Note: Because oral absorption is saturable at doses >25 mg, administering single oral doses >25 mg is not recommended (convert to parenteral therapy). Leucovorin calcium is a substrate for glucarpidase and may compete with methotrexate for binding sites; when administering glucarpidase concomitantly with leucovorin calcium, administer leucovorin calcium ≥2 hours before or 2 hours after the glucarpidase dose (Ramsey 2018). Do not administer leucovorin intrathecally; the use of intrathecal leucovorin is not advised (Jardine 1996; Smith 2008).
Acute lymphocytic leukemia (off-label use): Hyper-CVAD alternating with high-dose methotrexate/cytarabine regimen: IV: 50 mg administered 12 hours after methotrexate completion, followed by 15 mg every 6 hours for 8 doses or until methotrexate level is <0.1 micromolar (adjust dose based on methotrexate level as needed) (Thomas 2004) or 15 mg administered 12 hours after methotrexate completion, followed by 15 mg every 6 hours for 8 total doses or until methotrexate level is <0.1 micromolar (adjust dose based on methotrexate level as needed) (Kantarjian 2004). Therapy consists of alternating cycles of hyper-CVAD (cyclophosphamide, mesna, vincristine, doxorubicin, and dexamethasone) and high-dose methotrexate/cytarabine; refer to protocol for details.
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).
Colorectal cancer, advanced: IV: 200 mg/m2/day over ≥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.
Roswell Park regimen (off-label dosing): IV: 500 mg/m2 over 2 hours on days 1, 8, 15, 22, 29, and 36 (in combination with fluorouracil, administered 1 hour after the start of leucovorin) every 8 weeks for 4 cycles (Haller 2005).
FOLFOX6 and mFOLFOX6 regimen (off-label dosing): IV: 400 mg/m2 over 2 hours on day 1 or 350 mg (flat dose) over 2 hours on day 1 (in combination with fluorouracil and oxaliplatin) every 2 weeks until disease progression or unacceptable toxicity (Cheeseman 2002; Maindrault-Goebel 1999).
FOLFIRI regimen (off-label dosing): IV: 400 mg/m2 over 2 hours on day 1 every 2 weeks (in combination with fluorouracil and irinotecan) until disease progression or unacceptable toxicity (Andre 1999).
Dermatomyositis/polymyositis (off-label use): Oral: 5 mg once per week (administered 8 to 12 hours after the methotrexate dose) (Briemberg 2003; Miller 2022).
Esophageal cancer, advanced or metastatic (off-label use):
FOLFIRI regimen: IV: 400 mg/m2 over 2 hours once every 2 weeks (in combination with fluorouracil and irinotecan) until disease progression or unacceptable toxicity (Guimbaud 2014).
FLO regimen: IV: 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).
FLOT regimen (locally advanced, resectable gastroesophageal junction adenocarcinoma): IV:200 mg/m2 on day 1 every 2 weeks (in combination with fluorouracil, oxaliplatin, and docetaxel) for 4 preoperative cycles and 4 postoperative cycles (Al-Batran 2019).
FOLFOX/nivolumab: IV: 400 mg/m2 on day 1 every 2 weeks (in combination with fluorouracil, oxaliplatin, and nivolumab) until disease progression or unacceptable toxicity (Janjigian 2021).
Folic acid antagonist (eg, trimethoprim, pyrimethamine) overdose: Oral: 5 to 15 mg once daily.
Gastric cancer, advanced or metastatic (off-label use):
FOLFIRI regimen: IV: 400 mg/m2 over 2 hours once every 2 weeks (in combination with fluorouracil and irinotecan) until disease progression or unacceptable toxicity (Guimbaud 2014).
FLO regimen: IV: 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).
FLOT regimen: IV: 200 mg/m2 on day 1 every 2 weeks (in combination with fluorouracil, oxaliplatin, and docetaxel) for 4 preoperative cycles and 4 postoperative cycles (Al-Batran 2019).
FOLFOX/nivolumab: IV: 400 mg/m2 on day 1 every 2 weeks (in combination with fluorouracil, oxaliplatin, and nivolumab) until disease progression or unacceptable toxicity (Janjigian 2021).
