Lederle Leucovorin (Folic Acid Derivative)



Citrovorum Factor

Folic Acid Derivative

Action And Clinical Pharmacology: Lederle Leucovorin Calcium (calcium folinate), the calcium salt of folinic acid (citrovorum factor), is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid. The biologically active compound of the mixture is the (-)-L-isomer. It is a metabolite of folic acid and an essential coenzyme for nucleic acid synthesis.

Leucovorin is a reduced form of folic acid, which is readily converted to other reduced folic acid derivatives (e.g., tetrahydrofolate).

Because it does not require reduction by dihydrofolate reductase as does folic acid, leucovorin is not affected by blockage of this enzyme by folic acid antagonists (dihydrofolate reductase inhibitors). This allows purine and thymidine synthesis, and thus DNA, RNA and protein synthesis, to occur. Leucovorin may limit methotrexate action on normal cells by competing with methotrexate for the same transport processes into the cell. Leucovorin rescues bone marrow and gastrointestinal cells from methotrexate but has no apparent effect on pre-existing methotrexate nephrotoxicity.

Leucovorin is extensively converted to 5-methyltetrahydrofolate in the intestine prior to absorption. In this form, it is a major component of the total active human serum folate. Oral absorption is saturable at doses above 25 mg.

Leucovorin enhances the cytotoxicity of fluoropyrimidines such as 5-fluorouracil (5-FU) by their metabolites, methylene tetrahydrofolate and fluorodeoxyuridine monophosphate, forming a stable ternary complex with thymidylate synthase, and thereby, decreasing intracellular levels of that enzyme and the product thymidylate. The cell then dies as a result of thymine starvation.

Caution: Do not administer leucovorin intrathecally.

Indications And Clinical Uses: To diminish the toxicity and counteract the effect of impaired methotrexate elimination. To treat the megaloblastic anemias due to folate deficiency, as in sprue, nutritional deficiency, megaloblastic anemias of pregnancy and infancy. For pre-treatment followed by 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer. For modulation of 5-FU as adjuvant therapy for patients with Dukes’ B and C colon cancer.

Contra-Indications: Not to be administered for the treatment of pernicious anemia or other megaloblastic anemias where vitamin B12 is deficient. A hematologic remission may occur while neurologic manifestations continue to progress.

Manufacturers’ Warnings In Clinical States: Since leucovorin may enhance the toxicity of fluorouracil, leucovorin/fluorouracil combination therapy for advanced colorectal cancer should be administered under the supervision of a physician experienced in the use of antimetabolite cancer chemotherapy. Particular care should be taken in the treatment of elderly or debilitated colorectal cancer patients, as these patients may be at increased risk of severe toxicity. Deaths from severe enterocolitis, diarrhea and dehydration have been reported in elderly patients receiving leucovorin and fluorouracil. Concomitant granulocytopenia and fever were present in some but not all of the patients.

In the treatment of accidental overdosages of folic acid antagonists, leucovorin should be administered as promptly as possible. As the time interval between the administration of antifolate and leucovorin increases, the effectiveness of leucovorin in counteracting toxicity decreases. Monitoring of the serum MTX concentration is essential in determining the optimal dose and duration of therapy. Delayed MTX excretion may be caused by a third space fluid accumulation (i.e., ascites, pleural effusion), renal insufficiency, low pH of urine, or inadequate hydration. Under such circumstances, higher doses of leucovorin or prolonged administration may be indicated. Do not administer leucovorin intrathecally.

Cryodesiccated powder reconstituted with Bacteriostatic Water for Injection containing benzyl alcohol should only be used at doses below 10 mg/m (see Precautions).

Treatment-related deaths have been sporadically reported in patients treated with leucovorin plus fluorouracil combination therapy regimens. In general, diarrhea or stomatitis/mucositis are the first indications that severe and potentially life-threatening toxicity could develop. Patients who experience these symptoms while receiving any combination therapy regimen incorporating leucovorin plus fluorouracil should be carefully followed and further therapy should be withheld until these symptoms resolve.

Leucovorin enhances the toxicity of fluorouracil. When these drugs are administered concurrently in the palliative therapy of advanced colorectal cancer, the dosage of fluorouracil must be reduced. Although the toxicities observed in patients treated with the combination of leucovorin plus fluorouracil are qualitatively similar to those observed in patients treated with fluorouracil alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be more severe in patients receiving the combination (see Precautions).

Therapy with leucovorin/fluorouracil must not be initiated or continued in patients who have symptoms of gastrointestinal toxicity of any severity, until those symptoms have resolved. Patients with diarrhea must be monitored with particular care until the diarrhea has resolved, as rapid clinical deterioration leading to death can occur. Elderly or debilitated patients are at greater risk for severe toxicity receiving this therapy.

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.

Precautions: Because of the Ca+content of leucovorin solutions, no more than 160 mg of leucovorin should be injected i.v./minute.

