Active substanceCalcium folinateCalcium folinate
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    Composition:

    1 ampoule of 3 ml contains:

    Active substance: calcium folinate pentahydrate 38.1 mg (corresponding to calcium folinate anhydrous 32.4 mg or folinic acid 30.0 mg). Excipients: water for injection up to 3.0 ml.

    1 ampoule / 10 ml bottle contains:

    Active substance: calcium folinate pentahydrate 127.0 mg (corresponding to calcium folinate anhydrous 108.0 mg or folinic acid 100.0 mg).

    Excipients: water for injection up to 10.0 ml.

    Description:Transparent solution, from colorless to slightly yellow, free from foreign particles.
    Pharmacotherapeutic group:Vitamin - antidote of folic acid antagonists (modifier of biological action of fluorouracil)
    ATX: & nbsp

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

    Pharmacodynamics:

    Calcium folinate is a 5-formyltetrahydrofolate of calcium. It is an active metabolite of folic acid and essential coenzyme for the synthesis of nucleic acids in cytotoxic therapy. Calcium folinate often used to reduce toxicity and neutralize the action of folic acid antagonists, such as methotrexate. Calcium folinate and folate antagonists are transported by the same transport agents and compete for each other for transport to the cell, which causes an outflow of folate antagonists. It also protects cells from the effects of the latter by reducing the pool of folate. Calcium folinate serves as a source of H4 folate; therefore, unlike folic acid, does not require the reduction of dihydrofolate reductase to convert to tetrahydrofolate, which allows using it to restore the broken process of biosynthesis of DNA, RNA and proteins. The protective action of calcium folinata is manifested only in relation to healthy cells.Prevents the toxic effect of methotrexate on the cells of the bone marrow and gastrointestinal tract, but does not significantly affect the already provided nephrotoxic effect of methotrexate.

    Also calcium folinate often used for biochemical modulation of fluorouracil 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, thus stabilizing the fluorouracil-thymidine synthetase complex and increasing its activity. Intravenously 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:

    Suction

    After intramuscular administration of an aqueous solution, the systemic bioavailability is comparable to that afterintravenous administration. However, the maximum concentration in the blood plasma is lower with intramuscular injection.

    Metabolism

    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.

    Distribution

    The volume of distribution of folic acid is unknown. The maximum plasma concentrations of the parent compound (formitetetrahydrofolic acid, folinic acid) are reached 10 minutes after intravenous administration.

    Average concentration for L-5-formyltetrahydrofolic acid and a dextrorotatory D-5methyltetrahydrofolic acid were 28.4 ± 3.5 mg min / l and 129 ± 11 mg min / l after administration of a dose of 25 mg. Concentration of the inactive dextrorotatory isomer is greater than L-5-formyltetrahydrofolate.

    Period half-life is 32 - 35 minutes for the active L-form and 352 - 485 minutes - for the inactive D-form. The entire half-life of active metabolites is about 6 hours (after intravenous and intramuscular injection).

    80 - 90% is displayed kidneys (5- and 10-formyltetrahydrofolates as inactive metabolites), 5 - 8% through the intestine.

    Indications:

    - Prevention of toxic effects of methotrexate, used in high doses.

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

    - Colorectal cancer (as part of combination therapy with fluorouracil).

    - Megaloblastic anemia, caused by a deficiency of folic acid (including against the background of malabsorption syndrome, malnutrition, pregnancy, sprue, in early childhood with congenital insufficiency dihydrofolate reductase).

    Contraindications:

    - Hypersensitivity to calcium folinate or any other component of the drug;

    - megaloblastic anemia due to deficiency of cyanocobalamin (vitamin B12).

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

    Since no controlled studies have been conducted in pregnant women, use during pregnancy is only possible if the intended benefit to the mother exceeds the potential risk to the fetus.

    It is not known whether the drug is excreted in breast milk, so if calcium folinate is needed during lactation, it is necessary to decide whether to stop breastfeeding.

    Dosing and Administration:

    The solution is administered intramuscularly or intravenously.

    When administered intravenously in one minute, no more than 160 mg of calcium folinate should be administered because of the calcium present in the solution.

    Before use with the intravenous route of administration calcium folinate can be diluted with 0.9% solution of sodium chloride or 5% solution of dextrose.

    When preparing the injection solution calcium folinate can be diluted with Ringer's solution, Ringer's solution with lactate, 10% dextrose solution, 5% dextrose solution, 0.9% sodium chloride solution to a concentration of 0.06 mg / ml to 1 mg / ml. The resulting solution remains stable for 24 hours. Do not use the remaining solution.

    Prevention of toxic effects of methotrexate, used in high doses

    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 following recommendations can serve as a guide for the determination of doses and the scheme for the protective use of calcium folinate in adults, the elderly and children.

