Instructions for Calcium Folinate-Vista solution for injection 200 mg bottle 20 ml No. 1
Composition
active ingredient:
1 ml of solution contains 10.8 mg of calcium folinate, which is equivalent to 10 mg of folinic acid;
1 vial contains 54 mg or 108 mg of calcium folinate, equivalent to 50 mg or 100 mg of folinic acid;
Excipients: sodium chloride, sodium hydrochloride, water for injections.
Dosage form
Solution for injection.
Main physicochemical properties: transparent yellowish solution, free from mechanical inclusions.
Pharmacotherapeutic group
Means used to eliminate the toxic effects of anticancer therapy. Calcium folinate. ATX code V03A F03.
Pharmacological properties
Pharmacodynamics.
Calcium folinate is the calcium salt of 5-formyltetrahydrofolic acid. It is an active metabolite of folinic acid and an important coenzyme required for nucleic acid synthesis in cytostatic therapy.
Calcium folinate is often used to reduce the toxic effect or neutralize the action of folate antagonists (e.g., methotrexate).
Calcium folinate and folate antagonists share the same membrane transporter and compete for transport into cells, thereby stimulating the efflux of folate antagonists. Calcium folinate also protects cells from the effects of folate antagonists by replenishing depleted folate stores. It is a source of reduced H4-folate. This allows it to 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 enhance the cytotoxic activity of fluorouracil (5-FU). 5-FU inhibits thymidylate synthase (TS), a key enzyme involved in pyrimidine biosynthesis. Calcium folinate enhances TS inhibition by increasing the intracellular folate pool, which stabilizes the 5-FU-TS complex and enhances its activity.
Intravenous calcium folinate also prevents folate deficiency and restores folate stores when oral folic acid is not available. This procedure is used in total parenteral nutrition and in severe cases of malabsorption. Intravenous calcium folinate is also indicated for the treatment of megaloblastic anemia caused by folic acid deficiency when oral administration is not possible.
Pharmacokinetics.
Absorption
When administered intramuscularly as an aqueous solution, the systemic bioavailability of calcium folinate is comparable to that after intravenous administration, but the maximum plasma concentration (Cmax) is lower.
Metabolism
Calcium folinate is a racemate. The active enantiomer is the L-form (L-5-formyltetrahydrofolic acid, L-5-formyltetrahydrofolate).
The main metabolite of folinic acid is 5-methyltetrahydrofolic acid (5-methyltetrahydrofolate), which is produced mainly in the liver and intestinal mucosa.
Distribution
The volume of distribution of folinic acid is unknown.
The maximum concentration of the parent compound in blood plasma (D/L-5-formyltetrahydrofolic acid, folinic acid) is reached 10 minutes after intravenous administration.
After a 25 mg dose, the area under the pharmacokinetic curve for L-5-formyltetrahydrofolate and 5-methyltetrahydrofolate is 28.4 ± 3.5 mg min/L and 129 ± 112 mg min/L, respectively. The inactive D-isomer is present in higher concentrations than L-5-formyltetrahydrofolate.
Elimination
The half-life of the active L-form is 32–35 minutes, and of the inactive D-form is 352–485 minutes.
The total terminal elimination half-life of the active metabolites is about 6 hours (after intravenous or intramuscular administration).
Excretion
Up to 80-90% of the dose is excreted in the urine (as 5- and 10-formyltetrahydrofolate and inactive metabolites), 5-8% of the dose is excreted in the feces.
Indication
- As a protective agent to prevent the 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 for the prevention and treatment of folate deficiency if oral folic acid is not possible.
Contraindication
Hypersensitivity to calcium folinate or to any other substance included in the composition of the drug;
pernicious anemia and other megaloblastic anemias caused by vitamin B12 deficiency.
Special safety measures.
Calcium folate - Vista can only be administered intravenously or intramuscularly. Intrathecal use of the drug is prohibited!
Calcium folinate solution for injection is for single use only. Calcium folinate should be inspected visually before use. The solution for injection should be clear and yellowish. If there is cloudiness or particles, the solution should be discarded.
Interaction with other medicinal products and other types of interactions
If calcium folinate is administered in combination with a folic acid antagonist (e.g. cotrimoxazole, pyrimethamine), the effect of the folic acid antagonist may be reduced or completely neutralized.
