Leucovorin-Teva, 10 mg/ml 5 ml

Pharmacotherapeutic group: vitamin, antidote of folic acid antagonists and modifier of biological action of fluorouracil.
ATC code: V03AF03
Pharmacological action
Pharmacodynamics
Calcium folinate is 5-formyltetrahydrofolate calcium. It is an active metabolite of folic acid and a coenzyme necessary for the synthesis of nucleic acids in cytotoxic therapy.
Calcium folinate is 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 (folate-binding protein, reduced folate transporter, etc.) and compete for their transport into the cell, which causes the outflow of folate antagonists and protects cells from the action of the latter by reducing the folate pool. Calcium folinate serves as a source of H4 folate; therefore, unlike folic acid, it does not require reduction by dihydrofolate reductase to become tetrahydrofolate, which allows it to restore the disturbed biosynthesis of DNA, RNA and proteins when used. The protective effect of calcium folinate appears only in healthy cells. It prevents toxic effect of methotrexate on bone marrow cells and gastrointestinal tract, but does not affect significantly the nephrotoxic effect of methotrexate.
Calcium folinate is also used for biochemical modulation of fluorouracil to enhance its cytotoxic effect. Fluorouracil inhibits the activity of thymidylate synthetase, a key enzyme involved in pyrimidine biosynthesis. The drug increases thymidine synthetase inhibition, increasing intracellular folate pool, thus stabilizing fluorouracil-thymidine synthetase complex and increasing its activity.
Intravenous calcium folinate is prescribed 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. Calcium folinate is also used for treatment of megaloblastic anemia caused by folic acid deficiency when oral administration is impossible.
Pharmacokinetics
Absorption. After intramuscular administration of the aqueous solution systemic bioavailability is comparable with that after intravenous administration. However, maximum plasma concentrations are lower with intramuscular administration.
Metabolism. Calcium folinate is racemate, 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.
Distribution. The volume of distribution of folinic acid is unknown. Maximum plasma concentrations of the parent compound (formyltetrahydrofolic acid, folinic acid) are reached 10 minutes after intravenous administration.
Mean concentrations for L-5-formyltetrahydrofolic acid and the right-handed 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-rotating isomer was greater than that of L-5-formyltetrahydrofolate.
The elimination half-life was 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 administration).
80-90% is excreted by the kidneys (5- and 10-formyltetrahydrofolate as inactive metabolites), 5-8% – through the intestine.

Indications

• Prevention of the toxic effects of methotrexate used in high doses.
• Intoxication with folic acid antagonists (methotrexate, trimethoprim and pyrimethamine).
• Colorectal cancer (as part of combination therapy with fluorouracil).
• Megaloblastic anemia caused by folic acid deficiency (including against the background of malabsorption syndrome, malnutrition, pregnancy, sprue, in early childhood with congenital deficiency of dihydrofolate reductase).

Pharmacological effect

Pharmacotherapeutic group: vitamin, antidote to folic acid antagonists and modifier of the biological action of fluorouracil.
ATX code: V03AF03
Pharmacological action
Pharmacodynamics
Calcium folinate is calcium 5-formyltetrahydrofolate. It is an active metabolite of folic acid and a coenzyme necessary for the synthesis of nucleic acids during cytotoxic therapy.
Calcium folinate is used to reduce the toxicity and neutralize the effects of folic acid antagonists such as methotrexate. Calcium folinate and folate antagonists are transported by the same transport agents (folate binding protein, reduced folate transporter, etc.) and compete for them to be transported into the cell, which causes the outflow of folate antagonists and protects cells from the action of the latter by reducing the folate pool. Calcium folinate serves as a source of H4 folate; therefore, unlike folic acid, it does not require reduction by dihydrofolate reductase to be converted into tetrahydrofolate, which allows its use to restore the impaired process of biosynthesis of DNA, RNA and proteins. The protective effect of calcium folinate occurs only in relation to healthy cells. It prevents the toxic effects of methotrexate on cells of the bone marrow and gastrointestinal tract, but does not significantly affect the nephrotoxic effect of methotrexate.
Calcium folinate is also used for biochemical modulation of fluorouracil to enhance its cytotoxic effect. Fluorouracil inhibits the activity of thymidylate synthetase, a key enzyme involved in pyrimidine biosynthesis. The drug enhances the inhibition of thymidine synthetase, increasing the intracellular pool of folates, thus stabilizing the fluorouracil-thymidine synthetase complex and increasing its activity.
Intravenous calcium folinate is prescribed for the prevention and treatment of folate deficiency when this condition cannot be corrected by oral administration of the drug, for example, with total parenteral nutrition and severe malabsorption syndrome. Calcium folinate is also used to treat megaloblastic anemia caused by folic acid deficiency when oral administration of the drug is not possible.
Pharmacokinetics
Suction. After intramuscular administration of an aqueous solution, systemic bioavailability is comparable to that after intravenous administration. However, maximum plasma concentrations are lower with intramuscular administration.
Metabolism. Calcium folinate is a racemate, the active enantiomer being the levorotatory form (L-5-formyltetrahydrofolate).
The main metabolite of calcium folinate is 5-methyltetrahydrofolic acid, which is predominantly formed in the liver and interstitial tissue.
Distribution. The volume of distribution of folinic acid is unknown. Maximum plasma concentrations of the parent compound (formyltetrahydrofolic acid, folinic acid) are achieved 10 minutes after intravenous administration.
The mean concentrations for L-5-formyltetrahydrofolic acid and dextrorotatory 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 dextrorotatory isomer is greater than L-5-formyltetrahydrofolate.
The 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 administration).
80-90% is excreted by the kidneys (5- and 10-formyltetrahydrofolates as inactive metabolites), 5-8% through the intestines.