    Prevention of toxic effects of methotrexate used in high doses is carried out by parenteral administration in patients with malabsorption syndrome or other pathology of the digestive tract, when intestinal absorption may be difficult. Doses of 25 to 50 mg should be administered parenterally due to saturable absorption of calcium folinate in the intestine.

    The dose and duration of calcium folinate, first of all, depend on the type and doses 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), introduced through 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.

    Also an essential supplement to the introduction of calcium folinate in the prevention of toxic effects of methotrexate,used in high doses, are activities that contribute to accelerate the excretion of methotrexate (maintenance of adequate urinary function and alkalization of urine). The kidney function should be monitored daily by measuring the concentration of serum creatinine.

    It is recommended to measure the concentration of methotrexate in the blood serum 48 hours after the start of the infusion. If the residual methotrexate concentration exceeding 0.5 mol / l, the calcium folinate dosage regimen should be adjusted according to the following table:

    Recommended calcium folinate correction therapy for the prevention of toxic action of methotrexate used in high doses, depending on the residual concentration

    Residual concentration

    Additional doses of calcium folinate,

    methotrexate in the blood after 48

    appointed every 6 hours for 48 hours

    hours after the beginning of the introduction

    or until the concentration of methotrexate

    methotrexate:

    below 0.05 μmol / l:

    > 0.5 μmol / l

    15 mg / m2

    >1,0 μmol / l

    100 mg / m2

    > 2.0 μmol / l

    200 mg / m2

    Cytotoxic therapy in combination with fluorouracil

    Apply different doses and regimens of the drug.

    Doses above 50 mg should be given parenterally. The use of higher doses does not lead to higher concentrations in the blood due to saturable absorption of calcium folinate.

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

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

    Weekly mode: calcium folinate in a dose of 20 mg / m2 administered intravenously bolus or from 200 to 500 mg / m2 Infusion for 2 hours and bolus introduction in the middle or late infusion of calcium folinate 500 mg / m fluorouracil.

    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 at the discretion of the attending physician. Data on the use of these combinations in children is 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 administered, then the drug is administered at 10 mg / m every 3 hours until the signs of toxicity disappear.

    Toxicity of trimethoprim

    After stopping the administration of trimethoprim, calcium folinate in a dose 3-10 mg / day until the recovery of the clinical blood count.

    The toxicity of pyrimethamine

    In the case of high doses of pyrimethamine or a prolonged period of treatment with low doses, calcium folinate in a dose 5-50 mg / day, depending on the parameters of the clinical blood test.

    Therapy should be discontinued with the number of leukocytes and blood platelets of less than 3.5 thousand and 100.0 thousand, respectively. Also, therapy should be discontinued if bleeding occurs from the gastrointestinal tract, severe diarrhea (> 7 times a day), exfoliative dermatitis.

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

    Side effects:

    According to the World Health Organization (WHO), unwanted effects are classified according to their frequency of development as follows: very often (≥1/10), often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1000 to <1/100), rarely (from ≥1 / 10000 to <1/1000), very rarely (<1/10000); frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

    Disorders from the immune system system: rarely: anaphylactoid / anaphylactic reactions (including shock), allergic reactions, urticaria.

    Disorders of the psyche: rarely: insomnia, anxiety, depression when applying high doses.

    Disorders from the gastrointestinal tract: rarely: nausea, dyspepsia (when applying high doses).

    Impaired nervous system: rarely: increased frequency of epileptic seizures.

    General disorders and disorders at the site of administration: infrequently: fever.

    When used with others drugs for the treatment of concomitant diseases have been reported cases of the syndrome of Stevens-Johnson and toxic epidermal necrolysis, sometimes fatal, in the development of which can not exclude the role of calcium folinate.

    When used in combination with fluorouracil:

    Monthly mode:

    Disorders from the gastrointestinal tract: Often: nausea, vomiting, diarrhea.

    Disturbances from the skin and subcutaneous tissues: Often: palmar-plantar erythrodysesthesia (palmar dyspnea syndrome).

    General disorders and disorders at the site of administration: Often: mucositis, including stomatitis, cheilitis, pharyngitis, esophagitis, proctitis. Toxic lesions of the gastrointestinal tract (mainly mucositis and diarrhea) and myelosuppression can lead to death. In patients with diarrhea, clinical deterioration can immediately lead to death. The absence of an improvement in the condition may be due to other toxic effects of fluorouracil (eg, neurotoxicity).

    Weekly mode:

    Disorders from the gastrointestinal tract: Often: diarrhea, severe dehydration, requiring hospitalization for drug-induced correction (may lead to death).

    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:

    With the simultaneous use of calcium folinate with antagonists of folic acid (eg, co-trimoxazole, pyrimethamine), the efficacy of folic acid antagonists can be reduced or completely eliminated.

