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Composition:


active ingredient: calcium folinate;


1 ml of the solution contains 10.8 mg of calcium folinate (when calculated for anhydrous substance, which corresponds to 10 mg of free folic acid) ;


excipients: sodium chloride, sodium hydroxide, diluted hydrochloric acid, water for injection.


Dosage form. Solution for injection.


Basic physical and chemical properties: clear yellowish solution.


Pharmacotherapeutic group. Drugs used to eliminate the toxic effects of antitumor therapy. ATX code V03A F03.


Pharmacological properties.


Pharmacodynamics.


Calcium folinate is the calcium salt of 5-formyltetrahydrofolic acid. It is an active metabolite of folic acid and an important coenzyme necessary for the synthesis of nucleic acids.


Calcium folinate is often used to prevent toxic effects or neutralize the effects of folic acid antagonists (in particular, methotrexate). Calcium folinate and folate antagonists compete for a single membrane transporter, which stimulates the outflow of folate antagonists. Calcium folinate also protects cells from the effects of folic acid antagonists by replenishing the body's reduced folate Reserve. It is a source of reduced tetrahydrofolate, so it can bypass the blockade of folate antagonists and be a source of various coenzyme forms of folic acid.


Calcium folinate is also often used as a biochemical modulator to increase the cytotoxic activity of 5-fluorouracil. 5-fluorouracil inhibits thymidylate synthase (a key enzyme involved in pyrimidine biosynthesis), and calcium folinate enhances the inhibition of thymidylate synthase by increasing the intracellular supply of folate, as a result of which the 5-fluorouracil-thymidylate synthase complex stabilizes and cytotoxic activity increases.


Pharmacokinetics.


Absorption


With intramuscular administration of an aqueous solution, the systemic bioavailability of calcium folinate is comparable to that of intravenous administration, but the maximum concentration in blood plasma (Cmax) is lower.


Metabolism


Calcium folinate is a racemate. The active enantiomer is the L-form (L-formyltetrahydrofolate, L‑5‑formyltetrahydrofolate). The main metabolite of folic acid is 5‑methyltetrahydro-folic acid, transformation occurs mainly in the liver and gastrointestinal mucosa.


Distribution


The volume of distribution of calcium folinate is unknown. The maximum concentration of the initial compound (folic acid, D/L-formyltetrahydrofolic acid) in blood plasma is reached 10 minutes after intravenous administration.


After administration of a dose of 25 mg, the area under the pharmacokinetic curve for L‑5‑formyltetrahydrofolate and 5-methyltetrahydrofolate is 28.4 ± 3.5 mg·min/L and 129 ± 11 mg·min/l, respectively. 


Elimination


The elimination half-life is 32-35 minutes for the active L-form and 352-485 minutes for the inactive D-form.


The Half-Life of active metabolites is about 6 hours (with intravenous and intramuscular administration).


Excretion


80-90% of the dose is excreted in the urine (in the form of 10-formyltetrahydrofolate and other inactive metabolites), 5-8% of the dose is excreted in the faeces.


Clinical characteristics.


Indications.


* As a protective agent for the Prevention of toxic effects of methotrexate when used in medium and high doses;


* as an antidote for overdose and intoxication with methotrexate and other folic acid antagonists;


* as part of combined cytotoxic therapy with 5-fluorouracil (as a biochemical modulator of 5-fluorouracil activity);


* for the treatment of megaloblastic anemia caused by folic acid deficiency, as well as the prevention and treatment of folate deficiency if oral folic acid administration is not possible.


Contraindications.


* Hypersensitivity to calcium folinate or other components of the drug.


* Pernicious anemia or other types of anemia caused by vitamin B12 deficiency.


Special security measures.


Calcium folinate "Ebeve" can only be administered intravenously or intramuscularly. Intrathecal use of the drug is prohibited!


Only a single selection of the drug from the bottle is allowed.


