Leucovorin

Mechanism-of-action class: Enzyme Interactions.

• Leucovorin calcium rescue is indicated after high dose methotrexate therapy in osteosarcoma. Leucovorin calcium is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent over dosages of folic acid antagonists.

• Leucovorin is improper therapy for pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B 12 . A hematologic remission may occur while neurologic manifestations continue to progress.contraindicated

Advanced Colorectal Cancer Either of the following two regimens is recommended: 1. Leucovorin is administered at 200 mg/m 2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-fluorouracil at 370 mg/m 2 by intravenous injection. 2. Leucovorin is administered at 20 mg/m 2 by intravenous injection followed by 5-fluorouracil at 425 mg/m 2 by intravenous injection. 5-Fluorouracil and leucovorin should be administered separately to avoid the formation of a precipitate. Treatment is repeated daily for five days. This five-day treatment course may be repeated at 4 week (28-day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course. In subsequent treatment course, the dosage of 5-fluorouracil should be adjusted based on patient tolerance of the prior treatment course. The daily dosage of 5-fluorouracil should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity (see PRECAUTIONS : Laboratory Tests ). For patients who experienced no toxicity in the prior treatment course, 5-fluorouracil dosage may be increased by 10%. Leucovorin dosages are not adjusted for toxicity.

In the treatment of accidental overdosages of folic acid antagonists, intravenous leucovorin should be administered as promptly as possible. As the time interval between antifolate administration (e.g., methotrexate) and leucovorin rescue increases, leucovorin's effectiveness in counteracting toxicity decreases. In the treatment of accidental overdosages of intrathecally adminstered folic acid antagonists, do not adminster leucovorin intrathecally. LEUCOVORIN MAY BE HARMFUL OR FATAL IF GIVEN INTRATHECALLY. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin. Delayed methotrexate excretion may be caused by a third space fluid accumulation (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration. Under such circumstances, higher doses of leucovorin or prolonged administration may be indicated. Doses higher than those recommended for oral use must be given intravenously. Because of the benzyl alcohol contained in certain diluents used for reconstituting Leucovorin Calcium for Injection, when doses greater than 10 mg/m 2 are administered, Leucovorin Calcium for Injection should be reconstituted with Sterile Water for Injection, USP, and used immediately (see DOSAGE AND ADMINISTRATION section). Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin should be injected intravenously per minute (16 mL of a 10 mg/mL, or 8 mL of a 20 mg/mL solution per minute). Leucovorin enhances the toxicity of 5-fluorouracil.

Allergic sensitization, including anaphylactoid reactions and urticaria, has been reported following the administration of both oral and parenteral leucovorin. No other adverse reactions have been attributed to the use of leucovorin per se . The following table summarizes significant adverse events occurring in 316 patients treated with the leucovorin/5-fluorouracil combinations compared against 70 patients treated with 5-fluorouracil alone for advanced colorectal carcinoma. These data are taken from the Mayo/NCCTG large multicenter prospective trial evaluating the efficacy and safety of the combination regimen. PERCENTAGE OF PATIENTS TREATED WITH LEUCOVORIN/FLUOROURACIL FOR ADVANCED COLORECTAL CARCINOMA REPORTING ADVERSE EXPERIENCES OR HOSPITALIZED FOR TOXICITY (High LV*) /5-FU (Low LV † ) /5-FU 5-FU Alone (N=155) (N=161) (N=70) Any ‡ Grade 3 +§ Any ‡ Grade 3 +§ Any ‡ Grade 3 +§ (%) (%) (%) (%) (%) (%) Leukopenia 69 14 83 23 93 48 Thrombocytopenia 8 2 8 1 18 3 Infection 8 1 3 1 7 2 Nausea 74 10 80 9 60 6 Vomiting 46 8 44 9 40 7 Diarrhea 66 18 67 14 43 11 Stomatitis 75 27 84 29 59 16 Constipation 3 0 4 0 1 - Lethargy/Malaise/Fatigue 13 3 12 2 6 3 Alopecia 42 5 43 6 37 7 Dermatitis 21 2 25 1 13 - Anorexia 14 1 22 4 14 - Hospitalization for Toxicity 5% 15% 7% * High LV = Leucovorin 200 mg/m 2 † Low LV = Leucovorin 20 mg/m 2 ‡ Any = percentage of patients reporting toxicity of any severity § Grade 3+ = percentage of patients reporting toxicity of Grade 3 or higher

Pregnancy Teratogenic Effects: Pregnancy Category C Adequate animal reproduction studies have not been conducted with leucovorin. It is also not known whether leucovorin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Leucovorin should be given to a pregnant woman only if clearly needed.

