Antidote (methotrexate rescue / folic acid antagonist)
Calcium folinate (leucovorin) is a reduced folate used mainly as an antidote: it protects cells from the toxic effects of methotrexate and other folic acid antagonists (used in chemotherapy and some infections). It is also used in cerebral folate transport deficiency (FOLR1-CFTD). It is given orally and only under medical supervision.
Also known as: Folinato de cálcio, Leucovorina, Leucovorin
Calcium folinate + phenytoin: antiepileptics may reduce folinate effectiveness — monitor seizure activity.
The FDA leucovorin label documents in the interactions section that certain antiepileptics may reduce folinate effectiveness ("Certain Antiepileptic Drugs: Increase monitoring for seizure activity in leucovorin-treated patients... Certain antiepileptic drugs may reduce the effectiveness of leucovorin"), and the Prontuário Terapêutico records the interaction in the opposite direction — folinate "may reduce the therapeutic activity of phenytoin and phenobarbital". The interaction is therefore bidirectional and clinically relevant in the epileptic patient receiving folinate as methotrexate rescue or for the treatment of folic acid antagonist toxicity: phenytoin may compromise the expected haematological recovery, and folinate may destabilise seizure control. Clinical monitoring for seizures and, when applicable, serum phenytoin level monitoring are the practical guidance. This is not an interaction requiring discontinuation, but active monitoring during the combination.
Calcium folinate + phenytoin: monitor seizure activity — antiepileptics may reduce folinate effectiveness (and folinate may reduce phenytoin activity).
The FDA leucovorin label documents: "Certain Antiepileptic Drugs: Increase monitoring for seizure activity in leucovorin-treated patients... Certain antiepileptic drugs may reduce the effectiveness of leucovorin". The Prontuário records the same in the opposite direction: "May reduce the therapeutic activity of phenytoin and phenobarbital". The interaction is bidirectional and relevant when folinate is used as methotrexate rescue in epileptic patients.
Clinical monitoring for seizures and, when applicable, phenytoin levels.
New-onset seizure, subtherapeutic phenytoin levels or absence of expected haematological recovery.
Monitor seizure activity in patients taking folinate with antiepileptics; monitor response to folinate (e.g., haematological recovery after methotrexate).
DailyMed/FDA (NIH/NLM) — approved Calcium Leucovorin label (Leading Pharma): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c8102043-79f2-421a-b849-94bac19007a6 ; approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7cbd9005-7df2-47ee-adb3-7244c1c69bc3 ; Prontuário Terapêutico do INFARMED (11th ed., 2012) — Calcium folinate, 17
Calcium folinate + phenobarbital: antiepileptics may reduce folinate effectiveness — monitor seizure activity.
The same rationale as the phenytoin interaction applies to phenobarbital: the FDA leucovorin label covers antiepileptics in general ("Certain Antiepileptic Drugs... may reduce the effectiveness of leucovorin") and the Prontuário Terapêutico explicitly names phenytoin and phenobarbital — folinate "may reduce the therapeutic activity" of both. In the epileptic patient undergoing methotrexate rescue or with folic acid antagonist toxicity, phenobarbital may attenuate the response to folinate, and folinate may interfere with seizure control. Clinical monitoring for seizures during the combination is the practical guidance; there is no contraindication to concomitant use, only active monitoring.
Calcium folinate + phenobarbital: monitor seizure activity — antiepileptics may reduce folinate effectiveness (and folinate may reduce phenobarbital activity).
The FDA leucovorin label includes antiepileptics in general ("Certain Antiepileptic Drugs... may reduce the effectiveness of leucovorin") and the Prontuário explicitly records phenytoin and phenobarbital: "May reduce the therapeutic activity of phenytoin and phenobarbital". The clinical relevance is the same as phenytoin — monitoring of seizure activity.
Clinical monitoring for seizures during the combination.
New-onset seizure or absence of expected response to folinate.
Monitor seizure activity and response to folinate in patients on barbiturates.