    Calcium folinate may decrease effectiveness antiepileptic drugs (phenobarbital, primidon and phenytoin, succinimides) and increase the frequency of epileptic seizures (due to a decrease in the concentration of enzyme inducers of antiepileptic drugs in blood plasma because of the acceleration of metabolic processes in the liver, since folates are one of the co-factors).

    When combined use of calcium folinate and fluorouracil The efficacy and toxicity of the latter are increased.

    There are reports of incompatibility of injection forms of calcium folinate with simultaneous use with injectable forms droperidol, fluorouracil, foscarnet and methotrexate, due to the formation of precipitate or turbidity of the solutions administered.

    Special instructions:

    Before administration, visually check the vial or ampoule with calcium folinate. The solution for intramuscular and intravenous administration should be clear and have a yellowish color. If turbidity or presence of inclusions is observed, then such a solution can not be used. Calcium folinate solution for injection or infusion is designed for single use. Any unused portions of the solution should be disposed of in accordance with the instructions.

    Calcium folinate should be administered intramuscularly or intravenously (injection or infusion), but can not be administered 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 if there are adequate controls.

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

    Many cytotoxic drugs cause the development of macrocytosis (in particular, direct and indirect inhibitors of the synthesis of deoxyribonucleic acid hydroxycarbamide, cytarabine, mercaptopurine, thioguanine).

    It is believed that such macrocytosis does not require treatment with folic acid.

    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 are recommended.

    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. Especially this applies to elderly patients and weakened patients. The most common side effects are leukopenia, inflammation of the mucous membranes and diarrhea. They can be dose-limiting.When fluorouracil is used in combination with calcium folinate, fluorouracil doses should be reduced more significantly in case of toxic effects than with monotherapy with fluorouracil. Do not start or continue combination therapy with fluorouracil and calcium folinate if the patient has signs of toxic damage to the digestive tract, regardless of the severity of the lesion. Combination therapy can be used only after the complete disappearance of all pathological symptoms from the gastrointestinal tract (eg, inflammation of the mucous membranes, diarrhea).

    Since diarrhea can be a toxic effect on the digestive system, patients with this side effect should be carefully monitored until the signs of diarrhea disappear completely. This is necessary because of the possible rapid deterioration of the clinical picture, leading to death. If diarrhea and / or stomatitis occurs in the treatment of a patient, it is recommended that the dose of fluorouracil be reduced until they disappear completely. Especially this applies to elderly and weakened patients who are most vulnerable to the toxic effects of this drug.

    In patients who underwent previous radiation therapy, as well as in elderly patients, it is recommended to start therapy with reduced doses of fluorouracil.

    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 non-hematologic toxic effects during methotrexate therapy (for example, from nephrotoxic effects due to precipitation of methotrexate or its metabolites in the renal tubules). Presence of a previous or methotrexate-induced renal failure, which is associated with delayed excretion of methotrexate. may require the use of higher doses or longer duration of calcium folate therapy.

    It should avoid the use of high doses of calcium folinate,since this can lead to a decrease in the antitumor activity of methotrexate, especially in tumors of the central nervous system, when calcium folate accumulation is observed after several courses of treatment.

    In the case of development of resistance to methotrexate due to deterioration of the functioning of the membrane transport, calcium folinate resistance also develops, since both substances are transported by the same transport system.

    In case of accidental overdose with a folic acid antagonist, such as methotrexate, it is necessary to provide emergency medical care, since an increase in the time interval between the administration of methotrexate and calcium folinate leads to a decrease in the effectiveness of the latter.

    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). If the product gets on the skin, immediately flush the skin with 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 and all instruments and materials used to prepare solutions for injection and infusion of the Calciumfonolate-Ebweve preparation must be disposed of 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.

    Effect on the ability to drive transp. cf. and fur:

    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.

    Form release / dosage:Solution for intravenous and intramuscular injection, 30 mg / 3 ml or 100 mg / 10 ml.
    Packaging:

    Ampoules

    For 30 mg / 3 ml or 100 mg / 10 ml in ampoules of brown glass, type 1 Heb. F. 5 ampoules of 10 ml or 5 ampoules of 3 ml in a closed or open blister of PVC.

    One blister with instructions for medical use put in a cardboard box.

    Bottles

    For 100 mg / 10 ml in a bottle of brown glass, type 1 Heb. F., sealed with a rubber stopper made of chlorobutyl rubber under an aluminum safety roll with hole for the needle in the center and closed with a protective plastic cover. 1 bottle with instructions for use is placed in a cardboard box.

    Storage conditions:

    Store in a dark place at a temperature of 2 to 8 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use after the expiry date printed on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:П N014892 / 03
    Date of registration:01.04.2008
    The owner of the registration certificate:Ebewe Pharma Gesmb.b. Nfg. KGEbewe Pharma Gesmb.b. Nfg. KG Austria
    Manufacturer: & nbsp
    Representation: & nbspSANDOZ SANDOZ Switzerland
    Information update date: & nbsp11.09.2015
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