Leucovorin is an active metabolite of folic acid and an essential coenzyme for nucleic acid synthesis.1 Leucovorin can be used to selectively "rescue" cells from the adverse effects of methotrexate or to increase the efficacy of fluorouracil. Methotrexate inhibits nucleic acid synthesis by blocking the activation of folic acid. Leucovorin is folic acid in its active (reduced) form, so it allows nucleic acid synthesis to proceed even in the presence of methotrexate. Leucovorin can also compete with methotrexate for the same transport processes into the cell.2 Leucovorin is usually administered 24 hours after methotrexate so that it does not interfere with the therapeutic effect of methotrexate. Leucovorin can also be used in overdose situations; it should be administered as soon as possible.2 Fluorouracil inhibits nucleic acid synthesis by several mechanisms, including binding to thymidylate synthetase. A leucovorin metabolite (5-methyl-tetrahydrofolate [5-MTHF]) stabilizes the bond formed between a fluorouracil metabolite (fluorodeoxyuridine monophosphate) and thymidylate synthetase.4 This causes a decrease in intracellular levels of that enzyme and a resulting decrease in the production of thymidylate. In this way, leucovorin can enhance or modulate the activity of fluorouracil. Leucovorin is usually administered just prior to fluorouracil. In Canada, leucovorin is available as a racemic mixture containing equal parts of d and l isomers (d,l-leucovorin); the biologically active isomer is the l isomer (l-leucovorin).2,5 In other parts of the world a pure l-leucovorin product is available e.g., in France (ELVORINE(r)) and in the UK (ISOVORIN(r)). Dosing for d,l-leucovorin is different than dosing for l-leucovorin.
| Oral Absorption | 90% absorbed after oral ingestion 3 ; saturable at doses 4 >25 mg | |
| Distribution | all tissues 6 | |
| cross blood brain barrier? | readily 6 | |
| volume of distribution | 3.2 L/kg | |
| plasma protein binding | 35-45% | |
| Metabolism | rapidly and extensively converted to 5-MTHF in the intestine prior to absorption | |
| active metabolite | 5-MTHF | |
| inactive metabolite | yes | |
| Excretion | rapidly excreted in the urine | |
| urine | 80-90% | |
| feces | 5-8% | |
| terminal half life | leucovorin: 15 min 5-MTHF: 35-45 min | |
| clearance | 3.9 mL/min/kg | |
Adapted from standard reference2,7 unless specified otherwise.
| Primary uses: | Other uses: |
| *Leucovorin rescue after methotrexate | |
| *Enhance cytotoxicity of fluorouracil | |
*Health Canada approved indication
Caution:
Absorption is saturable; doses >25 mg should be given IV.4
Doses >1000 mg/m2 q6h are associated with cardiac arrhythmias resulting from hypercalcemia.8
Intrathecal administration not recommended.2
Increases the cytotoxicity and toxicity of fluorouracil.2
Carcinogenicity:
no information found.
Mutagenicity:
no information found.
Fertility: 2
no problems have been documented.
Pregnancy: FDA Pregnancy Category C9. Animal studies have shown fetal risks and there are no controlled studies in women or studies in women and animals are not available. Drug should be given only if the potential benefit justifies the potential risk to the fetus.
Breastfeeding: 6
Leucovorin enters breast milk; caution should be used when administering leucovorin to nursing mothers.
Special populations: Elderly patients 2 Susceptible children 2
are at greater risk of developing severe toxicity when treated with the combination of leucovorin plus fluorouracil for the palliative treatment of colorectal cancer.
experience an increase in the frequency of seizures.
The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important.10,11 When placebo-controlled trials are available, adverse events are included if the incidence is
>
5% higher in the treatment group.
| ORGAN SITE | SIDE EFFECT | ONSET | |||
| Clinically important side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years) | |||||
| allergy/immunology | allergic sensitization (<1%), including anaphylactoid reactions | I | |||
| blood/bone marrow/ febrile neutropenia | in combination with fluorouracil: leucopenia (i.e., fluorouracil toxicity enhanced) | I | |||
| constitutional symptoms | fatigue | I | E | ||
| dermatology/skin | extravasation hazard: none 12 | ||||
| ORGAN SITE | SIDE EFFECT | ONSET | |||
| Clinically important side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years) | |||||
| erythema, hives, rash, pruritus, urticaria 7 | I | E | |||
| gastrointestinal | emetogenic potential: non-emetogenic | ||||
| in combination with fluorouracil: stomatitis, diarrhea (i.e., fluorouracil toxicity enhanced) | I | E | |||
| neurology | seizures (<1%) | I | |||
| pulmonary | wheezing 7 | I | |||
Adapted from standard reference4 unless specified otherwise.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
| capecitabine 7 | increased cytotoxic and toxic effects of capecitabine | capecitabine is metabolized to fluorouracil; leucovorin stabilizes the bond to thymidylate synthetase | monitor toxicity |
| fluorouracil 2 | increased cytotoxic and toxic effects of fluorouracil | leucovorin stabilizes the bond to thymidylate synthetase | some protocols are designed to take advantage of this effect; monitor toxicity closely |
| methotrexate | decreased toxicity of methotrexate | leucovorin "rescues" normal cells from toxic effects of methotrexate | administer leucovorin after methotrexate if required |
| phenobarbital 4 | decreased efficacy of phenobarbital | unknown | primarily a concern with high doses of leucovorin; monitor for seizure control |
| phenytoin 4,13 | decreased efficacy of phenytoin | phenytoin requires folate for microsomal metabolism; leucovorin may interfere with this action | primarily a concern with high doses of leucovorin; monitor for seizure control |
| primidone 4 | decreased efficacy of primidone | unknown | primarily a concern with high doses of leucovorin; monitor for seizure control |
| raltitrexed 14 | decreased efficacy of raltitrexed | raltitrexed is a folate analogue that inhibits thymidylate synthetase; leucovorin may interfere with this action | do not coadminister raltitrexed and leucovorin |
| trimethoprim 2,15 | decreased efficacy of trimethoprim | unknown | if concomitant therapy is necessary, monitor for treatment efficacy |
Tablets: Wyeth supplies leucovorin as a 5 mg tablet.4 Selected non-medicinal ingredients: lactose. Store at room temperature and protect from light.