Gestational trophoblastic neoplasia (off-label use):
Low-risk disease: 8-day regimen: Oral: 30 mg every 48 hours (on days 2, 4, 6, and 8) for 4 doses (30 hours after each methotrexate dose), repeat cycle every 14 days until hCG level is normal, followed by 2 to 3 more cycles as consolidation therapy (SOGC [Eiriksson 2021]).
High-risk metastatic disease: Note: The oral route would be preferred over IM in patients with thrombocytopenia.
EMA-CO regimen: Oral, IM: 15 mg every 12 hours for 4 doses, beginning 24 hours after the start of methotrexate (in combination with etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine); patients with brain metastases received a higher methotrexate dose and, therefore, the leucovorin calcium dose was increased to 30 mg every 12 hours for 6 doses, beginning 32 hours after the start of methotrexate. Continue for ≥2 treatment cycles after a normal human chorionic gonadotropin (hCG) level (Escobar 2003; Lurain 2006).
EMA-EP regimen: Oral, IM: 15 mg every 12 hours for 4 doses beginning on day 2 (in combination with etoposide, methotrexate, dactinomycin, and cisplatin); patients with brain metastases received a higher methotrexate dose and, therefore, an increased leucovorin calcium dose of 30 mg every 12 hours. Continue for 2 to 4 treatment cycles after a normal hCG level (Ghaemmaghami 2004).
EP-EMA regimen: Oral, IM: 15 mg every 12 hours for 4 doses, beginning 24 hours after the start of methotrexate (in combination with etoposide, cisplatin, methotrexate, and dactinomycin); if mucositis develops, may double the dose and duration of leucovorin calcium (Newlands 2000).
Graft-vs-host disease, acute (prophylaxis) (off-label use): IV, Oral: 15 mg every 6 hours for 3 doses on day 2, then 15 mg every 6 hours for 4 doses on days 4, 7, and 12 (in combination with methotrexate and cyclosporine); initiate leucovorin 24 hours after each methotrexate dose (methotrexate is administered on days 1, 3, 6, and 11; may omit day 11 methotrexate for ≥ grade 2 toxicity) (EBMT-ELN [Ruutu 2013]).
Granulomatosis with polyangiitis and microscopic polyangiitis (maintenance therapy after remission induction) (off-label use): Oral: 5 to 10 mg once weekly administered 24 hours after methotrexate (Langford 2003) or 25 mg once weekly administered 48 hours after methotrexate (Pagnoux 2008).
Hepatobiliary cancers, advanced (off-label use): IV: 25 mg/m2 immediately prior to fluorouracil infusion on days 1, 8, and 15 every 4 weeks (in combination with gemcitabine and fluorouracil) (Alberts 2005).
Megaloblastic anemia, folate-deficient: IM, IV: ≤1 mg once daily.
Methanol toxicity, adjunctive cofactor therapy (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 (AACT [Barceloux 2002]).
Methotrexate-rescue, high-dose methotrexate: 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. Monitor hydration and electrolyte status, as well as urine alkalinization. Adjust dose per institutional protocol or 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.
Methotrexate overdose, inadvertent: Note: 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 >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.
Methotrexate overexposure, high-dose methotrexate: 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 calcium is initially dosed at 1,000 mg/m2 IV every 6 hours.
For methotrexate levels of ≥10 to <100 micromolar at 24 hours, leucovorin calcium is initially dosed at 100 mg/m2 IV every 3 or 6 hours.
For methotrexate levels of ~1 to 10 micromolar at 24 hours, leucovorin calcium is initially dosed at 10 mg/m2 IV or orally every 3 or 6 hours.
At 48 hours:
For methotrexate levels of ≥100 micromolar at 48 hours, leucovorin calcium is dosed at 1,000 mg/m2 IV every 6 hours.
For methotrexate levels of ≥10 to <100 micromolar at 48 hours, leucovorin calcium is dosed at 100 mg/m2 IV every 3 hours.
For methotrexate levels of ~1 to 10 micromolar at 48 hours, leucovorin calcium is dosed at 100 mg/m2 IV every 6 hours or 10 mg/m2 IV or orally to 100 mg/m2 IV every 3 hours.
