What is the protocol for calcium folinate (leucovorin) injections in individuals with Methylenetetrahydrofolate Reductase (MTHFR) mutations?

Calcium Folinate Injection Protocols for MTHFR

There is no established medical indication for calcium folinate (leucovorin) injections specifically for MTHFR mutations in otherwise healthy individuals, and routine MTHFR genetic testing is not clinically recommended. 1

Why MTHFR Testing and Injectable Folinate Are Not Indicated

• MTHFR genetic testing should not be ordered as it provides no clinically actionable information beyond what direct homocysteine measurement provides, and thrombotic risk should not be attributed to heterozygous MTHFR status alone. 1

• The American College of Cardiology recommends measuring plasma homocysteine levels directly rather than genotype testing, as this is more clinically useful, with cardiovascular risk beginning to increase when fasting plasma homocysteine exceeds 10 μmol/L. 1

• Injectable calcium folinate (leucovorin) is FDA-approved only for specific indications: methotrexate rescue after high-dose chemotherapy, colorectal cancer treatment in combination with 5-fluorouracil, and megaloblastic anemia due to folate deficiency (up to 1 mg daily maximum). 2

Appropriate Management of MTHFR-Related Hyperhomocysteinemia

Oral Supplementation Is the Standard Approach

• For moderate hyperhomocysteinemia (15-30 μmol/L), oral folic acid 0.4-1 mg daily reduces homocysteine by 25-30%, with vitamin B12 0.02-1 mg daily providing an additional 7% reduction. 1

• For patients with MTHFR 677TT genotype specifically, 5-methyltetrahydrofolate (5-MTHF) is preferred over folic acid because it bypasses the deficient enzyme and doesn't require conversion by MTHFR. 1, 3, 4

• Research demonstrates that cells with low MTHFR activity require 5-MTHF supplementation to overcome metabolic defects, as folic acid supplementation alone does not increase intracellular 5-MTHF levels in these individuals. 4

Dosing Considerations by Genotype

• Individuals with MTHFR 677TT genotype show significantly higher reductions in serum homocysteine with folate supplementation compared to those with 677CC or 677CT genotypes. 5

• Individuals with MTHFR 677CT genotype appear to benefit more from folinic acid than 5-methylfolate supplementation based on homocysteine reduction. 5

• Both folinic acid and 5-methylfolate effectively reduce homocysteine levels, though folinic acid produces higher serum folate levels without additional homocysteine-lowering benefit. 5

Critical Safety Considerations

When Injectable Folinate IS Indicated

Injectable calcium folinate is only appropriate in these specific scenarios:

• Methotrexate rescue: 15 mg IV/IM every 6 hours for 10 doses starting 24 hours after methotrexate infusion, with dose adjustments based on methotrexate levels and renal function. 2

• Severe MTHFR deficiency with neurological involvement: In patients with enzyme activity ≤1% of controls and undetectable CSF 5-MTHF, oral 5-MTHF (calcium mefolinate) at 15-60 mg/kg/day is required, as folic acid and calcium folinate do not increase CSF 5-MTHF levels. 3

• Megaloblastic anemia: Up to 1 mg daily parenterally when oral administration is not feasible; doses exceeding 1 mg provide no additional benefit. 2

Absolute Contraindications

• Never administer leucovorin intrathecally - this may be harmful or fatal. 2

• Do not exceed 160 mg of leucovorin IV per minute (16 mL of 10 mg/mL solution) due to calcium content. 2

• Always check vitamin B12 levels before starting folate supplementation to avoid masking B12 deficiency while neurological damage progresses. 1

Special Populations

• Patients with renal disease may require higher oral doses of folic acid (1-5 mg/day), particularly those on dialysis to replace dialysis losses. 1

• Neonates with stroke and MTHFR mutation: It is reasonable to give oral folate and B vitamins to normalize homocysteine levels (Class IIa recommendation). 1

• Patients with established vascular disease or diabetes: Combination therapy with vitamins B6, B12, and folic acid reduced stroke risk by 25% (RR 0.75; 95% CI 0.59-0.97). 1

Common Clinical Pitfalls

• Do not order MTHFR genetic testing as part of routine thrombophilia workup or for asymptomatic individuals - this is a waste of resources and provides no actionable information. 1

• Do not use injectable folinate for routine MTHFR supplementation when oral formulations are appropriate and effective. 2

• Do not assume all folate formulations are equivalent - patients with MTHFR 677TT genotype specifically benefit from 5-MTHF over folic acid. 1, 3, 4

• Do not supplement folate without B12 assessment - this can mask pernicious anemia while allowing irreversible neurological damage. 1