Calcium folinate - instructions for use, dose, side effects, contraindications

A restored form of folic acid, readily metabolized to other reduced derivatives of the latter (eg, tetrahydrofolates). It is an active metabolite of folic acid and a necessary coenzyme for the synthesis of nucleic acids in cytotoxic therapy. Since this process does not require the participation of dihydrofolate reductase, it is not disturbed by blocking this enzyme with folic acid antagonists (inhibitors of dihydrofolate reductase), thereby supporting the synthesis of thymidine and purine and, respectively, DNA, RNA and protein.It can limit the effect of methotrexate on normal cells, competing for transport processes inside them. When administered at the appropriate time, it protects the bone marrow and GIT cells from the toxic effect of methotrexate, which makes it possible to use methotrexate in higher doses. Nephrotoxicity of methotrexate has no effect.

Calcium folinate is often used for biochemical modulation of fluorouracil in order to enhance its cytotoxic effect. Fluorouracil inhibits thymidylate synthetase, a key enzyme involved in the biosynthesis of pyrimidine. Calcium folinate enhances the inhibition of thymidine synthetase by increasing the intracellular folate pool, thereby stabilizing the fluorouracil-thymidine synthetase complex and increasing its activity. Intravenous administration of calcium folinate is prescribed for the prevention and treatment of folate deficiency, when this condition can not be corrected by oral administration of the drug, for example, with complete parenteral nutrition and severe malabsorption syndrome. Also calcium folinate is indicated for the treatment of megaloblastic anemia caused by a deficiency of folic acid, if oral administration of the drug is not possible.

Pharmacokinetics:

After intramuscular administration of the aqueous solution, the systemic bioavailability is comparable to that after intravenous administration. However, C_max in the blood plasma lower with intramuscular injection. Quickly absorbed from the gastrointestinal tract (saturation of absorption is achieved when administered at doses of more than 25 mg). Absorption - 97% with a dose of 25 mg, 75% with a dose of 50 mg and 37% with a dose of 100 mg.

C_max in the blood plasma of the parent compound (formitetetrahydrofolic acid, folinic acid) is reached 10 minutes after intravenous administration. In moderation, it penetrates the blood-brain barrier, accumulates in the liver.

Calcium folinate is a racemate, where the active enantiomer is the levorotatory form (L-5-formyltetrahydrofolate).

The main metabolite of calcium folinate is 5-methyltetrahydrofolic acid, which is mainly formed in the liver and interstitial tissue.

With parenteral administration, the elimination half-life is 32-35 minutes for the active L-form and 352-485 minutes for the inactive D-form. The entire half-life active metabolites is about 6 hours (after intravenous and intramuscular injection).80-90% is excreted by the kidneys (5- and 10-formyltetrahydrofolates as inactive metabolites), 5-8% - through the intestine.

Indications:

Intoxication with folic acid antagonists (methotrexate, trimethoprim, pyrimethamine); megaloblastic anemia against a background of folic acid deficiency with ineffectiveness of oral therapy with folic acid preparations (including malabsorption syndrome, malnutrition, congenital insufficiency of dihydrofolate reductase); cancer of the large intestine, including the rectum (as an auxiliary therapy).

ICD-10

II.C15-C26.C18 Malignant neoplasm of colon

II.C15-C26.C19 Malignant neoplasm of rectosigmoidal joint

II.C76-C80.C78.5 Secondary malignant neoplasm of large intestine and rectum

III.D50-D53.D52 Folic deficiency anemia

XIX.T36-T50.T37 Poisoning by other anti-infectious and antiparasitic agents of systemic action

XIX.T36-T50.T45.1 Poisoning with antitumor and immunosuppressive drugs

Contraindications:

Megaloblastic anemia due to deficiency of cyanocobalamin (vitamin B₁₂); increased sensitivity to calcium folinate.

Carefully:

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

Pregnancy and lactation:

Controlled studies in humans have not been conducted. It is recommended for the treatment of megaloblastic anemia in pregnancy. There is no information on the penetration into breast milk. Features of use in children are not described.

