Levoleucovorin

Levoleucovorin is a prescription medication used for the treatment of metastatic colorectal cancer and bone cancer (after methotrexate therapy). Levoleucovorin is also used for diminishing toxicity and counteracting the effects of impaired methotrexate elimination and inadvertent overdosage of folic acid antagonists.

• Levoleucovorin is available under the following different brand names: Fusilev, Khapzory

Common side effects of levoleucovorin include:

• nausea
• vomiting
• diarrhea
• stomach pain
• upset stomach
• numbness or tingling
• loss of appetite
• unusual or unpleasant taste in the mouth
• weakness
• tired feeling
• hair loss
• mild skin rash

Serious side effects of levoleucovorin include:

• belching
• blistering, crusting, irritation, itching, or reddening of the skin
• chest tightness
• cracked, dry, scaly skin
• fever
• heartburn
• indigestion
• sores, ulcers, or white spots on the lips, tongue, or inside the mouth
• stomach discomfort, upset, or pain
• stomach distention
• swelling of the mouth
• troubled breathing
• watery or bloody diarrhea.

Rare side effects of levoleucovorin include:

• seizures 
• fainting

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, coordination loss, unsteady, very stiff muscles, high fever, profuse sweating, or tremors;
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult and pediatric dosage

Injectable solution

• 175 mg/17.5 mL (generic)
• 250 mg/25 mL (generic)
• Injection, of lyophilized powder for reconstitution
• 50 mg/vial (Fusilev, generic); vial contains 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin)
• 175 mg/vial (Khapzory, generic)
• 300 mg/vial (Khapzory)

High-dose methotrexate rescue

Adult dosage

• Recommended initial dose of 7.5 mg every 6 hours is based on a methotrexate IV dose of 12 g/m²
• Monitor serum creatinine and methotrexate levels at least once daily; continue levoleucovorin, hydration, and urinary alkalinization (pH more than 7) until methotrexate level less than 5 * 10-8 M (0.05 micromolar)
• Normal methotrexate elimination
  • Serum methotrexate level of approximately 10 micromolar at 24 hours, 1 micromolar at 48 hours, and less than 0.2 micromolar at 96 hours post methotrexate infusion
  • Initiate at 7.5 mg (approximately 5 mg/m²) every 6 hours 24 hours after beginning methotrexate infusion for 60 hours (10 doses)
• Delayed late methotrexate elimination
  • Serum methotrexate levels of more than 0.2 micromolar at 72 hours and more than 0.05 micromolar at 96 hours post-methotrexate infusion
  • Continue 7.5 mg IV every 6 hours until the methotrexate level is less than 0.05 micromolar
  • Delayed early methotrexate elimination and/or evidence of acute renal injury
  • Serum methotrexate level of more than 50 micromolar at 24 hours, more than 5 micromolar at 48 hours, or serum creatinine level increased above 100% at 24 hours post methotrexate infusion
  • 75 mg IV every 3 hours until methotrexate level is less than 1 micromolar, followed by 7.5 mg IV every 3 hours until methotrexate level is less than 0.05 micromolar
  • Extend levoleucovorin treatment for an additional 24 hours (total of 14 doses) in subsequent cycles if there is significant clinical toxicity in the presence of impaired methotrexate elimination or renal impairment
  • Delayed methotrexate elimination due to third space fluid accumulation, renal insufficiency, or inadequate hydration
  • May require higher Levoleucovorin doses or prolonged administration

Pediatric dosage

• Children aged younger than 6 years: Safety and efficacy not established
• Children aged 6 years and above
  • Recommended initial dose of 7.5 mg every 6 hours based on a methotrexate IV dose of 12 g/m²
  • Monitor serum creatinine and methotrexate levels at least once daily; continue Levoleucovorin, hydration, and urinary alkalinization (pH more than 7) until methotrexate level under 5 x 10-8 M (0.05 micromolar)
• Normal methotrexate elimination
  • Serum methotrexate level of approximately 10 micromolar at 24 hours, 1 micromolar at 48 hours, and less than 0.2 micromolar at 96 hours post methotrexate infusion
  • Initiate at 7.5 mg (approximately 5 mg/m²) every 6 hours 24 hours after beginning methotrexate infusion for 60 hours (10 doses)
• Delayed late methotrexate elimination
  • Serum methotrexate levels above 0.2 micromolar at 72 hours and above 0.05 micromolar at 96 hours post-methotrexate infusion
  • Continue 7.5 mg IV every 6 hours until the methotrexate level is below 0.05 micromolar
• Delayed early methotrexate elimination and/or evidence of acute renal injury
  • Serum methotrexate levels of more than 50 micromolar at 24 hours, more than 5 micromolar at 48 hours, or serum creatinine levels increased above 100% at 24 hours post methotrexate infusion
  • 75 mg IV every 3 hours until the methotrexate level is below 1 micromolar, followed by 7.5 mg IV every 3 hours until the methotrexate level is below 0.05 micromolar
  • Extend Levoleucovorin treatment for additional 24 hours (total of 14 doses) in subsequent cycles if there is significant clinical toxicity in the presence of impaired methotrexate elimination or renal impairment
  • Delayed methotrexate elimination due to third space fluid accumulation, renal insufficiency, or inadequate hydration
  • May require higher Levoleucovorin doses or prolonged administration
  • Folic acid antagonists’ overdose or impaired elimination