Concomitant use of calcium folinate with antiepileptic drugs phenobarbital, phenytoin, primidone and succinimide causes a decrease in their antiepileptic activity and may increase the frequency of seizures (a decrease in plasma levels of enzyme-inducing anticonvulsant drugs may occur, since hepatic metabolism is activated due to the fact that folates are one of the cofactors).
Calcium folinate may lead to an increase in both the therapeutic and toxic effects of 5-fluorouracil, therefore, when used together, the dose of 5-fluorouracil must be reduced.
Application features
Calcium folinate can only be administered intravenously or intramuscularly. Intrathecal use of the drug is prohibited. Treatment with calcium folinate in combination with methotrexate or 5-fluorouracil should be carried out under the supervision of an experienced oncologist.
Calcium folinate may mask the symptoms of pernicious anemia and other anemias caused by vitamin B12 deficiency.
Many cytotoxic drugs that are direct or indirect inhibitors of DNA synthesis cause macrocytosis (including hydroxycarbamide, cytarabine, mercaptopurine, thioguanine). Such macrocytosis should not be treated with folinic acid.
In patients with epilepsy taking 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 the blood plasma. Therefore, in such cases, close clinical supervision is required, as well as, if necessary, monitoring of the concentration of antiepileptic drugs in the blood plasma and correction of their doses during the period of calcium folinate treatment and after its withdrawal.
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 of methotrexate therapy (e.g. nephrotoxicity due to precipitation of methotrexate and/or its metabolites in the renal tubules). Patients with delayed early elimination of methotrexate are more likely to develop reversible renal failure and other toxic effects associated with methotrexate. Renal failure (which develops during methotrexate therapy or is present before treatment) is associated with delayed methotrexate excretion, and in such cases, higher doses or longer duration of calcium folinate may be necessary.
Excessive doses of calcium folinate should be avoided as this may lead to a reduction in the antitumor activity of methotrexate, especially in the case of central nervous system tumors in which calcium folinate accumulation is observed after several courses of treatment.
When resistance to methotrexate develops due to impaired membrane transport, resistance to calcium folinate also develops, since both substances are transported by the same transport system.
In case of overdose with folic acid antagonists (e.g. methotrexate), calcium folinate should be administered as soon as possible. The effectiveness of calcium folinate as an antidote decreases with increasing time interval between methotrexate and calcium folinate administration.
When detecting abnormalities in laboratory parameters or clinical symptoms of toxicity, it is always necessary to check whether the patient is taking other drugs that interact with methotrexate (for example, affect the elimination of methotrexate or its binding to plasma proteins).
Use of calcium folinate in combination with 5-fluorouracil
Calcium folinate may potentiate the toxic effects of 5-fluorouracil, especially in elderly and debilitated patients. The most common manifestations of toxicity are leukopenia, inflammation of the mucous membranes, stomatitis, diarrhea. These side effects may be dose-limiting. If it is necessary to reduce the dose 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 continued until symptoms of gastrointestinal toxicity, regardless of their severity, have completely disappeared.
Since diarrhea may be a sign of gastrointestinal toxicity (which can lead to rapid clinical deterioration and even death), patients with diarrhea should be closely monitored until symptoms resolve. Particular caution is required in the treatment of debilitated and elderly patients.
It is recommended to prescribe lower initial doses of 5-fluorouracil to elderly patients and those who have previously received radiotherapy.
Calcium folinate should not be mixed with 5-fluorouracil in the same intravenous injection or infusion.
This medicinal product contains sodium. This should be taken into account when prescribing the drug to patients on a controlled sodium diet.
Use during pregnancy or breastfeeding
There is no evidence that calcium folinate has a harmful effect when used during pregnancy, however, adequate and well-controlled studies of use during pregnancy or breastfeeding have not been conducted.
If methotrexate or other folic acid antagonists are prescribed during pregnancy or breastfeeding (which is possible only under 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 breastfeeding is contraindicated. This also applies to combination therapy with 5-fluorouracil in combination with calcium folinate.
More detailed information on this subject is provided in the instructions for medical use of methotrexate, other folic acid antagonists and 5-fluorouracil.