For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.
For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.
Compatibility of selected drugs16:
The following are compatible with leucovorin via Y-site injection: filgrastim, furosemide, granisetron, heparin, metoclopramide, tacrolimus. The following are compatible with leucovorin in the same syringe at certain concentrations: fluorouracil, furosemide, heparin, metoclopramide.
Incompatibility of selected drugs2:
The following are incompatible with leucovorin via Y-site injection: droperidol, fluorouracil, sodium bicarbonate. Leucovorin is incompatible in the same syringe with droperidol at certain concentrations.
Additional information16:
Fluorouracil and leucovorin will precipitate at various concentrations and temperatures; they should not be considered compatible in the same container.
| BCCA administration guideline noted in bold , italics | |
| Subcutaneous | no information found |
| Intramuscular | can be used 2+ |
| Direct intravenous | by slow injection over a minimum of 3 min 17 * |
| Intermittent infusion | in a suitable volume of compatible IV solution * |
| Continuous infusion | no information found |
| Intraperitoneal | can be used 3 |
| Intrapleural | no information found |
| Intrathecal | has been used; not recommended 2,17 |
| Intra-arterial | no information found |
| Intravesical | no information found |
*rate not exceeding 160 mg/min due to calcium content16
+for doses >10mg/m2 do not use diluents containing benzyl alcohol if reconstituting leucovorin from powder16
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.
Adults: Cycle Length: BCCA usual dose noted in bold, italics
Leucovorin modulation of fluorouracil:
1-4 weeks
18-
20 mg/m2 IV for one dose on days 1-5 (total dose per cycle 1000 mg/m2)
27-30400 mg/m2 IV for one dose on day 1. (total dose per cycle 400 mg/m2)
2 weeks
:
Fluorouracil is usually given after, or at the midpoint of, a leucovorin infusion.17 Doses of leucovorin are not adjusted for toxicity but would be delayed or omitted if fluorouracil is delayed or omitted.6
Leucovorin rescue after methotrexate: Leucovorin rescue31: is required in some methotrexate regimens.
Methotrexate dose:
>500 mg/m2 requires leucovorin rescue.
100-500 mg/m2 may require leucovorin rescue.
Reference: Bleyer WA. The clinical pharmacology of methotrexate - new applications of an old drug. Cancer 1978; 41: 36-51
Note: 0.05 umol/L = 5 x 10-2 micromoles/L
Leucovorin dose PO/IV/IM (see Bleyer nomogram):
10-25 mg/m2 every 6 hours for approximately 8 to 10 doses, starting 24 hours after the start of methotrexate infusion.31-36
Leucovorin dose modifications begin on day 3, if required, based on methotrexate levels taken that morning (i.e., level taken 36-48 hours following the start of the methotrexate infusion). Methotrexate levels are repeated every morning and leucovorin adjusted based on the graph to
follow.32-34
Continue until the methotrexate level is 0.05 umol/L.31,37 17
Some clinicians use a range for the methotrexate level i.e., continue leucovorin until the methotrexate level is between 0.01-0.1 umol/L.
Notes: Leucovorin doses >25 mg should be given IV4 If impaired elimination of methotrexate is suspected, monitor serum creatinine and methotrexate levels, and adjust the dose of leucovorin upwards according to the Bleyer nomogram.11 See the Acute renal failure paragraph in the methotrexate monograph regarding the possible use of Carboxypeptidase-G2.
Concurrent radiation20,21,25: can be used with variable schedules and dosing; specific treatment protocols must be consulted Dosage in myelosuppression: no adjustment required Dosage in renal failure: no adjustment required Dosage in hepatic failure: no adjustment required Dosage in dialysis: no information found
Children:
Leucovorin modulation of fluorouracil:
Leucovorin rescue after methotrexate *:
not indicated for colorectal cancer in pediatric patients31 15 mg (10 mg/m2) PO/IV/IM q6h starting 24 h after beginning of methotrexate infusion; continue until methotrexate level < 0.05umol31 *Methotrexate doses above 100 to 300 mg/m2, which are usually administered by continuous infusion, must be followed by leucovorin rescue.38
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