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Leucovorin 10mg/ml Inj, 10ml

Manufacturer FRESENIUS KABI USA Active Ingredient Leucovorin Injection(loo koe VOR in) Pronunciation LOO-koh-VOR-in
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.
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Drug Class
Antidote; Antineoplastic adjunct
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Pharmacologic Class
Folinic acid derivative
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Pregnancy Category
Category C
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FDA Approved
Mar 1953
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DEA Schedule
Not Controlled

Overview

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What is this medicine?

Leucovorin is a type of vitamin (folinic acid) that helps protect healthy cells from the harmful effects of certain cancer medications, like methotrexate. It can also be used to boost the effects of other cancer drugs, like 5-fluorouracil, or to treat certain types of anemia.
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How to Use This Medicine

To use this medication correctly, follow your doctor's instructions and carefully read all accompanying information. Take this medication exactly as directed, and be sure to follow all instructions provided. This drug is administered via injection into a muscle or vein.

For proper storage and disposal, consult with your doctor, nurse, or pharmacist to determine the best approach if you need to store this medication at home.

If you miss a dose, contact your doctor immediately to receive guidance on the next steps to take.
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Lifestyle & Tips

  • Follow all instructions from your healthcare provider regarding dosing and timing, especially if you are receiving it as a 'rescue' after chemotherapy.
  • Maintain good hydration as instructed by your doctor, especially during high-dose chemotherapy.
  • Report any side effects promptly, such as mouth sores, diarrhea, fever, or unusual bleeding/bruising.
  • Avoid taking other vitamin supplements containing folic acid unless specifically instructed by your doctor, as high doses of folic acid can interfere with leucovorin.
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Available Forms & Alternatives

Available Strengths:

Dosing & Administration

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Adult Dosing

Standard Dose: Highly variable depending on indication. Examples: Methotrexate rescue: 10-15 mg/m2 IV/IM/PO every 6 hours for 10 doses, starting 24 hours after methotrexate. 5-FU potentiation: 200 mg/m2 IV over 30 minutes, followed by 5-FU. Megaloblastic anemia: 1 mg/day IM/PO.
Dose Range: 1 - 500 mg

Condition-Specific Dosing:

Methotrexate Rescue: Dose and duration depend on methotrexate dose, serum methotrexate levels, and renal function. Typically 10-15 mg/m2 IV/IM/PO every 6 hours for 10 doses, starting 24 hours after methotrexate. May require higher doses or longer duration based on methotrexate levels.
5-Fluorouracil Potentiation: 200 mg/m2 IV over 30 minutes, followed by 5-FU, or 20 mg/m2 IV bolus followed by 5-FU. Specific regimens vary widely.
Megaloblastic Anemia (Folate Deficiency): 1 mg/day IM/PO. Max 1 mg/day.
Trimethoprim/Pyrimethamine Overdose: 5-15 mg/day PO/IM/IV until hematopoiesis recovers.
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Pediatric Dosing

Neonatal: Not established for routine use, but used off-label for specific indications (e.g., methotrexate toxicity) with careful monitoring.
Infant: Dosing for methotrexate rescue or other indications is typically weight- or body surface area-based, similar to adult regimens but adjusted for pediatric specificities. E.g., Methotrexate rescue: 10-15 mg/m2 IV/IM/PO every 6 hours.
Child: Dosing for methotrexate rescue or other indications is typically weight- or body surface area-based, similar to adult regimens but adjusted for pediatric specificities. E.g., Methotrexate rescue: 10-15 mg/m2 IV/IM/PO every 6 hours.
Adolescent: Dosing generally follows adult guidelines based on body surface area.
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Dose Adjustments

Renal Impairment:

Mild: No specific adjustment generally required, but close monitoring of methotrexate levels and leucovorin response is crucial in methotrexate rescue.
Moderate: Increased risk of methotrexate toxicity; higher and/or prolonged leucovorin rescue may be required. Monitor methotrexate levels and adjust leucovorin accordingly.
Severe: Increased risk of methotrexate toxicity; higher and/or prolonged leucovorin rescue is often required. Monitor methotrexate levels and adjust leucovorin accordingly. Consider continuous infusion.
Dialysis: Leucovorin is dialyzable. Methotrexate is dialyzable. In methotrexate rescue, continue leucovorin after dialysis. Specific dosing depends on methotrexate levels and clinical status.