Special instructions

Calcium folinate should be administered intramuscularly or intravenously (by injection or infusion), but should not be administered intrathecally.

Intrathecal administration of folinic acid after intrathecal overdose of methotrexate can result in death.

Treatment with methotrexate and calcium folinate, as well as fluorouracil and calcium folinate, should be carried out by a qualified oncologist with the necessary controls in place.

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 inhibitors of deoxyribonucleic acid synthesis – hydroxycarbamide, cytarabine, mercaptopurine, thioguanine). This macrocytosis is not thought to require treatment with folinic acid.

Patients with epilepsy treated with phenobarbital, primidone, phenytoin or succinimides are at risk of increased frequency of epileptic seizures due to decreased plasma concentrations of antiepileptic drugs. In this case, clinical monitoring, control of drug concentrations in the blood plasma and, if necessary, dose adjustment of antiepileptic drugs are recommended during the use of calcium folinate and after completion 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 developing toxic effects increases. This is especially true for elderly and debilitated patients. The most commonly observed dose-dependent side effects are leukopenia, inflammation of the mucous membranes and diarrhea. When using fluorouracil in combination with calcium folinate, the dose of fluorouracil in the event of toxic effects should be reduced more significantly than with fluorouracil monotherapy. Combination therapy with fluorouracil and calcium folinate should not be initiated or continued if the patient has signs of gastrointestinal toxicity, regardless of the severity of the injury. Combination therapy can be used only after the complete disappearance of all pathological symptoms from the gastrointestinal tract (for example, inflammation of the mucous membranes, diarrhea).

Since diarrhea can be a manifestation of toxic effects on the digestive system, patients with this side effect should be closely monitored until signs of diarrhea completely disappear. This is necessary because of the possible rapid deterioration of the clinical picture, leading to death. If the patient experiences diarrhea and/or stomatitis during treatment, it is recommended to reduce the dose of fluorouracil until they disappear completely. This is especially true for elderly and debilitated patients, who are most vulnerable to the toxic effects of this drug.

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

Calcium folinate should not be mixed with fluorouracil during simultaneous intravenous administration (injection or infusion).

In patients receiving combination therapy of fluorouracil with calcium folinate, the concentration of calcium ions in the blood plasma should be monitored. When low concentrations are detected, concomitant therapy with appropriate calcium preparations is necessary.

Calcium folinate/methotrexate

Calcium folinate does not protect against non-hematologic toxic effects during methotrexate therapy (eg, nephrotoxicity due to renal tubular precipitation of methotrexate or its metabolites). The presence of pre-existing or methotrexate-induced renal failure, which is associated with delayed excretion of methotrexate, may require higher doses or a longer course of calcium folinate therapy.

The use of 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 accumulation of calcium folinate is observed after several courses of treatment.

If resistance to methotrexate develops due to deterioration in the functioning of membrane transport, resistance to calcium folinate also develops, since both substances are transported by the same transport systems.

In case of accidental overdose of a folic acid antagonist such as methotrexate, emergency medical attention should be provided, as increasing the time interval between the administration of methotrexate and calcium folinate leads to a decrease in the effectiveness of the latter.

When clinical toxicity or laboratory abnormalities occur, the possibility that the patient is taking other drugs that interact with methotrexate (for example, drugs that may interfere with the elimination of methotrexate or bind to plasma proteins) should always be considered.

