Pharmacotherapeutic group: vitamin, antidote of folic acid antagonists and modifier of biological action of fluorouracil.
ATC code: V03AF03
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.
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.
– Intoxication by 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, constipation, in early childhood with congenital deficiency of dihydrofolate reductase).
The solution contains: active substance: calcium folinate 10.8 mg (the theoretical amount of 100% calcium folinate in terms of anhydrous substance (equivalent to 10.0 mg of folinic acid)); excipients: sodium chloride 8.0 mg; sodium hydroxide 1 N solution – enough (used to adjust pH); hydrochloric acid 1 N solution – enough (used to adjust pH); water for injection up to 1 ml.
How to take, the dosage
Bottle with calcium folinate should be visually checked before administration. The solution for intramuscular and intravenous administration should be transparent and yellowish in color. If turbidity or the presence of inclusions is observed, the solution should not be used. Calcium folinate solution for injection or infusion is intended for single use.
Unused solution should be disposed in accordance with the procedure for disposal of cytotoxic substances.
The solution is administered intramuscularly or intravenously, it is prohibited to administer the drug intrathecally. When folinic acid is administered intrathecally after intrathecal overdose of methotrexate, fatal cases have been described.
When administered intravenously, no more than 160 mg of calcium folinate should be administered per minute because of the calcium in the solution.
Calcium folinate can be diluted with 0.9% sodium chloride solution or 5% dextrose solution before intravenous administration.
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 from 0.06 mg/ml to 1 mg/ml during preparation of solution for injection. The resulting solution is stable for 24 hours. The remaining solution should not be used.
Prevention of toxic effects of methotrexate used in high doses Calcium folinate treatment regimens depend on medium and high dose methotrexate therapy regimens, so it is advisable to refer to the appropriate methotrexate treatment protocol for necessary information.
The following recommendations may 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 administered at high doses is by parenteral administration in patients with malabsorption syndrome or other gastrointestinal pathology when 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 type and doses 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 hours (no later than 24 hours) after the start of methotrexate infusion. The same dose is administered every 6 hours for 72 hours. After parenteral administration of several doses of the drug can be replaced by the use of oral forms.
Also an integral addition to the use 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 urine). Renal function should be monitored daily by measuring the serum creatinine concentration.
It is recommended to measure the methotrexate serum concentration 48 hours after the start of infusion. If the residual methotrexate concentration is greater than 0.5 µmol/L, the calcium folinate dosing regimen should be adjusted according to the following table:
Recommended correction of calcium folinate therapy in the prevention
of the toxic effects of methotrexate administered at high doses depending
on its residual concentration
The residual concentration of methotrexate in the blood 48 hours after initiation of methotrexate: Additional doses of calcium folinate administered every 6 hours for 48 hours or until methotrexate concentration drops below
> 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
Different doses and regimens of the drug are used.
The following recommendations may serve as a guideline for determining doses and regimen of protective use of calcium folinate with fluorouracil in adults and elderly.
There are no data on the use of calcium folinate with fluorouracil combinations in children.
Doses over 50 mg should be administered parenterally. Application of higher doses does not result in higher blood concentrations due to saturable absorption of calcium folinate.
Two-month regimen: intravenous infusion of calcium folinate at a dose of 200 mg/m2 for two hours, followed by bolus infusion of 400 mg/m2 fluorouracil and 22-hour fluorouracil infusion (600 mg/m2) for 2 consecutive days every 2 weeks.
Monthly regimen: calcium folinate at a dose of 20 mg/m2 administered by intravenous bolus or 200-500 mg/m2 infusion for 2 hours immediately after an intravenous bolus 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 intravenously by bolus or from 200-500 mg/m2 infusion for 2 hours and bolus infusion in the middle or end of calcium folinate infusion of 500 mg/m2 fluorouracil.
When using a combination with fluorouracil, modification of the treatment regimen may be required by alternating therapy periods with no treatment intervals. Depending on the patient’s condition, clinical response and manifestations of therapy toxicity, fluorouracil dose adjustment may be required (see the instructions for use of fluorouracil). The number of repeated cycles is determined by the attending physician.
The therapy should be discontinued when blood leukocyte and platelet counts are less than 3.5 thousand/mm3 and 100.0 thousand/mm3, respectively. Also the therapy should be discontinued in case of gastrointestinal bleeding, severe diarrhea (≥7 times per day), exfoliative dermatitis.
Intoxication with folic acid antagonists (methotrexate, trimethoprim, pyrimethamine).
Calcium folinate is administered in a dose equal to or greater than the administered dose of methotrexate within 1 hour after the administered dose of methotrexate, then the drug is administered 10 mg/m2 every 3 hours until signs of toxicity disappear.
Toxicity of trimethoprim
After stopping the administration of trimethoprim, calcium folinate at a dose of 3-10 mg/day until clinical blood counts recover.
Toxicity of pyrimethamine
In case of high doses of pyrimethamine or prolonged treatment with low doses, calcium folinate should be administered simultaneously at a dose of 5-50 mg/day, depending on clinical blood counts.
Therapy should be stopped when blood leukocyte and platelet counts are below 3.5 thousand/mm3. and 100.0 thousand/mm3, respectively. Also the therapy should be stopped in case of gastrointestinal bleeding, severe diarrhea (≥7 times per day), exfoliative dermatitis.
