Leucovorin Calcium 500mg Inj, 1vial
It is used with methotrexate to avoid side effects.It may lower the side effects of some drugs.It is used with fluorouracil to help fight colorectal cancer.It is used to help with some kinds of anemia.It may be given to you for other reasons. Talk with the doctor.
Drug Class
Antidote; Antineoplastic adjunct
Pharmacologic Class
Folic acid analog; Reduced folate
Pregnancy Category
C
FDA Approved
Mar 1953
DEA Schedule
Not Controlled
Overview
What is this medicine?
Leucovorin is a form of folic acid that helps protect healthy cells from the harmful effects of certain cancer medications, like methotrexate. It can also boost the effectiveness of other cancer drugs, like fluorouracil, or treat certain types of anemia.
How to Use This Medicine
To use this medication correctly, follow your doctor's instructions and carefully read all the information provided. Adhere to the dosage and administration guidelines closely. This medication is administered via injection into a muscle or vein.
For storage and disposal, consult with your doctor, nurse, or pharmacist to determine the best approach if you need to keep this medication at home.
If you miss a dose, contact your doctor promptly to receive guidance on the next steps to take.
For storage and disposal, consult with your doctor, nurse, or pharmacist to determine the best approach if you need to keep this medication at home.
If you miss a dose, contact your doctor promptly to receive guidance on the next steps to take.
Lifestyle & Tips
- Report any signs of infection (fever, chills, sore throat) or unusual bleeding/bruising immediately.
- Maintain good oral hygiene to help prevent mouth sores (mucositis).
- Stay well-hydrated as advised by your doctor, especially during methotrexate therapy.
- Avoid taking any other medications, including over-the-counter drugs, vitamins, or herbal supplements, without consulting your doctor or pharmacist.
Available Forms & Alternatives
Available Strengths:
- Leucovorin Calcium 5mg Tablets
- Leucovorin Calcium 10mg Tablets
- Leucovorin Calcium 15mg Tablets
- Leucovorin Calcium 25mg Tablets
- Leucovorin Calcium 50mg Inj, 1 Vial
- Leucovorin Calcium 100mg Inj, 1vial
- Leucovorin Calcium 350mg Inj, 1vl
- Leucovorin Calcium 500mg Inj, 1vial
- Leucovorin 10mg/ml Inj, 10ml
- Leucovorin 500mg/50ml Inj, 50ml
- Leucovorin Ca 200mg Inj, 1 Vial
Dosing & Administration
Adult Dosing
Standard Dose:
Highly variable based on indication. For Methotrexate rescue: typically 10-15 mg/m² IV/IM/PO every 6 hours for 10 doses, starting 24 hours after methotrexate initiation. For Fluorouracil modulation: typically 200 mg/m² IV over 2 minutes, followed by fluorouracil.
Dose Range:
5 - 500 mg
Condition-Specific Dosing:
Methotrexate Rescue:
Initial dose 10-15 mg/m² IV/IM/PO every 6 hours for 10 doses, adjusted based on methotrexate levels and renal function. Doses up to 1000 mg/m² may be used for high-dose methotrexate toxicity.
Fluorouracil Modulation (Colorectal Cancer):
200 mg/m² IV over 2 minutes, followed by fluorouracil, or 20 mg/m² IV daily for 5 days with fluorouracil.
Megaloblastic Anemia (Folate Deficiency):
1 mg IM/IV daily.
Pediatric Dosing
Neonatal:
Not established for routine use; specific protocols for methotrexate rescue may exist.
Infant:
Dosing for methotrexate rescue is similar to adults on a mg/m² basis, adjusted based on methotrexate levels.
Child:
Dosing for methotrexate rescue is similar to adults on a mg/m² basis, adjusted based on methotrexate levels. For megaloblastic anemia, 1 mg IM/IV daily.
Adolescent:
Dosing for methotrexate rescue and fluorouracil modulation is similar to adults on a mg/m² basis.
Dose Adjustments
Renal Impairment:
Mild:
No specific adjustment required, but monitor methotrexate levels closely if used for rescue.