Before use, it is necessary to visually check the appearance of the drug. It should be transparent and yellowish in color. If the solution is cloudy or has visible mechanical inclusions, you can not use such a preparation.


Interactions with other drugs and other types of interactions.


Calcium folinate can reduce the effectiveness or completely neutralize the action of folic acid antagonists (for example, co-trimoxazole, pyrimethamine).


Calcium folinate can reduce the effectiveness of antiepileptic drugs (phenobarbital, phenytoin, primidone, succinamides), as a result of which the frequency of epileptic seizures may increase (since folate is one of the cofactors that intensify hepatic metabolism, the levels of enzyme inducers of anticonvulsants in blood plasma may decrease).


The combined use of calcium folinate and 5-fluorouracil increases both the therapeutic and toxic effects of 5-fluorouracil.

Application features.


Treatment with calcium folinate in combination with methotrexate or 5-fluorouracil should be carried out under the supervision of an experienced oncologist.


Calcium folinate can mask the symptoms of pernicious anemia and other anemia caused by vitamin B12 deficiency.


Many cytotoxic drugs that are direct or indirect inhibitors of DNA synthesis cause macrocytosis (in particular, hydroxycarbamide, cytarabine, mercaptopurine, thioguanine). Such macrocytosis should not be treated with folic acid.


In patients with epilepsy who take phenobarbital, phenytoin, primidone and succinamides, the frequency of epileptic seizures may increase during calcium folinate therapy due to a decrease in the concentration of antiepileptic drugs in blood plasma. Therefore, in such cases, close clinical monitoring is necessary, as well as, if necessary, monitoring the concentration of antiepileptic drugs in blood plasma and adjusting their doses during treatment with calcium folinate and after its withdrawal.


Use of calcium folinate in combination with 5-fluorouracil


Calcium folinate may increase the toxic effect of 5-fluorouracil, especially in elderly and debilitated patients. The most common manifestations of toxic effects are leukopenia, inflammation of the mucous membranes, stomatitis, diarrhea. These side effects may be dose-limiting. If it is necessary to reduce doses due to toxic effects with the combined use of 5‑fluorouracil and calcium folinate, the dose of 5-fluorouracil should be reduced more than with 5‑fluorouracil monotherapy.


Treatment with 5-fluorouracil in combination with calcium folinate should not be initiated or continued until the symptoms of gastrointestinal toxicity completely disappear, regardless of their severity. Since diarrhea can be a sign of gastrointestinal toxicity (which can lead to rapid clinical deterioration of the patient's condition up to death), patients with diarrhea should be closely monitored until the corresponding symptoms completely disappear. If diarrhea and/or stomatitis occur, it is recommended to reduce the dose of 5 - fluorouracil until the symptoms are completely eliminated. Special care should be taken in the treatment of debilitated patients and elderly patients.


It is recommended to prescribe lower initial doses of 5-fluorouracil to elderly patients and those who have previously received radiation therapy.


Calcium folinate and 5-fluorouracil should be administered separately.


In combination therapy with 5‑fluorouracil and calcium folinate, calcium levels should be monitored and, if necessary, calcium supplements should be prescribed.


Use of calcium folinate in combination with methotrexate


Recommendations for preventing toxic effects during methotrexate therapy are given in the instructions for medical use of methotrexate.


Calcium folinate does not protect against non-hematological toxic effects during methotrexate therapy (for example, from nephrotoxic effects due to precipitation of methotrexate and/or its metabolites in the renal tubules). Patients with delayed elimination of methotrexate at an early stage are more likely to develop reversible renal failure and other toxic effects associated with the use of methotrexate. Renal failure (which developed during methotrexate therapy or is present before treatment) is potentially associated with delayed methotrexate excretion, so in such cases it may be necessary to use calcium folinate in high doses or for a longer time.


Excessive doses of calcium folinate should be avoided, as this may lead to a decrease in the antitumor activity of methotrexate, especially in the case of central nervous system tumors in which calcium folinate accumulates after several courses of treatment.


