Leucovorin Calcium Tablets contain either 5 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 5.40 mg or 27.01 mg of anhydrous leucovorin calcium. In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The 25mg tablet also contains D&C yellow no. 10 and FD&C blue no. 1.

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

Last updated on RxList: 6/25/2008

Leucovorin calcium tablets 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.

Impaired Methotrexate Elimination or Inadvertent Overdosage

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 WARNINGS). Leucovorin 15 mg (10 mg/m²) should be administered IM, IV, or PO every 6 hours until serum methotrexate level is less than 10 -8 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 -6 M or the 48 hour level is greater than 9 x 10^-7 M, the dose of leucovorin should be increased to 150 mg (100 mg/m²) IV every 3 hours until the methotrexate level is less than 10^-8 M. Doses greater then 25 mg should be given parenterally (see CLINICAL PHARMACOLOGY).

Hydration (3L/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 serum methotrexate level has fallen to 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.

Leucovorin Calcium Tablets, USP are available as:

White, round, unscored, biconvex tablets. Debossed with stylized b on one side and 484 on the other side. Available in bottles of:

20................................NDC 0555-0484-18

5 mg:

30................................NDC 0555-0484-01
100................................NDC 0505-0484-02
1000................................NDC 0555-0484-05

Pale green, round, unscored, biconvex tablets. Debossed with stylized b on one side and 485 on the other side. Available in bottles of:

25 mg:

25................................NDC 0555-0485-27
500................................NDC 0555-0485-04

Protect from light and moisture.

Dispense with a child-resistant closure in a tight, light-resistant container.

Store at controlled room temperature 15°-25°C (59°-77°F) [See USP].

REFERENCES

1. Grem JL, Shoemaker DD, Petrelli NJ, Douglas HO Jr: 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.

MANUFACTURED BY BARR LABORATORIES, INC. POMONA, NY 10970. OCTOBER 2002. FDA Rev date: 12/26/2000

Last updated on RxList: 6/25/2008

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

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 CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than 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 WARNINGS).

Last updated on RxList: 6/25/2008

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.

General

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.

Pregnancy

Teratogenic Effects

Pregnancy Category C.

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.

Nursing Mothers

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.

Pediatric Use

See DRUG INTERACTIONS.

Last updated on RxList: 6/25/2008

Excessive amounts of leucovorin may nullify the chemotherapeutic effect 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 neurological manifestations continue to progress.

Last updated on RxList: 6/25/2008

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:

1. Time to peak serum folate concentration: 1.72 ± 0.08 hours,
2. Peak serum folate concentration achieved: 268 ± 18 ng/mL,
3. Serum folate half-disappearance time: 3.5 hours.

Oral tablets yielded areas under 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.

Last updated on RxList: 6/25/2008

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Last updated on RxList: 6/25/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

LEUCOVORIN - ORAL

(lew-ko-VORE-in)

USES: This medication is used as a "rescue" treatment for people who have developed very serious blood and immune system problems (thrombocytopenia, neutropenia) due to certain drugs for cancer or infections (antifolate drugs such as methotrexate, trimethoprim, or pyrimethamine). This drug works by entering healthy cells and protecting them from the toxic effects of the antifolate drugs while still allowing the antifolate drugs to work.

HOW TO USE: Take this medication by mouth, usually 4 times daily or as directed by your doctor.

Dosage is based on your medical condition and response to treatment. The manufacturer recommends that you do not take more than 25 milligrams per dose.

This drug works best when taken as soon as possible (usually 6 to 24 hours) after methotrexate or other antifolate drugs. Your doctor may adjust your leucovorin treatment if you have symptoms of methotrexate toxicity. Tell your doctor immediately if you have stomach/abdominal swelling, change in amount of urine, dizziness, or unusual thirst.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day for as long as your doctor directs.

Tell your doctor if your condition does not improve, if it worsens, or if you are unable to take this medicine because of nausea/vomiting.

SIDE EFFECTS: Leucovorin treatment usually has few side effects.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking leucovorin, tell your doctor or pharmacist if you are allergic to it; or to folic acid; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: anemia due to lack of vitamin B12 (e.g., pernicious anemia).

Caution is advised when using this drug in the elderly who are also taking fluorouracil because they may be more sensitive to side effects when these drugs are used together.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: certain anticonvulsants (phenobarbital, phenytoin, primidone).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Drink plenty of fluids while taking antifolate drugs unless directed otherwise by your doctor.

Laboratory and/or medical tests (e.g., kidney function tests, antifolate blood levels) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.