Moderate:
No specific adjustment required, but monitor methotrexate levels closely if used for rescue. Increased risk of toxicity with methotrexate.
Severe:
No specific adjustment required, but monitor methotrexate levels closely if used for rescue. Increased risk of toxicity with methotrexate; consider higher or prolonged leucovorin rescue.
Dialysis:
Leucovorin is dialyzable. Methotrexate is dialyzable. Dosing should be guided by methotrexate levels and clinical response.
Hepatic Impairment:
Mild:
No specific adjustment.
Moderate:
No specific adjustment.
Severe:
No specific adjustment.
Pharmacology
Mechanism of Action
Leucovorin is a reduced form of folic acid (folinic acid) that does not require reduction by dihydrofolate reductase. It is rapidly converted to 5-methyltetrahydrofolate, an active metabolite. In methotrexate rescue, leucovorin provides a source of reduced folates, bypassing the dihydrofolate reductase enzyme inhibited by methotrexate, thereby allowing purine and pyrimidine synthesis to proceed and protecting normal cells from methotrexate's cytotoxic effects. In combination with fluorouracil, leucovorin enhances the cytotoxic effect of fluorouracil by stabilizing the binding of fluorodeoxyuridine monophosphate (FdUMP), a metabolite of fluorouracil, to thymidylate synthase, thereby inhibiting DNA synthesis and repair.
Pharmacokinetics
Absorption:
Bioavailability:
Oral bioavailability is variable and dose-dependent (e.g., ~97% for 25 mg, ~75% for 100 mg). IV administration is 100%.
Tmax:
Oral: 1.7 hours (for 5-formyltetrahydrofolate); IV: 0.6 hours (for 5-methyltetrahydrofolate).
FoodEffect:
Food may delay absorption but does not significantly alter the extent of absorption.
Distribution:
Vd:
Not readily available for leucovorin itself, but its active metabolite 5-methyltetrahydrofolate distributes widely.
ProteinBinding:
Not extensively protein bound.
CnssPenetration:
Limited penetration into the CNS at standard doses; higher doses may achieve therapeutic levels in CSF.
Elimination:
HalfLife:
Approximately 6.2 hours (for total reduced folates after IV administration).
Clearance:
Not readily available as a single value due to complex metabolism and interconversion.
ExcretionRoute:
Primarily renal (80-90%) and fecal (5-8%).
Unchanged:
Less than 1% of the administered dose is excreted unchanged in urine.
Pharmacodynamics
OnsetOfAction:
Rapid, within minutes of IV administration.
PeakEffect:
Within 1-2 hours for active metabolites.
DurationOfAction:
Dependent on dose and indication, typically several hours to days for methotrexate rescue.
Safety & Warnings
Side Effects
Urgent Side Effects: Seek Medical Help Right Away
Although rare, some people may experience severe and potentially life-threatening side effects while taking this medication. If you notice any of the following symptoms, contact your doctor or seek immediate medical attention:
Signs of an allergic reaction, which may include:
+ Rash
+ Hives
+ Itching
+ Red, swollen, blistered, or peeling skin (with or without fever)
+ Wheezing
+ Tightness in the chest or throat
+ Difficulty breathing, swallowing, or talking
+ Unusual hoarseness
+ Swelling of the mouth, face, lips, tongue, or throat
Seizures
* Severe dizziness or fainting
Other Possible Side Effects
Like all medications, this drug can cause side effects. However, many people do not experience any side effects or only have mild ones. If you have any side effects that bother you or do not go away, contact your doctor for advice.
Reporting Side Effects
This list does not include all possible side effects. If you have questions or concerns about side effects, talk to your doctor. You can also report side effects to the FDA at 1-800-332-1088 or online at https://www.fda.gov/medwatch.
