leucovorin

Trade Name:

Lederle Leucovorin® (multiple brands available)

Synonym:

calcium folinate

citrovorum factor

folinic acid

Appearance:

Faint yellow solution

Also available as tablets.

Monograph Name:

leucovorin

Monograph Body:

Drug Monograph

A - Drug Name

leucovorin

SYNONYM(S): calcium folinate; citrovorum factor; folinic acid; GA; LV

COMMON TRADE NAME(S): Lederle Leucovorin® (multiple brands available)

B - Mechanism of Action and Pharmacokinetics

Leucovorin calcium (folinic acid) is a reduced form of folic acid. It is usually used 24 hours after methotrexate to selectively “rescue” normal cells from the adverse effects of methotrexate caused by inhibition of production of reduced folates. It is not used simultaneously with methotrexate, as it might then nullify the therapeutic effect of the methotrexate. Leucovorin has also been used to enhance the activity of fluorouracil by binding to the enzyme thymidylate synthetase and decreasing intracellular levels of thymidylate. Commercially available leucovorin in Canada is the racemic mixture of D and L isomers; the L stereoisomer is the active moiety.

Absorption

Bioavailability

oral: Rapidly absorbed; 97% at 25mg; saturable at doses above 25 mg.

Distribution

Distributed to all tissues, concentrates in liver and CSF.

Cross blood brain barrier?

yes

PPB

35 - 45 %

Volume of distribution

3.2 L/kg

Metabolism

Rapidly and extensively converted to 5-methyltetrahydrofolate derivatives in the intestine prior to absorption.

Active metabolites

5-methyltetrahydrofolate

Inactive metabolites

yes

Elimination

Mainly eliminated in urine, small amounts in feces.

Urine

80-90% of dose.

Half-life

Parent drug: 32 minutes

Active metabolite: 227 minutes.

Clearance

3.9 mL/min/kg.

C - Indications and Status

Health Canada Approvals:

Leucovorin rescue after methotrexate (higher dose regimens/overdose)
Adjuvant or advanced colorectal cancer in combination with fluorouracil.
Megaloblastic anemias due to folate deficiency

Other Uses:

In combination with fluorouracil for gastrointestinal cancers (gastroesophageal, hepatobiliary, pancreatic and small bowel and appendix)

D - Adverse Effects

Emetogenic Potential:

Minimal

Extravasation Potential: None

ORGAN SITE	SIDE EFFECT* (%)	ONSET**
Dermatological	Hand-foot syndrome (in combination with fluorouracil i.e., toxicity is enhanced)	E
Gastrointestinal	Diarrhea (common, in combination with fluorouracil, i.e., toxicity is enhanced)	I E
	Mucositis (common; in combination with flourouracil, i.e., toxicity is enhanced)	I E
Hematological	Myelosuppression (in combination with flourouracil, i.e., toxicity is enhanced)	E
Hypersensitivity	Anaphylaxis (including shock- rare)	I
	Drug reaction (skin rash, hives, pruritus, wheezing- rare)	I
Nervous System	Seizure (rare)	E
	Syncope (rare)	E

* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)

Deaths from severe enterocolitis, diarrhea and dehydration have been reported in elderly or debilitated patients receiving leucovorin and fluorouracil. Seizures or syncope have been reported rarely, usually in combination with fluorouracil and in patients with cerebral metastases, although a causal relationship has not been confirmed.

E - Dosing

Refer to protocol by which patient is being treated. Leucovorin is rarely given to rescue doses of methotrexate <100 mg/m².

Adults:

With fluorouracil:

q4w: 20 mg/m² IV x 5 days
q2w: 400mg/m² on day 1 (as in FOLFIRI)

Refer to specific regimen for details. Order of administration is important; leucovorin should be given prior to fluorouracil.

Rescue after methotrexate:

Administer as IV, IV infusion, IM, or PO within 24-36 hours.
Doses > 25 mg should be given IV.
Other than for low dose, methotrexate levels should be monitored daily until <0.1μM and doses of leucovorin adjusted. Delayed methotrexate excretion may be due to third space fluid accumulation, renal insufficiency, low urine pH or inadequate hydration. Ensure patient is hydrated (at least 3L/d) and maintain urine alkalinization at pH ≥ 8 before and during methotrexate and pH > 7 after the dose.

