Folinic Acid (also known as 5-formyl tetrahydrofolic acid or leucovorin) is the 5-formyl derivative of the tetrahydrofolic acid, a necessary co-factor in the body. Leucovorin is used principally as its calcium salt as an antidote to folic acid antagonists which block the conversion of folic acid to folinic acid.

Commercially available leucovorin is composed of a 1:1 racemic mixture of the dextrorotary and levorotary isomers, while levoleucovorin contains only the pharmacologically active Levo-isomer. In vitro, the levo-isomer has been shown to be rapidly converted to the biologically available methyl-tetrahydrofolate form while the dextro form is slowly excreted by the kidneys. Despite this difference in activity, the two commercially available forms have been shown to be pharmacokinetically identical and may be used interchangeably with limited differences in efficacy or side effects (Kovoor et al, 2009).

Mechanism of Action of Folinic Acid

As leucovorin is a derivative of folic acid, it can be used to increase levels of folic acid under conditions favoring folic acid inhibition (following treatment of folic acid antagonists such as methotrexate). Leucovorin enhances the activity of fluorouracil by stabilizing the bond of the active metabolite (5-FdUMP) to the enzyme thymidylate synthetase. Leucovorin is one of several active, chemically reduced derivatives of folic acid. It is useful as an antidote to drugs which act as folic acid antagonists. Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF). The biologically active compound of the mixture is the (-)-l-isomer, known as Citrovorum factor or (-)-folinic acid. Leucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties. Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. Leucovorin has also been used to enhance the activity of fluorouracil.

Indications of Folinic Acid

• Anemia, megaloblastic
• Colorectal cancer
• Folic acid ntagonist overdose
• Methotrexate overdosage
• Methotrexate rescue
• Pneumocystis pneumonia
• Pneumocystis pneumonia prophylaxis
• Toxoplasmosis
• Toxoplasmosis, prophylaxis
• Advanced colorectal cancer
• Advanced esophageal cancers
• Advanced gastric cancer
• Bladder cancers
• Folic acid antagonist overdose
• Pancreatic cancer Metastatic
• Methotrexate toxicity
• Pyrimethamine hematologic toxicity
• For the treatment of osteosarcoma (after high dose methotrexate therapy). Used to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists, and to treat megaloblastic anemias due to folic acid deficiency. Also used in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer.

Folate deficiency due to

• inadequate dietary intake
• MTHFR gene polymorphisms
• malabsorption syndromes, e.g. coeliac and Crohn’s disease
• long-term medication use, e.g. oral contraceptive pill, antacids, folate antagonists
• alcoholism

The Dosage of Folinic Acid

Strengths:  5 mg; 10 mg;15 mg; 25 mg; 10 mg/mL; 100 mg; 350 mg; 200 mg; 50 mg; 500 mg

Colorectal Cancer

• 200 mg/m2, by slow IV injection (minimum 3 minutes), followed by 5-fluorouracil (the manufacturer product information should be consulted), once a day for 5 days or
• 20 mg/m2, IV, followed by 5-fluorouracil (the manufacturer product information should be consulted), once a day for 5 days

Methotrexate Rescue

Leucovorin Rescue

• 15 mg (approximately 10 mg/m2), orally, IV, or IM, every 6 hours for 10 doses; start 24 hours after the beginning of methotrexate infusion (based on a methotrexate dose of 12 to 15 g/m2 IV over 4 hours)

Impaired Methotrexate Elimination or Inadvertent Overdosage

• 10 mg/m2 orally, IV, or IM, every 6 hours until methotrexate level is less than 10(-8) mol

Methotrexate Overdosage

Leucovorin Rescue

• 15 mg (approximately 10 mg/m2), orally, IV, or IM, every 6 hours for 10 doses; start 24 hours after the beginning of methotrexate infusion (based on a methotrexate dose of 12 to 15 g/m2 IV over 4 hours)

Impaired Methotrexate Elimination or Inadvertent Overdosage

• 10 mg/m2 orally, IV, or IM, every 6 hours until methotrexate level is less than 10(-8) mol

Megaloblastic Anemia

• Up to 1 mg, IV or IM, once a day

Pneumocystis Pneumonia

• 20 mg/m2 or 0.5 mg/kg, IV or orally, every 6 hours, continued for 3 days after last trimetrexate dose

Side Effects of Folinic Acid

Important things to remember about the side effects of leucovorin

• The side effects with the treatment of leucovorin are likely attributable to other chemotherapy medications being given in combination with leucovorin.
• When given in combination with fluorouracil (5-FU) the side effects of fluorouracil may be more severe. (see fluorocuracil).
• When given in combination with methotrexate, leucovorin is given to lessen the side effects of methotrexate. (see methotrexate)

The following are possible side effects of Folinic Acid

• Allergic reaction: rash, itching, facial flushing.  Rarely severe.
• Nausea and vomiting (rare)

Drug interactions of Folinic Acid

Fluorouracil: Folinic acid may increase the toxicity associated with fluorouracil if the two are administered together. Some adverse effects that have occurred, particularly in elderly patients, include severe enterocolitis, diarrhea, and dehydration.

Sulfamethoxazole-trimethoprim: A potential drug interaction exists with the concomitant use of sulfamethoxazole-trimethoprim and folinic acid. Folinic acid has been shown to decrease the efficacy of sulfamethoxazole-trimethoprim in the treatment of Pneumocystis jirovecii (formerly known as Pneumocystis carinii), a common cause of pneumonia in AIDS patients.

Pregnancy & Lactation of Folinic Acid

FDA pregnancy category C

Pregnancy

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Lactation

It is not known whether the folinic acid is excreted into human milk. A similar compound, folate (folic acid) is actively excreted into human milk. Adverse effects in nursing infants have not been associated with the use of folic acid during lactation.

References