Folinic acid - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Vitamins and vitamin-like remedies

Detoxifying agents, including antidotes

Included in the formulation

Natriopholin medec

solution in / in

medac GmbH Germany

АТХ:

V.03.A.F Drugs that reduce the toxicity of cytostatic therapy

Pharmacodynamics:

Folinic acid is a formyl derivative of tetrahydrofolic acid and is an active form of folic acid. Folinic acid participates in a number of metabolic processes, including the synthesis of purines, the synthesis of pyrimidine nucleotides and the metabolism of amino acids. Folinic acid It is used as an antidote for medicines that act as antagonists of folic acid.

There is a biochemical justification for the expediency of the combination of disodium folinate with fluorouracil: fluorouracil inhibits the synthesis of DNA by binding to thymidylate synthetase. The combined action of disodium folinate with fluorouracil is the formation of a stable three-component complex consisting of thymidylate synthetase, 5-fluorodeoxyuridine monophosphate and 5,10-methylenetetrahydrofolate. This results in a more intense block of thymidylate synthetase with increased inhibition of DNA synthesis, resulting in an increase in cytotoxicity compared to that of monotherapy with fluorouracil.

Pharmacokinetics:

The bioequivalence of disodium folinate versus licensed calcium folinate preparations was studied in the framework of pharmacokinetic studies and was evaluated on the basis of compliance of pharmacokinetic parameters for D- and L-folinic acids and for metabolite 5-methyltetrahydrofolic acid. Studies have shown that calcium folinate and disodium folinate are bioequivalent. The volume of folinic acid distribution is not established. When intravenously administered, the peak concentration of D / L-Formyltetrahydrofolic acid, folinic acid in blood plasma is reached after 10 minutes.

The active isomer, L-5-formyltetrahydrofolic acid, in the liver is rapidly converted to 5-methyltetrahydrofolic acid. It is assumed that this conversion is not associated with the presence of dehydrofolate reductase and occurs most rapidly and completely when ingested than with parenteral administration. The inactive isomer D-5-formyltetrahydrofolic acid is excreted unchanged by the kidneys. The active isomer - L-5-formyltetrahydrofolic acid is partially excreted by the kidneys, but is mainly metabolized to folic acid.

Indications:

Intoxication with folic acid antagonists (methotrexate, trimethoprim and pyrimethamine).
Prevention of toxic effects of methotrexate when used in high and high doses.
Colorectal cancer (as part of combination therapy with fluorouracil).

ICD-10

II.C15-C26.C18 Malignant neoplasm of colon

II.C15-C26.C20 Malignant neoplasm of rectum

XIX.T36-T50 Poisoning with medicines, medicines and biological substances

Contraindications:

Hypersensitivity to disodium folinate or any other component in the formulation.
Pernicious anemia or other anemia caused by a deficiency of cyanocobalamin (vitamin B12).
Pregnancy and lactation.

Carefully:

Alcoholism, epilepsy, chronic renal failure, children under 2 years of age (safety and efficacy for children not established).

Pregnancy and lactation:

Contraindicated in pregnancy and during lactation.

Dosing and Administration:

Intravenously sprayed or infused. Do not enter intrathecally.

When choosing a dose and mode of administration in each individual case should be guided by special medical literature.

The administration of antidotes of folic acid antagonists is recommended after the use of methotrexate in a dose ≥ 100 mg / m2 of the body surface of the patient. It should be borne in mind that disodium folinate is used in the same dosages as calcium folinate. After intravenous infusion of high doses of methotrexate (from 500 mg / m2 to 12-15 g / m2), the drug is usually administered 24 hours after the end of methotrexate administration and is continued for 72 hours or until the methotrexate concentration in the blood plasma is less than 0 , 5 μmol / l. Uniform recommendations for the use of the drug does not exist. The use of folinic acid in these cases is recommended to be based on the mandatory determination of the concentration of methotrexate in blood plasma.

To prevent the development of chronic renal failure, hydration (3 l / day) is performed and administered sodium hydrogen carbonate to maintain urine pH at 7 or higher.