Breast-feeding
It is not known whether calcium folinate is excreted in breast milk. If necessary, calcium folinate can be used during breastfeeding according to therapeutic indications. If treatment is necessary, breastfeeding should be discontinued.
Ability to influence reaction speed when driving vehicles or other mechanisms
There is no information on the ability of calcium folinate to affect driving or operating other mechanisms.
Method of administration and doses
Calcium folate - Vista is intended for intravenous or intramuscular use only. The rate of intravenous administration should not exceed 160 mg/min, given the calcium content of the solution.
Solutions for intravenous infusions are prepared by diluting the drug with 0.9% sodium chloride solution or 5% glucose solution.
Calcium folinate protection during methotrexate therapy
Since the doses and schedules of calcium folinate depend on the doses and schedules of medium and high-dose methotrexate therapy, it is advisable to refer to the methotrexate treatment protocol for appropriate dosing information.
Calcium folinate should be administered parenterally in patients with malabsorption syndromes or other gastrointestinal diseases where intestinal absorption of the drug is not guaranteed. Doses above 25-50 mg should be administered parenterally only, taking into account the saturation effect on the absorption of calcium folinate in the gastrointestinal tract.
Calcium folinate protection is necessary when methotrexate is used in doses above 500 mg/m2 of body surface area and is advisable for methotrexate doses of 100–500 mg/m2 of body surface area.
Below are recommendations for the use of calcium folinate in adults, elderly patients, and children.
The doses and duration of calcium folinate therapy are determined taking into account the doses and regimen of methotrexate treatment, the presence of symptoms of toxic effects, as well as individual methotrexate excretion rates. 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. Then the same doses of calcium folinate are administered every 6 hours for 72 hours. After several parenteral administrations, you can switch to oral administration of the drug in the form of capsules.
48 hours after the start of the methotrexate infusion, the residual concentration of methotrexate in the blood is measured. If it is less than 0.5 μmol/l, calcium folinate therapy can be stopped. If the methotrexate concentration exceeds 0.5 μmol/l, protective therapy must be continued and intensified. Calcium folinate is administered in the following doses every 6 hours for another 48 hours or until the methotrexate concentration is < 0.05 μmol/l:
· at a methotrexate concentration ≥ 0.5 μmol/l – at a dose of 15 mg/m2 of body surface;
· at a methotrexate concentration ≥ 1.0 μmol/l – at a dose of 100 mg/m2 of body surface area;
· at a methotrexate concentration ≥ 2.0 μmol/l – at a dose of 200 mg/m2 of body surface.
In addition to calcium folinate therapy, measures should be taken to accelerate methotrexate excretion (maintaining high diuresis, alkalinizing urine), and serum creatinine levels should be measured daily to monitor renal function.
Combination therapy in combination with 5-fluorouracil
Various regimens of 5-fluorouracil in combination with calcium folinate have been used, but no single regimen has been shown to be superior. Some regimens are described below for adults and elderly patients with advanced or metastatic colorectal cancer. There are no data on the use of these combinations in children.
Weekly repeated course regimen: calcium folinate is administered at a dose of 20 mg/m2 of body surface area by intravenous bolus injection or at a dose of 200-500 mg/m2 of body surface area by two-hour intravenous infusion; 5-fluorouracil at a dose of 500 mg/m2 of body surface area is administered by intravenous bolus injection in the middle or at the end of the calcium folinate infusion.
Monthly repeating regimen: for the first 5 days of the course, calcium folinate is administered daily at a dose of 20 mg/m2 of body surface area by intravenous bolus injection or at a dose of 200-500 mg/m2 of body surface area by two-hour intravenous infusion, followed immediately by 5-fluorouracil at a dose of 425 or 370 mg/m2 of body surface area by intravenous bolus injection.
During combined therapy with 5-fluorouracil and calcium folinate, it may be necessary to adjust the doses of 5-fluorouracil and the intervals between its administrations, depending on the patient's condition, clinical response to therapy and dose-limiting toxic effects. The corresponding recommendations are given in the instructions for medical use of 5-fluorouracil. A reduction in the doses of calcium folinate is not required.
The required number of therapy courses is determined by the doctor.
