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Colorectal cancer, advanced: Injection: Palliative treatment of advanced colorectal cancer to prolong survival (in combination with 5-fluorouracil).
Methotrexate toxicity:
Injection: Rescue agent after high-dose methotrexate treatment in osteosarcoma and to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists.
Oral: Rescue agent to diminish toxicity and counteract effects of impaired methotrexate elimination and inadvertent overdoses of folic acid antagonists.
Megaloblastic anemia: Injection: Treatment of megaloblastic anemias due to folic acid deficiency (when oral therapy is not feasible).
Pernicious anemia and other megaloblastic anemias secondary to vitamin B12-deficiency
Colorectal cancer, advanced: IV: 200 mg/m2/day over at least 3 minutes for 5 days every 4 weeks for 2 cycles, then every 4 to 5 weeks (in combination with fluorouracil) or 20 mg/m2/day for 5 days every 4 weeks for 2 cycles, then every 4 to 5 weeks (in combination with fluorouracil). Note: Multiple leucovorin-containing regimens are available for the treatment of colorectal cancer. Refer to appropriate literature/guidelines for additional details.
Folic acid antagonist (eg, trimethoprim, pyrimethamine) overdose: Oral: 5 to 15 mg once daily
Folate-deficient megaloblastic anemia: IM, IV: ≤1 mg once daily
High-dose methotrexate-rescue: Initial: Oral, IM, IV: 15 mg (~10 mg/m2); start 24 hours after beginning methotrexate infusion; continue every 6 hours for 10 doses, until methotrexate level is <0.05 micromolar. Adjust dose as follows:
Normal methotrexate elimination (serum methotrexate level ~10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and <0.2 micromolar at 72 hours): Oral, IM, IV: 15 mg every 6 hours for 60 hours (10 doses) beginning 24 hours after the start of methotrexate infusion
Delayed late methotrexate elimination (serum methotrexate level remaining >0.2 micromolar at 72 hours and >0.05 micromolar at 96 hours after administration): Continue leucovorin calcium 15 mg (oral, IM or IV) every 6 hours until methotrexate level is <0.05 micromolar
Delayed early methotrexate elimination and/or acute renal injury (serum methotrexate level ≥50 micromolar at 24 hours, or ≥5 micromolar at 48 hours, or a doubling of serum creatinine level at 24 hours after methotrexate administration): IV: 150 mg every 3 hours until methotrexate level is <1 micromolar, then 15 mg every 3 hours until methotrexate level is <0.05 micromolar
High-dose methotrexate overexposure: Leucovorin nomogram dosing for high-dose methotrexate overexposure (off-label dosing; generalized dosing derived from reference nomogram figures, refer to each reference [Bleyer, 1978; Bleyer, 1981; Widemann, 2006] or institution-specific nomogram for details):
At 24 hours:
For methotrexate levels of ≥100 micromolar at ~24 hours, leucovorin is initially dosed at 1,000 mg/m2 every 6 hours
For methotrexate levels of ≥10 to <100 micromolar at 24 hours, leucovorin is initially dosed at 100 mg/m2 every 3 or 6 hours
For methotrexate levels of ~1 to 10 micromolar at 24 hours, leucovorin is initially dosed at 10 mg/m2 every 3 or 6 hours
At 48 hours:
For methotrexate levels of ≥100 micromolar at 48 hours, leucovorin is dosed at 1,000 mg/m2 every 6 hours
For methotrexate levels of ≥10 to <100 micromolar at 48 hours, leucovorin is dosed at 100 mg/m2 every 3 hours
For methotrexate levels of ~1 to 10 micromolar at 48 hours, leucovorin is dosed at 100 mg/m2 every 6 hours or 10 to 100 mg/m2 every 3 hours
At 72 hours:
For methotrexate levels of ≥10 micromolar at 72 hours, leucovorin is dosed at 100 to 1,000 mg/m2 every 3 to 6 hours
For methotrexate levels of ~1 to 10 micromolar at 72 hours, leucovorin is dosed at 10 to 100 mg/m2 every 3 hours
For methotrexate levels of ~0.1 to 1 micromolar at 72 hours, leucovorin is dosed at 10 mg/m2 every 3 to 6 hours
If serum creatinine is increased more than 50% above baseline, increase the standard leucovorin dose to 100 mg/m2 every 3 hours, then adjust according to methotrexate levels above.
