WARNINGS
In the treatment of accidental overdosages of folic acid antagonists, intravenous 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 toxicity decreases. In the treatment of accidental overdosages of intrathecally adminstered folic acid antagonists, do not adminster leucovorin intrathecally. LEUCOVORIN 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.
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.
Because of the benzyl alcohol contained in certain diluents used for reconstituting Leucovorin Calcium for Injection, when doses greater than 10 mg/m2 are administered, Leucovorin Calcium for Injection should be reconstituted with Sterile Water for Injection, USP, and used immediately (see DOSAGE AND ADMINISTRATION section).
Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin 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 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 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 and 20% when treated with 5-fluorouracil in combination with 20 mg/m2 of leucovorin. 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/5-fluorouracil combination than in patients treated with the high dose combination — 11% versus 3%. Therapy with leucovorin 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, 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, 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 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 placebo-controlled study.
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 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 enhances the toxicity of fluorouracil, leucovorin/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/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.
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 pediatric patients.
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 5-fluorouracil (see WARNINGS section).
Pregnancy
Teratogenic Effects: Pregnancy Category C
Adequate 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 PRECAUTIONS, Drug Interactions subsection.
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