Calcium folinate-vista ac

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CALCIUM FOLINATE-VISTA AC (CALCIUM FOLINATE-VISTA AC)

Composition:

Active substance: 1 ml of solution contains 10.8 mg of calcium folinate, equivalent to 10 mg of folic acid;

1 vial contains 54 mg, 108 mg, 216 mg, 378 mg, 540 mg, or 1080 mg of calcium folinate, equivalent to 50 mg, 100 mg, 200 mg, 350 mg, 500 mg, or 1000 mg of folic acid, respectively;

Excipients: sodium chloride, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear yellowish solution.

Pharmacotherapeutic group. Agents used to counteract toxic effects of antineoplastic therapy. Calcium folinate. ATC code V03AF03.

Pharmacological Properties

Pharmacodynamics

Calcium folinate is the calcium salt of 5-formyltetrahydrofolic acid. It is an active metabolite of folic acid and an essential cofactor required for nucleic acid synthesis during cytostatic therapy.

Calcium folinate is commonly used to reduce or neutralize the toxic effects of folate antagonists (e.g., methotrexate).

Calcium folinate and folate antagonists utilize the same membrane transporter and compete for cellular uptake, thereby promoting the efflux of folate antagonists. Calcium folinate also protects cells from the action of folate antagonists by replenishing depleted folate stores. It serves as a source of reduced H4-folate, enabling it to bypass the blockade caused by folate antagonists and act as a source of various cofactor forms of folic acid.

Calcium folinate is also frequently used as a biochemical modulator to enhance the cytotoxic activity of 5-fluorouracil (5-FU). 5-FU inhibits thymidylate synthase (TS), a key enzyme involved in pyrimidine biosynthesis. Calcium folinate enhances TS inhibition by increasing intracellular folate pools, thereby stabilizing the 5-FU–TS complex and enhancing its activity.

Intravenous administration of calcium folinate also prevents folate deficiency and restores folate stores when oral folic acid supplementation is not feasible. This approach 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

Following intramuscular administration of the aqueous solution, the systemic bioavailability of calcium folinate is comparable to that after intravenous administration, although 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 primary metabolite of folic acid is 5-methyltetrahydrofolate, which is predominantly produced in the liver and the gastrointestinal mucosa.

Distribution

The volume of distribution of folic acid is unknown.

The maximum plasma concentration of the parent compound (D/L-5-formyltetrahydrofolic acid, folic acid) is reached within 10 minutes after intravenous administration.

After a 25 mg dose, the area under the pharmacokinetic curve (AUC) 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 at higher concentrations than the L-5-formyltetrahydrofolate.

Elimination

The elimination half-life of the active L-form is 32–35 minutes, while that of the inactive D-form is 352–485 minutes.

The overall terminal half-life of active metabolites is approximately 6 hours (following either intravenous or intramuscular administration).

Excretion

Up to 80–90% of the administered dose is excreted in urine (as 5- and 10-formyltetrahydrofolate and inactive metabolites), and 5–8% of the dose is excreted in feces.

Clinical characteristics.

Indications.

• As a protective agent for the prevention of toxic effects of methotrexate when used in moderate and high doses;
• as an antidote in cases of methotrexate 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 due to folic acid deficiency, as well as for the prevention and treatment of folate deficiency when oral administration of folic acid is not possible.

Contraindications.

• Hypersensitivity to calcium folinate or to any other component of the medicinal product;
• pernicious anemia and other megaloblastic anemias caused by vitamin B12 deficiency.

Special precautions.

Calcium folinate-Vista AS may be administered only intravenously or intramuscularly. Intrathecal administration of the medicinal product is prohibited.

There has been a report of a fatal case following intrathecal administration of folic acid after intrathecal overdose of methotrexate.

The calcium folinate injection solution is intended for single use only. The calcium folinate solution should be inspected visually prior to administration. The injection solution should be clear and yellowish. If turbidity or particulate matter is present, the solution should be discarded.

Interaction with other medicinal products and other forms of interaction.