Moderate-dose methotrexate:

15-25 mg p.o q6h x 6-12 doses, starting 24 hours after methotrexate

High-dose methotrexate:

Use in specialized cancer units ONLY. Ensure hydrated and urine alkalinized. Follow local recommendations for dosing. The following are general recommendations:

Excretion	Methotrexate levels	Leucovorin dose
Normal	24 hours: ≤ 10µM 48 hours: ≤ 1 µM 72 hours: < 0.1µM	15 mg q6h for 10 doses
Delayed late elimination	72 hours: > 0.1µM	Continue q6h doses until ≤ 0.1 µM
Delayed early elimination and renal failure	24 hours: > 10µM OR 100% ↑ Creatinine 48 hours: > 1 µM	150mg (or 100 mg/m²) IV q3h until < 1 µM then 15mg q3h until < 0.1 µM

Dosage with Toxicity:

Dosage with myelosuppression:

No adjustment required

Dosage with Hepatic Impairment:

No adjustment required.

Dosage with Renal Impairment:

No adjustment required.

F - Administration Guidelines

Doses ≤100mg may be given by IV push through sidearm of free flowing IV (5% Dextrose, Normal Saline or 2/3-1/3). The injection must not exceed 160mg/min of leucovorin (due to calcium content).
May be mixed in 50mL Normal Saline or 5% Dextrose minibag (doses up to 500mg) or 100mL minibag (doses >500mg) or in 100mL fluid in graduated administration set (5% Dextrose, Normal Saline or 2/3-1/3); Give over 15 minutes.
Continuous infusion using CADD pump or similar device.
Cryodesiccated powder reconstituted with Bacteriostatic Water for Injection containing benzyl alcohol should only be used at doses below 10 mg/m²
Leucovorin should not be mixed in the same infusion as 5-fluorouracil as a precipitate may form.
Keep refrigerated; protect from light.

LEUCOVORIN ORAL

Oral self-administration; drug available by outpatient prescription.

G - Special Precautions

Other:

Leucovorin is not to be administered for the treatment of pernicious anemia or other megaloblastic anemias where vitamin B₁₂ is deficient. Hematologic remission may occur while neurologic manifestations continue to progress. It is contraindicated for intrathecal use. The oral formulation contains lactose and should not be used in patients with hereditary glucose-galactose or lactase deficiencies.

Leucovorin should be administered as soon as possible in case of folic acid antagonist overdose. It has no apparent effect on pre-existing methotrexate nephrotoxicity.

Teratogenic, mutagenic and carcinogenic potentials are unknown in humans, although teratogenic effects have been seen in animals. Leucovorin’s safety in pregnancy and its effect on fertility have not been established. Breast feeding is not recommended due to the potential secretion into breast milk.

H - Interactions

AGENT	EFFECT	MECHANISM	MANAGEMENT
Fluorouracil	↑ cytotoxic and toxic effects of fluorouracil.	Stabilizes bond to thymidylate synthetase	Monitor toxicity closely
methotrexate	↓ toxicity of methotrexate.	‘Rescues’ normal cells from toxic effect of methotrexate	Administer within 6-24 hours after methotrexate.
Methotrexate (intrathecal)	↓ effect	Crosses blood brain barrier and ameliorates effect, especially with high leucovorin doses.	Caution
Phenobarbital, phenytoin, primidone, succimides.	↑ seizures	↓ plasma concentrations of antiepileptics.	Caution; check levels
Other folic acid antagonists (i.e. cotrimoxazole, pyrimethamine)	↓ efficacy		If must use, monitor for treatment efficacy

I - Recommended Clinical Monitoring

Refer to monitoring parameters in related regimen monographs.

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

J - Supplementary Public Funding

ODB - General Benefit (

ODB Formulary

)

leucovorin - oral tablets ()

K - References

Bleyer WA. The clinical pharmacology of methotrexate: new applications of an old drug. Cancer 1978;41(1):36-51.

Leucovorin: e-Drugdex, Micromedex Healthcare Series.

McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 3680-3.

Leucovorin: Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA).

Product Monograph: Lederle Leucovorin Calcium. Wyeth Canada, January 25, 2008.

Product Monograph: Leucovorin Calcium Injection. Hospira Healthcare Corp., June 7, 2007.

Product Monograph: Leucovorin Calcium Injection. Novopharm Ltd., December 21, 1998.

October 2017 edited indications

L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.

Info Sheet Name:

leucovorin(IV/PO) (patient)

Info Sheet Introduction:

Leucovorin is not an anticancer drug
It may be used to reduce some of the side effects of the anticancer drug methotrexate
It may be used to increase the activity of the anticancer drug 5-fluorouracil (5-FU)

Info Sheet Date: Jeudi, avril 11, 2019 Info Sheet body:

Medication Information Sheet

leucovorin (loo-co-VOR-in)

This document provides general information about your medication. It does not replace the advice of your health care professional. Always discuss your therapy with your health care professional and refer to the package insert for more details.

Other Name: Generic brand(s) available

Appearance:

Faint yellow solution

Also available as tablets.

What is this medication for?

Leucovorin is not an anticancer drug
It may be used to reduce some of the side effects of the anticancer drug methotrexate
It may be used to increase the activity of the anticancer drug 5-fluorouracil (5-FU)

What should I do before I have this medication?