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


In case of overdose of folic acid antagonists (for example, methotrexate), it is necessary to start administration of calcium folinate as soon as possible. As the time interval between the administration of methotrexate and calcium folinate increases, the effectiveness of the latter as an antidote decreases.


If laboratory abnormalities or clinical symptoms of toxic effects are detected, it is always necessary to check whether the patient is taking other medications that interact with methotrexate (for example, they affect the elimination of methotrexate or its binding to plasma proteins).


Infusion solutions prepared by diluting the drug with 0.9% sodium chloride solution or 5% glucose solution are physically and chemically stable for at least 24 hours if stored at a temperature not exceeding 25 °C.


From a microbiological point of view, the infusion solution should be administered immediately after preparation. If the solution is not used immediately, the duration and conditions of its storage should be monitored by medical personnel. Usually, the storage time should not exceed 24 hours at a temperature of 2-8°C, unless the solution was prepared under controlled and certified aseptic conditions.


Use during pregnancy or lactation.


There is no evidence that calcium folinate can have a harmful effect when used during pregnancy, but there are no adequate data on the use of calcium folinate for the treatment of pregnant women.


If methotrexate or other folic acid antagonists are prescribed during pregnancy or lactation (which is only possible for strict indications, when the expected benefit of therapy for the mother clearly outweighs the potential risk to the fetus), there are no restrictions on the use of calcium folinate to prevent side effects or neutralize the toxic effects of methotrexate.


The use of 5-fluorouracil during pregnancy or lactation is contraindicated. The same applies to combination therapy with 5‑fluorouracil in combination with calcium folinate.


For more information on this issue, see the instructions for medical use of methotrexate, other folic acid antagonists, and 5-fluorouracil.


It is not known whether calcium folinate passes into breast milk. If necessary, calcium folinate can be used during breast-feeding in accordance with therapeutic indications.


Ability to influence the reaction rate when driving vehicles or other mechanisms.


No information available.

Dosage and administration.


Calcium folinate "Ebeve" can only be administered intravenously or intramuscularly.


Intrathecal use of the drug is not allowed!


All the following doses are based on folic acid.


The rate of intravenous administration should not exceed 160 mg/min, taking into account the calcium content in the preparation.


Solutions for infusions should be prepared by diluting the drug with 0.9% sodium chloride solution or 5% glucose solution.


Calcium folinate protection in methotrexate therapy


Since the doses and regimens of calcium folinate depend on the doses and treatment regimens of medium and high doses of methotrexate, it is advisable to refer to the methotrexate treatment protocol for relevant information.


Calcium folinate should be administered parenterally to patients with malabsorption syndrome or other gastrointestinal diseases, when intestinal absorption of the drug is not guaranteed. Doses greater than 25-50 mg should only be administered parenterally, taking into account the saturation effect of calcium folinate absorption in the gastrointestinal tract.


Calcium folinate protection is necessary when using methotrexate in doses above 500 mg/m2 of the body surface and is advisable – at doses of methotrexate 100-500 mg/m2 of the body surface.


The following are approximate recommendations for the use of calcium folinate in adults, elderly patients, and children.


Doses and duration of calcium folinate therapy are determined primarily taking into account the doses and treatment regimen of methotrexate, the presence of symptoms of toxic effects, as well as individual indicators of methotrexate excretion. Usually, calcium folinate should be administered at a dose of 15 mg (6-12 mg/m2 of body surface area) 12-24 hours (no later than 24 hours) after the start of the methotrexate infusion. The same doses of calcium folinate are then administered every 6 hours for 72 hours. After several parenteral injections, you can switch to oral administration of the drug in the form of capsules.