Use of calcium folinate as an antidote to the folic acid antagonists trimetrexate, trimethoprim, and pyrimethamine
Prevention of trimetrexate toxicity: Calcium folinate is administered daily during trimetrexate treatment and for 72 hours after the last dose of trimetrexate. Calcium folinate can be administered intravenously over 5 to 10 minutes at a dose of 20 mg/m2 of body surface area every 6 hours (daily dose 80 mg/m2 of body surface area) or orally at 20 mg/m2 of body surface area 4 times a day at equal intervals. The daily dose of calcium folinate should be adjusted according to the symptoms of hematological toxicity of trimetrexate.
Treatment of trimetrexate overdose: In the event of overdose (which is possible with trimetrexate doses exceeding 90 mg/m2 of body surface area 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 area every 6 hours for three days.
Prevention of toxic effects of trimethoprim: after discontinuation of trimethoprim therapy, calcium folinate is administered at a dose of 3–10 mg/day until hematological parameters normalize.
Prevention of toxic effects of pyrimethamine: during therapy with high doses of pyrimethamine or long-term treatment with low doses, concomitant calcium folinate therapy is prescribed in doses from 5 to 50 mg/day, depending on the number of formed elements in the peripheral blood.
The injectable form of calcium folinate is used to treat megaloblastic anemia caused by folic acid deficiency, as well as to prevent and treat folate deficiency when oral folic acid is not possible or ineffective (for example, with parenteral nutrition or in the presence of severe malabsorption syndrome).
Children.
Calcium folinate is indicated for use in children as a protective agent to prevent the toxic effects of methotrexate, as well as as an antidote for overdose and intoxication with methotrexate and other folic acid antagonists.
Overdose
No adverse effects have been observed in patients when calcium folinate was administered in doses significantly higher than recommended. However, calcium folinate in excessive doses may 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
When used according to all indications
On the part of the immune system
Very rare (<0.01%): cases of allergic reactions, including anaphylactoid reactions and urticaria.
Mental disorders
Rare (0.01 - 0.1%): insomnia, agitation and depression when using high doses.
Gastrointestinal tract
Rare (0.01 - 0.1%): gastrointestinal disorders after high doses.
From the nervous system
Rare (0.01 - 0.1%): increased frequency of epileptic seizures.
General disorders and local reactions
Uncommon (0.1 - 1%): fever after administration of calcium folinate solution for injection.
In combination therapy with 5-fluorouracil
In general, the safety profile depends on the 5-fluorouracil treatment regimen, as the toxicity of 5-fluorouracil is enhanced when used in combination.
Treatment regimen with repeated therapeutic courses every month
From the digestive tract
Very common (> 10%): vomiting and nausea.
General disorders and local reactions
Very common (> 10%): inflammation of the mucous membranes (severe).
Calcium folinate does not potentiate other toxic effects of 5-fluorouracil (e.g. neurotoxicity).
Treatment regimen with repeated therapeutic courses every week
From the digestive tract
Very common (> 10%): severe diarrhea and dehydration requiring hospitalization of the patient, in isolated cases even with fatal outcome.
Expiration date
30 months.
Storage conditions
Store in the original packaging, protected from light, at a temperature of 2°C to 8°C (in the refrigerator). Keep out of the reach of children!
Calcium folinate solutions should not be mixed with infusion solutions containing bicarbonates due to their chemical instability. 5-fluorouracil and folinic acid should be administered separately to prevent precipitation.
For intravenous infusion, the drug should be diluted with 5% glucose solution or 0.9% sodium chloride solution.
Only one-time withdrawal of the drug from the vial is allowed.
Before use, it is necessary to visually check the appearance of the drug. It should be transparent, colorless or light yellow. If the solution is cloudy or has visible mechanical inclusions, such a drug cannot be used.
Packaging
5 ml or 10 ml of solution in amber glass vials. Vials are closed with rubber stoppers, which are crimped with aluminum caps with polypropylene discs. 1 vial in cardboard boxes.
Vacation category
According to the recipe.
Producer
Haupt Pharma Wolfratshausen GmbH.
Location of the manufacturer and address of its place of business
Pfaffenrieder Strasse 5, 82515 Wolfratshausen, Germany.