At 72 hours:
For methotrexate levels of ≥10 micromolar at 72 hours, leucovorin calcium is dosed at 100 to 1,000 mg/m2 IV every 3 to 6 hours.
For methotrexate levels of ~1 to 10 micromolar at 72 hours, leucovorin calcium is dosed at 10 mg/m2 IV or orally to 100 mg/m2 IV every 3 hours.
For methotrexate levels of ~0.1 to 1 micromolar at 72 hours, leucovorin calcium is dosed at 10 mg/m2 IV or orally every 3 to 6 hours.
If serum creatinine is increased >50% above baseline, increase the standard leucovorin calcium dose to 100 mg/m2 IV every 3 hours, then adjust according to methotrexate levels above.
Follow methotrexate levels daily, leucovorin calcium may be discontinued when methotrexate level is <0.1 micromolar.
Some regimens use the following equation when calculating the leucovorin calcium dose (if the methotrexate plasma concentration is >5 micromolar) (Ramsey 2018):
Plasma methotrexate concentration (micromolar) × body weight (kg)
Non-Hodgkin lymphoma, Burkitt (off-label use):
CODOX-M/IVAC regimen: IV, Oral: 15 mg/m2 IV every 3 hours for 5 doses beginning at hour 36 after the start of methotrexate, then 15 mg/m2 IV every 6 hours until methotrexate level is <0.05 micromolar. In addition, leucovorin calcium 15 mg (flat dose) orally is administered 24 hours after intrathecal methotrexate (Mead 2008). CODOX-M cycle (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate with leucovorin calcium rescue, intrathecal cytarabine, and intrathecal methotrexate) alternates with IVAC cycle (etoposide, ifosfamide, mesna, cytarabine, and intrathecal methotrexate (with leucovorin calcium rescue); refer to protocol for details.
Hyper-CVAD alternating with high-dose methotrexate/cytarabine regimen: IV, Oral: 50 mg IV administered 12 hours after methotrexate completion, followed by 15 mg IV every 6 hours for 8 doses or until methotrexate level is <0.1 micromolar (adjust dose based on methotrexate level as needed) (Thomas 2006) or 50 mg IV administered 24 hours after the end of methotrexate infusion, followed by 15 mg orally every 6 hours for 8 doses (adjust dose based on methotrexate level as needed) (Khouri 1998). Therapy consists of alternating cycles of hyper-CVAD (cyclophosphamide, mesna, vincristine, doxorubicin, and dexamethasone) and high-dose methotrexate/cytarabine; refer to protocol for details.
Nonleukemic meningeal cancer (off-label use): Oral: 10 mg every 6 hours for 8 doses, beginning 24 hours after each intrathecal methotrexate dose (Glantz 1999).
Pancreatic cancer, advanced or metastatic (off-label use):
FOLFIRINOX regimen: IV: 400 mg/m2 over 2 hours once every 2 weeks (in combination with fluorouracil, oxaliplatin, and irinotecan) for ≥6 months (Conroy 2011).
OFF regimen (second-line therapy): IV: 200 mg/m2 on days 1, 8, 15, and 22 every 6 weeks (in combination with fluorouracil and oxaliplatin) until disease progression or unacceptable toxicity (Oettle 2014; Pelzer 2011).
Pancreatic cancer, potentially curable, adjuvant therapy (off-label use): Note: American Society of Clinical Oncology (ASCO) guidelines recommend 6 months of adjuvant therapy if recovery is complete; if preoperative chemotherapy therapy was received, a total of 6 months of adjuvant therapy (including the preoperative regimen) is recommended (ASCO [Khorana 2019]).
FOLFIRINOX regimen: IV: 400 mg/m2 over 2 hours once every 2 weeks (in combination with fluorouracil, irinotecan, and oxaliplatin; modified FOLFIRINOX regimen) for 24 weeks (Conroy 2018). According to ASCO guidelines, mFOLFIRINOX is the preferred first-line adjuvant regimen for potentially curable disease (ASCO [Khorana 2019]).