FDA recommendation category C.

Dosing and Administration:

The regimens of calcium folinate treatment depend on the regimens of therapy with medium and high doses of methotrexate, so it is advisable to consult the appropriate protocol for the treatment of methotrexate for the necessary information.

The dose and duration of calcium folinate use primarily depend on the dosage and type of methotrexate therapy, the appearance of signs of toxicity and the specific features of methotrexate excretion. Typically, the first dose of calcium folinate is 15 mg (6-12 mg / m²), administered after 12-24 hours (no later than 24 hours) after the start of infusion of methotrexate. The same dose is prescribed every 6 hours for 72 hours. After parenteral administration, several doses of the drug can be replaced by the use of oral forms.

It is recommended to measure the concentration of methotrexate in the serum 48 hours after the start of the infusion and adjust the dosage regimen depending on its residual concentration.

Cytotoxic therapy in combination with fluorouracil

Apply different doses and regimens of the drug.

Two-month mode: Intravenous infusion of calcium folinata in a dose of 200 mg / m² for 2 hours, followed by a bolus injection of 400 mg / m²fluorouracil and a 22-hour infusion of fluorouracil (600 mg / m²) for 2 consecutive days every 2 weeks.

Monthly mode: calcium folinate in a dose of 20 mg / m² administered intravenously bolus or 200-500 mg / m² infuzionno within 2 hours immediately after intravenous bolus 425 mg / m²or 370 mg / m² fluorouracil, for 5 consecutive days.

Weekly mode: calcium folinate at a dose of 20 mg / m² administered intravenously bolus or 200-500 mg / m² infuzionno for 2 hours and bolus injection in the middle or at the end of calcium folinate infusion 500 mg / m²fluorouracil. When a combination with fluorouracil is used, it may be necessary to modify the treatment regimen by alternating periods of therapy at intervals without treatment.This depends on the patient's condition, clinical response and dose limiting toxicity, as stated in the drug information fluorouracil. A decrease in the dose of calcium folinate is not required. The number of repeated cycles is determined by the attending physician. Data on the use of these combinations the children are not available.

Intoxication with folic acid antagonists (methotrexate, trimethoprim, pyrimethamine)

Methotrexate overdose: Calcium folinate is administered at a dose equal to or greater than the dose of methotrexate administered no later than 1 hour after the dose of methotrexate, then the drug is administered at 10 mg / m² every 3 hours until the signs of toxicity disappear.

Toxicity of trimethoprim: after the cessation of the administration of trimethoprim, calcium folinate in a dose of 3-10 mg per day until the recovery of the parameters of a clinical blood test.

The toxicity of pyrimethamine: In the case of high doses of pyrimethamine or long-term treatment with low doses, calcium folinate in a dose of 5-50 mg per day, depending on the parameters of the clinical blood test.

Therapy should be discontinued with the number of leukocytes and platelets of blood less than 3.5 thousand and 100 thousand, respectively. Also, therapy should be discontinued if there is bleeding from the gastrointestinal tract, severe diarrhea (more than 7 times a day), exfoliative dermatitis.

With megaloblastic anemia, caused by a deficiency of folic acid, calcium folinate appoint a dose of up to 5 mg per day (maximum 15 mg per day).

Side effects:

Allergic reactions (anaphylactic shock, urticaria) are rare.

Insomnia, anxiety, depression when using high doses, increasing the incidence of epileptic seizures - is rare.

Nausea, dyspepsia (with high doses). Fever.

In combination with fluorouracil: often - nausea, vomiting, diarrhea, dehydration, requiring immediate medical correction; toxic damage to the mucous membranes.

Overdose:

The dose of calcium folinate that was significantly higher than the recommended dose was not reported. However, high doses of calcium folinate can neutralize the chemotherapeutic effect of folic acid antagonists.

If an overdose occurs with a combination of fluorouracil with calcium folinate, follow the instructions for fluorouracil to take the necessary measures.