Adult dosage

• 7.5 mg (approximately 5 mg/m²) every 6 hours until the methotrexate level is below 0.05 micromolar
• Start immediately after methotrexate overdosage or 24 hours of delayed elimination
• Increase the dose to 50 mg/m² every 3 hours until the methotrexate level is below 0.05 micromolar for the following:
• If serum creatinine at 24 hours increases by 50% and more compared to the baseline
• If methotrexate level at 24 hours is above 5 * 10^6 M
• If methotrexate level at 48 hours is above 9 * 10^7 M
• Continue hydration (3 L/day) and urinary alkalinization with sodium bicarbonate. Adjust bicarbonate dose to maintain urine pH at more than 7

Metastatic colorectal cancer

Adult dosage

• Regimens are used for the treatment of colorectal cancer
• Levoleucovorin 100 mg/m² IV over a minimum of 3 min, followed by 5-FU 370 mg/m² once a day for 5 consecutive days OR
• Levoleucovorin 10 mg/m² IV followed by 5-FU 425 mg/m2 once a day for 5 consecutive days
• Repeat every 4 weeks for 2 courses, then every 4-5 weeks, if the patient recovered from toxicity from the prior course
• Do not adjust Levoleucovorin dosage for toxicity
• Refer to fluorouracil prescribing information for information on dosage and dosage modifications for adverse reactions

Dosage Considerations – Should be Given as Follows:

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, healthcare provider, or pharmacist first.

• Levoleucovorin has severe interactions with no other drugs
• Levoleucovorin has serious interactions with the following drug:
  • trimethoprim
• Levoleucovorin has moderate interactions with no other drugs
• Levoleucovorin has minor interactions with no other drugs

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, health questions, or concerns.

Contraindications

• Hypersensitivity reactions to leucovorin products, folic acid, or folinic acid

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Levoleucovorin?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Levoleucovorin?”

Cautions

• Increased gastrointestinal toxicities with 5-FU; monitor patients for gastrointestinal toxicities; do not initiate or continue therapy with fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved
• Do not initiate or continue therapy with levoleucovorin and 5-FU in patients with symptoms of gastrointestinal toxicity until symptoms resolve; monitor patients with diarrhea until it resolves
• Increased rates of treatment failure and morbidity with concomitant use of d, l-leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis jiroveci pneumonia in patients with HIV
• Exercise caution when taking folinic acid in combination with anticonvulsant drugs
• Drug interaction overview
  • Increased rates of failure and morbidity in the acute treatment of Pneumocystis jirovecii pneumonia in HIV patients when coadministered with trimethoprim-sulfamethoxazole
  • Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin, and primidone and increase the frequency of seizures in susceptible children; it is not known whether folinic acid has the same effects; however, both folic and folinic acids share some common metabolic pathways; monitor patients taking folinic acid in combination with antiepileptic drugs
  • Leucovorin products increase the toxicity of fluorouracil; do not initiate or continue therapy with fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved; monitor patients with diarrhea until diarrhea has resolved, as rapid deterioration leading to death can occur

Pregnancy and Lactation

• There are limited data on pregnant women
• The drug is administered with methotrexate or fluorouracil, which can cause embryo-fetal harm; refer to methotrexate and fluorouracil prescribing information for additional information
• Lactation
  • There is no data on the presence of levoleucovorin in human milk or its effects on the breastfed infant or milk production
  • Levoleucovorin is administered with methotrexate or fluorouracil; refer to methotrexate and fluorouracil prescribing information for additional information