Leucovorin/fluorouracil: IV: 20 mg/m2/day (bolus) days 1 to 5 every 28 days (in combination with fluorouracil) for 6 cycles (Neoptolemos 2004; Neoptolemos 2010). According to ASCO guidelines for potentially curable pancreatic cancer, fluorouracil/leucovorin may be considered as an alternative therapy if toxicity/tolerance is a concern (ASCO [Khorana 2019]).
Prevention of pyrimethamine hematologic toxicity in patients with HIV (off-label use; HHS [OI adult 2020]):
Cystoisosporiasis (formerly Isosporiasis):
Treatment: Oral: 10 to 25 mg once daily (in combination with pyrimethamine).
Chronic maintenance (secondary prophylaxis): Oral: 5 to 10 mg once daily (in combination with pyrimethamine).
Pneumocystis pneumonia: Prophylaxis (primary and secondary): Oral: 25 mg once weekly (in combination with pyrimethamine and dapsone) or 10 mg once daily (in combination with pyrimethamine and atovaquone).
Toxoplasma gondii encephalitis:
Primary prophylaxis: Oral: 25 mg once weekly (in combination with pyrimethamine and dapsone) or 10 mg once daily (in combination with pyrimethamine and atovaquone).
Treatment: Oral: 10 to 25 mg once daily as part of an appropriate combination regimen. Note: May increase leucovorin to 50 mg once or twice daily in cases of pyrimethamine toxicity (rash, nausea, bone marrow suppression).
Chronic maintenance (secondary prophylaxis): Oral: 10 to 25 mg once daily (in combination with pyrimethamine with either sulfadiazine or clindamycin) or 10 mg once daily (in combination with pyrimethamine and atovaquone).
Primary CNS lymphoma (off-label use): IV, Oral: 20 to 25 mg every 6 hours beginning 24 hours after methotrexate infusion (in combination with rituximab, methotrexate, vincristine, and procarbazine, followed by radiotherapy, cytarabine, and intra-Ommaya methotrexate), continue for ≥72 hours or until methotrexate level is <0.1 micromolar; may increase dose to 40 mg every 4 hours for elevated methotrexate levels (Shah 2007) or 100 mg/m2 IV every 6 hours starting 24 hours after methotrexate infusion, continue until methotrexate level is <0.05 micromolar (in combination with methotrexate, temozolomide, and rituximab, followed by high-dose consolidation therapy) (Batchelor 2003; Rubenstein 2013) or 25 mg IV every 6 hours starting 24 hours after methotrexate, continue until appropriate methotrexate level is reached (in combination with methotrexate, temozolomide, and rituximab, followed by whole brain radiotherapy) (Glass 2016).
Tubal ectopic pregnancy (off-label use) (in combination with a multidose methotrexate regimen): IM: Methotrexate on days 1, 3, 5, and 7 alternating with leucovorin calcium 0.1 mg/kg on days 2, 4, 6, and 8. Measure serum hCG on each day of methotrexate administration. If serum hCG decreases by >15% from previous measurement, discontinue methotrexate and leucovorin (total treatment may be between 1 and 4 doses each). If serum hCG decreases by <15% from previous measurement, administer methotrexate (maximum 4 doses) and then leucovorin calcium the next day (ACOG 193 2018; ASRM 2013; Sauer 1987; Stovall 1989).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling.
There are no dosage adjustments provided in the manufacturer’s labeling.
(For additional information see "Leucovorin: Pediatric drug information")
Note: Dosing in pediatric patients presented in mg, mg/m2 and mg/kg; use caution. Because oral absorption is saturable at doses >25 mg, administration of single oral doses >25 mg is not recommended (convert to parenteral therapy). Also consider parenteral administration instead of oral in patients with GI toxicity, nausea, vomiting, or who may be unreliable with the precisely timed administration (eg, infants and young children) needed for some indications.
Cerebral folate deficiency; treatment: Limited data available: Children and Adolescents: Oral: Initial: 0.5 to 1 mg/kg/day; titrate in 0.5 mg/kg/day increments at monthly intervals based on 5-methyltetrahydrofolate (5MTHF) levels in the cerebrospinal fluid (CSF); doses up to 2 to 3 mg/kg/day may be required. (Al-Baradie 2014; Ramaekers 2002; Ramaekers 2004). Daily doses of 15 to 30 mg have been reported in adolescent patients (Hansen 2005; Ramaekers 2002).