Interaction:

Reduces the effect of antagonists of folic acid.

Anticonvulsants, hydantoin derivatives, barbiturates, primidon - calcium folinate in high doses can reduce the anticonvulsant effect of these drugs.

Sulfamethoxazole, trimethoprim - may increase the incidence of resistance in the treatment of pneumonia caused by Pneumocystis carinii, in HIV-infected patients.

Pharmaceutically incompatible with a solution of fluorouracil (precipitation is possible).

Fluorouracil - intensification of therapeutic and toxic effects in parallel application; Despite the widespread use of combined regimes, it should be used with caution.

There are reports of incompatibility of injection forms of calcium folinate with injectable forms of droperidol, fluorouracil, foscarnet and methotrexate when they are used simultaneously due to the formation of precipitate or turbidity of injectable solutions.

Special instructions:

Calcium folinate solution for injection or infusion is designed for single use. Any unused portions of the solution should be destroyed. Can not enter intrathecally.When intrathecal administration of folinic acid after an intrathecal overdose of methotrexate, a lethal outcome is possible.

Treatment of methotrexate and calcium folinate, as well as fluorouracil and calcium folinate should be performed by a qualified oncologist with the necessary controls.

The use of calcium folinate can mask the clinical picture of a pernicious or other kind of anemia caused by vitamin B deficiency₁₂.

In patients with epilepsy receiving treatment with phenobarbital, primidon, phenytoin, or succinimides, there is a risk of an increased incidence of epileptic seizures due to a decrease in plasma concentrations of antiepileptic drugs. In this case, clinical monitoring, control of the concentration of drugs in the blood plasma and, if necessary, correction of the dose of antiepileptic drugs during the application of calcium folinate and after the termination of the course of therapy.

Calcium folinate / fluorouracil

With the combined use of fluorouracil and calcium folinate, the toxic effect of fluorouracil is enhanced and the risk of toxic effects increases. They can be dose-limiting.Especially this applies to elderly patients and weakened patients.

Calcium folinate can not be mixed with fluorouracil with simultaneous intravenous injection (injection or infusion).

In patients receiving combined therapy of fluorouracil with calcium folinate, the concentration of calcium ions in plasma should be monitored. When determining low concentrations, it is necessary to conduct concomitant therapy with appropriate calcium preparations.

Calcium folinate / methotrexate

Calcium folinate does not protect against toxic effects of non-hematological nature during the therapy with methotrexate. High doses of calcium folinate should be avoided, as this may lead to a decrease in the antitumor activity of methotrexate, especially in tumors of the central nervous system, when folate accumulation is observed after several courses of treatment. In the case of development of resistance to methotrexate due to the deterioration of the functioning of the membrane transport, resistance to folate calcium also develops, since both substances are transferred by the same transport system.

If clinical manifestations of toxicity or abnormalities occur in laboratory tests, the likelihood of the patient using other drugs that interact with methotrexate (for example, drugs that may affect the elimination of methotrexate or bind to blood plasma proteins) should always be considered.

When working with calcium folinate, it is necessary to observe the rules for handling cytotoxic substances. It is recommended to treat the contaminated surface with a dilute solution of sodium hypochlorite (containing 1% chlorine). In case of contact with the skin, immediately wash the skin with plenty of soap and water or a solution of sodium bicarbonate; In case of contact with eyes, remove eyelids and rinse eyes (eyes) with plenty of water for 15 minutes. The remnants of the preparation, all tools and materials used for the preparation of solutions for injection and infusion, must be destroyed in accordance with the standard hospital procedure for the disposal of cytotoxic substances, taking into account the existing regulatory acts on the destruction of hazardous waste.

Impact on the ability to drive vehicles and manage mechanisms

With the use of calcium folinate, there was no effect on the ability to drive vehicles and to engage in other activities that require concentration and speed of psychomotor reactions.

Instructions

Calcium folinate (Calcii folinas)