Hepatic Impairment:

Mild: No specific adjustment generally required.
Moderate: No specific adjustment generally required.
Severe: No specific adjustment generally required, but caution is advised in patients with severe hepatic dysfunction, especially when used with other hepatotoxic agents.

Pharmacology

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Mechanism of Action

Leucovorin is a reduced form of folic acid (folinic acid) that does not require reduction by the enzyme dihydrofolate reductase. It is rapidly converted to 5-methyltetrahydrofolate, an active metabolite. It acts as a biochemical rescue agent by providing the necessary cofactors for purine and pyrimidine synthesis, thereby bypassing the enzymatic block caused by folic acid antagonists (e.g., methotrexate, trimethoprim, pyrimethamine). In combination with 5-fluorouracil (5-FU), leucovorin enhances the cytotoxic effects of 5-FU by stabilizing the binding of 5-FU's active metabolite (FdUMP) to thymidylate synthase, thereby inhibiting DNA synthesis and repair.
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Pharmacokinetics

Absorption:

Bioavailability: Oral bioavailability is variable, generally 90% for doses up to 25 mg, decreasing with higher doses due to saturable absorption. IV bioavailability is 100%.
Tmax: Oral: 1.7 hours (for leucovorin), 2.8 hours (for 5-methyltetrahydrofolate). IV: Rapid (within minutes for leucovorin), 0.6 hours (for 5-methyltetrahydrofolate).
FoodEffect: Not significantly affected by food.

Distribution:

Vd: Not readily available, but distributes widely into body tissues, including CSF (though CSF penetration is limited with standard doses).
ProteinBinding: Not significantly protein bound.
CnssPenetration: Limited at standard doses; higher doses or intrathecal administration are required for significant CNS penetration.

Elimination:

HalfLife: Leucovorin: 0.5 hours. 5-methyltetrahydrofolate: 6-7 hours.
Clearance: Not readily available, but primarily renal.
ExcretionRoute: Primarily renal (80-90%), with some fecal excretion (5-8%).
Unchanged: Less than 1% of leucovorin is excreted unchanged in urine.
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Pharmacodynamics

OnsetOfAction: Rapid (within minutes for IV administration).
PeakEffect: Not directly applicable as it's a rescue agent or potentiator; effect is seen as reversal of toxicity or enhanced cytotoxicity.
DurationOfAction: Dependent on the duration of exposure to the antagonist or the duration of 5-FU therapy; 5-methyltetrahydrofolate has a longer half-life, providing sustained effect.

Safety & Warnings

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Side Effects

Urgent Side Effects: Seek Medical Help Right Away

While rare, some people may experience severe and potentially life-threatening side effects when taking this medication. If you notice any of the following symptoms, contact your doctor or seek immediate medical attention:

Signs of an allergic reaction, such as:
+ Rash
+ Hives
+ Itching
+ Red, swollen, blistered, or peeling skin (with or without fever)
+ Wheezing
+ Tightness in the chest or throat
+ Trouble 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. Although many people may not experience any side effects or only minor ones, it's essential to discuss any concerns with your doctor. If you experience side effects that bother you or persist, contact your doctor for guidance.

Reporting Side Effects

This list is not exhaustive, and you may have questions about other potential side effects. If you do, don't hesitate to reach out to your doctor for advice. You can also report side effects to the FDA at 1-800-332-1088 or online at https://www.fda.gov/medwatch.
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Seek Immediate Medical Attention If You Experience:

  • Severe mouth sores or ulcers (mucositis)
  • Severe diarrhea
  • Fever, chills, or other signs of infection (due to low white blood cells)
  • Unusual bleeding or bruising (due to low platelets)
  • Severe nausea or vomiting
  • Signs of allergic reaction (rash, itching, swelling, dizziness, trouble breathing)
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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. To ensure your safety, tell your doctor and pharmacist about:
 All prescription and over-the-counter (OTC) medications you are taking.
Any natural products or vitamins you are using.
 All your health problems, as they may interact with this medication.