Excessive amounts of leucovorin may nullify the chemotherapeutic effect of folic acid antagonists.

• Sep 14, 1987ANDAANDA089384Hikma
• Sep 24, 1987ANDAANDA071198Barr
• Sep 24, 1987ANDAANDA071199Barr
• Mar 28, 1988ANDAANDA089717Hikma
• Feb 22, 1993ANDAANDA072733Hikma
• Feb 22, 1993ANDAANDA072734Hikma
• Feb 22, 1993ANDAANDA072735Hikma
• Feb 3, 2026NDANDA220406Avyxa Holdings

1. 1Diarrhoea1,7489.4%
2. 2Nausea1,3427.2%
3. 3Vomiting1,1015.9%
4. 4Neutropenia1,0665.8%
5. 5Pyrexia9815.3%
6. 6Off Label Use9114.9%
7. 7Fatigue8584.6%
8. 8Disease Progression7504.1%
9. 9Drug Ineffective7023.8%
10. 10Dyspnoea6943.7%
11. 11Asthenia6583.6%
12. 12Abdominal Pain6443.5%
13. 13Febrile Neutropenia6293.4%
14. 14Thrombocytopenia6093.3%
15. 15Dehydration5763.1%

Recent PubMed references pinned to Leucovorin as a MeSH major topic. Citations link to pubmed.ncbi.nlm.nih.gov.

• Glucarpidase efficacy in mitigating methotrexate toxicity is unaffected by concurrent administration of folinic acid.
  Cancer chemotherapy and pharmacology · 2026 · Wahlestedt M, Hansson K, Bill A, et al.
  PMID 42101491DOI 10.1007/s00280-026-04880-2
• Emerging Discussions on Folinic Acid and Acetaminophen in Autism.
  Journal of autism and developmental disorders · 2026 · Balkanas M, Durcan G, Doğangün B, et al.
  PMID 41854993DOI 10.1007/s10803-026-07307-2
• Efficient and Simultaneous LC-MS/MS Detection of N-Nitroso and Di-Nitroso Leucovorin in Leucovorin Drug Products: Method Development and Validation.
  Rapid communications in mass spectrometry : RCM · 2026 · Yalamanchili J, Ganja H, Salakolusu S, et al.
  PMID 41807320DOI 10.1002/rcm.70049
• Clinical concerns and considerations for leucovorin use in autism spectrum disorder.
  Current opinion in pediatrics · 2026 · Howard C, Mekhail J, Ravikoff LM, et al.
  PMID 41670435DOI 10.1097/MOP.0000000000001547
• Home-based treatment of low-risk gestational trophoblastic neoplasia with 8-day methotrexate/folinic acid.
  Gynecologic oncology · 2026 · Maesta I, Silva VAR, Costa RAA, et al.
  PMID 41380306DOI 10.1016/j.ygyno.2025.12.002
• Valproic acid-induced placental toxicity: mechanistic insights and the therapeutic potential of bioactive folates.
  Naunyn-Schmiedeberg's archives of pharmacology · 2026 · Shehzadi N, Ahmad M, Baqir F, et al.
  PMID 41251752DOI 10.1007/s00210-025-04798-1
• Treatment of methanol toxicity through ethanol and folinic acid: A mathematical study.
  Journal of theoretical biology · 2026 · Sardar S, Roy PK, Ahammed SM, et al.
  PMID 41224143DOI 10.1016/j.jtbi.2025.112304
• Nanoliposomal Irinotecan With Fluorouracil and Folinic Acid in Older Versus Younger Patients With Unresectable Pancreatic Cancer: The Multicenter NAPOLEON-2 Study.
  Asia-Pacific journal of clinical oncology · 2026 · Kakihara A, Takeshita S, Shimokawa M, et al.
  PMID 41186933DOI 10.1111/ajco.70041

