Leucovorin injection

You should not be treated with leucovorin if you have pernicious anemia or other types of anemia caused by a lack of vitamin B12.

Usual Adult Dose for Colorectal Cancer:

200 mg/m2, by slow IV injection (minimum 3 minutes), followed by 5-fluorouracil (the manufacturer product information should be consulted), once a day for 5 days
OR
20 mg/m2, IV, followed by 5-fluorouracil (the manufacturer product information should be consulted), once a day for 5 days

Comments:
-Do not be mix in the same infusion as 5-fluorouracil; a precipitate may form.
-May repeat 5 day treatment course at 4 week (28 day) intervals for 2 courses, then repeat at 4 to 5 week (28 to 35 day) intervals provided the patient is completely recovered from toxicities of the prior course.

Use: For use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer.

Usual Adult Dose for Methotrexate Rescue:

Leucovorin Rescue:
15 mg (approximately 10 mg/m2), orally, IV, or IM, every 6 hours for 10 doses; start 24 hours after beginning of methotrexate infusion (based on a methotrexate dose of 12 to 15 g/m2 IV over 4 hours)

Impaired Methotrexate Elimination or Inadvertent Overdosage:
10 mg/m2 orally, IV, or IM, every 6 hours until methotrexate level is less than 10(-8) mol

Comments:
-Determine serum creatinine and methotrexate levels at least once a day.
-Continue leucovorin, hydration, and urinary alkalization until methotrexate levels are below 5 x 10(-8) mol.
-Give parenterally if gastrointestinal toxicity, nausea, or vomiting are present.

Uses: Leucovorin rescue after high dose methotrexate therapy; diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages.

Usual Adult Dose for Methotrexate Overdosage:

Leucovorin Rescue:
15 mg (approximately 10 mg/m2), orally, IV, or IM, every 6 hours for 10 doses; start 24 hours after beginning of methotrexate infusion (based on a methotrexate dose of 12 to 15 g/m2 IV over 4 hours)

Impaired Methotrexate Elimination or Inadvertent Overdosage:
10 mg/m2 orally, IV, or IM, every 6 hours until methotrexate level is less than 10(-8) mol

Comments:
-Determine serum creatinine and methotrexate levels at least once a day.
-Continue leucovorin, hydration, and urinary alkalization until methotrexate levels are below 5 x 10(-8) mol.
-Give parenterally if gastrointestinal toxicity, nausea, or vomiting are present.

Uses: Leucovorin rescue after high dose methotrexate therapy; diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages.

Usual Adult Dose for Megaloblastic Anemia:

Up to 1 mg, IV or IM, once a day

Comments:
-There is no evidence that doses above 1 mg daily have greater efficacy; additionally, urinary folate loss becomes roughly logarithmic as the amount administered exceeds 1 mg.

Use: Treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible

Usual Adult Dose for Folic Acid Antagonist Overdose:

5 to 15 mg orally once a day

Use: Diminish the toxicity and counteract the effects of inadvertent overdosages of folic acid antagonists.

Usual Adult Dose for Pneumocystis Pneumonia:

Treatment of pneumocystis pneumonia is not is not a labeled indication.

20 mg/m2 or 0.5 mg/kg, IV or orally, every 6 hours, continued for 3 days after last trimetrexate dose

Comments:
-Use in combination with trimetrexate.

Use: Treatment of pneumocystis pneumonia in HIV infected patients

Usual Adult Dose for Pneumocystis Pneumonia Prophylaxis:

Prophylaxis of pneumocystis pneumonia is not a labeled indication.

25 mg, orally, once a week, in combination with dapsone and pyrimethamine

Comments:
-Prophylaxis in HIV infected patients usually begins when the CD4+ count is less than 200 cells/mm or for a history of oropharyngeal candidiasis.
-Prophylaxis is usually discontinued when CD4+ count is 200 cells/mm or higher for 3 months.

Use: Pneumocystis pneumonia prophylaxis in immunocompromised patients

Usual Adult Dose for Toxoplasmosis:

Use in the treatment of toxoplasmosis is not a labeled indication.

Ocular toxoplasmosis:
5 to 25 mg orally, IV, or IM, with each dose of pyrimethamine

Acute/primary treatment of toxoplasma encephalitis in AIDS patients:
Standard dose: 10 to 20 mg, orally, IM, or IV, once a day, during and for 1 week after pyrimethamine treatment
Maximum dose: 50 mg once a day

Use: Toxoplasmosis treatment

Usual Pediatric Dose for Colorectal Cancer:

200 mg/m2, by slow IV injection (minimum 3 minutes), followed by 5-fluorouracil (the manufacturer product information should be consulted), once a day for 5 days
OR
20 mg/m2, IV, followed by 5-fluorouracil (the manufacturer product information should be consulted), once a day for 5 days

Comments:
-Do not be mix in the same infusion as 5-fluorouracil; a precipitate may form.
-May repeat 5 day treatment course at 4 week (28 day) intervals for 2 courses, then repeat at 4 to 5 week (28 to 35 day) intervals provided the patient is completely recovered from toxicities of the prior course.