If calcium folinate is administered in combination with a folic acid antagonist (e.g., co-trimoxazole, pyrimethamine), the effect of the folic acid antagonist may be reduced or completely neutralized.

Concomitant use of calcium folinate with antiepileptic drugs such as phenobarbital, phenytoin, primidone, and succinimides may lead to decreased antiepileptic activity and may increase the frequency of seizures (this may occur due to decreased plasma levels of anticonvulsant drugs that are enzyme inducers, as hepatic metabolism is enhanced since folates act as one of the cofactors).

Calcium folinate may enhance both the therapeutic and toxic effects of 5-FU; therefore, when used concomitantly, the dose of 5-FU should be reduced.

Special precautions for use.

Calcium folinate should be administered only intravenously or intramuscularly. Intrathecal administration of the drug is contraindicated.

Treatment with calcium folinate in combination with methotrexate or 5-FU must 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 may cause macrocytosis (e.g., hydroxyurea, cytarabine, mercaptopurine, thioguanine). Such macrocytosis should not be treated with folic acid. In patients with epilepsy receiving phenobarbital, phenytoin, primidone, or succinimides, administration of calcium folinate may increase the frequency of epileptic seizures due to decreased plasma concentrations of antiepileptic drugs. Therefore, careful clinical monitoring is required in such cases, and, if necessary, monitoring of plasma concentrations of antiepileptic drugs and dose adjustments during and after calcium folinate therapy.

Use of calcium folinate in combination with methotrexate.

Recommendations for prevention of toxic effects during methotrexate therapy are provided in the methotrexate product information.

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 renal tubules). Patients with delayed elimination of methotrexate at an early stage have a higher risk of developing reversible renal failure and other toxic effects associated with methotrexate use. Renal impairment (either developing during methotrexate therapy or present before treatment initiation) is associated with delayed methotrexate excretion; therefore, in such cases, administration of higher doses of calcium folinate or prolonged treatment duration may be required.

Administration of excessive doses of calcium folinate should be avoided, as this may reduce the antitumor activity of methotrexate, especially in tumors of the central nervous system, where accumulation of calcium folinate may occur after several treatment cycles.

Resistance to methotrexate due to impaired membrane transport also results in resistance to calcium folinate, as both substances are transported by the same transport system.

In cases of overdose with folic acid antagonists (e.g., methotrexate), calcium folinate administration should be initiated as soon as possible. The effectiveness of calcium folinate as an antidote decreases with increasing time interval between methotrexate and calcium folinate administration.

If laboratory abnormalities or clinical signs of toxicity occur, it is essential to verify whether the patient is taking other drugs that interact with methotrexate (e.g., those affecting methotrexate elimination or plasma protein binding).

Use of calcium folinate in combination with 5-FU.

Calcium folinate may enhance the toxicity of 5-FU, particularly in elderly and debilitated patients. The most common toxic effects include leukopenia, mucositis, stomatitis, and diarrhea. These adverse effects may be dose-limiting. If dose reductions are necessary due to toxicity during combined administration of 5-FU and calcium folinate, the dose of 5-FU should be reduced more than during 5-FU monotherapy. Treatment with 5-FU in combination with calcium folinate should not be initiated until gastrointestinal toxicity symptoms have completely resolved, regardless of their severity. Since diarrhea may be a sign of gastrointestinal toxicity (which may rapidly lead to clinical deterioration and even fatal outcome), patients with diarrhea require close monitoring until all symptoms have fully resolved. Particular caution is required when treating debilitated patients and elderly individuals.

Lower initial doses of 5-FU are recommended for elderly patients and for those who have previously received radiation therapy.

Calcium folinate and 5-fluorouracil should not be mixed in the same intravenous injection or infusion.

During combined therapy with 5-FU and calcium folinate, serum calcium levels should be monitored, and calcium supplements should be administered if necessary.

Solutions for infusion prepared by diluting the drug with 0.9% sodium chloride or 5% glucose solution are physically and chemically stable for at least 24 hours when stored at temperatures not exceeding 25°C.