Although rare, some people may experience severe and potentially life-threatening side effects while taking this medication. If you notice any of the following symptoms, contact your doctor or seek immediate medical attention:
Signs of an allergic reaction, which may include:
+ Rash
+ Hives
+ Itching
+ Red, swollen, blistered, or peeling skin (with or without fever)
+ Wheezing
+ Tightness in the chest or throat
+ Difficulty breathing, swallowing, or talking
+ Unusual hoarseness
+ Swelling of the mouth, face, lips, tongue, or throat
Seizures
* Severe dizziness or fainting
Other Possible Side Effects
Like all medications, this drug can cause side effects. However, many people do not experience any side effects or only have mild ones. If you have any side effects that bother you or do not go away, contact your doctor for advice.
Reporting Side Effects
This list does not include all possible side effects. If you have questions or concerns about side effects, talk to your doctor. You can also report side effects to the FDA at 1-800-332-1088 or online at https://www.fda.gov/medwatch.
Seek Immediate Medical Attention If You Experience:
- Severe diarrhea
- Mouth sores or painful swallowing
- Unusual bleeding or bruising
- Signs of infection (fever, chills, persistent sore throat)
- Severe nausea or vomiting
- Skin rash or itching
- Swelling of the face, lips, tongue, or throat (signs of allergic reaction)
Before Using This Medicine
Before Taking This Medication: Important Information to Share with Your Doctor
It is essential to inform your doctor about the following:
Any allergies you have, including allergies to this medication, its components, or other substances, such as foods or drugs. Be sure to describe the allergic reaction you experienced, including any symptoms that occurred.
If you have anemia caused by a vitamin B12 deficiency.
If you have any stomach or bowel problems.
This list is not exhaustive, and it is crucial to discuss all your health concerns with your doctor. Additionally, provide your doctor and pharmacist with a comprehensive list of all the medications you are taking, including:
Prescription medications
Over-the-counter (OTC) medications
Natural products
* Vitamins
It is vital to verify that it is safe to take this medication with all your existing medications and health conditions. Never start, stop, or change the dosage of any medication without first consulting your doctor.
It is essential to inform your doctor about the following:
Any allergies you have, including allergies to this medication, its components, or other substances, such as foods or drugs. Be sure to describe the allergic reaction you experienced, including any symptoms that occurred.
If you have anemia caused by a vitamin B12 deficiency.
If you have any stomach or bowel problems.
This list is not exhaustive, and it is crucial to discuss all your health concerns with your doctor. Additionally, provide your doctor and pharmacist with a comprehensive list of all the medications you are taking, including:
Prescription medications
Over-the-counter (OTC) medications
Natural products
* Vitamins
It is vital to verify that it is safe to take this medication with all your existing medications and health conditions. Never start, stop, or change the dosage of any medication without first consulting your doctor.
Precautions & Cautions
It is essential to inform all your healthcare providers, including doctors, nurses, pharmacists, and dentists, that you are taking this medication. Regular blood work and laboratory tests should be conducted as directed by your doctor.
When this medication is used in combination with fluorouracil, the risk of side effects associated with fluorouracil may increase. This may lead to more frequent, severe, or prolonged occurrences of diarrhea, mouth irritation, and mouth sores. In older adults, the combination of this medication with fluorouracil has been linked to severe bowel problems, diarrhea, and dehydration, which can be fatal. If you have any questions or concerns, consult your doctor.
If you are 65 years or older, exercise caution when using this medication, as you may be more susceptible to side effects.
Before taking this medication, inform your doctor if you are pregnant, planning to become pregnant, or breastfeeding. It is crucial to discuss the potential benefits and risks of this medication to both you and your baby.
Some formulations of this medication contain benzyl alcohol, which can be hazardous to newborns and infants. Serious side effects can occur in these young patients when benzyl alcohol is administered, particularly when combined with other medications containing benzyl alcohol. Consult your doctor to determine which formulations contain benzyl alcohol and to discuss alternative options.
When this medication is used in combination with fluorouracil, the risk of side effects associated with fluorouracil may increase. This may lead to more frequent, severe, or prolonged occurrences of diarrhea, mouth irritation, and mouth sores. In older adults, the combination of this medication with fluorouracil has been linked to severe bowel problems, diarrhea, and dehydration, which can be fatal. If you have any questions or concerns, consult your doctor.