Use: For use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer.

Usual Pediatric Dose for Methotrexate Rescue:

Leucovorin Rescue:
15 mg (approximately 10 mg/m2), orally, IV, or IM, every 6 hours for 10 doses; start 24 hours after beginning of methotrexate infusion (based on a methotrexate dose of 12 to 15 g/m2 IV over 4 hours)

Impaired Methotrexate Elimination or Inadvertent Overdosage:
10 mg/m2 orally, IV, or IM, every 6 hours until methotrexate level is less than 10(-8) mol


Comments:
-Determine serum creatinine and methotrexate levels at least once a day.
-Continue leucovorin, hydration, and urinary alkalization until methotrexate levels are below 0.05 micromol.
-Give parenterally if gastrointestinal toxicity, nausea, or vomiting are present.

Uses: Leucovorin rescue after high dose methotrexate therapy; diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages.

Usual Pediatric Dose for Megaloblastic Anemia:

Up to 1 mg, IV or IM, once a day

Comments:
-There is no evidence that doses above 1 mg daily have greater efficacy; additionally, urinary folate loss becomes roughly logarithmic as the amount administered exceeds 1 mg.

Use: Treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible

Usual Pediatric Dose for Folic Acid Antagonist Overdose:

5 to 15 mg orally once a day

Use: Diminish the toxicity and counteract the effects of inadvertent overdosages of folic acid antagonists.

• Your pharmacist can provide more information about leucovorin.

• Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.
• Disclaimer: Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 1.01.

Date modified: October 13, 2017
Last reviewed: August 21, 2017

• If you have an allergy to leucovorin or any other part of leucovorin injection.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have anemia caused by a lack of vitamin B12.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take leucovorin injection with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Use leucovorin injection as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as a shot into a muscle or vein.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF). The biologically active compound of the mixture is the (-)-I-isomer, known as Citrovorum factor or (-)-folinic acid.  Leucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties.

I-Leucovorin (I-5-formyltetrahydrofolate) is rapidly metabolized (via 5, 10-methenyltetrahydrofolate then 5, 10-methylenetetrahydrofolate) to I,5-methyltetrahydrofolate. I,5-Methyltetrahydrofolate can in turn be metabolized via other pathways back to 5,10-methylenetetrahydrofolate, which is converted to 5-methyltetrahydrofolate by an irreversible, enzyme catalyzed reduction using the cofactors FADH2 and NADPH.

Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase.

In contrast, leucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy, such as 5-fluorouracil.  Concurrent administration of leucovorin does not appear to alter the plasma pharmacokinetics of 5-fluorouracil. 5-Fluorouracil is metabolized to fluorodeoxyuridylic acid, which binds to and inhibits the enzyme thymidylate synthase (an enzyme important in DNA repair and replication).

Leucovorin is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of fluorodeoxyridylic acid to thymidylate synthase and thereby enhances the inhibition of this enzyme.

The pharmacokinetics after intravenous, intramuscular and oral administration of a 25 mg dose of leucovorin were studied in male volunteers.  After intravenous administration, serum total reduced folates (as measured by Lactobacillus casei assay) reached a mean peak of 1,259 ng/mL (range 897 to 1,625). The mean time to peak was 10 minutes.  This initial rise in total reduced folates was primarily due to the parent compound 5-formyl-THF (measured by Streptococcus faecalis assay) which rose to 1,206 ng/mL at 10 minutes.  A sharp drop in parent compound followed and coincided with the appearance of the active metabolite 5-methyl-THF which became the predominant circulating form of the drug.

The mean peak of 5-methyl-THF was 258 ng/mL and occurred at 1.3 hours.  The terminal half-life for total reduced folates was 6.2 hours.  The area under the concentration versus time curves (AUCs) for I-leucovorin, d-leucovorin and 5-methyltetrahydrofolate were 28.4 ± 3.5, 956 ± 97 and 129 ± 12 (mg/min/L ± S.E.).  When a higher dose of d,I-leucovorin (200 mg/m2) was used, similar results were obtained.  The d-isomer persisted in plasma at concentrations greatly exceeding those of the I-isomer.

