Levofolinic Acid

Levofolinic acid (L-5-formyltetrahydrofolate, as calcium levofolinate) is the pharmacologically active isomer of folinic acid and an essential coenzyme for nucleic acid synthesis in cytotoxic therapy. It does not need to be reduced by dihydrofolate reductase (DHFR) before it takes part in reactions that use folates as a source of one-carbon units.

Mechanism of Action

• Rescue from folic acid antagonists: methotrexate and similar medicines block DHFR. Levofolinic acid is a pre-reduced source of tetrahydrofolate, so it bypasses the block and supplies the coenzyme forms of folate, “rescuing” normal cells and preventing the toxicity.
• Competition for transport: the L-form of folinic acid and folate antagonists share the same membrane transport system and compete for uptake into cells, which promotes the efflux of the antagonist. It also protects cells by replacing their depleted folate pool.
• Modulation of 5-fluorouracil: 5-fluorouracil inhibits thymidylate synthase, a key enzyme in pyrimidine synthesis. Levofolinic acid increases the intracellular folate pool, which stabilises the complex of 5-fluorouracil with thymidylate synthase and raises the cytotoxic activity.
• Intracellular activation: in the body it is converted to L-5-methyltetrahydrofolate (5-methyl-THF), the main circulating active reduced folate. Both forms are polyglutamated inside cells by folylpolyglutamate synthetase, and the folylpolyglutamates are active in reactions that need reduced folates.

Pharmacokinetics

• Absorption: after intramuscular injection of the aqueous solution, systemic availability is comparable to intravenous injection, though peak concentrations are lower. Absolute bioavailability after intravenous injection is 100%; that after intramuscular injection has not been established. Enteral absorption is saturable.
• Distribution: the volume of distribution and plasma protein binding have not been determined in the SmPC; DrugBank reports no binding to serum albumin. After a rapid 15 mg intravenous dose in healthy men, peak total tetrahydrofolate was 1,722 ng/mL and peak L-5-methyl-THF 275 ng/mL, at about 0.9 hours.
• Metabolism: the main metabolite is L-5-methyl-THF, formed mainly in the liver and intestinal mucosa.
• Elimination: the half-life of active levofolinate is 32–35 minutes, and the terminal half-life of the active metabolites about 6 hours (total THF 5.1 hours, L-5-methyl-THF 6.8 hours) after intravenous or intramuscular dosing. 80–90% is excreted in urine, as inactive 5- and 10-formyl-tetrahydrofolates, and 5–8% in faeces.

Indications of the two Spanish national products covered here:

• Isovorin 175 mg powder for solution for injection and for infusion:
  • to reduce the toxicity and counteract the action of folic acid antagonists such as methotrexate in cytotoxic therapy, and in overdose (in cytotoxic therapy this is commonly known as calcium folinate rescue);
  • in combination with 5-fluorouracil in cytotoxic therapy.
• Isovorin 5 mg and 7.5 mg tablets:
  • treatment of megaloblastic anaemia due to folate deficiency;
  • to reduce the toxicity and counteract the action of folic acid antagonists such as methotrexate in cytotoxic therapy, and in overdose (calcium folinate rescue).

• Hypersensitivity to levofolinic acid or to any of the excipients.
• Pernicious anaemia and other megaloblastic anaemias secondary to vitamin B12 deficiency.
• Use of levofolinic acid with methotrexate or 5-fluorouracil in pregnancy and breastfeeding is generally contraindicated (see Pregnancy, Breastfeeding and Fertility, and the SmPCs of those medicines).

Reactions with levofolinic acid itself are uncommon to very rare. When it is given with 5-fluorouracil, the safety profile mainly reflects the toxicity of 5-fluorouracil, which levofolinic acid potentiates.

Uncommon (≥1/1,000 to <1/100): pyrexia (listed this way in the injection SmPC; the tablet SmPC lists it with unknown frequency).

Rare (≥1/10,000 to <1/1,000): insomnia, agitation and depression (after high doses), convulsions and/or syncope, and gastrointestinal disorders (after high doses).

Very rare (<1/10,000): hypersensitivity reactions including anaphylactic reactions and anaphylactic shock, and urticaria.