If the cryodesiccated powder is reconstituted with Bacteriostatic Water for Injection containing 0.9% benzyl alcohol doses greater than 10 mg/mare not recommended due to the benzyl alcohol content. If greater doses are required (see Dosage), leucovorin calcium for injection (cryodesiccated powder) should be reconstituted with Sterile Water for Injection USP and used immediately, or the preservative-free liquid form, leucovorin calcium injection should be used.

Leucovorin should not be mixed in the same infusion as 5-fluorouracil as a precipitate may form.

Drug Interactions: 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 Warnings).

Pregnancy: Teratogenic Effects: Reproduction studies have been performed in rats and rabbits at doses at least 50 times the human dose and have revealed no evidence of harm to the fetus due to leucovorin.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Lactation: 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.

Children: See Drug Interactions.

Adverse Reactions: Allergic sensitization, including anaphylactoid reactions and urticaria, has been reported following both oral and parenteral administration of folinic acid. In combination regimens, the toxicity profile of 5-FU is enhanced by leucovorin. The most common manifestations are mucositis, stomatitis, leukopenia, and/or diarrhea which may be dose-limiting. In clinical trials with this drug combination, these toxicities were found to be reversible with appropriate modification of 5-FU administration.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Folic acid is a water soluble vitamin converted in the body by the action of folate reductase to folinic acid (Leucovorin) which is rapidly eliminated in the urine.

Folic acid has low acute and chronic toxicities in man. No adverse effects have been noted in adults after the ingestion of 400 mg/day for 5 months or 10 mg/day for 5 years.

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

Dosage And Administration: Impaired Methotrexate Elimination or Accidental 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 10 mg/mshould be administered i.v., i.m. or orally every 6 hours until the serum methotrexate level is less than 108. In the presence of gastrointestinal toxicity, nausea or vomiting, leucovorin should be administered parenterally. Because absorption is saturable, doses greater than 25 mg should be given i.v.

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´106 or the 48-hour level is greater than 9´107, the dose of leucovorin should be increased to 100 mg/mi.v. every 3 hours until the methotrexate level is less than 108.

Hydration (3 L/day) and urinary alkalinization with NaHCO3 should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

Megaloblastic Anemia Due to Folic Acid Deficiency: Up to 1 mg daily. There is no evidence that doses greater than 1 mg daily have greater efficacy than doses of 1 mg. The loss of folate in the urine becomes roughly logarithmic as the amount administered exceeds 1 mg.

Advanced Colorectal Cancer: Leucovorin is administered at 200 mg/mby slow i.v. injection immediately prior to dosing with 370 mg/m5-FU (fluorouracil) by slow i.v. injection, for 5 consecutive days.

This 5-day treatment course may be repeated at 4-week (28-day) intervals, provided that the patient has completely recovered from the toxic effects of the prior treatment course.

In subsequent treatment courses, the dosage of fluorouracil should be adjusted based on patient tolerance of the prior treatment course. The daily dosage of fluorouracil should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity. For patients who experienced no toxicity in the prior treatment course, fluorouracil dosage may be increased by 10%. Leucovorin dosages are not adjusted for toxicity.

Adjuvant Therapy for Patients with Dukes B and C Colon Cancer: Leucovorin is administered i.v. as a 2-hour infusion at a dosage of 500 mg/mweekly for 6 consecutive weeks followed by a 2-week rest. This regimen is repeated for a total of 6 cycles.

Treatment is repeated 21 days after the sixth dose of the previous course. Fluorouracil (5/FU) is administered at a dose of 500 mg/m on the same schedule as leucovorin, i.v. via bolus 1 hour after the i.v. has been started.

Do not administer leucovorin intrathecally.

Availability And Storage: Powder: 50 mg: Each vial of lyophilized powder contains: leucovorin (as calcium) 50 mg. Also contains sodium chloride 40 mg and sodium hydroxide and/or hydrochloric acid to adjust pH. Preservative-free. Boxes of 10. Store at 15 to 30°C.

350 mg: Each vial of lyophilized powder contains: leucovorin (as calcium) 350 mg. Also contains sodium chloride 140 mg and sodium hydroxide and/or hydrochloric acid to adjust pH. Preservative-free. Single vials, boxes of 10. Store at 15 to 30°C.

Tablets: Each round, light yellow, scored tablet, engraved “LL5” and “U2”, contains: leucovorin (as calcium) 5 mg. Nonmedicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate and starch pregelatinized. Tartrazine-free. Bottles of 24 and 100. Store at 15 to 30°C.

Vials: Each mL of solution contains: leucovorin (as calcium) 10 mg. Also contains sodium chloride 7.7 mg and sodium hydroxide and/or hydrochloric acid to adjust pH. Preservative-free. Vials of 35 mL, boxes of 10. Store between 2 to 8°C. Avoid freezing.

LEDERLE LEUCOVORIN® CALCIUM Wyeth-Ayerst Citrovorum Factor Folic Acid Derivative

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