Follow methotrexate levels daily, leucovorin may be discontinued when methotrexate level is <0.1 micromolar
Methotrexate overdose (inadvertent) (begin as soon as possible after overdose): Oral, IM, IV: 10 mg/m2 every 6 hours until the methotrexate level is < 0.01 micromolar. If serum creatinine is increased more than 50% above baseline 24 hours after methotrexate administration, if 24 hour methotrexate level is >5 micromolar, or if 48 hour methotrexate level is >0.9 micromolar, increase leucovorin dose to 100 mg/m2 IV every 3 hours until the methotrexate level is <0.01 micromolar.
Do not administer leucovorin intrathecally; the use of intrathecal leucovorin is not advised (Jardine, 1996; Smith, 2008).
Bladder cancer, neoadjuvant treatment (off-label use): IV, Oral: 15 mg every 6 hours for 4 doses on days 2 and 9, starting 24 hours after each methotrexate dose (in combination with methotrexate, vinblastine, and cisplatin) (Griffiths, 2011).
Cofactor therapy in methanol toxicity (off-label use): IV: 1 mg/kg (maximum dose: 50 mg) over 30 to 60 minutes every 4 to 6 hours. Therapy should continue until methanol and formic acid have been completely eliminated (Barceloux, 2002).
Esophageal cancer, advanced or metastatic (off-label use): IV: 400 mg/m2 over 2 hours once every 2 weeks (in combination with fluorouracil and irinotecan [FOLFIRI]) until disease progression or unacceptable toxicity (Guimbaud, 2014) or 200 mg/m2 over 2 hours once every 2 weeks (in combination with fluorouracil and oxaliplatin) until disease progression or unacceptable toxicity (Al-Batran, 2008).
Gastric cancer, advanced or metastatic (off-label use): IV: 400 mg/m2 over 2 hours once every 2 weeks (in combination with fluorouracil and irinotecan [FOLFIRI]) until disease progression or unacceptable toxicity (Guimbaud, 2014) or 200 mg/m2 over 2 hours once every 2 weeks (in combination with fluorouracil and oxaliplatin) until disease progression or unacceptable toxicity (Al-Batran, 2008).
Pancreatic cancer, metastatic (off-label use): IV: 400 mg/m2 over 2 hours once every 2 weeks (in combination with fluorouracil, oxaliplatin, and irinotecan [FOLFIRINOX]) for at least 6 months (Conroy, 2011).
Pemetrexed toxicity (off-label dose): IV: 100 mg/m2 once, followed by 50 mg/m2 every 6 hours for 8 days (used in clinical trial for CTC grade 4 leukopenia ≥3 days; CTC grade 4 neutropenia ≥3 days; immediately for CTC grade 4 thrombocytopenia, bleeding associated with grade 3 thrombocytopenia, or grade 3 or 4 mucositis) (Alimta [prescribing information], 2013).
Prevention of pyrimethamine hematologic toxicity in HIV-infected patients (off-label use; HHS [OI adult 2015]): Oral:
Isosporiasis (Isospora belli):
Treatment: 10 to 25 mg once daily (in combination with pyrimethamine)
Chronic maintenance (secondary prophylaxis): 5 to 10 mg once daily (in combination with pyrimethamine)
Pneumocystis pneumonia (PCP): Prophylaxis (primary and secondary): 25 mg once weekly (in combination with pyrimethamine [with dapsone]) or 10 mg once daily (in combination with pyrimethamine [with atovaquone])
Toxoplasma gondii encephalitis:
Primary prophylaxis: 25 mg once weekly (in combination with pyrimethamine [with dapsone]) or 10 mg once daily (in combination with pyrimethamine [with atovaquone])
Treatment: 10 to 25 mg once daily (in combination with pyrimethamine [with either sulfadiazine, clindamycin, atovaquone, or azithromycin]). Note: May increase leucovorin to 50 to 100 mg/day in divided doses in cases of pyrimethamine toxicity (rash, nausea, bone marrow suppression).