Stevens-Johnson syndrome and toxic epidermal necrolysis, some fatal, have been reported in patients given calcium levofolinate together with other medicines known to be linked with these disorders; a contribution of levofolinate cannot be excluded.

With 5-fluorouracil (additional reactions)

Very common (≥1/10): nausea, vomiting, diarrhoea, stomatitis and cheilitis; bone marrow failure (including fatal cases) with anaemia, neutropenia, leukopenia and thrombocytopenia; mucositis (fatal cases have occurred).

Common (≥1/100 to <1/10): palmar-plantar erythrodysaesthesia.

Not known: hyperammonaemia.

Deaths have occurred from gastrointestinal toxicity (mainly mucositis and diarrhoea) and myelosuppression. In patients with diarrhoea, rapid clinical deterioration leading to death can occur.

• Folic acid antagonists (co-trimoxazole, pyrimethamine): the effect of the antagonist may be reduced or completely neutralised.
• Antiepileptics (phenobarbital, phenytoin, succinimides, primidone): high doses of folates can partly counteract the antiepileptic effect and increase seizure frequency; plasma levels of enzyme-inducing anticonvulsants may fall because of increased liver metabolism. Monitor clinically during and after levofolinic acid, check plasma levels where possible, and adjust the antiepileptic dose if needed.
• Chloramphenicol: given with folic acid in folate-deficient patients, it may antagonise the blood-forming response to folic acid.
• Intrathecal methotrexate: with intrathecal methotrexate and d,l-folinic acid together, cerebrospinal fluid methotrexate levels were 1 to 3 times lower than usual (preliminary animal and human data), because small amounts of 5-methyltetrahydrofolate enter the fluid. High doses of levofolinic acid may therefore reduce the efficacy of intrathecal methotrexate.
• 5-Fluorouracil, tegafur and capecitabine: levofolinic acid increases both the efficacy and the toxicity of these medicines.
• Other medicines that interact with methotrexate (for example, those that impair its elimination or bind to serum albumin) should always be considered when laboratory abnormalities or clinical toxicity appear.
• Pharmaceutical incompatibility: do not mix levofolinic acid with 5-fluorouracil in the same infusion or injection, as a precipitate can form.

The two products are used differently. The injection (powder for solution) is for intravenous and intramuscular use only, never intrathecal, and is used with methotrexate or 5-fluorouracil under the direct supervision of a physician experienced in antineoplastic chemotherapy. The tablets are taken by mouth.

Injection: Method of Administration

• Intravenous or intramuscular use only; never intrathecal.
• By intravenous injection, give no more than 160 mg of calcium levofolinate per minute because of the calcium content of the solution.
• For intravenous infusion the reconstituted solution may be diluted before use; see SmPC sections 6.3 and 6.6 for reconstitution and dilution.

Injection: Methotrexate Rescue

• Protocol: the rescue regimen depends largely on the dose and method of the intermediate- or high-dose methotrexate protocol, which therefore determines the levofolinic acid regimen.
• When: rescue is necessary when methotrexate exceeds 500 mg/m² of body surface area, and should be considered at 100–500 mg/m².
• Usual schedule (illustrating regimens used in adults, elderly patients and children): a first dose of 7.5 mg (3 to 6 mg/m²) 12–24 hours (at most 24 hours) after the start of the methotrexate infusion, then the same dose every 6 hours for 72 hours. After several parenteral doses, treatment may be switched to the oral form.
• Parenteral route: rescue must be given parenterally in malabsorption syndromes or other gastrointestinal disorders when enteral absorption is not assured. Doses above 12.5 to 25 mg should be given parenterally because enteral absorption is saturable.
• Supportive measures: prompt methotrexate excretion (a high urine output and alkalinised urine) is an integral part of rescue; renal function is monitored with daily serum creatinine.
• Residual methotrexate level: measured 48 hours after the start of the methotrexate infusion. If it is above 0.5 µmol/L, additional levofolinic acid is given every 6 hours for 48 hours or until levels fall below 0.05 µmol/L: 7.5 mg/m² at 0.5 µmol/L or more, 50 mg/m² at 1.0 µmol/L or more, and 100 mg/m² at 2.0 µmol/L or more.

Injection: Combination With 5-Fluorouracil

Different regimens and doses are used, and none has been shown to be optimal. The following were used in adults and elderly patients with advanced or metastatic colorectal cancer and are given as examples; there are no data in children.