In patients with acid urine reaction, exudative effusions, impaired renal function, intestinal obstruction, a higher dose and / or longer duration of treatment may be required, since the excretion of methotrexate in this group of patients may be delayed. When combined with fluorouracil folinic acid is entered:

- in a dose of 500 mg / m intravenously drip for 1-2 hours in combination with intravenous jet fluorouracil administration at a dose of 600 mg / m2 1 hour after the onset of folinic acid infusion or followed by an intravenous 24 hour infusion of fluorouracide at a dose of 2600 mg / m2, once a week for 6 weeks with an interval between repeated courses of 2 weeks.

- at a dose of 200 mg / m2 intravenously slowly (at least 3 minutes) or intravenously drip followed by intravenous administration of fluorouracil at a dose of 370 mg / m2 daily for 5 days with an interval of 4-5 weeks between repeated courses.

- in a dose of 20 mg / m2 intravenously followed by intravenous administration of fluorouracil at a dose of 425 mg / m2 daily for 5 days with an interval of 4-5 weeks between repeated courses.

Folinic acid can be used undiluted in the case of injections, or diluted in the case of infusions. Preparation of a solution for infusions must be carried out in accordance with the rules of asepsis. The drug can be diluted with 0.9% sodium chloride solution.

You can use only a clean solution, with no visible foreign particles and impurities. The drug is intended for single use only. Unused medication is subject to destruction.

Side effects:

Adverse reactions are rare.When parenteral administration, there were cases of hyperthermia. There were individual cases of allergic reactions, including anaphylactic reactions and rash. Dyspeptic disorders are possible with high doses.

Overdose:The drug is not toxic. Even with very high doses of signs of overdose is not observed.

Interaction:

Primidone. Folinic acid when combined, reduces the anticonvulsant activity of primidone.

Phenytoin. Folinic acid, when combined, reduces the anticonvulsant activity of phenytoin.

Phenobarbital. Folinic acid when combined, reduces the anticonvulsant activity of phenobarbital.

Fluorouracil. Folinic acid may lead to an increase in both the therapeutic and toxic effects of fluorouracil, and therefore the combined use of a dose of fluorouracil should be reduced.

Folinic acid in the form of a solution for intravenous administration is pharmaceutically compatible with fluorouracil.

Special instructions:

Folic acid should be used only under the supervision of physicians with experience in the use of antitumor chemotherapeutic drugs.

Except for cases of overdose with folic acid antagonists, folinic acid should not be used concurrently with antitumor drugs - folic acid antagonists (for example, methotrexate) in order to compensate or reduce toxicity, since the therapeutic effect of the antagonists can be leveled.

The concomitant use of folinic acid does not reduce the antibacterial activity of folic acid antagonists such as trimethoprim and pyrimethamine. In the combined use with fluorouracil, the toxicity profile of fluorouracil may be increased or altered by folic acid. The most common manifestations in this case are leukopenia, mucositis, stomatitis and / or diarrhea, which can cause a dose restriction. When carrying out therapy with folinic acid and fluorouracil, the dose of fluorouracil in case of toxic effects should be reduced more than in the case of fluorouracil in monotherapy.

In the treatment of a random overdose of folic acid antagonists, folinic acid should be assigned as soon as possible.With an increase in the time interval between administration of antifolate (methotrexate) and the beginning of folinic acid support, the effectiveness of counteracting toxic manifestations decreases. To determine the optimal dose and duration of therapy with folic acid, monitoring of serum concentrations of methotrexate should be performed. The delay in excretion of methotrexate can be caused by its delay in places of accumulation of pathological fluids (such as ascites, pleural effusion), renal insufficiency, unbalanced hydration, the use of nonsteroidal anti-inflammatory drugs or salicylates. In such cases, the administration of folic acid at higher doses or prolonged administration may be indicated. Folinic acid does not affect the non-hematologic toxicity of methotrexate, such as nephrotoxicity caused by the precipitation of the drug and / or its metabolites in the kidneys.

In patients with epilepsy receiving phenobarbital, phenytoin, primidon, there is a risk of an increased frequency of seizures due to a decrease in the concentration of antiepileptic drugs in the blood.During folinic acid therapy and after its discontinuation it is recommended to carry out clinical observation, control the concentration of antiepileptic drugs in the plasma, and, if necessary, adjust their doses.

The use of folinic acid in pernicious and other megaloblastic anemias caused by a deficiency of cyanocobalamin (vitamin B12) can lead to hematological remission with a simultaneous progression of neurological disorders.

Instructions

Folinic acid (Acidum folinicum)