Chronic maintenance (secondary prophylaxis): 10 to 25 mg once daily (in combination with pyrimethamine [with either sulfadiazine or clindamycin]) or 10 mg once daily (in combination with pyrimethamine [with atovaquone])
Refer to adult dosing.
Folic acid antagonist (eg, trimethoprim, pyrimethamine) overdose: Refer to adult dosing.
Folate-deficient megaloblastic anemia: Refer to adult dosing.
High-dose methotrexate-rescue: Refer to adult dosing.
Cofactor therapy in methanol toxicity (off-label use): Refer to adult dosing.
Prevention of pyrimethamine hematologic toxicity in HIV-exposed/-positive patients (off-label uses; CDC, 2009):
Infants and Children >1 month of age: Note: Leucovorin should continue for 1 week after pyrimethamine is discontinued.
Toxoplasmosis (Toxoplasma gondii):
Primary prophylaxis: Oral: 5 mg once every 3 days (in combination with pyrimethamine [with either dapsone or atovaquone])
Secondary prophylaxis: Oral: 5 mg once every 3 days (in combination with pyrimethamine [with either sulfadiazine, atovaquone, or clindamycin])
Treatment (congenital): Oral or IM: 10 mg with every pyrimethamine dose (in combination with either sulfadiazine or clindamycin); treatment duration: 12 months
Treatment (acquired): Oral: Acute induction: 10-25 mg once daily (in combination with pyrimethamine [with either sulfadiazine, clindamycin, or atovaquone]) for ≥6 weeks
Adolescents: Refer to adult dosing
There are no dosage adjustments provided in the manufacturer 's labeling.
There are no dosage adjustments provided in the manufacturer 's labeling.
Powder for injection: Reconstitute with SWFI or BWFI; dilute in D5W or NS for infusion. When doses >10 mg/m2 are required, reconstitute using sterile water for injection, not a solution containing benzyl alcohol.
For methanol toxicity, dilute in D5W (Barceloux, 2002).
Due to calcium content, do not administer IV solutions at a rate >160 mg/minute; not intended for intrathecal use.
Refer to individual protocols. Should be administered IM, IV push, or IV infusion (15 minutes to 2 hours). Leucovorin should not be administered concurrently with methotrexate. It is commonly initiated 24 hours after the start of methotrexate. Toxicity to normal tissues may be irreversible if leucovorin is not initiated by ~40 hours after the start of methotrexate.
As a rescue after folate antagonists: Administer by IV bolus, IM, or orally.
Do not administer orally in the presence of nausea or vomiting. Doses >25 mg should not be administered orally (should be converted to parenteral therapy).
Combination therapy with fluorouracil: Fluorouracil is usually given after, or at the midpoint, of the leucovorin infusion. Leucovorin is usually administered by IV bolus injection or short (10 to 120 minutes) IV infusion. Other administration schedules have been used; refer to individual protocols.
For the treatment of methanol toxicity, infuse over 30 to 60 minutes (Barceloux, 2002)
Solutions for injection contain calcium 0.004 mEq per leucovorin 1 mg
Powder for injection: Store at room temperature of 25 °C (77 °F). Protect from light. Solutions reconstituted with bacteriostatic water for injection U.S.P., must be used within 7 days. Solutions reconstituted with SWFI must be used immediately. Parenteral admixture is stable for 24 hours stored at room temperature (25 °C) and for 4 days when stored under refrigeration (4 °C).
Solution for injection: Prior to dilution, store vials under refrigeration at 2 °C to 8 °C (36 °F to 46 °F). Protect from light.
Tablet: Store at room temperature of 15 °C to 30 °C (59 °F to 86 °F).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Injection [strength expressed as base]:
Generic: 100 mg/10 mL (10 mL [DSC]); 300 mg/30 mL (30 mL [DSC])
Solution Reconstituted, Injection [strength expressed as base]:
Generic: 100 mg (1 ea); 200 mg (1 ea); 350 mg (1 ea); 500 mg (1 ea)
Solution Reconstituted, Injection [strength expressed as base, preservative free]:
Generic: 50 mg (1 ea); 100 mg (1 ea); 200 mg (1 ea); 350 mg (1 ea)
Tablet, Oral [strength expressed as base]:
Generic: 5 mg, 10 mg, 15 mg, 25 mg
A 5 mg/mL oral suspension may be prepared with tablets, Cologel, and a 2:1 mixture of simple syrup and wild cherry syrup. Crush twenty-four 25 mg tablets in a glass mortar and reduce to a fine powder; transfer powder to amber bottle. Add 30 mL Cologel and shake mixture thoroughly. Add a quantity of syrup mixture sufficient to make 120 mL. Label "shake well " and "refrigerate " . Stable for 28 days refrigerated.