From a microbiological standpoint, the infusion solution should be administered immediately after preparation. If not used immediately, storage duration and conditions should be closely monitored by medical personnel. Generally, storage time should not exceed 24 hours at 2–8°C, unless the solution was prepared under controlled and validated aseptic conditions.

Excipients.

This medicinal product contains less than 1 mmol/dose (8.25 mg/mL) of sodium, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

There is no evidence that calcium folinate has harmful effects when used during pregnancy; however, adequate and well-controlled studies on its use during pregnancy or breastfeeding have not been conducted.

If methotrexate or other folic acid antagonists are administered during pregnancy or breastfeeding (which is possible only under strict indications when the expected benefit to the mother clearly outweighs the potential risk to the fetus), there are no restrictions on the use of calcium folinate for prevention of adverse effects or neutralization of methotrexate toxicity.

Use of 5-FU during pregnancy or breastfeeding is contraindicated. This also applies to combination therapy with 5-FU and calcium folinate. Further information on this subject is provided in the product information for methotrexate, other folic acid antagonists, and 5-FU.

Breastfeeding period.

It is unknown whether calcium folinate is excreted in breast milk. If necessary, calcium folinate may be used during breastfeeding according to therapeutic indications. However, if treatment is required, breastfeeding should be discontinued.

Ability to influence the ability to drive vehicles or operate machinery.

There is no information available on the ability of calcium folinate to affect the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

Calcium folinate-Vista AS is intended for intravenous or intramuscular use only.

Intrathecal administration of the medicinal product is strictly prohibited.

The intravenous infusion rate should not exceed 160 mg/min, taking into account the calcium content in the solution.

Solutions for intravenous infusion are prepared by diluting the medicinal product with 0.9% sodium chloride solution or 5% glucose solution.

Calcium folinate rescue therapy in methotrexate treatment

Since the doses and regimens of calcium folinate depend on the dosage and treatment protocols of moderate- and high-dose methotrexate therapy, appropriate dosing information should be obtained from the methotrexate treatment protocol.

Calcium folinate should be administered parenterally to patients with malabsorption syndrome or other gastrointestinal disorders where intestinal absorption of the drug cannot be ensured. Doses exceeding 25–50 mg should be administered only parenterally due to saturation effects in gastrointestinal absorption of calcium folinate.

Calcium folinate rescue is necessary when methotrexate is administered at doses exceeding 500 mg/m² body surface area and is advisable at methotrexate doses of 100–500 mg/m² body surface area. Below are recommendations for the use of calcium folinate in adults, elderly patients, and children.

The dose and duration of calcium folinate therapy should be determined based on the dose and regimen of methotrexate treatment, presence of signs of toxic effects, and individual parameters of methotrexate excretion. Calcium folinate should be administered at a dose of 15 mg (6–12 mg/m² body surface area) 12–24 hours (no later than 24 hours) after initiation of methotrexate infusion. Subsequently, the same doses of calcium folinate should be administered every 6 hours for 72 hours. After several parenteral administrations, transition to oral administration in capsule form may be considered.

Residual methotrexate concentration in blood should be measured 48 hours after initiation of methotrexate infusion. If the concentration is below 0.5 µmol/L, calcium folinate therapy may be discontinued. If methotrexate concentration exceeds 0.5 µmol/L, rescue therapy should be continued and intensified. Calcium folinate should be administered at the following doses every 6 hours for an additional 48 hours or until methotrexate concentration drops below 0.05 µmol/L:

• at methotrexate concentration ≥0.5 µmol/L – 15 mg/m² body surface area;
• at methotrexate concentration ≥1.0 µmol/L – 100 mg/m² body surface area;
• at methotrexate concentration ≥2.0 µmol/L – 200 mg/m² body surface area.

In addition to calcium folinate therapy, measures to accelerate methotrexate excretion (maintaining high diuresis, urine alkalinization) should be implemented, and serum creatinine levels should be monitored daily to assess renal function.