DailyMed/FDA (NIH/NLM) — approved Calcium Leucovorin label (Leading Pharma): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c8102043-79f2-421a-b849-94bac19007a6 ; approved Phenobarbital label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e ; Prontuário Terapêutico do INFARMED (11th ed., 2012) — Calcium folinate, 17
The label states that the effect of food on folinate pharmacokinetics has not been evaluated; as a highly soluble and well absorbed drug, no relevant food interactions are documented.
May be taken with or without food; keep the same dosing routine.
DailyMed/FDA (NIH/NLM) — approved Calcium Leucovorin label (Leading Pharma): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c8102043-79f2-421a-b849-94bac19007a6
The label states that available data on the intermittent use of folinate during pregnancy have not identified an associated risk of major birth defects or miscarriage; however, chemotherapy administered in combination may cause fetal harm ("Risks with Concomitant Use of leucovorin and Chemotherapy Drugs administered in combination with leucovorin may cause fetal harm").
Use only when the benefit justifies the risk; consider the risks of the associated chemotherapy (consult the cytotoxic prescribing information).
DailyMed/FDA (NIH/NLM) — approved Calcium Leucovorin label (Leading Pharma): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c8102043-79f2-421a-b849-94bac19007a6
The label is explicit: folinate "is not indicated for the treatment of pernicious anemia or other megaloblastic anemias, due to the lack of vitamin B12, because of the risk of progression of neurologic manifestations despite hematologic remission" — using it in B12-deficient megaloblastic anaemia would mask haematological remission and allow neurological progression.
Exclude vitamin B12 deficiency before using folinate in megaloblastic anaemias; do not use as therapy for pernicious anaemia.
DailyMed/FDA (NIH/NLM) — approved Calcium Leucovorin label (Leading Pharma): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c8102043-79f2-421a-b849-94bac19007a6
Data on intermittent use during pregnancy have not identified an associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes; there are no adequate data on use for FOLR1-CFTD in pregnant women and adequate animal reproductive studies have not been conducted (label, section 8.1). Associated chemotherapy may cause fetal harm.
No documented risk with intermittent use; assess risk-benefit, considering the associated chemotherapy.
No data on presence in breast milk, effects on the breastfed infant or on milk production ("There are no data on the presence of leucovorin in human milk") — weigh breastfeeding benefits and the mother's clinical need.
In the oncology setting, follow the contraception recommendations of the associated chemotherapy regimen.
DailyMed/FDA (NIH/NLM) — approved Calcium Leucovorin label (Leading Pharma): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c8102043-79f2-421a-b849-94bac19007a6
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Reduced folate analogue that restores intracellular tetrahydrofolate, enabling DNA and RNA synthesis when dihydrofolate reductase is blocked by folic acid antagonists (methotrexate, trimethoprim). Levoleucovorin is the pharmacologically active isomer.
Levoleucovorin, a reduced folate and the pharmacologically active isomer of folinate (5-formyl-tetrahydrofolate), bypasses DHFR inhibition: "can mitigate the toxic effects of folate antagonists, including methotrexate and other agents that inhibit dihydrofolate reductase (DHFR). Inhibition of DHFR blocks the formation of tetrahydrofolate, an essential cofactor for DNA synthesis and repair" (label). In FOLR1-CFTD it increases 5-MTHF levels (active folate metabolite).
After oral administration, the apparent bioavailability of levoleucovorin is 97% (25 mg), 75% (50 mg) and 37% (100 mg); dextroleucovorin is ~19% (25 mg), 20% (50 mg) and 7% (100 mg). Peak serum folate concentration occurs 1.7 hours after a single oral 15 mg dose ("time to peak serum folate concentration is 1.7 hours"). The effect of food has not been evaluated; highly soluble and well absorbed drug.
Folinate is metabolised to active folate derivatives (including 5-MTHF); levoleucovorin is the active isomer and dextroleucovorin is metabolised and eliminated. The main metabolic pathway involves methenyltetrahydrofolate synthetase (MTHFS) — hence the relative contraindication in deficiency of this enzyme.
No single half-life is documented in the label; folinate is a pro-folate whose activity depends on cellular conversion to active derivatives (levoleucovorin, 5-MTHF), with dose-proportional exposure up to 25 mg and less than proportional above that.
