Calciumfolinate-Ebeve 10 mg/ml 3 ml, 5 pcs.

The antidote of folic acid antagonists. It is an active metabolite of folic acid and an essential coenzyme for nucleic acid synthesis in cytotoxic therapy.

Calcium folinate is often used to reduce toxicity and neutralize the effects of folic acid antagonists such as methotrexate. Calcium folinate and folate antagonists are carried by the same transport agents and compete for them with each other for transport into the cell, causing the folate antagonists to drain.

It also protects cells from the effects of the latter by reducing the folate pool. Calcium folinate serves as a source of H4 folate, so unlike folic acid it does not require reduction by dihydrofolate reductase for conversion into tetrahydrofolate, which allows in its application to restore the disrupted biosynthesis of DNA, RNA and proteins. The protective effect of calcium folinate occurs only in healthy cells. It prevents toxic effect of methotrexate on bone marrow and gastrointestinal tract cells, but does not significantly influence nephrotoxic effect of methotrexate already produced.

Calcium folinate is often used to biochemically modulate fluorouracil to enhance its cytotoxic effects. Fluorouracil inhibits thymidylate synthetase, a key enzyme involved in pyrimidine biosynthesis. Calcium folinate enhances thymidine synthetase inhibition by increasing intracellular folate pool, thus stabilizing the fluorouracil-thymidine synthetase complex and increasing its activity.

Intravenous calcium folinate is indicated for prevention and treatment of folate deficiency when this condition cannot be corrected by oral administration of the drug, for example, in complete parenteral nutrition and pronounced malabsorption syndrome. Also calcium folinate is indicated for treatment of megaloblastic anemia caused by folic acid deficiency when oral administration of the drug is not possible.

Indications

Active ingredient

Composition

1 ml of solution contains calcium folinate 38.1 mg, which corresponds to the content of: calcium folinate anhydrous 32.4 mg or folinic acid 30 mg.

Excipients:

water d / i – up to 3 ml.

How to take, the dosage

The solution is administered in m/m or intravenously.

In the intravenous route of administration, no more than 160 mg of calcium folinate should be administered in 1 minute because of the calcium content of the solution.

Before using the IV route of administration, calcium folinate may be diluted with 0.9% sodium chloride solution or 5% dextrose solution.

In preparation of solution for injection 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 solution concentration of 0.06-1 mg/ml. The resulting solution is stable for 24 h. The remaining solution should not be used.

Prevention of the toxic effects of methotrexate used in high doses

The treatment regimens for calcium folinate depend on medium and high-dose methotrexate therapy regimens, so it is helpful to refer to the appropriate methotrexate treatment protocol for necessary information.

The recommendations below can serve as a guide for determining doses and protective regimens for calcium folinate in adults, the elderly, and children.

Prevention of the toxic effects of methotrexate used in high doses is achieved by parenteral administration in patients with malabsorption syndrome or other gastrointestinal pathology where absorption in the gut may be difficult. Doses of 25-50 mg should be administered parenterally because of the saturable absorption of calcium folinate in the intestine.

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

Also integral to the administration of calcium folinate in the prevention of the toxic effects of methotrexate used in high doses are measures to accelerate excretion of methotrexate (ensuring adequacy of urinary function and alkalinization of the urine). Renal function should be monitored daily by measuring serum creatinine concentration.

It is recommended that methotrexate serum concentrations be measured 48 h after the start of infusion. If the residual methotrexate concentration is greater than 0.5 µmol/L, the calcium folinate dosing regimen should be adapted according to the following table.

Table. Recommended correction of calcium folinate therapy in the prevention of toxic effects of methotrexate administered at high doses as a function of its residual concentration

Cytotoxic therapy in combination with fluorouracil

Different doses and regimens of the drug are used. Doses over 50 mg should be administered parenterally. Use of higher doses does not lead to higher blood concentrations due to saturable absorption of calcium folinate.

The two-month regimen: IV infusion of calcium folinate at a dose of 200 mg/m2 for 2 h, followed by a bolus infusion of 400 mg/m2 fluorouracil and a 22-hour infusion of fluorouracil (600 mg/m2) for 2 consecutive days every 2 weeks.

Monthly regimen: Calcium folinate at a dose of 20 mg/m2 administered by IV bolus or 200-500 mg/m2 infusion for 2 h immediately after an IV bolus injection of 425 mg/m2 or 370 mg/m2 fluorouracil, for 5 consecutive days.

Weekly regimen: Calcium folinate at a dose of 20 mg/m2 administered by IV bolus or 200-500 mg/m2 infusion for 2 h and a bolus infusion in the middle or end of a calcium folinate infusion of 500 mg/m2 fluorouracil.

