Calcium folinate calcex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CALCIUM FOLINATE KALCEKS (CALCIUM FOLINATE KALCEKS)

Composition:

Active substance: calcium folinate;

1 ml of solution contains calcium folinate 10.8 mg, equivalent to 10 mg of folinic acid;

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

Pharmaceutical form. Solution for injection or infusion.

Main physicochemical properties: clear, colorless or slightly yellow solution.

Pharmacotherapeutic group

Agents used to counteract toxic effects of antineoplastic therapy. Calcium folinate. ATC code V03A F03.

Pharmacological Properties

Pharmacodynamics

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

Calcium folinate is commonly used to reduce toxicity and counteract the toxic effects of folate antagonists, particularly methotrexate. Calcium folinate and folate antagonists are transported by 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, and calcium folinate enhances the inhibition of TS by increasing the intracellular folate pool, thereby stabilizing the 5-FU–TS complex and increasing its activity.

Calcium folinate may be administered intravenously for the prevention and treatment of folate deficiency when it cannot be prevented or corrected by oral administration of folic acid. This approach is used in total parenteral nutrition and in severe cases of malabsorption. Intravenous administration of calcium folinate is also indicated for the treatment of megaloblastic anemia caused by folic acid deficiency when oral administration is not feasible.

Pharmacokinetics

Absorption

After intramuscular administration of the aqueous solution, the systemic bioavailability of calcium folinate is comparable to that after intravenous administration, although the maximum plasma concentration (C_max) is lower.

Distribution

The volume of distribution of folinic acid is unknown. Peak levels of the parent compound (D/L-5-formyltetrahydrofolate, folinic acid) in plasma are achieved within 10 minutes after intravenous administration.

Following a 25 mg dose, the area under the pharmacokinetic curve (AUC) for L-5-formyltetrahydrofolate and L-5-formyl-THF 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 active L-5-formyltetrahydrofolate.

Biotransformation

Calcium folinate is a racemate, with the L-form (L-5-formyltetrahydrofolate, L-5-formyl-THF) being the active enantiomer. The main metabolic product of folic acid is 5-methyltetrahydrofolate (5-methyl-THF), which is primarily formed in the liver and intestinal mucosa.

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).

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

Clinical Characteristics

Indications

• For reducing toxicity and counteracting folic acid antagonists such as methotrexate in cytotoxic therapy and in cases of overdose in adults and children. In cytotoxic therapy, this procedure is widely known as "Calcium folinate rescue".
• As part of combination cytotoxic therapy with 5-fluorouracil.

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Pernicious anemia or other anemias due to vitamin B12 deficiency.

Regarding the use of calcium folinate with methotrexate or 5-fluorouracil during pregnancy or breastfeeding, see section "Use during pregnancy or breastfeeding" for methotrexate and 5-fluorouracil-containing medicinal products.

Special precautions

The solution should be inspected visually before use. The medicinal product must not be used if there are any visible signs of deterioration (e.g., particles). Only clear solutions without visible particles should be used.

Calcium folinate Calces solution is intended for single use only.

Calcium folinate Calces solution and 5-fluorouracil should not be mixed in the same syringe due to the possibility of precipitate formation.

After opening the vial, any unused portion of the medicinal product must be disposed of according to local regulations.

Interaction with other medicinal products and other forms of interaction

When calcium folinate is administered concomitantly with folic acid antagonists (e.g., co-trimoxazole, pyrimethamine, other antibiotics with antifolate effect, methotrexate), the efficacy of the folic acid antagonist may be reduced or completely neutralized.

Calcium folinate may reduce the effect of antiepileptic medicinal products: phenobarbital, phenytoin, primidone, and succinimides, and may also increase the frequency of seizures (a decrease in plasma levels of enzyme-inducing anticonvulsants may be observed due to increased hepatic metabolism, as folates are one of the cofactors) (see section "Special instructions for use").

It has been shown that concomitant administration of calcium folinate with 5-fluorouracil increases both the efficacy and toxicity of 5-fluorouracil (see sections "Method and dosage", "Special instructions for use", "Adverse reactions").

Special precautions for use

Calcium folinate should only be administered by intramuscular or intravenous injection. Intrathecal administration of the drug is contraindicated. Fatal cases have been reported when calcium folinate was administered intrathecally following intrathecal overdose of methotrexate.

General considerations

Calcium folinate in combination with methotrexate or 5-fluorouracil should only be used under the direct supervision of a physician experienced in the use of cytotoxic chemotherapeutic agents.

Calcium folinate may mask the symptoms of pernicious anemia and other anemias caused by vitamin B₁₂ deficiency.

Many cytotoxic agents 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 calcium folinate.

In patients with epilepsy receiving phenobarbital, phenytoin, primidone, or succinimides, there is a risk of increased seizure frequency due to decreased plasma concentrations of antiepileptic drugs. Clinical monitoring is recommended, and possibly monitoring of plasma concentrations of antiepileptic drugs, with dose adjustments as needed during and after calcium folinate treatment (see section "Interaction with other medicinal products and other forms of interaction").