Folic acid antagonist (eg, pyrimethamine, trimethoprim) overdose: Infants, Children, and Adolescents: Oral: 5 to 15 mg daily.
Folinic-acid responsive seizures: Very limited data available: Infants and Children: Oral: Initial: 2.5 to 5 mg twice daily; may gradually increase for seizure recurrence; doses up to 8 mg/kg/day (eg, 25 mg 3 times daily) have been reported. Dosing based on small case series and case reports in patients with refractory seizures who were on multiple antiseizure medications with or without pyridoxine (Djukic 2007; Eichenwald 2017; Frye 2003; Gallagher 2009; Hyland 1995; Nicolai 2006; Torres 1999).
Megaloblastic anemia secondary to folate deficiency: Infants, Children, and Adolescents: IM, IV: ≤1 mg/day; Note: Although an FDA-approved indication, folic acid is generally used to treat folate deficiency due to inadequate intake (eg, dietary, increased requirements) (Devalia 2014; Kliegman 2020).
Methotrexate rescue, high-dose: Note: Leucovorin calcium is a substrate for glucarpidase and may compete with methotrexate for binding sites; when administering glucarpidase concomitantly with leucovorin calcium, administer leucovorin calcium ≥2 hours before or 2 hours after the glucarpidase dose (Ramsey 2018). Do not administer leucovorin intrathecally; the use of intrathecal leucovorin is not advised (Jardine 1996; Smith 2008).
Infants, Children, and Adolescents: Dosing regimens variable, refer to specific protocols. Manufacturer labeling:
Initial: Oral, IM, IV: 15 mg (~10 mg/m2) every 6 hours; start 24 hours after beginning of methotrexate infusion (based on a methotrexate dose of 12 to 15 g/m2 IV over 4 hours). Leucovorin (and hydration and urinary alkalinization) should be continued and/or adjusted until the methotrexate level is <0.05 micromolar (5 x 10-8 M); the manufacturer labeling suggests 10 doses; although some patients may require more. 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 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): Oral, IM, IV: Continue leucovorin calcium 15 mg 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.
Methotrexate overexposure (high dose): Limited data available: Note: Leucovorin calcium is a substrate for glucarpidase and may compete with methotrexate for binding sites; when administering glucarpidase concomitantly with leucovorin calcium, administer leucovorin calcium ≥2 hours before or 2 hours after the glucarpidase dose (Ramsey 2018). Do not administer leucovorin intrathecally; the use of intrathecal leucovorin is not advised (Jardine 1996; Smith 2008).
Infants, Children, and Adolescents: Leucovorin nomogram dosing for high-dose methotrexate overexposure (generalized dosing derived from reference nomogram figures, refer to each reference [Bleyer 1978; Bleyer 1981; Widemann 2006] or protocol-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 IV every 6 hours.
For methotrexate levels of ≥10 to <100 micromolar at 24 hours, leucovorin is initially dosed at 100 mg/m2 IV every 3 or 6 hours.
For methotrexate levels of ~1 to 10 micromolar at 24 hours, leucovorin is initially dosed at 10 mg/m2 IV or orally 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 IV every 6 hours.
For methotrexate levels of ≥10 to <100 micromolar at 48 hours, leucovorin is dosed at 100 mg/m2 IV every 3 hours.
For methotrexate levels of ~1 to 10 micromolar at 48 hours, leucovorin is dosed at 100 mg/m2 IV every 6 hours or 10 mg/m2 IV or orally to 100 mg/m2 IV 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 IV every 3 to 6 hours
For methotrexate levels of ~1 to 10 micromolar at 72 hours, leucovorin is dosed at 10 mg/m2 IV or orally to 100 mg/m2 IV every 3 hours
For methotrexate levels of ~0.1 to 1 micromolar at 72 hours, leucovorin is dosed at 10 mg/m2 IV or orally every 3 to 6 hours
If serum creatinine is increased more than 50% above baseline, increase the standard leucovorin dose to 100 mg/m2 IV 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; some have suggested <0.08 micromolar (8 x 10-8 M) is preferable (Bleyer 1978).