48 hours after starting the methotrexate infusion, measure the residual concentration of methotrexate in the blood. If it is less than 0.5 mmol/L, calcium folinate therapy can be discontinued. If the concentration of methotrexate exceeds 0.5 mmol/L, protective therapy should be continued and intensified. Calcium folinate should be administered at the following doses every 6 hours for another 48 hours or until the methotrexate concentration is reached


* at a methotrexate concentration ≥ 0.5 mmol / L – at a dose of 15 mg/m2 of body surface area;


* at a methotrexate concentration ≥ 1.0 mmol / L – at a dose of 100 mg/m2 of body surface area;


* at a methotrexate concentration ≥ 2.0 mmol/L – at a dose of 200 mg / m2 of body surface area.


In addition to calcium folinate therapy, measures should be taken to accelerate the excretion of methotrexate (maintaining high diuresis, alkalinization of urine), as well as daily determination of serum creatinine levels to monitor renal function.


Combination therapy in combination with 5-fluorouracil


Use various therapy regimens with 5-fluorouracil in combination with calcium folinate, but the advantage of any of them has not yet been proven. Some treatment regimens for adults and elderly patients with advanced or metastatic colorectal cancer are described below. There are no data on the use of these combinations for the treatment of children.


The scheme with repeated courses every two weeks: on the first and second days of the course, calcium folinate should be administered at a dose of 200 mg/m2 of the body surface by a two – hour intravenous infusion, and then 5‑fluorouracil at a dose of 400 mg/m2 of the body surface by an intravenous bolus injection and 5‑fluorouracil at a dose of 600 mg/m2 of the body surface by a 22-hour intravenous infusion for the next 2 days, every two weeks on Days 1 and 2.


Scheme with repeated courses weekly: calcium folinate is administered at a dose of 20 mg/m2 of the body surface by intravenous bolus injection or at a dose of 200-500 mg/m2 of the body surface by two‑hour intravenous infusion; 5-fluorouracil at a dose of 500 mg/m2 of the body surface is administered by intravenous bolus injection in the middle or at the end of the calcium folinate infusion.


Scheme with repeated courses monthly: in the first 5 days of the course, calcium folinate is administered daily at a dose of 20 mg/m2 of the body surface by intravenous bolus injection or at a dose of 200-500 mg/m2 of the body surface by two‑hour intravenous infusion, and then 5-fluorouracil is immediately administered at a dose of 425 or 370 mg/m2 of the body surface by intravenous bolus injection.


In combination therapy with 5‑fluorouracil and calcium folinate, it may be necessary to adjust the doses of 5-fluorouracil and the intervals between its administration, depending on the patient's condition, clinical response to therapy and dose-limiting toxic effects. The relevant recommendations are given in the instructions for medical use of 5‑fluorouracil. Reducing the dose of calcium folinate is not necessary.


The required number of courses of therapy is determined by the doctor.


Use of calcium folinate as an antidote to folic acid antagonists trimetrexate, trimethoprim and pyrimethamine:


Prevention of toxic effects of trimetrexate: calcium folinate should be administered daily during treatment with trimetrexate and for another 72 hours after the last dose of trimetrexate. Calcium folinate can be administered intravenously for 5-10 minutes at a dose of 20 mg/m2 of body surface every 6 hours (a daily dose of 80 mg/m2 of body surface) or taken orally at 20 mg/m2 of Surface 4 times a day at regular intervals. The daily dose of calcium folinate should be adjusted depending on the symptoms of hematological toxicity of trimetrexate.


Treatment of trimetrexate overdose: in case of overdose (which is possible with doses of trimetrexate above 90 mg/m2 of body surface without concomitant use of calcium folinate), trimetrexate therapy should be discontinued and calcium folinate should be administered intravenously at a dose of 40 mg/m2 of body surface every 6 hours for three days.


Prevention of toxic effects of trimethoprim: after discontinuation of trimethoprim therapy, calcium folinate should be administered at a dose of 3-10 mg/day until hematological parameters normalize.


Prevention of toxic effects of pyrimethamine: with high-dose pyrimethamine therapy or long-term low-dose treatment, concomitant calcium folinate therapy should be prescribed in doses from 5 to 50 mg/day, depending on the number of shaped elements in the peripheral blood.