The 10 most recently updated of 2,272 ClinicalTrials.gov registrations naming Leucovorin as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

• Substudy 06E: Umbrella Study of Combination Therapies in Esophageal Cancer (MK-3475-06E/KEYMAKER-U06)
  Recruiting · Phase 1 · Phase 2 · Interventional · 298 enrolled · Merck Sharp & Dohme LLC
  NCT06780111updated 2026-06-12
• Targeted Therapy Directed by Genetic Testing in Treating Patients With Locally Advanced or Advanced Solid Tumors, The ComboMATCH Screening Trial
  Recruiting · Phase 2 · Interventional · 2,900 enrolled · National Cancer Institute (NCI)
  NCT05564377updated 2026-06-12
• A Study to Assess Intravenous (IV) Telisotuzumab Adizutecan in Combination With Fluorouracil, Folinic Acid, and Oxaliplatin (FOLFOX) Compared to Standard of Care in Adult Participants With First-Line Metastatic Pancreatic Ductal Adenocarcinoma
  Recruiting · Phase 2 · Phase 3 · Interventional · 900 enrolled · AbbVie
  NCT07490301updated 2026-06-12
• Neratinib In Combination With Chemotherapy/Trastuzumab/Pembrolizumab In HER2 Gastroesophageal Cancer
  Active not recruiting · Phase 2 · Interventional · 8 enrolled · H. Lee Moffitt Cancer Center and Research Institute
  NCT06109467updated 2026-06-12
• A Study to Evaluate the Adverse Events, and Efficacy of Intravenous (IV) of Telisotuzumab Adizutecan in Combination With IV Oxaliplatin, Fluorouracil, Folinic Acid/Leucovorin, Bevacizumab, Panitumumab in Adult Participants With Metastatic Colorectal Cancer
  Recruiting · Phase 2 · Interventional · 390 enrolled · AbbVie
  NCT06820463updated 2026-06-12
• A Study of Fruquintinib Plus FOLFIRI as Second-Line Treatment for Participants With Metastatic Colorectal Cancer (FRUITFUL)
  Recruiting · Phase 2 · Interventional · 60 enrolled · SCRI Development Innovations, LLC
  NCT07011576updated 2026-06-12
• Personalize (Signature Driven) Neoadjuvant Chemotherapy Trial for Patients With Resectable Borderline Pancreatic Ductal Adenocarcinoma.
  Not yet recruiting · Phase 2 · Interventional · 110 enrolled · Federation Francophone de Cancerologie Digestive
  NCT07616362updated 2026-06-11
• A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer
  Active not recruiting · Phase 3 · Interventional · 841 enrolled · Pfizer
  NCT04607421updated 2026-06-11
• First in Human Study of AZD9592 in Solid Tumors
  Active not recruiting · Phase 1 · Interventional · 167 enrolled · AstraZeneca
  NCT05647122updated 2026-06-11
• Chemotherapy Followed by Pelvic Reirradiation Versus Chemotherapy Alone as Pre-operative Treatment for Locally Recurrent Rectal Cancer
  Active not recruiting · Phase 3 · Interventional · 58 enrolled · University Hospital, Bordeaux
  NCT03879109updated 2026-06-11

Frequently asked questions

How does Leucovorin work?

Mechanism-of-action class: Enzyme Interactions.

What is Leucovorin used for?

According to FDA labeling, Leucovorin carries indications including: Leucovorin calcium rescue is indicated after high dose methotrexate therapy in osteosarcoma. Leucovorin calcium is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent over dosages of folic acid antagonists.. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.

What class of drug is Leucovorin?

Leucovorin is classified as Folate Analog, Enzyme Interactions, Cellular Activity Alteration.

What are the brand names for Leucovorin?

Leucovorin is marketed under brand names including Vykoura.

What are the contraindications for Leucovorin?

Leucovorin labeling lists contraindications including: Leucovorin is improper therapy for pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B 12 . A hematologic remission may occur while neurologic manifestations continue to progress.. Always consult the full prescribing information and a clinician.