When working with calcium folinate, you must follow the rules for handling cytotoxic substances. It is recommended to treat the surface contaminated with the drug with a diluted solution of sodium hypochloride (containing 1% chlorine). If the drug gets on the skin, immediately wash the skin thoroughly with soap and water or sodium bicarbonate solution; In case of contact with the eyes, pull back the eyelids and rinse the eye(s) with plenty of water for 15 minutes.

Residues of the drug and all instruments and materials used to prepare solutions for injection and infusion of Leucovorin-Teva must be destroyed in accordance with the hospital’s standard procedure for the disposal of cytotoxic waste, taking into account applicable hazardous waste disposal regulations.

Impact on the ability to drive vehicles and machinery

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

Active ingredient

Calcium folinate

Composition

1 ml of solution contains:
active ingredient: calcium folinate 10.8 mg (theoretical amount of 100% calcium folinate in terms of anhydrous substance (equivalent to 10.0 mg folinic acid)); excipients: sodium chloride 8.0 mg; sodium hydroxide 1 N solution – sufficient amount (used to adjust pH); hydrochloric acid 1 N solution – a sufficient amount (used to adjust the pH); water for injections up to 1 ml.

Pregnancy

Since there have been no controlled studies of the drug in pregnant women, its use during pregnancy is only possible if the expected benefit to the mother outweighs the potential risk to the fetus.
It is not known whether the drug is excreted into breast milk, therefore, if it is necessary to use calcium folinate during lactation, it is necessary to decide on stopping breastfeeding.

Contraindications

• Hypersensitivity to calcium folinate or any other component of the drug.
• Megaloblastic anemia caused by deficiency of cyanocobalamin (vitamin B12);
With caution
Alcoholism, epilepsy, chronic renal failure (CRF), children under 2 years of age (safety and effectiveness have not been established).
There are no data on the use of combinations of calcium folinate with fluorouracil in children under 18 years of age.

Side Effects

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

Immune system disorders: very rarely – anaphylactoid/anaphylactic reactions (including shock), allergic reactions, urticaria.

Nervous system disorders: rarely – insomnia, anxiety, depression (when using high doses), increased frequency of epileptic seizures.

Gastrointestinal disorders: very often – severe diarrhea, as well as dehydration requiring hospital treatment, rarely – nausea, vomiting, dyspepsia (when using high doses).

General disorders and disorders at the injection site: uncommon – fever.

When used with other drugs to treat concomitant diseases, cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, sometimes fatal, have been reported, in the development of which the role of calcium folinate cannot be excluded.

Additional adverse reactions when used in combination with fluorouracil

The safety profile may depend on the treatment regimen used due to increased adverse reactions caused by fluorouracil.

Disorders of the blood and lymphatic system: very often – myelopenia.

Metabolic and nutritional disorders: frequency unknown – hyperammonemia.

Gastrointestinal disorders: very common – nausea, vomiting, diarrhea, severe dehydration requiring hospitalization (can be fatal).

Disorders of the skin and subcutaneous tissues: often – palmar-plantar erythrodysesthesia (palm-plantar syndrome).

General disorders and disorders at the injection site: very often – mucositis, including stomatitis, cheilitis, pharyngitis, esophagitis, proctitis.

Gastrointestinal toxicity (mainly mucositis and diarrhea) and myelosuppression can lead to death. In patients with diarrhea, clinical deterioration may lead immediately to death. Lack of improvement may be due to other toxic effects of fluorouracil (eg, neurotoxicity).

Interaction

When calcium folinate is used concomitantly with folic acid antagonists (for example, co-trimoxazole, pyrimethamine), the effectiveness of folic acid antagonists may be reduced or completely lost.

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

With the combined use of calcium folinate and fluorouracil, the effectiveness and toxicity of the latter increases. Therefore, when used together, doses of fluorouracil should be reduced (see sections “Special instructions” and “Side effects”).

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

Overdose

The effects of using a dose of calcium folinate significantly higher than the recommended dose have not been reported. However, high doses of calcium folinate may counteract the chemotherapeutic effect of folic acid antagonists.
If an overdose occurs when using a combination of fluorouracil with calcium folinate, you must follow the instructions for fluorouracil to take the necessary measures.

Storage conditions

At temperatures from 2 to 8 °C in the original packaging (bottle in a pack) to protect from light.
Keep out of the reach of children!

Shelf life

2 years.
Do not use after expiration date

Manufacturer

Farmahemi B.V., Netherlands