When using a combination with fluorouracil, it may be necessary to modify the treatment regimen by alternating periods of therapy with intervals without treatment. This depends on the patient’s condition, clinical response, and dose-limiting toxicity as stated in the information for fluorouracil. Decreasing the dose of calcium folinate is not necessary.

The number of repeat cycles is determined by the treating physician.

There are no data on the use of these combinations in children.

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 h after the administered dose of methotrexate, then the drug is administered at 10 mg/m2 every 3 h until signs of toxicity disappear.

Trimethoprim toxicity: after discontinuation of trimethoprim administration, calcium folinate at a dose of 3-10 mg/day until recovery of clinical blood counts.

Pyrimethamine toxicity: if high doses of pyrimethamine are used or if low-dose treatment is prolonged, calcium folinate should be administered simultaneously at a dose of 5-50 mg/day, depending on clinical blood counts.

The therapy should be discontinued when blood leukocyte and platelet counts are less than 3.5 thousand and 100 thousand, respectively. Therapy should also be discontinued in case of bleeding from the gastrointestinal tract, severe diarrhea (>7 times a day), exfoliative dermatitis.

In megaloblastic anemia caused by folic acid deficiency, calcium folinate is prescribed in a dose of up to 5 mg/day (maximum 15 mg/day).

Interaction

In concomitant use of calcium folinate with folic acid antagonists (e.g., co-trimoxazole, pyrimethamine) the effectiveness of folic acid antagonists may be reduced or completely eliminated.

Calcium folinate may decrease the effectiveness of antiepileptic drugs (phenobarbital, primidone and phenytoin, succinimides) and increase the frequency of epileptic seizures (due to decreased concentration of enzyme inducers of antiepileptic drugs in plasma due to accelerated metabolic processes in the liver, since folate is one of the co-factors).

When calcium folinate and fluorouracil are used in combination, the effectiveness and toxicity of the latter are increased.

There have been reports of incompatibility of injectable forms of calcium folinate with injectable forms of droperidol, fluorouracil, foscarnet and methotrexate when used simultaneously, due to precipitate formation or clouding of injectable solutions.

Special Instructions

Before administering the drug, visually check the vial or ampoule with calcium folinate. The solution for intravenous and intravenous administration should be transparent and yellowish in color. If turbidity or presence of inclusions is observed, the solution should not be used. Calcium folinate solution for injection or infusion is intended for single use. Any unused portions of the solution should be disposed of as directed.

Calcium folinate should be administered by injection or infusion, but should not be administered intrathecally. If folinic acid is administered intrathecally after an intrathecal methotrexate overdose, death may occur.

The treatment with methotrexate and calcium folinate and fluorouracil and calcium folinate must be given by a qualified oncologist with the necessary controls.

The use of calcium folinate may mask the clinical picture of pernicious or other types of anemia caused by vitamin B12 deficiency.

Many cytotoxic drugs cause the development of macrocytosis (in particular, direct and indirect DNA synthesis inhibitors – hydroxycarbamide, cytarabine, mercaptopurine, thioguanine). It is believed that such macrocytosis does not require treatment with folinic acid.

In patients with epilepsy treated with phenobarbital, primidone, phenytoin or succinimides, there is a risk of increased frequency of epileptic seizures due to decreased plasma concentrations of antiepileptic drugs. In this case clinical monitoring, control of plasma concentrations of drugs and, if necessary, adjustment of antiepileptic agents dose during the use of calcium folinate and after therapy is recommended.

Calcium folinate/fluorouracil

When fluorouracil and calcium folinate are used in combination, the toxic effects of fluorouracil are enhanced and the risk of toxic effects increases. This is especially true for elderly patients and weakened patients. Side effects such as leukopenia, inflammation of mucous membranes and diarrhea are the most common. They may be dosolimiting. When fluorouracil is used in combination with calcium folinate, doses of fluorouracil should be reduced more significantly if toxic effects occur than in fluorouracil monotherapy. Combination therapy with fluorouracil and calcium folinate should not be started or continued if the patient has signs of toxic lesions of the digestive tract, regardless of the severity of the lesion. Combination therapy can be used only after all pathological symptoms from the gastrointestinal tract have completely disappeared (e.g., mucosal inflammation, diarrhea).

Since diarrhea may be a manifestation of a toxic effect on the digestive system, patients with this side effect should be monitored closely until the signs of diarrhea have completely disappeared. This is because of a possible rapid worsening of the clinical picture, which can be fatal. If diarrhea and/or stomatitis occur during treatment, it is recommended that the dose of fluorouracil be reduced until these have completely disappeared. This is especially true for elderly and weakened patients who are most vulnerable to the toxic effects of this drug.