Methotrexate overdose (inadvertent): Note: For oncology patients, refer to protocol-specific nomograms for dosing. Manufacturer labeling:
Infants, Children, and Adolescents: Oral, IM, IV: 10 mg/m2/dose every 6 hours until the methotrexate level is <0.01 micromolar begin as soon as possible after overdose. 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.
Note: Do not administer leucovorin intrathecally; use of intrathecal leucovorin is not advised (Jardine 1996; Smith 2008).
Pyrimethamine hematologic toxicity, prevention: Note: Leucovorin is administered in combination with pyrimethamine and other medications in the treatment of various infections (eg, toxoplasmosis, Pneumocystis jirovecii pneumonia (PCP), cystoisosporiasis); dosing varies with disease process and regimen; consult pyrimethamine specific monograph for additional details; duration of therapy varies based on disease state; however, leucovorin should typically continue for 1 week after pyrimethamine is discontinued (HHS [pediatric 2020]); consultant specific guidelines; usual regimens include:
Toxoplasmosis (Toxoplasma gondii):
Treatment:
Congenital toxoplasmosis: Infants:
HIV-exposed/-infected: IM, Oral: 10 mg with every pyrimethamine dose; treatment duration: 12 months (HHS [pediatric 2020]).
Non-HIV-exposed/-infected: IM, Oral: 10 mg 3 times weekly for 12 months (McAuley 2008).
Acquired infection:
HIV-exposed/-infected: Infants, Children, and Adolescents: Acute induction: Oral: 10 to 25 mg once daily for ≥6 weeks (HHS [adult 2019]; HHS [pediatric 2020]). Note: In adolescents, leucovorin may be increased to 50 to100 mg/day in divided doses (twice-daily doses) in cases of pyrimethamine toxicity (rash, nausea, bone marrow suppression) (HHS [adult 2019]).
Non-HIV-exposed/-infected: Chorioretinitis: Infants, Children, and Adolescents: Oral: 10 to 20 mg three times weekly (McAuley 2008).
Prophylaxis:
Primary:
HIV-exposed/-infected:
Infants and Children: Oral: 5 mg once every 3 days (HHS [pediatric 2020]).
Adolescents: Oral: 25 mg once weekly (with pyrimethamine and dapsone) or 10 mg once daily (with pyrimethamine and atovaquone) (HHS [adult 2019]).
Hematopoietic stem cell transplantation recipients:
Children: Oral: 5 mg every 3 days; initiate after engraftment and administer as long as the patient remains on immunosuppressive therapy (Tomblyn 2009).
Adolescents: Oral: 10 to 25 mg once daily; initiate after engraftment and administer as long as the patient remains on immunosuppressive therapy (Tomblyn 2009).
Secondary (suppressive therapy): HIV-exposed/-infected:
Infants and Children: Oral: 5 mg once every 3 days (HHS [pediatric 2020]).
Adolescents: Oral: 10 to 25 mg once daily (HHS [adult 2019]).
Pneumocystis jirovecii pneumonia (PCP): Prophylaxis (primary and secondary): Adolescents: Oral: 25 mg once weekly (in combination with pyrimethamine and dapsone) or 10 mg once daily (in combination with pyrimethamine and atovaquone) (HHS [adult 2019]).
Cystoisosporiasis (formerly isosporiasis), HIV-exposed/-infected:
Treatment, acute infection:
Infants and Children: Oral: 5 to 15 mg once daily in combination with pyrimethamine (HHS [pediatric 2020]).
Adolescents: Oral: 10 to 25 mg once daily in combination with pyrimethamine (HHS [adult 2019]).
Prophylaxis, secondary:
Infants and Children: Oral: 5 to 15 mg once daily (HHS [pediatric 2020]).
Adolescents: Oral: 5 to 10 mg once daily (HHS [adult 2019]).
Methanol toxicity; adjunctive cofactor therapy: Limited data available: Infants, Children, and Adolescents: IV: 1 mg/kg/dose (maximum dose: 50 mg/dose) over 30 to 60 minutes every 4 to 6 hours. Therapy should continue until methanol and formic acid have been completely eliminated (AACT [Barceloux 2002]). Note: Administration during methanol toxicity is especially important in patients who abuse ethanol as these patients may have chronic folate deficiency.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Infants, Children, and Adolescents: There are no dosage adjustments provided in manufacturer's labeling.