Combination therapy with 5-FU

Various regimens of 5-FU in combination with calcium folinate have been used, but superiority of any specific regimen has not been established. Below are described some treatment regimens for adults and elderly patients with advanced or metastatic colorectal cancer. Data on the use of these combinations in pediatric patients are lacking.

Biweekly regimen: On days 1 and 2 of each cycle, calcium folinate is administered at a dose of 200 mg/m² body surface area via a 2-hour intravenous infusion, followed by 5-fluorouracil at a dose of 400 mg/m² body surface area as an intravenous bolus injection and 5-fluorouracil at a dose of 600 mg/m² body surface area via a 22-hour intravenous infusion over the next 2 days, repeated every 2 weeks on days 1 and 2.

Weekly regimen: Calcium folinate is administered at a dose of 20 mg/m² body surface area as an intravenous bolus injection or at a dose of 200–500 mg/m² body surface area via a 2-hour intravenous infusion; 5-fluorouracil at a dose of 500 mg/m² body surface area is administered as an intravenous bolus injection during or at the end of the calcium folinate infusion.

Monthly regimen: For the first 5 days of each cycle, calcium folinate is administered daily at a dose of 20 mg/m² body surface area as an intravenous bolus injection or at a dose of 200–500 mg/m² body surface area via a 2-hour intravenous infusion, immediately followed by 5-fluorouracil at a dose of 425 mg/m² or 370 mg/m² body surface area as an intravenous bolus injection.

During combination therapy with 5-fluorouracil and calcium folinate, dose adjustments of 5-fluorouracil and intervals between administrations may be required depending on the patient's condition, clinical response, and dose-limiting toxic effects. Appropriate recommendations are provided in the 5-fluorouracil medical instructions. Dose reduction of calcium folinate is not required.

The required number of treatment cycles is determined by the physician.

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

Prevention of trimetrexate toxic effects: Calcium folinate should be administered daily during trimetrexate therapy and for 72 hours after the last dose of trimetrexate. Calcium folinate may be administered intravenously over 5–10 minutes at a dose of 20 mg/m² body surface area every 6 hours (daily dose: 80 mg/m² body surface area) or orally at 20 mg/m² body surface area four times daily at regular intervals. The daily dose of calcium folinate should be adjusted based on signs of hematological toxicity from trimetrexate.

Treatment of trimetrexate overdose: In cases of overdose (possible with trimetrexate doses exceeding 90 mg/m² body surface area without concomitant calcium folinate), trimetrexate therapy should be discontinued and calcium folinate administered intravenously at a dose of 40 mg/m² body surface area every 6 hours for three days.

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

Prevention of pyrimethamine toxic effects: During high-dose pyrimethamine therapy or prolonged low-dose treatment, concomitant calcium folinate therapy should be administered at doses ranging from 5 to 50 mg/day, depending on the count of formed elements in peripheral blood.

The injectable form of calcium folinate is indicated for the treatment of megaloblastic anemia due to folic acid deficiency, as well as for the prevention and treatment of folate deficiency when oral folic acid administration is impossible or ineffective (e.g., during 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 methotrexate toxicity, as well as an antidote in cases of overdose or intoxication with methotrexate and other folic acid antagonists.

Overdose

Symptoms: No adverse consequences have been observed in patients receiving calcium folinate at doses significantly higher than recommended. However, excessive doses of calcium folinate may neutralize the chemotherapeutic effect of folic acid antagonists.

Treatment: In cases of 5-fluorouracil overdose in combination with calcium folinate, measures recommended for 5-fluorouracil overdose should be implemented.

Adverse Reactions

Undesirable adverse reactions are listed by system organ class and frequency: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000), frequency not known (cannot be estimated from available data).

When used for all indications

Immune system disorders: rare – allergic reactions, including anaphylactoid/anaphylactic reactions and urticaria.

Psychiatric disorders: uncommon – insomnia, agitation, and depression when high doses of the medicinal product are administered.