After intramuscular injection, the mean peak of serum total reduced folates was 436 ng/mL (range 240 to 725) and occurred at 52 minutes.  Similar to IV administration, the initial sharp rise was due to the parent compound.  The mean peak of 5-formyl-THF was 360 ng/mL and occurred at 28 minutes.  The level of the metabolite 5-methyl-THF increased subsequently over time until at 1.5 hours it represented 50% of the circulating total folates.  The mean peak of 5-methyl-THF was 226 ng/mL at 2.8 hours.  The terminal half-life of total reduced folates was 6.2 hours.  There was no difference of statistical significance between IM and IV administration in the AUC for total reduced folates, 5-formyl-THF, or 5-methyl-THF.

After oral administration of leucovorin reconstituted with aromatic elixir, the mean peak concentration of serum total reduced folates was 393 ng/mL (range 160 to 550).  The mean time to peak was 2.3 hours and the terminal half-life was 5.7 hours. The major component was the metabolite 5-methyltetrahydrofolate to which leucovorin is primarily converted in the intestinal mucosa.  The mean peak of 5-methyl-THF was 367 ng/mL at 2.4 hours. The peak level of the parent compound was 51 ng/mL at 1.2 hours.  The AUC of total reduced folates after oral administration of the 25 mg dose was 92% of the AUC after intravenous administration.

Following oral administration, leucovorin is rapidly absorbed and expands the serum pool of reduced folates.  At a dose of 25 mg, almost 100% of the I-isomer but only 20% of the d-isomer is absorbed.  Oral absorption of leucovorin is saturable at doses above 25 mg.  The apparent bioavailability of leucovorin was 97% for 25 mg, 75% for 50 mg, and 37% for 100 mg.

In a randomized clinical study conducted by the Mayo Clinic and the North Central Cancer Treatment Group (Mayo/NCCTG) in patients with advanced metastatic colorectal cancer three treatment regimens were compared: Leucovorin (LV) 200 mg/m2 and 5-fluorouracil (5-FU) 370 mg/m2 versus LV 20 mg/m2 and 5-FU 425 mg/m2 versus 5-FU 500 mg/m2.  All drugs were administered by slow intravenous infusion daily for 5 days repeated every 28 to 35 days.  Response rates were 26% (p=0.04 versus 5-FU alone), 43% (p=0.001 versus 5-FU alone) and 10% for the high dose leucovorin, low dose leucovorin and 5-FU alone groups respectively.  Respective median survival times were 12.2 months (p=0.037), 12 months (p=0.05), and 7.7 months.  The low dose LV regimen gave a statistically significant improvement in weight gain of more than 5%, relief of symptoms, and improvement in performance status.  The high dose LV regimen gave a statistically significant improvement in performance status and trended toward improvement in weight gain and in relief of symptoms but these were not statistically significant.1

In a second Mayo/NCCTG randomized clinical study the 5-FU alone arm was replaced by a regimen of sequentially administered methotrexate (MTX), 5-FU, and LV.  Response rates with LV 200 mg/m2 and 5-FU 370 mg/m2 versus LV 20 mg/m2 and 5-FU 425 mg/m2 versus sequential MTX and 5-FU and LV were respectively 31% (p=<.01), 42% (p=<.01), and 14%. Respective median survival times were 12.7 months (p=<.04), 12.7 months (p=<.01), and 8.4 months.  No statistically significant difference in weight gain of more than 5% or in improvement in performance status was seen between the treatment arms.2

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

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 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 hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity (see PRECAUTIONS, Laboratory Tests).  For patients who experienced no toxicity in the prior treatment course, 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 (see methotrexate package insert for full prescribing information).4  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).  The leucovorin dose should be adjusted or leucovorin rescue extended based on the following guidelines:

                                                                                                         GUIDELINES FOR LEUCOVORIN DOSAGE AND ADMINISTRATION

                                                                                                                    DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY

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 alkalization, 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 abnormalities described in the table 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.

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 a delayed excretion (see WARNINGS).  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/d) and urinary alkalinization 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.

Each 200 mg vial of Leucovorin Calcium for Injection when reconstituted with 20 mL, of sterile diluent yields a leucovorin concentration of 10 mg per mL.  Each 500 mg vial of Leucovorin Calcium for Injection when reconstituted with 50 mL of sterile diluent yields a leucovorin concentration of 10 mg per mL.  Leucovorin Calcium for Injection contains no preservative.  Reconstitute the lyophilized vial products with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved), or Sterile Water for Injection, USP.  When reconstituted with Bacteriostatic Water for Injection, USP, the resulting solution must be used within 7 days.  If the product is reconstituted with Sterile Water for Injection, USP, use immediately and discard any unused portion.

Because of the benzyl alcohol contained in Bacteriostatic Water for Injection, USP, 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 WARNINGS).

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).

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Leucovorin should not be mixed in the same infusion as 5-fluorouracil, since this may lead to the formation of a precipitate.