The injectable form of calcium folinate should be used for the treatment of megaloblastic anemia caused by folic acid deficiency, as well as for the prevention and treatment of folate deficiency, when oral administration of folic acid is impossible or ineffective (for example, with parenteral nutrition or in the presence of severe malabsorption syndrome).


Children.


Calcium folinate should be used in children as a protective agent for the Prevention of toxic effects of methotrexate, as well as as an antidote for overdose and intoxication with methotrexate and other folic acid antagonists.


Overdose.


When using calcium folinate in doses significantly higher than recommended, no negative effects were observed. However, excessive doses of calcium folinate can neutralize the chemotherapeutic effect of folic acid antagonists.


In case of overdose of 5-fluorouracil in combination with calcium folinate, it is necessary to take the measures recommended for overdose of 5-fluorouracil.


Adverse reactions.


Adverse adverse reactions are listed under the frequency headings: very frequent (≥1/10); frequent (≥1/100,


When used for all indications


From the nervous system: isolated - in isolated cases, an increase in the frequency of epileptic seizures is possible.


From the digestive tract: isolated-there have been isolated reports of gastrointestinal disorders with the use of calcium folinate in high doses.


General effects and local reactions: infrequent - cases of fever have been reported.


From the immune system: rare - cases of allergic reactions have been recorded, in particular urticaria, anaphylactoid reactions.


Mental disorders: isolated-insomnia, agitation and depression when using calcium folinate in high doses.


In combination therapy with 5-fluorouracil


In general, the safety profile depends on the treatment regimen with 5-fluorouracil, since this combined use increases the toxicity of 5-fluorouracil.


From the blood and lymphatic system: very common - bone marrow failure, including deaths.


From the side of metabolism and nutrition: frequency unknown - hyperammonemia.


General disorders and condition of the injection site: very common - inflammation of the mucous membranes, including stomatitis and cheilitis. There were deaths as a result of inflammation of the mucous membranes.


Skin and subcutaneous tissue disorders: frequent-Palmar-plantar erythrodysesthesia syndrome.


Side effects in the treatment regimen with monthly administration of drugs


From the digestive tract: very frequent - nausea and vomiting.


General disorders and condition of the injection site: very frequent – (severe) inflammation of the mucous membranes.

Storage conditions.


Store in the original packaging at a temperature of 2-8 °C.


Keep out of reach of children.


Incompatibility.


Incompatibility (precipitation) was found when mixing calcium folinate solutions with solutions with solutions of droperidol, fluorouracil, foscarnet and methotrexate.


Droperidol


- When 1.25 mg/0.5 ml of droperidol and 5 mg/0.5 ml of calcium folinate were directly mixed in a syringe for 5 minutes at a temperature of 25 oC, followed by centrifugation for 8 minutes, sediment formation was observed.


- When mixing 2.5 mg/0.5 ml of droperidol with 10 mg/0.5 ml of calcium folinate, sediment formation was observed immediately after sequential administration of drugs into the U-shaped splitter, without washing the side outlet of the U-shaped branch between injections.


Fluorouracil


Calcium folinate and 5-fluorouracil should be administered separately, as a precipitate may form when mixed. Incompatibility of 5-fluorouracil at a dose of 50 mg/mL and calcium folinate at a dose of 20 mg/mL with or without 5% dextrose solution in water was found when mixed in various quantities and stored in polyvinyl chloride containers and at a temperature of 40 ° C, 23 ° C or 32 ° C.


Foscarnet


When mixing a 24 mg/mL foscarnet solution with a 20 mg/mL calcium folinate solution, a cloudy yellow color of the solution was observed.


Calcium folinate "Ebeve" should not be mixed with other medicines.


Packaging.


3 mL (30 mg), or 5 ml (50 mg), or 10 ml (100 mg), or 20 ml (200 mg) in a brown glass bottle, sealed with a rubber stopper and aluminum crimp cap; 1 bottle in a cardboard box.

Tags: Calcium folinate