If you are 65 years or older, exercise caution when using this medication, as you may be more susceptible to side effects.
Before taking this medication, inform your doctor if you are pregnant, planning to become pregnant, or breastfeeding. It is crucial to discuss the potential benefits and risks of this medication to both you and your baby.
Some formulations of this medication contain benzyl alcohol, which can be hazardous to newborns and infants. Serious side effects can occur in these young patients when benzyl alcohol is administered, particularly when combined with other medications containing benzyl alcohol. Consult your doctor to determine which formulations contain benzyl alcohol and to discuss alternative options.
Overdose Information
Overdose Symptoms:
- Generally considered non-toxic in overdose, as it is a vitamin derivative.
- However, very high doses could theoretically mask symptoms of vitamin B12 deficiency, leading to neurological damage if not properly diagnosed.
What to Do:
Leucovorin is generally well-tolerated even at high doses. Management is typically supportive. In cases of suspected overdose, contact a poison control center (e.g., 1-800-222-1222) or seek emergency medical attention.
Drug Interactions
Major Interactions
- Fluorouracil (synergistic toxicity, particularly gastrointestinal and hematologic, when not used intentionally for modulation)
- Trimethoprim/Sulfamethoxazole (antagonistic effect, may reduce antimicrobial efficacy)
- Pyrimethamine (antagonistic effect, may reduce antimalarial/antiparasitic efficacy)
Moderate Interactions
- Phenytoin (may decrease phenytoin levels, leading to loss of seizure control)
- Phenobarbital (may decrease phenobarbital levels)
- Primidone (may decrease primidone levels)
- Capecitabine (synergistic toxicity, similar to fluorouracil)
Monitoring
Baseline Monitoring
Complete Blood Count (CBC) with differential
Rationale: To establish baseline hematologic status, especially when used with myelosuppressive agents like methotrexate or fluorouracil.
Timing: Prior to initiation of chemotherapy and leucovorin.
Renal Function (Serum Creatinine, BUN)
Rationale: Renal impairment can delay methotrexate excretion, necessitating prolonged leucovorin rescue.
Timing: Prior to initiation of methotrexate and leucovorin.
Liver Function Tests (ALT, AST, Bilirubin)
Rationale: To assess baseline hepatic function, as some chemotherapies are hepatotoxic.
Timing: Prior to initiation of chemotherapy and leucovorin.
Routine Monitoring
Methotrexate Plasma Levels
Frequency: At specific time points (e.g., 24, 48, 72 hours) after methotrexate administration, as per protocol.
Target: Protocol-specific, typically aiming for rapid decline below toxic thresholds (e.g., <0.1 µM at 48 hours, <0.05 µM at 72 hours).
Action Threshold: Elevated or persistently high methotrexate levels necessitate increased leucovorin dose and/or prolonged administration.
Complete Blood Count (CBC) with differential
Frequency: Daily or every 2-3 days during chemotherapy cycles, or as clinically indicated.
Target: Maintain adequate neutrophil and platelet counts.
Action Threshold: Significant myelosuppression (e.g., ANC <500/mm³, platelets <50,000/mm³) may require dose modification of chemotherapy or supportive care.
Renal Function (Serum Creatinine, BUN)
Frequency: Daily during high-dose methotrexate therapy.
Target: Within normal limits or stable baseline.
Action Threshold: Significant increase in creatinine may indicate delayed methotrexate clearance, requiring increased leucovorin and hydration.
Electrolytes (Potassium, Magnesium, Calcium)
Frequency: As clinically indicated, especially with aggressive hydration protocols.
Target: Within normal limits.
Action Threshold: Imbalances should be corrected.