Lam MS. Extemporaneous Compounding of Oral Liquid Dosage Formulations and Alternative Drug Delivery Methods for Anticancer Drugs. Pharmacotherapy. 2011;31(2):164-192.[PMID: 21275495]Stable in D10NS, D5W, D10W, LR, SWFI, bacteriostatic water, NS, bacteriostatic NS.
Y-site administration: Incompatible with amphotericin B cholesteryl sulfate complex, droperidol, foscarnet, sodium bicarbonate.
Capecitabine: Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Capecitabine. Monitor therapy
Fluorouracil (Systemic): Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Fluorouracil (Systemic). This effect is associated with the ability of leucovorin or levoleucovorin to enhance the anticancer effects of fluorouracil. Monitor therapy
Fluorouracil (Topical): Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Fluorouracil (Topical). Monitor therapy
Fosphenytoin: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of Fosphenytoin. Monitor therapy
Glucarpidase: May decrease serum concentrations of the active metabolite(s) of Leucovorin Calcium-Levoleucovorin. Specifically, 6S-5-methyltetrahydrofolateconcentrations may be reduced. Glucarpidase may decrease the serum concentration of Leucovorin Calcium-Levoleucovorin. Management: Avoid leucovorin administration within 2 hours of glucarpidase dosing. Continue to administer the pre-glucarpidase leucovorin dose for at least the first 48 hours after glucarpidase administration, and dose based on methotrexate concentration thereafter. Consider therapy modification
PHENobarbital: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of PHENobarbital. Monitor therapy
Phenytoin: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of Phenytoin. Monitor therapy
Primidone: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of Primidone. Additionally, leucovorin/levoleucovorin may decrease concentrations of active metabolites of primidone (e.g., phenobarbital). Monitor therapy
Raltitrexed: Leucovorin Calcium-Levoleucovorin may diminish the therapeutic effect of Raltitrexed. Avoid combination
Tegafur: Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Tegafur. This effect is associated with the ability of leucovorin or levoleucovorin to enhance the anticancer effects of fluorouracil. Monitor therapy
Trimethoprim: Leucovorin Calcium-Levoleucovorin may diminish the therapeutic effect of Trimethoprim. Management: Avoid concurrent use of leucovorin or levoleucovorin with trimethoprim (plus sulfamethoxazole) for Pneumocystis jiroveci pneumonia. If trimethoprim is used for another indication, monitor closely for reduced efficacy. Avoid combination
High-dose methotrexate therapy: Plasma methotrexate concentration; leucovorin is continued until the plasma methotrexate level <0.05 micromolar. With 4- to 6-hour high-dose methotrexate infusions, plasma drug values in excess of 50 and 1 micromolar at 24 and 48 hours after starting the infusion, respectively, are often predictive of delayed methotrexate clearance.
Fluorouracil therapy: CBC with differential and platelets, liver function tests, electrolytes
Frequency not defined. Toxicities (especially gastrointestinal toxicity) of fluorouracil are enhanced when used in combination with leucovorin.
Dermatologic: Erythema, pruritus, skin rash, urticaria
Hematologic & oncologic: Thrombocythemia
Hypersensitivity: Anaphylactoid reaction, hypersensitivity reaction
Respiratory: Wheezing
Concerns related to adverse effects:
- Hypersensitivity: Hypersensitivity, including allergic reactions, anaphylactoid reactions, and urticaria have been reported with leucovorin. Because leucovorin is typically administered in combination with other chemotherapy agents, it may be difficult to determine the causative agent for hypersensitivity reactions. In a series of 44 patients with hypersensitivity to leucovorin-containing regimens, hypersensitivity/infusion reaction to leucovorin was confirmed in 5 patients; reactions also occurred with subsequent rechallenge with LEVOleucovorin (Ure ħa-Tavera, 2015).
