Leucovorin Calcium may be given orally, or parenterally by intramuscular injection, intravenous injection or intravenous infusion. Leucovorin Calcium should not be administered intrathecally.
For Hospital Use Only.
DBL Leucovorin Calcium Injection contains no antimicrobial agent. This product is for single use in one patient only.
When required for intravenous infusion, leucovorin calcium may be diluted in 1 litre of 5% w/v glucose in water for injections or normal saline. Such solutions are stable for 24 hours when stored between 2 to 8°C. However, to avoid microbial contamination hazards, infusion should be commenced as soon as practicable after preparation of the solution. Infusion should be completed within 24 hours and any residue discarded.
Oral doses should be taken on an empty stomach or in the fasting state since studies of bioavailability of oral tablets have been done with fasting patients only.
In the treatment of accidental overdosage of folic acid antagonists, e.g. methotrexate, leucovorin calcium should be administered as promptly as possible. As the time interval between antifolate administration and leucovorin calcium rescue increases, leucovorin calcium's effectiveness in counteracting toxicity diminishes.
Monitoring of serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin calcium. Delayed methotrexate excretion may be caused by a third space fluid accumulation (ie ascites, pleural effusion), renal insufficiency or inadequate hydration. Under such circumstances, higher doses of leucovorin calcium or prolonged administration may be indicated. Because absorption is saturable, oral administration of doses greater than 25 mg is not recommended. Doses higher than those recommended for oral use must be given intravenously.
Patients being treated with leucovorin calcium following methotrexate therapy, including inadvertent overdose, or patients with impaired methotrexate elimination, should have serum creatinine and methotrexate levels determined at intervals of 24 hours. Leucovorin Calcium dosage should be adjusted on the basis of laboratory test results.
Leucovorin rescue after methotrexate therapy.
The recommendations for leucovorin calcium rescue are based on a methotrexate dose of 12 to 15 g/m2
administered by intravenous infusion over four hours (see product information for methotrexate). Leucovorin Calcium rescue at a dose of 15 mg (approximately 10 mg/m2
) every six hours for ten doses starts 24 hours after the beginning of the methotrexate infusion. In the presence of gastrointestinal toxicity, nausea or vomiting, calcium folinate should be administered parenterally. Serum creatinine and methotrexate levels should be determined at least once daily. Leucovorin Calcium administration, hydration and urinary alkalinisation (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10-8
M (0.05 micromolar). The leucovorin calcium dose should be adjusted or leucovorin rescue extended based on the following guidelines.
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Patients who experience delayed methotrexate elimination are likely to develop reversible renal failure. In addition to appropriate leucovorin calcium therapy, these patients require continuing hydration and urinary alkalinisation and close monitoring of fluid and electrolyte status until the 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 than the abnormalities described above. 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 of 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.
The above dosage recommendations do not necessarily apply to experimental high dose methotrexate therapy. High dose methotrexate therapy should only be administered by qualified specialists and in hospitals where the necessary facilities are available. Recent published literature should be consulted for details at all times.
Impaired methotrexate elimination or inadvertent overdosage.
Leucovorin Calcium rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion. Leucovorin Calcium 10 mg/m2
should be administered intravenously, intramuscular or orally every six hours until the serum methotrexate level is less than 10-8
M. In the presence of gastrointestinal toxicity, nausea or vomiting, leucovorin calcium should be administered parenterally. Serum creatinine and methotrexate levels should be determined at intervals of 24 hours. 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 calcium should be increased to 100 mg/m2
intravenously every three hours until the methotrexate level is less than 10-8
Hydration (3 L/day) and urinary alkalinisation with sodium bicarbonate solution should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.
Treatment of megaloblastic anaemias. Parenteral administration.
Up to 1 mg daily. There is no evidence that doses greater than 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg.
Daily doses of 5 to 15 mg.
Treatment of pyrimethamine overdosage.
The dosage of pyrimethamine in treating toxoplasmosis is 10 to 20 times its dosage for malaria and approaches the toxic level. Since leucovorin calcium is not utilised by protozoa, it can be given simultaneously without impairing the effectiveness of therapy. The usual dosage is 3 to 9 mg/day by intramuscular injection for three days or until the platelet and leucocyte counts have reached safe levels.