• Two-weekly regimen: levofolinic acid 100 mg/m² by intravenous infusion over 2 hours, then 5-fluorouracil 400 mg/m² as an intravenous bolus and a 22-hour infusion of 5-fluorouracil 600 mg/m², on days 1 and 2 every 2 weeks.
• Weekly regimen: 10 mg/m² by intravenous bolus, or 100 to 250 mg/m² by intravenous infusion over 2 hours, plus 5-fluorouracil 500 mg/m² as an intravenous bolus in the middle or at the end of the infusion.
• Monthly regimen: 10 mg/m² by intravenous bolus, or 100 to 250 mg/m² by intravenous infusion over 2 hours, followed at once by 5-fluorouracil 425 or 370 mg/m² as an intravenous bolus for 5 consecutive days.

The dose of 5-fluorouracil and the treatment-free interval may need to change with the patient’s condition, clinical response and dose-limiting toxicity; the levofolinic acid dose need not be reduced. The number of cycles is left to the physician.

Injection: Other Folic Acid Antagonists

• Trimethoprim toxicity: after stopping trimethoprim, 1.5 to 5 mg of levofolinic acid daily until the blood count is normal.
• Pyrimethamine toxicity: with high doses or prolonged low-dose treatment, 2.5 to 25 mg of levofolinic acid at the same time, guided by peripheral blood counts.
• Trimetrexate: to prevent toxicity, give levofolinic acid every day during trimetrexate and for 72 hours after the last dose, either intravenously at 10 mg/m² over 5 to 10 minutes every 6 hours up to 40 mg/m² a day, or orally as four doses of 20 mg/m² at equal intervals. Adjust the daily dose to the blood toxicity of trimetrexate. After an overdose (possibly with trimetrexate above 90 mg/m² without folinate), give 20 mg/m² every 6 hours for 3 days after stopping trimetrexate.

Tablets (5 mg and 7.5 mg)

• Megaloblastic anaemia due to folate deficiency: 2.5 to 5 mg every 24 hours (generally one tablet a day), usually for 10–15 days.
• Maximum single oral dose: 22.5 mg, because intestinal absorption is saturable.
• Methotrexate rescue: the methotrexate protocol sets the regimen, with the same principles as for the injection (rescue needed above 500 mg/m² of methotrexate and considered at 100–500 mg/m²; usual first dose 7.5 mg (3 to 6 mg/m²) 12–24 hours after the start of the methotrexate infusion, repeated every 6 hours for 72 hours; parenteral dosing in malabsorption or above 12.5 to 25 mg). The tablet SmPC gives further detail.

Special Populations

• Children: the rescue regimens illustrate use in adults, elderly patients and children; there are no data on the 5-fluorouracil combination in children.
• Elderly and debilitated patients: they are at particular risk of 5-fluorouracil toxicity; start with a reduced 5-fluorouracil dose in elderly patients and in those who have had radiotherapy.
• Renal impairment: existing or methotrexate-induced kidney impairment may delay methotrexate excretion and increase the need for higher doses or longer use of levofolinic acid.

Never Give Intrathecally

Levofolinic acid (as calcium levofolinate) must be given only intramuscularly or intravenously and must not be given intrathecally. Deaths have been recorded when calcium levofolinate was given intrathecally after an intrathecal methotrexate overdose.

Supervision and Vitamin B12 Deficiency

The injection should be used with methotrexate or 5-fluorouracil only under the direct supervision of a physician experienced in antineoplastic chemotherapy. Levofolinic acid may mask pernicious anaemia and other megaloblastic anaemias caused by vitamin B12 deficiency. Macrocytosis caused by cytotoxic agents (hydroxycarbamide, cytarabine, mercaptopurine, tioguanine) should not be treated with folinic acid.