In patients who have had prior radiation therapy and in elderly patients, it is recommended that therapy be started with reduced doses of fluorouracil.

Calcium folinate must not be mixed with fluorouracil when administered simultaneously intravenously (injection or infusion).

In patients receiving combined therapy of fluorouracil and calcium folinate, plasma calcium ion concentrations should be monitored. If low concentrations are determined, concomitant therapy with appropriate calcium preparations is necessary.

Calcium folinate/methotrexate

Calcium folinate does not protect against non-hematologic toxic effects during methotrexate therapy (e.g., nephrotoxic effects due to precipitation of methotrexate or its metabolites in renal tubules). The presence of prior or methotrexate-induced renal failure associated with delayed methotrexate excretion may require higher doses or longer duration of calcium folinate therapy.

High doses of calcium folinate should be avoided because it may lead to decreased antitumor activity of methotrexate, especially in CNS tumors where accumulation of calcium folinate after several courses of treatment is observed.

If resistance to methotrexate develops due to impaired membrane transport function, resistance to calcium folinate also develops because both substances are transported by the same transport system.

In accidental overdose with a folic acid antagonist such as methotrexate, immediate medical attention should be given because increasing the time interval between administration of methotrexate and calcium folinate decreases the effectiveness of the latter.

If there are clinical signs of toxicity or abnormalities in laboratory tests, always consider the possibility of the patient using other medications that interact with methotrexate (for example, drugs that may interfere with methotrexate elimination or bind to plasma proteins).

Calcium folinate must be handled according to the rules for handling cytotoxic substances. It is recommended to treat the surface contaminated by the drug with diluted solution of sodium hypochloride (containing 1% chlorine). In case of contact of the drug on the skin one should immediately perform abundant washing of the skin with soap and water or sodium bicarbonate solution; in case of contact with eyes – pull back eyelids and rinse the eye (eyes) with plenty of water for 15 minutes.

The remains of the drug, all instruments and materials that have been used to prepare solutions for injection and infusion of Calciumfolinate-Ebeve must be disposed of in accordance with standard hospital procedures for the disposal of cytotoxic waste, taking into account the applicable regulations on the disposal of hazardous waste.

The effect on the ability to drive and operate machinery

There has been no observed effect on the ability to drive vehicles and engage in other activities requiring concentration and rapid psychomotor reactions when using calcium folinate.

Features

Assimilation

The systemic bioavailability is comparable to that after IV administration of aqueous solution. However, Cmax in plasma is lower when administered in v/m.

Distribution

The Vd of folinic acid is unknown. Cmax in plasma of the parent compound (formyltetrahydrofolic acid, folinic acid) is reached 10 minutes after IV administration.

The mean concentrations for L-5-formyltetrahydrofolic acid and D-5-methyltetrahydrofolic acid were 28.4±3.5 mg/min/L and 129±11 mg/min/L after a 25 mg dose. The concentration of the inactive right-hand isomer was greater than that of L-5-formyltetrahydrofolate.

Metabolism

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

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

Elevation

The T1/2 is 32-35 minutes for the active L-form and 352-485 minutes for the inactive D-form. The entire T1/2 of active metabolites is about 6 h (after IV and IM administration).

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

Contraindications

With caution: alcoholism, epilepsy, CKD, children under 2 years of age (safety and effectiveness in children has not been established).

Side effects

According to the WHO adverse effects are classified according to their frequency of development as follows: very common (≥10%), common (≥1%, <10%), infrequent (≥0.1%, <1%), rare (≥0.01%, <0.1%, very rare (<0.01%, including single cases).

Immune system disorders: very rare – allergic reactions, including anaphylactic shock and urticaria.

CNS disorders: rarely – insomnia, anxiety, depression when using high doses, increased incidence of epileptic seizures.

The digestive system: rarely – nausea, dyspepsia (in high doses).

General disorders: infrequent – fever.

When used in combination with fluorouracil

Monthly regimen

Digestive system disorders: very often – nausea, vomiting.

General disorders: very often – marked toxic lesions of the mucous membranes.

Weekly regimen

Digestive system disorders: very common – diarrhea, severe dehydration requiring hospitalization for medication correction (can be fatal).

Overdose

The effects of using significantly higher than the recommended dose of calcium folinate have not been reported. However, high doses of calcium folinate may offset the chemotherapeutic effect of folic acid antagonists.

If an overdose has occurred when using a combination of fluorouracil and calcium folinate, the instructions for fluorouracil for the necessary interventions should be followed.