Remember, before starting, stopping, or changing the dose of any medication, including this one, you must consult with your doctor to confirm it is safe for you to do so.
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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 used in combination with fluorouracil, this drug may increase the severity and frequency of side effects associated with fluorouracil, such as diarrhea, mouth irritation, and mouth sores. In older adults, the combination of this drug with fluorouracil has been linked to severe bowel problems, diarrhea, and dehydration, which can be life-threatening. If you have any concerns or questions, 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.

Prior to initiating treatment, inform your doctor if you are pregnant, planning to become pregnant, or breastfeeding. Your doctor will discuss the potential benefits and risks of this medication to you and your baby.

Some formulations of this drug contain benzyl alcohol, which can be hazardous to newborns and infants. To minimize risks, it is recommended to avoid products containing benzyl alcohol in these age groups, especially when used in conjunction with other medications that contain benzyl alcohol. Consult your doctor to determine which formulations contain benzyl alcohol and to discuss alternative options.
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Overdose Information

Overdose Symptoms:

  • While leucovorin itself is generally well-tolerated, very high doses could theoretically lead to folate excess, though this is rare and not typically associated with acute toxicity.
  • The main concern with 'overdose' is if it's given inappropriately with methotrexate, which would reduce methotrexate's effectiveness.

What to Do:

If you suspect an overdose or inappropriate administration, contact your healthcare provider or emergency services immediately. For general poison control, call 1-800-222-1222.

Drug Interactions

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Major Interactions

  • Methotrexate (if given concurrently for non-rescue purposes, as leucovorin antagonizes methotrexate's antineoplastic effect)
  • 5-Fluorouracil (potentiates 5-FU toxicity, requiring careful dose adjustment and monitoring)
  • Trimethoprim (leucovorin can antagonize the antimicrobial effect of trimethoprim)
  • Pyrimethamine (leucovorin can antagonize the antimicrobial effect of pyrimethamine)
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Moderate Interactions

  • Phenytoin (leucovorin may decrease phenytoin levels)
  • Phenobarbital (leucovorin may decrease phenobarbital levels)
  • Primidone (leucovorin may decrease primidone levels)
  • Folic acid (high doses of folic acid may compete with leucovorin for transport)

Monitoring

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Baseline Monitoring

Complete Blood Count (CBC) with differential and platelets

Rationale: To assess baseline hematologic status, crucial for monitoring myelosuppression, especially when used with myelosuppressive agents like methotrexate or 5-FU.

Timing: Prior to initiation of therapy.

Renal function (Serum Creatinine, BUN)

Rationale: To assess baseline renal function, as impaired renal function can affect methotrexate elimination and necessitate leucovorin dose adjustments.

Timing: Prior to initiation of therapy.

Liver function tests (ALT, AST, Bilirubin)

Rationale: To assess baseline hepatic function, especially when used with hepatotoxic agents.

Timing: Prior to initiation of therapy.

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Routine Monitoring

Serum Methotrexate levels

Frequency: As per protocol (e.g., 24, 48, 72 hours after methotrexate administration) for methotrexate rescue.

Target: Specific levels vary by protocol and time point (e.g., <0.1 micromolar at 48 hours, <0.05 micromolar at 72 hours).

Action Threshold: Elevated or persistently high methotrexate levels necessitate increased leucovorin dose and/or extended duration.

Complete Blood Count (CBC) with differential and platelets

Frequency: Daily or every 2-3 days during methotrexate rescue or 5-FU therapy.

Target: Maintain adequate neutrophil and platelet counts.

Action Threshold: Significant drops in counts (e.g., ANC < 500/mm3, platelets < 50,000/mm3) may indicate myelosuppression requiring intervention.

Renal function (Serum Creatinine, BUN)

Frequency: Daily during methotrexate rescue.

Target: Maintain within normal limits or baseline.

Action Threshold: Significant increase indicates impaired methotrexate clearance, requiring leucovorin adjustment.

