Leucovorin Calcium

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Overview

What is Leucovorin Calcium?

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 5.40 mg, 10.80 mg, 16.21 mg or 27.01 mg of anhydrous leucovorin calcium, respectively. In addition, each tablet contains the following : microcrystalline cellulose, corn starch, croscarmellose sodium, povidone, colloidal silicon dioxide, magnesium stearate, D&C yellow #10 (15mg and 25 mg).

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:

CHCaNO M.W. 511.51

What does Leucovorin Calcium look like?

What are the available doses of Leucovorin Calcium?

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What should I talk to my health care provider before I take Leucovorin Calcium?

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How should I use Leucovorin Calcium?

Leucovorin Calcium Tablets USP are indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages 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 rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion (see ). Leucovorin 15 mg (10 mg/m) should be administered IM, IV, or PO every 6 hours until the serum methotrexate level is less than 10 M. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally.

Serum creatinine and methotrexate levels should be determined at 24-hour intervals. If the 24-hour serum creatinine has increased 50% over baseline or if the 24-hour methotrexate level is greater than 5 x 10 M or the 48-hour level is greater than 9 x 10 M, the dose of leucovorin should be increased to 150 mg (100 mg/m) IV every 3 hours until the methotrexate level is less than 10M. Doses greater than 25 mg should be given parenterally (see ).

Hydration (3 L/d) and urinary alkalinization with sodium bicarbonate should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

The recommended dose of leucovorin to counteract hematologic toxicity from folic acid antagonists with less affinity for mammalian dihydrofolate reductase than methotrexate (i.e., trimethoprim, pyrimethamine) is substantially less, and 5 to 15 mg of leucovorin per day has been recommended by some investigators.

Patients who experience delayed early methotrexate elimination are likely to develop reversible non-oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen below 0.05 micromolar and the renal failure has resolved.

Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

What interacts with Leucovorin Calcium?

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

What are the warnings of Leucovorin Calcium?

If isosorbide mononitrate is used in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia.

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. 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 pneumonia in patients with HIV infection was associated with increased rates of treatment failure and mortality in a placebo-controlled study.

What are the precautions of Leucovorin Calcium?

Parenteral administration is preferable to oral dosing if there is a possibility that the patient may vomit or not absorb the leucovorin. Leucovorin has no effect on other established toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney.

Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible children.

Preliminary animal and human studies have shown that small quantities of systemically administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate.

Leucovorin may enhance the toxicity of fluorouracil (see ).

Teratogenic Effects:

Animal reproduction studies have not been conducted with leucovorin. It is also not known whether leucovorin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Leucovorin should be given to a pregnant woman only if clearly needed.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when leucovorin is administered to a nursing mother.

See subsection.

What are the side effects of Leucovorin Calcium?

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

What should I look out for while using Leucovorin Calcium?

Leucovorin is improper therapy for pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B. 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. 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 pneumonia in patients with HIV infection was associated with increased rates of treatment failure and mortality in a placebo-controlled study.

What might happen if I take too much Leucovorin Calcium?

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

How should I store and handle Leucovorin Calcium?

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Keep out of reach of children.Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Keep out of reach of children.Leucovorin Calcium Tablets USP are available for oral administration as:5 mg white, scored tablets (Identified 54 293).Protect From Light and Moisture.Relabeling and Repackaging by:Leucovorin Calcium Tablets USP are available for oral administration as:5 mg white, scored tablets (Identified 54 293).Protect From Light and Moisture.Relabeling and Repackaging by:Leucovorin Calcium Tablets USP are available for oral administration as:5 mg white, scored tablets (Identified 54 293).Protect From Light and Moisture.Relabeling and Repackaging by:Leucovorin Calcium Tablets USP are available for oral administration as:5 mg white, scored tablets (Identified 54 293).Protect From Light and Moisture.Relabeling and Repackaging by:

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Clinical Information

Chemical Structure

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Clinical Pharmacology

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 , or (-)-folinic acid. Leucovorin does 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 ) 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/m) of leucovorin calcium and serum folate concentrations were assayed with . 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.

Non-Clinical Toxicology

Leucovorin is improper therapy for pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B. 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. 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 pneumonia in patients with HIV infection was associated with increased rates of treatment failure and mortality in a placebo-controlled study.

The vasodilating effects of isosorbide mononitrate may be additive with those of other vasodilators. Alcohol, in particular, has been found to exhibit additive effects of this variety.

Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination. Dose adjustments of either class of agents may be necessary.

Parenteral administration is preferable to oral dosing if there is a possibility that the patient may vomit or not absorb the leucovorin. Leucovorin has no effect on other established toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney.

Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible children.

Preliminary animal and human studies have shown that small quantities of systemically administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate.

Leucovorin may enhance the toxicity of fluorouracil (see ).

Teratogenic Effects:

Animal reproduction studies have not been conducted with leucovorin. It is also not known whether leucovorin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Leucovorin should be given to a pregnant woman only if clearly needed.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when leucovorin is administered to a nursing mother.

See subsection.

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

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Professional

Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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