Methotrexate Rescue

• Accidental overdose of folate antagonists such as methotrexate must be treated promptly as a medical emergency. The longer the interval between methotrexate and levofolinic acid rescue, the less effective the rescue is.
• Levofolinic acid does not affect the non-blood toxicity of methotrexate, such as kidney damage from precipitation of methotrexate or its metabolite. Patients with delayed methotrexate elimination are prone to reversible renal failure and all methotrexate-related toxicities.
• Excessive levofolinic acid should be avoided, because it may weaken the antitumour activity of methotrexate, especially in central nervous system tumours where levofolinic acid accumulates after repeated treatment.
• Methotrexate resistance caused by reduced membrane transport also means resistance to folinic acid rescue, because both use the same transport system.
• Check serum creatinine and methotrexate levels at least once a day. In methotrexate overdose or delayed excretion, monitor urine pH to keep it at 7.0 or above.

Combination With 5-Fluorouracil

• Levofolinic acid can increase the toxicity of 5-fluorouracil, particularly in elderly or debilitated patients. The most common effects are leukopenia, mucositis, stomatitis and/or diarrhoea, which may limit the dose. When the two are given together, the 5-fluorouracil dose should be lower than when it is used alone.
• Do not start or continue the combination in a patient with any symptom of gastrointestinal toxicity until all such symptoms have completely resolved. Diarrhoea may signal gastrointestinal toxicity, and rapid deterioration leading to death can occur, so patients with diarrhoea need careful monitoring. If diarrhoea and/or stomatitis occurs, reduce the 5-fluorouracil dose.
• Check a full blood count with platelets before every cycle, weekly during the first two cycles and then once per cycle; check electrolytes and liver function before each cycle. Reduce 5-fluorouracil by 20% for moderate diarrhoea and/or stomatitis (leukocyte nadir 1,000–1,900/mm³, platelet nadir 25,000–75,000/mm³) and by 30% for severe (leukocyte nadir below 1,000/mm³, platelet nadir below 25,000/mm³).
• Delay the next cycle if leukocytes are below 4,000/mm³ or platelets below 130,000/mm³; start only when both are at or above these figures, and stop treatment if they are not reached within two weeks. If there is no toxicity, the 5-fluorouracil dose may be increased by 10%.
• Monitor calcium levels; give calcium supplements if they are low.

Antiepileptic Treatment

High doses of folates can partly antagonise phenobarbital, phenytoin, succinimides and primidone. Monitor clinically during and after levofolinic acid and adjust the antiepileptic dose if needed.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no adequate, well-controlled clinical studies in pregnant women, and animal studies are insufficient for reproductive toxicity; there is no indication that folic acid is harmful in pregnancy. Methotrexate should be given in pregnancy only under strict conditions that weigh the benefit to the mother against the danger to the foetus. 5-Fluorouracil and methotrexate are generally contraindicated in pregnancy and breastfeeding, as is the combined use of levofolinic acid with either.
• Breastfeeding: it is not known whether calcium folinate passes into human milk. Calcium levofolinate may be used during breastfeeding if necessary for its therapeutic indications.
• Fertility: folinic acid is an intermediate in folic acid metabolism and occurs naturally in the body. No animal fertility studies have been done with calcium folinate.

Sodium and Lactose

The injection contains less than 1 mmol (23 mg) of sodium per dose, that is, it is essentially sodium-free. The tablets contain lactose anhydrous (211.3 mg in the 5 mg tablet and 316 mg in the 7.5 mg tablet); patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them.

Effect on Driving

The influence on the ability to drive and use machines is nil or negligible.

• Powder for solution (Isovorin 175 mg): do not store above 30 °C. Keep the vial in the original package to protect it from light. Supplied in clear Type I glass vials with bromobutyl rubber stoppers and green flip-off aluminium/plastic caps, one vial per pack.
• Tablets (Isovorin 5 mg and 7.5 mg): store below 25 °C and protect from light.
• No refrigeration is needed for the unopened products.

• Powder for solution: 2 years unopened.
• After reconstitution: with bacteriostatic 0.9% saline containing benzyl alcohol, chemically and physically stable for one week at room temperature or four weeks refrigerated. With 0.9% saline, 5% glucose or glucose-saline, use within 24 hours, kept refrigerated, for reasons of sterility. See SmPC sections 6.3 and 6.6 for further details on dilution.
• Tablets: 2 years.

Prescription only (Rx). The injection is used with methotrexate or 5-fluorouracil under the supervision of a physician experienced in antineoplastic chemotherapy and is given in a hospital or clinic, so it is supplied to the hospital or clinic that administers it. The tablets are taken by the patient and are supplied to the patient or to the treating clinic on prescription.