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Leucovorin Calcium Injection

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Leucovorin Calcium Injection

Warnings
Precautions

WARNINGS

In the treatment of accidental overdosages of folic acid antagonists, intravenous leucovorin (leucovorin calcium) should be administered as promptly as possible. As the time interval between antifolate administration (e.g., methotrexate) and leucovorin (leucovorin calcium) rescue increases, leucovorin (leucovorin calcium) 's effectiveness in counteracting toxicity decreases. In the treatment of accidental overdosages of intrathecally adminstered folic acid antagonists, do not adminster leucovorin (leucovorin calcium) intrathecally. LEUCOVORIN (leucovorin calcium) MAY BE HARMFUL OR FATAL IF GIVEN INTRATHECALLY.

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

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 (leucovorin calcium) 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 reconstituting Leucovorin (leucovorin calcium) Calcium for Injection, when doses greater than 10 mg/m2 are administered, Leucovorin (leucovorin calcium) Calcium for Injection should be reconstituted with Sterile Water for Injection, USP, and used immediately (see DOSAGE AND ADMINISTRATION).

Because of the calcium content of the leucovorin (leucovorin calcium) solution, no more than 160 mg of leucovorin (leucovorin calcium) should be injected intravenously per minute (16 mL of a 10 mg/mL, or 8 mL of a 20 mg/mL solution per minute).

Leucovorin (leucovorin calcium) 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 (leucovorin calcium) 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/m2 of leucovorin (leucovorin calcium) and 20% when treated with 5-fluorouracil in combination with 20 mg/m2 of leucovorin (leucovorin calcium) . 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 (leucovorin calcium) /5-fluorouracil combination than in patients treated with the high dose combination — 11% versus 3%. Therapy with leucovorin (leucovorin calcium) and 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-fluorouracil and leucovorin (leucovorin calcium) , elderly and/or debilitated patients were found to be at greater risk for severe gastrointestinal toxicity.3

Seizures and/or syncope have been reported rarely in cancer patients receiving leucovorin (leucovorin calcium) , 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.5

The concomitant use of leucovorin (leucovorin calcium) 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 place-bo-controlled study.

REFERENCES

3. Grem, J.L., Shoemaker, D.D., Petrelli, N.J., Douglas, H.O., "Severe and Fatal Toxic Effects Observed in Treatment with High- and Low-Dose Leucovorin (leucovorin calcium) Plus 5- Fluorouracil for Colorectal Carcinoma", Cancer Treat Rep 71:1122, 1987.

5. Meropol NJ, Creaven PJ, White RM, et al. "Seizures Associated With Leucovorin (leucovorin calcium) Administration in Cancer Patients," JNCL 1995; 87 (1):56-58.

PRECAUTIONS

General

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

Since leucovorin (leucovorin calcium) enhances the toxicity of fluorouracil, leucovorin (leucovorin calcium) /5-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.

Laboratory Tests

Patients being treated with the leucovorin (leucovorin calcium) /5-fluorouracil combination should have a CBC with differential and platelets prior to each treatment. During the first two courses a CBC with differential and platelets has to be repeated weekly and thereafter once each cycle at the time of anticipated WBC nadir. Electrolytes and liver function tests should be performed prior to each treatment for the first three cycles then prior to every other cycle. Dosage modifications of fluorouracil should be instituted as follows, based on the most severe toxicities:

Diarrhea and/or Stomatitis WBC/mm3 Nadir Platelets/mm3 Nadir 5-FU Dose
Moderate 1,000 - 1,900 25-75,000 decrease 20%
Severe < 1,000 < 25,000 decrease 30%

If no toxicity occurs, the 5-fluorouracil dose may increase 10%. Treatment should be deferred until WBCs are 4,000/mm3 and platelets 130,000/mm3. If blood counts do not reach these levels within two weeks, treatment should be discontinued. Patients should be followed up with physical examination prior to each treatment course and appropriate radiological examination as needed. Treatment should be discontinued when there is clear evidence of tumor progression.

Pregnancy

Teratogenic Effects

Pregnancy Category C. Adequate animal reproduction studies have not been conducted with leucovorin (leucovorin calcium) . It is also not known whether leucovorin (leucovorin calcium) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Leucovorin (leucovorin calcium) 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 (leucovorin calcium) is administered to a nursing mother.

Pediatric Use

See PRECAUTIONS: DRUG INTERACTIONS.

Last reviewed on RxList: 2/24/2009
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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