Infants, Children, and Adolescents: There are no dosage adjustments provided in manufacturer's labeling.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection [strength expressed as base, preservative free]:
Generic: 100 mg/10 mL (10 mL); 500 mg/50 mL (50 mL)
Solution Reconstituted, Injection [strength expressed as base]:
Generic: 100 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); 500 mg (1 ea)
Tablet, Oral [strength expressed as base]:
Generic: 5 mg, 10 mg, 15 mg, 25 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection:
Generic: 50 mg/5 mL (5 mL); 200 mg/20 mL (20 mL); 1000 mg/100 mL (100 mL)
Solution, Intravenous:
Generic: 10 mg/mL (5 mL, 30 mL, 50 mL)
Tablet, Oral [strength expressed as base]:
Generic: 5 mg, 15 mg
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. Leucovorin calcium is a substrate for glucarpidase and may compete with methotrexate for binding sites; when administering glucarpidase concomitantly with leucovorin calcium, administer leucovorin calcium at least 2 hours before or 2 hours after the glucarpidase dose (Ramsey 2018).
As a rescue after folate antagonists: Administer by IV bolus, IM, or orally.
Do not administer orally in the presence of nausea or vomiting. Because oral absorption is saturable at doses >25 mg, administering oral doses >25 mg is not recommended (convert 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 (AACT [Barceloux 2002]).
Oral: Do not administer orally in the presence of nausea or vomiting. Because oral absorption is saturable at doses above 25 mg, administering oral doses >25 mg is not recommended (convert to parenteral therapy).
Parenteral: 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.
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 (AACT [Barceloux 2002])
Colorectal cancer, advanced: Injection: Palliative treatment of advanced colorectal cancer to prolong survival (in combination with fluorouracil).
Megaloblastic anemia: Injection: Treatment of megaloblastic anemias due to folic acid deficiency (when oral therapy is not feasible).
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.
Acute lymphocytic leukemia; Bladder cancer (neoadjuvant treatment); Dermatomyositis/polymyositis; Esophageal cancer (advanced or metastatic); Gastric cancer (advanced or metastatic); Gestational trophoblastic neoplasia (low risk); Gestational trophoblastic neoplasia (high risk); Graft-vs-host disease, acute (prophylaxis); Granulomatosis with polyangiitis and microscopic polyangiitis (maintenance therapy after remission induction); Hepatobiliary cancers (advanced); Methanol toxicity (adjunctive cofactor therapy); Non-Hodgkin lymphoma; Nonleukemic meningeal cancer; Pancreatic cancer (advanced or metastatic); Pancreatic cancer, potentially curable, adjuvant therapy; Prevention of pyrimethamine hematologic toxicity in patients with HIV; Primary CNS lymphoma (newly diagnosed); Tubal ectopic pregnancy
Leucovorin calcium may be confused with Leukeran, Leukine, LEVOleucovorin
Folinic acid may be confused with folic acid
Folinic acid is an error prone synonym and should not be used
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. As reported in combination with 5-fluorouracil.
>10%:
Central nervous system: Fatigue (≤13%), lethargy (≤13%), malaise (≤13%)
Dermatologic: Alopecia (42% to 43%), dermatitis (21% to 25%)
Gastrointestinal: Stomatitis (75% to 84%; grades ≥3: 27% to 29%), nausea (74% to 80%), diarrhea (66% to 67%), vomiting (44% to 46%), anorexia (14% to 22%)
Miscellaneous: Drug toxicity
1% to 10%:
Gastrointestinal: Constipation (3% to 4%)
Infection: Infection (3% to 8%)
Frequency not defined: Gastrointestinal: Gastrointestinal toxicity
Postmarketing: Anaphylactic shock, anaphylaxis, hypersensitivity reaction, nonimmune anaphylaxis, seizure, syncope, urticaria
Pernicious anemia and other megaloblastic anemias secondary to vitamin B12-deficiency
Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to leucovorin or any component of the formulation; intrathecal administration
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 (Ureña-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:
• 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: The combination of leucovorin and sulfamethoxazole-trimethoprim for the acute treatment of Pneumocystis jirovecii pneumonia 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. Because oral absorption is saturable at doses >25 mg, administering oral doses >25 mg is not recommended (convert to parenteral therapy).