Symptom Monitoring
- Signs of myelosuppression (fever, chills, unusual bleeding/bruising, fatigue)
- Gastrointestinal toxicity (severe diarrhea, mucositis, stomatitis, nausea, vomiting)
- Signs of allergic reaction (rash, itching, swelling, dizziness, trouble breathing)
- Signs of neurotoxicity (rare, but possible with very high doses or prolonged use)
Special Patient Groups
Pregnancy
Category C. Leucovorin is generally considered safe for use during pregnancy when indicated, particularly for methotrexate rescue, as the benefits of preventing severe methotrexate toxicity outweigh potential risks. However, it should only be used if clearly needed.
Trimester-Specific Risks:
First Trimester:
Risk of masking vitamin B12 deficiency, which can lead to neurological damage in the mother. Use with caution.
Second Trimester:
Generally considered safe when indicated.
Third Trimester:
Generally considered safe when indicated.
Lactation
Leucovorin and its metabolites are excreted into breast milk. Due to the potential for serious adverse reactions in the breastfed infant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Infant Risk:
Low risk for direct toxicity from leucovorin itself, but potential for masking vitamin B12 deficiency in the infant. The primary concern is the co-administered chemotherapy agent (e.g., methotrexate, fluorouracil) which is often contraindicated during breastfeeding.
Pediatric Use
Dosing is typically based on body surface area (mg/m²) and adjusted based on specific protocols, especially for methotrexate rescue. Close monitoring of methotrexate levels and renal function is crucial. Generally well-tolerated in pediatric patients.
Geriatric Use
No specific dose adjustments are generally required based on age alone. However, elderly patients may have reduced renal function, which can affect the clearance of co-administered drugs like methotrexate, necessitating careful monitoring and potential adjustments to leucovorin rescue protocols. Increased susceptibility to myelosuppression and gastrointestinal toxicity when used with fluorouracil.
Clinical Information
Clinical Pearls
- Leucovorin is NOT a rescue for all antifolates; it is specifically for methotrexate and other dihydrofolate reductase inhibitors. It is ineffective for non-folate antagonists.
- Always ensure adequate hydration and urinary alkalinization during high-dose methotrexate therapy to prevent renal toxicity and facilitate methotrexate excretion.
- Leucovorin rescue must be initiated within 24-42 hours of methotrexate administration for optimal efficacy; delayed administration significantly increases toxicity risk.
- When used with fluorouracil, leucovorin enhances fluorouracil's cytotoxicity, which can lead to increased gastrointestinal and hematologic toxicities. Careful monitoring is essential.
- Oral leucovorin is generally not recommended for high-dose methotrexate rescue due to variable absorption; IV administration is preferred for critical situations.
Alternative Therapies
- Glucarpidase (Voraxaze): Used for rapid reduction of toxic plasma methotrexate concentrations in patients with delayed methotrexate elimination due to impaired renal function.
- Folic Acid: While related, folic acid requires reduction by dihydrofolate reductase and cannot be used for methotrexate rescue. It is used for general folate deficiency.
Cost & Coverage
Average Cost:
Varies widely by dose and manufacturer (e.g., $50 - $500+ per 500mg vial) per 500mg vial
Generic Available:
Yes
Insurance Coverage:
Tier 2 or 3 (Specialty/Non-Preferred Brand, or Preferred Generic)
General Drug Facts
If your symptoms or health problems persist or worsen, it is essential to contact your doctor promptly. To ensure safe use, never share your medication with others, and do not take medication prescribed for someone else. Store all medications in a secure location, out of reach of children and pets, to prevent accidental ingestion. Dispose of unused or expired medications properly; do not flush them down the toilet or pour them down the drain unless instructed to do so by a healthcare professional. If you are unsure about the correct disposal method, consult your pharmacist, who can also inform you about potential drug take-back programs in your area. Some medications may come with an additional patient information leaflet, which your pharmacist can provide. If you have any questions or concerns about your medication, discuss them with your doctor, nurse, pharmacist, or other healthcare provider. In the event of a suspected overdose, immediately contact your local poison control center or seek emergency medical attention. Be prepared to provide information about the medication taken, the amount, and the time it was taken to ensure prompt and effective treatment.