Tell your doctor if you have or had significant medical condition(s), especially if you have or had problems with your stomach, bowels or kidneys, or have any allergies.

People with cancer have a higher risk of getting other cancers or developing blood clots. Some cancer medications may increase these risks, especially if used for a long period of time. Discuss any concerns about this medication with your health care team.

How will this medication affect sex, pregnancy and breastfeeding?

The use of this medication along with chemotherapy in men or women may cause harm to the unborn baby if pregnancy occurs. Let your health care team know if you or your partner is pregnant, becomes pregnant during treatment, or if you are breastfeeding
If there is any chance that you or your partner may become pregnant, you and your partner together must:
► Use 2 effective forms of birth control at the same time while taking this drug. Keep using birth control for at least 6 months after your last dose unless your health care team told you differently. Talk to your health care team to figure out the best method(s) for you and/or your partner.
Do not breastfeed while using this drug.

How is this medication given?

Injection:

This medication is given by injection into a vein.
When used with methotrexate, leucovorin is given for a specific number of doses at precise times after your injection of methotrexate. This is called Leucovorin Rescue.
When used with 5-fluorouracil, leucovorin is usually given before your 5-fluorouracil dose.

Tablets:

Swallow whole with a glass of water, with or without food.
Take it exactly as directed by your doctor. Make sure you understand the instructions.
Tablets are usually not started until 24 hours AFTER you receive methotrexate

What else do I need to know while on this medication?

This medication can interact with other medications and can result in the treatment not working as well or cause severe side effects.
Make sure your health care team knows about all your medications (prescription, over-the-counter, herbals and supplements). Check with your health care team before starting or stopping any of them.
For mild aches and pain or fever:
- If you feel unwell, take your temperature before taking any medications for pain or fever. They may hide a fever.
- You may take acetaminophen (Tylenol®) tablets. Ask your health care team about the right dose for you.
- Ibuprofen (Advil®, Motrin®), naproxen (Aleve®) or aspirin (acetylsalicylic acid, ASA), including low dose aspirin for heart conditions, may increase your chance of bleeding. Talk to your health care team before you start or stop these medications.
- Talk to your health care team or go to the closest emergency room right away if you have a fever. See the Fever pamphlet for more information.
Drinking alcohol and smoking during your treatment may increase some side effects and make your medication less effective. Speak to your health care team about smoking and drinking alcohol while on treatment.

How should I safely store this medication?

For tablets:

Keep this medication in the original packaging at room temperature in a dry place, away from heat and light. Keep out of sight and reach of children and pets.
Do not throw out any unused medications at home. Bring them to your pharmacy to be thrown away safely.

What are the side effects of this medication?

The following side effects have been seen in people using leucovorin with other chemotherapy drugs, so some of these effects may be caused by chemotherapy.

Common side effects usually occur in more than 1 out of every 10 patients. Other side effects are less common, but may be severe. You may not have all of the side effects below. You may have side effects that are not listed.

Less Common Side Effects (10 to 24 out of 100 people)
Side effects and what to do	When to contact health care team
Allergic reaction The most common symptoms include fever, itchiness, rash, swollen lips, face or tongue, chest and throat tightness. It may occur during or shortly after the medication is given to you. Let your health care team know right away if this happens to you.	Get emergency medical help right away
Seizures	Get emergency medical help right away
Fainting	Get emergency medical help right away

For more links on how to manage your symptoms go to www.cancercareontario.ca/symptoms.

The information set out in the medication information sheets, regimen information sheets, and symptom management information (for patients) contained in the Drug Formulary (the "Formulary") is intended to be used by health professionals and patients for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or side effects of a certain drug, nor should it be used to indicate that use of a particular drug is safe, appropriate or effective for a given condition.

A patient should always consult a healthcare provider if he/she has any questions regarding the information set out in the Formulary. The information in the Formulary is not intended to act as or replace medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

Info Sheet (English):

PO patient.pdf Info Sheet (French):

PO pour le patient.pdf Monograph:

leucovorin.pdf Funding Program: ODB - General Benefit Funding Instance:

leucovorin - oral tablets

Phonetic Spelling:

loo-co-VOR-in

Cancer Type: Gastrointestinal Colorectal Esophagus Gastric / Stomach Hepatobiliary / Liver / Bile Duct Pancreas Small bowel and appendix Gynecologic Gestational Trophoblastic Disease Hematologic Lymphoma - Non-Hodgkin's High Grade Type of Content: Drug Monograph Status: Null Info Sheet Status: Null Global Date: Mardi, août 9, 2016 Universal Date: 2019-04-11 00:00:00 AddThis: Title URL: leucovorin Drug Display Status: Active Revision Summary:

edited indications