• 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 suggest 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.
• Methanol toxicity: Leucovorin is the reduced form of folic acid; leucovorin is rapidly converted to tetrahydrofolic acid derivatives, which are the storage forms of folate in the body. Because leucovorin does not require metabolic reduction, it is the preferred form of folate in the treatment of methanol toxicity. Administration during methanol toxicity is especially important in patients with chronic alcohol use disorder as these patients may have chronic folate deficiency. Clinicians should note that leucovorin is an adjunctive therapy and should never be used as the sole intervention in the management of methanol toxicity (AACT [Barceloux 2002]).
• 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 to be increased or administration prolonged in situations where methotrexate excretion may be delayed (eg, ascites, pleural effusion, renal insufficiency, inadequate hydration). Never administer leucovorin intrathecally.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Fluorouracil Products: Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Fluorouracil Products. Risk C: Monitor therapy
Fosphenytoin: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of Fosphenytoin. Risk C: 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. Risk D: Consider therapy modification
PHENobarbital: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of PHENobarbital. Risk C: Monitor therapy
Phenytoin: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of Phenytoin. Risk C: 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). Risk C: Monitor therapy
Raltitrexed: Leucovorin Calcium-Levoleucovorin may diminish the therapeutic effect of Raltitrexed. Risk X: Avoid combination
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 jirovecii pneumonia. If trimethoprim is used for another indication, monitor closely for reduced efficacy. Risk X: Avoid combination
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.
Leucovorin is a biologically active form of folic acid. Adequate amounts of folic acid are recommended in breastfeeding patients. The manufacturer recommends caution be used if administered to a breastfeeding patient. Refer to Folic Acid monograph.
Solutions for injection contain calcium 0.004 mEq per leucovorin 1 mg
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
Tubal ectopic pregnancy (in combination with mulitdose methotrexate) (off-label use): Prior to therapy, serial hCG measurements 2 to 7 days apart along with other procedures to exclude the presence of a viable intrauterine pregnancy (ACOG 193 2018; RCOG [Elson 2016]). CBC with differential, liver function tests, serum creatinine, blood type and Rh (ASRM 2013). Evaluate for medical conditions considered absolute contraindications for methotrexate treatment of ectopic pregnancy (ACOG 193 2018). Measure serum hCG on days of methotrexate administration. Once decrease is >15%, continue to measure serum hCG weekly until reaching a non-pregnant level. Consider surgical management if serum hCG does not decrease after 4 doses (ACOG 193 2018).
Leucovorin calcium is 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. Leucovorin 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 2020]).
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 (AACT [Barceloux 2002]).
Absorption: Oral, IM: Well absorbed
Metabolism: Intestinal mucosa and hepatically to 5-methyl-tetrahydrofolate (5MTHF; active)
Bioavailability: Saturable at oral doses >25 mg; 25 mg (97%), 50 mg (75%), 100 mg (37%)
Half-life elimination: ~4 to 8 hours
Time to peak: Oral: ~2 hours; IV: Total folates: 10 minutes; 5MTHF: ~1 hour; IM: Total folates: 52 minutes; 5MTHF: 2.8 hours
Excretion: Urine (primarily); feces
Solution (Leucovorin Calcium Injection)
100 mg/10 mL (per mL): $2.89
500 mg/50 mL (per mL): $2.84
Solution (reconstituted) (Leucovorin Calcium Injection)
50 mg (per each): $12.00
100 mg (per each): $19.20 - $24.00
200 mg (per each): $12.00 - $48.00
350 mg (per each): $22.74 - $84.00
500 mg (per each): $103.43 - $120.00
Tablets (Leucovorin Calcium Oral)
5 mg (per each): $1.68 - $2.36
10 mg (per each): $8.41
15 mg (per each): $11.78
25 mg (per each): $11.18 - $24.73
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