Electrolytes (Potassium, Magnesium, Phosphate)

Frequency: Daily during high-dose methotrexate therapy.

Target: Maintain within normal limits.

Action Threshold: Imbalances may indicate renal toxicity or other complications.

Hydration status and urine output

Frequency: Continuously during high-dose methotrexate therapy.

Target: Maintain adequate hydration and urine output (>100 mL/hr).

Action Threshold: Decreased urine output or dehydration can impair methotrexate excretion.

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Symptom Monitoring

  • Signs of myelosuppression (fever, chills, sore throat, unusual bleeding/bruising, fatigue)
  • Signs of gastrointestinal toxicity (stomatitis, mucositis, diarrhea, nausea, vomiting)
  • Signs of renal dysfunction (decreased urine output, swelling)
  • Signs of allergic reaction (rash, itching, hives, swelling, difficulty breathing)

Special Patient Groups

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Pregnancy

Leucovorin is Pregnancy Category C. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Its use is often critical in situations like methotrexate rescue where the mother's life is at risk, or in combination with 5-FU for cancer treatment.

Trimester-Specific Risks:

First Trimester: Potential for fetal harm, especially if used with other teratogenic agents. Risk vs. benefit must be carefully weighed.
Second Trimester: Risk vs. benefit must be carefully weighed.
Third Trimester: Risk vs. benefit must be carefully weighed.
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Lactation

Leucovorin and its metabolites are excreted in human 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. L3 (Moderately Safe) by Hale's classification, but caution is advised, especially if used with cytotoxic agents.

Infant Risk: Low risk for leucovorin itself, but potential for interference with infant's folate metabolism. Higher risk if mother is also receiving cytotoxic agents.
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Pediatric Use

Leucovorin is widely used in pediatric oncology, particularly for methotrexate rescue. Dosing is typically based on body surface area. Close monitoring of methotrexate levels and hematologic parameters is essential. Safety and efficacy are generally similar to adults when appropriately dosed.

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Geriatric Use

No specific dose adjustments are generally required based solely on age. However, elderly patients may have age-related decreases in renal function, which could impact methotrexate clearance and thus necessitate careful monitoring and adjustment of leucovorin rescue doses. Increased susceptibility to myelosuppression and gastrointestinal toxicities when used with chemotherapy agents should be considered.

Clinical Information

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Clinical Pearls

  • Leucovorin is NOT folic acid. They are different compounds and cannot be interchanged.
  • The timing and dose of leucovorin are critical for effective methotrexate rescue. Deviations can lead to severe toxicity or treatment failure.
  • When used with 5-fluorouracil, leucovorin significantly enhances 5-FU's toxicity, particularly gastrointestinal and hematologic. Close monitoring is essential.
  • Ensure adequate hydration and urine alkalinization during high-dose methotrexate therapy to facilitate methotrexate excretion and reduce renal toxicity.
  • Leucovorin can be given orally, intramuscularly, or intravenously. Oral administration is generally reserved for lower doses or maintenance, while IV is preferred for rescue or high-dose regimens.
  • Always check serum methotrexate levels to guide leucovorin dosing and duration during rescue protocols.
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Alternative Therapies

  • Glucarpidase (Voraxaze) is an alternative for rapid reduction of toxic plasma methotrexate concentrations in patients with delayed methotrexate elimination due to impaired renal function.
  • Folic acid (for folate deficiency, but not as a rescue agent for methotrexate toxicity).
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Cost & Coverage

Average Cost: Varies widely, typically $50 - $500+ per 10mg/ml, 10ml vial
Generic Available: Yes
Insurance Coverage: Tier 1 or Tier 2 (Generic), Tier 3 (Brand) for most insurance plans, often covered under medical benefit for oncology use.
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General Drug Facts

If your symptoms or health issues 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. Unless instructed otherwise, avoid flushing medications down the toilet or pouring them down the drain. If you are unsure about the proper disposal method, consult your pharmacist for guidance. Many communities offer drug take-back programs, which your pharmacist can help you locate. Some medications may come with an additional patient information leaflet; check with your pharmacist for more information. 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 details about the medication taken, the amount, and the time it occurred.