.

Leucovorin may enhance the toxicity of fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.1 Concomitant granulocytopenia and fever were present in some but not all of the patients.

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 mortality in a placebo-controlled study.

Allergic sensitization, including anaphylactoid reactions and urticaria, has been reported following the administration of both oral and parenteral leucovorin.

Excessive amounts of leucovorin may nullify the chemotherapeutic effect of folic acid antagonists.

Leucovorin calcium tablets are intended for oral administration. Because absorption is saturable, oral administration of doses greater than 25 mg is not recommended.

Leucovorin Calcium Tablets, USP

5 mg tablets are supplied as an off-white, round, slightly biconvex tablet; scored on one side and product identification “54 293” debossed on the other side.

NDC 0054-8496-19: 5x10 Unit-Dose

NDC 0054-4496-13: Bottle of 30 Tablets

NDC 0054-4496-25: Bottle of 100 Tablets

10 mg tablets are supplied as an off-white, round, slightly biconvex tablet; scored on one side and product identification “54 942” debossed on the other side.

NDC 0054-4497-05: Bottle of 12 Tablets

NDC 0054-4497-10: Bottle of 24 Tablets

15 mg tablets are supplied as an yellow, round, slightly biconvex tablet; scored on one side and product identification “54 650” debossed on the other side.

NDC 0054-4498-10: Bottle of 24 Tablets

25 mg tablets are supplied as an yellow, round, slightly biconvex tablet; scored on one side and product identification “54 013” debossed on the other side.

NDC 0054-4499-11: Bottle of 25 Tablets

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Protect From Light and Moisture.

References

1.

Grem JL, Shoemaker DD, Petrelli NJ, Douglas HO. Severe and fatal toxic effects observed in treatment with high- and low-dose leucovorin plus 5-fluorouracil for colorectal carcinoma. Cancer Treat Rep 1987;71:1122.

2.

Link MP, Goorin AM, Miser AW et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 1986;314:1600-1606.

Distributed by: Hikma
Pharmaceuticals USA Inc.
Berkeley Heights, NJ 07922

 

C50000693/01

Revised June 2023