- Seizures: Seizures or syncope have been reported (rarely) in patients with cancer receiving leucovorin, usually in association with fluoropyrimidine administration, and most commonly in patients with CNS metastases or other predisposing factors; a causal relationship has not been established.
Disease-related concerns:
- Anemias: Leucovorin is inappropriate treatment for pernicious anemia and other megaloblastic anemias secondary to a lack of vitamin B12; a hematologic remission may occur while neurologic manifestations progress.
- Renal impairment: Leucovorin is excreted renally; the risk for toxicities may be increased in patients with renal impairment.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
- Fluorouracil: Leucovorin may increase the toxicity of 5-fluorouracil; deaths from severe enterocolitis, diarrhea, and dehydration have been reported (in elderly patients); granulocytopenia and fever have also been reported.
- Sulfamethoxazole-trimethoprim: Combination of leucovorin and sulfamethoxazole-trimethoprim for the acute treatment of PCP in patients with HIV infection has been reported to cause increased rates of treatment failure.
Dosage form specific issues:
- Administration route: Parenteral administration may be preferred to oral if vomiting or malabsorption is likely.
- Benzyl alcohol and derivatives: When doses >10 mg/m2 are required using the powder for injection, reconstitute using sterile water for injection, not a solution containing benzyl alcohol; large amounts of benzyl alcohol ( ≥99 mg/kg/day) have been associated with a potentially fatal toxicity ( "gasping syndrome " ) in neonates; the "gasping syndrome " consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP [Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer 's labeling.
- Injection: Due to calcium content, do not administer IV solutions at a rate >160 mg/minute. Not intended for intrathecal use.
Other warnings and precautions:
- Folic acid antagonist overdose: When used for the treatment of accidental folic acid antagonist overdose, administer as soon as possible.
- Methotrexate overdose: When used for the treatment of a methotrexate overdose, administer IV leucovorin as soon as possible. Monitoring of the serum methotrexate concentration is essential to determine the optimal dose/duration of leucovorin; however, do not wait for the results of a methotrexate level before initiating leucovorin. It is important to adjust the leucovorin dose once a methotrexate level is known. The dose may need to be increased or administration prolonged in situations in which methotrexate excretion may be delayed (eg, ascites, pleural effusion, renal insufficiency, inadequate hydration). Never administer leucovorin intrathecally.
- Methotrexate rescue therapy: Methotrexate serum concentrations should be monitored to determine dose and duration of leucovorin therapy. Dose may need increased or administration prolonged in situations where methotrexate excretion may be delayed (eg, ascites, pleural effusion, renal insufficiency, inadequate hydration). Never administer leucovorin intrathecally.
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Animal reproduction studies have not been conducted. Leucovorin is a biologically active form of folic acid. Adequate amounts of folic acid are recommended during pregnancy. Refer to Folic Acid monograph.
A reduced form of folic acid, leucovorin supplies the necessary cofactor blocked by methotrexate. Leucovorin actively competes with methotrexate for transport sites, displaces methotrexate from intracellular binding sites, and restores active folate stores required for DNA/RNA synthesis. Stabilizes the binding of 5-dUMP and thymidylate synthetase, enhancing the activity of fluorouracil. When administered with pyrimethamine for the treatment of opportunistic infections, leucovorin reduces the risk for hematologic toxicity (HHS [OI adult 2015]).
Methanol toxicity treatment: Formic acid (methanol 's toxic metabolite) is normally metabolized to carbon dioxide and water by 10-formyltetrahydrofolate dehydrogenase after being bound to tetrahydrofolate. Administering a source of tetrahydrofolate may aid the body in eliminating formic acid (Barceloux, 2002).
Oral, IM: Well absorbed
Intestinal mucosa and hepatically to 5-methyl-tetrahydrofolate (5MTHF; active)
Urine (primarily); feces
Oral: ~2 hours; IV: Total folates: 10 minutes; 5MTHF: ~1 hour; IM: Total folates: 52 minutes; 5MTHF: 2.8 hours
~4 to 8 hours
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Have patient report immediately to prescriber seizures, severe dizziness, or passing out (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.