Gastrointestinal disorders: uncommon – gastrointestinal disturbances after administration of high doses of the medicinal product.

Nervous system disorders: uncommon – increased frequency of epileptic seizures.

Skin and subcutaneous tissue disorders: frequency not known – Stevens-Johnson syndrome and toxic epidermal necrolysis. In patients who received folic acid in combination with other medicinal products known to cause the aforementioned syndromes, fatal cases have been reported. It cannot be excluded that folic acid contributed to the occurrence of the aforementioned syndromes.

General disorders and administration site conditions: uncommon – pyrexia.

In combination therapy with 5-fluorouracil

Overall safety profile depends on the 5-fluorouracil treatment regimen, as the toxicity of 5-fluorouracil is enhanced when used in combination.

Blood and lymphatic system disorders: very common – bone marrow suppression, including fatal cases.

Metabolism and nutrition disorders: frequency not known – hyperammonaemia.

General disorders and administration site conditions: very common – mucositis, including stomatitis and cheilitis. Fatal cases due to mucositis have been reported.

Skin and subcutaneous tissue disorders: common – palmar-plantar erythrodysesthesia syndrome.

Monthly repeated treatment regimen

Gastrointestinal disorders: very common – vomiting and nausea.

General disorders and administration site conditions: very common – severe mucositis.

Calcium folinate does not enhance other toxic effects of 5-fluorouracil (e.g. neurotoxicity).

Weekly repeated treatment regimen

Gastrointestinal disorders: very common – severe diarrhoea and dehydration requiring hospitalization of the patient, in rare cases even with fatal outcome.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life

30 months.

Storage conditions

Store in the original packaging, protected from light, at 2°C to 8°C (in the refrigerator). Keep out of the reach of children.

Incompatibilities

Solutions of calcium folinate must not be mixed with infusion solutions containing bicarbonates due to chemical instability. 5-Fluorouracil and folic acid should be administered separately to prevent precipitation.

Incompatibility (precipitation) has been observed when mixing solutions of calcium folinate with droperidol, fluorouracil, foscarnet, and methotrexate.

Droperidol

When 1.25 mg/0.5 ml droperidol and 5 mg/0.5 ml calcium folinate were mixed directly in a syringe at 25°C for 5 minutes followed by centrifugation for 8 minutes, precipitate formation was observed.

When 2.5 mg/0.5 ml droperidol was mixed with 10 mg/0.5 ml calcium folinate, precipitate formation occurred immediately after sequential injection of the medicinal products into a Y-type connector, without flushing the side arm of the Y-connector between injections.

Fluorouracil

Calcium folinate and 5-fluorouracil should be administered separately, as precipitation may occur when they are mixed. Incompatibility between 5-fluorouracil at a concentration of 50 mg/ml and calcium folinate at a concentration of 20 mg/ml, with or without 5% dextrose solution in water, has been demonstrated when mixed in various proportions and stored in polyvinyl chloride containers at 4°C, 23°C, or 32°C.

Foscarnet

When a 24 mg/ml foscarnet solution was mixed with a 20 mg/ml calcium folinate solution, a cloudy yellow discoloration of the solution was observed.

Calcium folinate must not be mixed with other medicinal products.

For intravenous infusion, the medicinal product should be diluted with 5% glucose solution or 0.9% sodium chloride solution.

Only a single withdrawal of the medicinal product from the vial is permitted.

The physical appearance of the medicinal product should be visually inspected before use. It should be clear, colorless or pale yellow. If the solution is cloudy or contains visible particulate matter, the medicinal product must not be used.

Packaging

5 ml, 10 ml, 20 ml, 35 ml, 50 ml, or 100 ml of solution in amber glass vials. The vials are closed with rubber stoppers sealed with aluminium caps and polypropylene discs. 1 vial per cardboard box.

Prescription category Prescription only.

Manufacturer

Haupt Pharma Wolfenbüttel GmbH.

Manufacturer's address and place of business Pfaffenrieder Strasse 5, Wolfratshausen, Bavaria, 82515, Germany.