Zovorin

Leucovorin is one of several active, chemically reduced derivatives of folic acid.

It is useful as an antidote to drugs which act as folic acid antagonists.

Also known as

• Folinic acid

• Citrovorum factor

• 5-formyl-5,6,7,8-tetrahydrofolic acid

This compound has the chemical designation of

Calcium N-[p-[[[(6RS)-2-amino-5-formyl-5,6,7,8-tetrahydro-4-hydroxy-6-pteridinyl]methyl]amino]benzoyl]-L-glutamate (1:1).

Leucovorin calcium rescue is indicated after high dose methotrexate therapy in osteosarcoma.

Leucovorin calcium is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists.

Leucovorin calcium is indicated in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible.

Leucovorin calcium is indicated for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer.

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

Leucovorin calcium is indicated in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible.

Leucovorin is also indicated for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer.

• Read the label carefully before use.

• Keep out of the reach of children.

Advanced Colorectal Cancer

Either of the following two regimens is recommended

1. Leucovorin is administered at 200 mg/m² by slow intravenous injection over a minimum of 3 minutes, followed by 5-fluorouracil at 370 mg/m² by intravenous injection.

2. Leucovorin is administered at 20 mg/m² by intravenous injection followed by 5-fluorouracil at 425 mg/m² by intravenous injection.

5-Fluorouracil and Leucovorin should be administered separately to avoid the formation of a precipitate.

Treatment is repeated daily for five days.

This five-day treatment course may be repeated at 4-week (28-day) intervals for 2 courses and then repeated at 4- to 5-week (28- to 35-day) intervals, provided that the patient has completely recovered from the toxic effects of the prior treatment course.

In a subsequent treatment course, the dosage of 5-fluorouracil should be adjusted based on patient tolerance of the prior treatment course.

The daily dosage of 5-fluorouracil should be reduced by:

• 20% for patients who experienced moderate haematologic or gastrointestinal toxicity in the prior treatment course

• 30% for patients who experienced no toxicity in the prior treatment course

The 5-fluorouracil dosage may be increased by 10%.

Leucovorin dosages are not adjusted for toxicity.

Several other doses and schedules of Leucovorin/5-fluorouracil therapy have also been evaluated in patients with advanced colorectal cancer; some of these alternative regimens may also have efficacy in the treatment of this disease.

However, further clinical research will be required to confirm the safety and effectiveness of these alternative Leucovorin/5-fluorouracil treatment regimens.

Leucovorin Rescue After High-Dose Methotrexate Therapy

The recommendations for leucovorin rescue are based on a methotrexate dose of 12 to 15 grams/m² administered by intravenous infusion over 4 hours.

Leucovorin rescue at a dose of 15 mg (approximately 10 mg/m²) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion.

In the presence of gastrointestinal toxicity, nausea or vomiting, leucovorin should be administered parenterally.

Do not administer Leucovorin intrathecally.

Serum creatinine and methotrexate levels should be determined at least once daily.

Leucovorin administration, hydration, and urinary alkalization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 X 10⁻⁸ M (0.05 micromolar).

Guidelines For Leucovorin Dosage And Administration

Normal Methotrexate Elimination

Serum methotrexate level approximately

• 10 micromolar at 24 hours after administration

• 1 micromolar at 72 hours

Dose

• 15 mg PO, IM, or IV every 6 hours for 60 hours (10 doses starting at 24 hours after the start of the methotrexate infusion)

Delayed Late Methotrexate Elimination

Serum methotrexate level remaining above

• 0.2 micromolar at 72 hours

• More than 0.05 micromolar at 96 hours after administration

Dose

• Continue 15 mg PO, IM or IV every 6 hours until the methotrexate level is less than 0.05 micromolar

Delayed Early Methotrexate Elimination And/Or Evidence Of Acute Renal Injury

A serum methotrexate level of

• 50 micromolar or more at 24 hours after administration

OR

• A 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration

Dose

• 150 mg IV every 3 hours until methotrexate level is less than 1 micromolar

Then

• 15 mg IV every 3 hours until methotrexate level is less than 0.05 micromolar

Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure.

In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalisation and close monitoring of fluid and electrolyte status until the serum methotrexate level has fallen below 0.05 micromolar and renal failure has resolved.

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.

Leucovorin 10 mg/m² should be administered IM, IV, or PO every 6 hours until the serum methotrexate level is less than 10⁻⁸ M.

In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally.

Do not administer Leucovorin intrathecally.

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

• 100 mg/m² IV every 3 hours

until the methotrexate level is less than 10⁻⁸ M.

Hydration (3 L/day) and urinary alkalisation with sodium bicarbonate solution 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/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.

Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin should be injected intravenously per minute.