In megaloblastic anemia caused by folic acid deficiency, calcium folinate is prescribed in dose up to 5 mg (maximum 15 mg) per day.
Concomitant use of calcium folinate with folic acid antagonists (e.g., co-trimoxazole, pyrimethamine) may reduce or completely lose the effectiveness of folic acid antagonists.
Calcium folinate may decrease the effectiveness of anti-epileptic drugs (phenobarbital, primidone, phenytoin, succinimides) and increase the frequency of epileptic seizures (due to decreased plasma concentrations of enzyme inducers of antiepileptic drugs due to accelerated metabolic processes in the liver, as folate is a co-factor).
When calcium folinate and fluorouracil are used in combination, the effectiveness and toxicity of the latter are increased. Because of this, doses of fluorouracil must be reduced when used together (see “Special Precautions” and “Side Effects”).
There have been reports of incompatibility of injectable forms of calcium folinate when used concomitantly with injectable forms of doperidol, fluorouracil, foscarnet and methotrexate, due to precipitate formation or turbidity of the injected solutions.
Calcium folinate should be administered intramuscularly or intravenously (as an injection or infusion), but should not be given 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 inhibitors of deoxyribonucleic acid synthesis – 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 the dose of antiepileptic drugs during the use of calcium folinate and after the end of therapy is recommended.
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 and debilitated patients. Most often there are dose-dependent side effects: leukopenia, inflammation of mucous membranes and diarrhea. When fluorouracil is used in combination with calcium folinate, doses of fluorouracil in case of toxic effects should be reduced significantly more 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).
We should closely monitor patients with this side effect until the diarrhea has completely disappeared, since diarrhea can be a manifestation of a toxic effect on the digestive system. 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 older 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 detected, concomitant therapy with appropriate calcium preparations is necessary.
. 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 the 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 central nervous system tumors when there is accumulation of calcium folinate after several courses of treatment.
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 systems.
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 skin – immediately rinse the skin with soap and water or sodium bicarbonate solution; in case of contact with eyes – pull back the eyelids and rinse the eye (eyes) with plenty of water for 15 minutes.
The remains of the drug and all instruments and materials used to prepare solutions for injection and infusion of Leucovorin-Teva must be disposed of in accordance with the standard hospital procedure for disposal of cytotoxic waste, taking into account the current regulations on the disposal of hazardous waste.
Influence on driving and operating ability
The use of calcium folinate has not been observed to affect driving ability and other activities requiring concentration and rapid psychomotor reactions.
Transparent solution from colorless to yellow in color.
– Megaloblastic anemia due to cyanocobalamin (vitamin B12) deficiency;
Alcoholism, epilepsy, chronic renal failure (CKD), children under 2 years (safety and effectiveness is not established).
No data on the use of calcium folinate combinations with fluorouracil in children under 18 years old.
According to the World Health Organization (WHO), adverse effects are classified according to their frequency of occurrence as follows: very frequently (≥1/10), frequently (≥1/100 to < 1/10), infrequently (≥1/10000 to < 1/1000), very rarely (< 1/10000); frequency is unknown – according to available data it was impossible to determine the frequency of occurrence.
Disorders of the immune s system: very rarely – anaphylactoid/anaphylactic reactions (including shock), allergic reactions, urticaria.
Nervous system disorders: rarely – insomnia, anxiety, depression (in high doses), increased incidence of epileptic seizures.
Gastrointestinal disorders: very often – severe diarrhea and dehydration requiring hospital treatment, rarely – nausea, vomiting, dyspepsia (in high doses).
General disorders and disorders at the site of administration: not infrequently – fever.
When used with other drugs to treat comorbidities, cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, sometimes fatal, in the development of which the role of calcium folinate cannot be excluded.
Additional adverse reactions when used in combination withfluorouracil
The safety profile may depend on the therapy regimen used because of increased fluorouracil-induced adverse reactions.
Blood and lymphatic system disorders: very common – myelopenia.
Disorders of the metabolism and nutrition: frequency unknown – hyperammonemia.
Gastrointestinal tract disorders: very common – nausea, vomiting, diarrhea, severe dehydration requiring hospitalization (can be fatal).
Dermal and subcutaneous tissue disorders: often – palmar-plantar erythrodysesthesia (palm-subcutaneous syndrome).
General disorders and disorders at the site of administration: very common – mucositis, including stomatitis, cheilitis, pharyngitis, esophagitis, proctitis.
Toxic gastrointestinal damage (mainly mucositis and diarrhea) and myelosuppression can lead to death. In patients with diarrhea, clinical deterioration can be immediately fatal. Lack of improvement may be associated with other toxic effects of fluorouracil (e.g., neurotoxicity).
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 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 measures should be followed.
Since there have been no controlled trials of the drug in pregnant women, its use during pregnancy is possible only if the expected benefits to the mother exceed the potential risk to the fetus. It is unknown whether the drug is excreted into the breast milk, therefore, if it is necessary to use calcium folinate during lactation, it is necessary to consider stopping breastfeeding.
2 years. Do not use after the expiration date
|Conditions of storage|
At 2 to 8 ° C in the original packaging (bottle in a package) to protect it from light. Keep out of reach of children!
Pharmahemi B.V., The Netherlands
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