Calcium folinate / 5-fluorouracil

Calcium folinate may increase the risk of 5-fluorouracil toxicity, particularly in elderly or debilitated patients. The most common manifestations are leukopenia, mucositis, stomatitis, and/or diarrhea, which may be dose-limiting. When calcium folinate is used concomitantly with 5-fluorouracil, the dose of 5-fluorouracil may need to be reduced more than when 5-fluorouracil is used alone in cases of toxicity.

Combined treatment with 5-fluorouracil in combination with calcium folinate should not be initiated or continued until gastrointestinal toxicity symptoms have completely resolved, regardless of their severity.

Since diarrhea may be a sign of gastrointestinal toxicity that could lead to rapid clinical deterioration and potentially fatal outcomes, patients with diarrhea should be closely monitored until symptoms have completely resolved. In the event of diarrhea and/or stomatitis, it is recommended to reduce the dose of 5-fluorouracil until symptoms have completely resolved.

Particular caution is required when treating debilitated patients and elderly patients. This patient group is particularly susceptible to an increased risk of toxicity.

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

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

Serum calcium levels should be monitored in patients receiving combined treatment with 5-fluorouracil / calcium folinate, and calcium supplements should be administered if calcium levels are low.

Calcium folinate / methotrexate

For detailed information on methotrexate toxicity reduction, refer to the methotrexate product information.

Calcium folinate does not affect non-hematological toxicity of methotrexate, such as nephrotoxicity resulting from methotrexate and/or its metabolites precipitation in the kidneys.

In patients with delayed early elimination of methotrexate, reversible renal failure and all methotrexate-related toxic effects are likely to occur.

Renal impairment (whether developed during methotrexate therapy or present before treatment initiation) is associated with delayed methotrexate excretion; therefore, calcium folinate may need to be administered in higher doses or for a prolonged duration in such cases.

Excessive doses of calcium folinate should be avoided, as they may compromise the antitumor effect of methotrexate, especially in CNS tumors, where calcium folinate accumulates after multiple treatment cycles.

Resistance to methotrexate due to reduced membrane transport also implies resistance to calcium folinate repletion, as both drugs share the same transport system.

In case of accidental overdose with a folic acid antagonist such as methotrexate, immediate medical intervention should be considered. The effectiveness of calcium folinate as an antidote decreases with increasing time interval between methotrexate and calcium folinate administration.

When laboratory abnormalities or clinical signs of toxicity are observed, it is essential to always check whether the patient is taking other medicinal products that interact with methotrexate (e.g., those affecting methotrexate elimination or its protein binding in plasma).

This medicinal product contains 3.15 mg of sodium per mL of solution, equivalent to 0.16% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Use during pregnancy or breastfeeding

Pregnancy

There are no adequate and well-controlled clinical studies of calcium folinate in pregnant or breastfeeding women. Studies on the toxic effects of calcium folinate on the reproductive system in animals have not been conducted. However, there are no indications that calcium folinate causes harmful effects when used during pregnancy.

Methotrexate should only be administered during pregnancy under strict indications, with careful consideration of the benefit to the mother and the potential risk to the fetus. If treatment with methotrexate or other folic acid antagonists is carried out despite pregnancy or lactation, there are no restrictions on the use of calcium folinate to reduce toxicity or counteract adverse reactions.

The use of 5-fluorouracil is contraindicated during pregnancy and breastfeeding. This also applies to the combined use of calcium folinate with 5-fluorouracil.

For detailed information, refer to the product information for methotrexate, 5-fluorouracil, and other medicinal products containing folic acid antagonists.

Breastfeeding

It is unknown whether calcium folinate is excreted in breast milk. Calcium folinate may be used during breastfeeding if clinically indicated.

Fertility

Calcium folinate is an intermediate in folic acid metabolism and is naturally formed in the body. Fertility studies with calcium folinate in animals have not been conducted.

Ability to affect driving or operating machinery

There is no information on the ability of calcium folinate to affect driving or operating machinery.

Method of Administration and Dosage

Calcium folinate must be administered only intravenously or intramuscularly. During intravenous administration, no more than 160 mg of the solution per minute should be infused due to the calcium content of the solution.

Calcium folinate Kalzeks solution must be diluted prior to intravenous infusion.

Dilution of solution for intravenous infusion

To administer the required dose of the medicinal product to a specific patient, under aseptic conditions, withdraw the necessary amount of Calcium folinate Kalzeks 10 mg/mL, solution for injection/infusion, from the vial and then dilute it with any of the compatible diluents listed below.

For intravenous infusion, the medicinal product can be diluted with the following solutions:

• Sodium chloride 9 mg/mL (0.9%) solution for injection
• Glucose 50 mg/mL (5%) solution for injection

Dosage

Calcium folinate rescue in methotrexate therapy

Since the dosing regimen of calcium folinate largely depends on the dosage and route of administration of intermediate or high doses of methotrexate, appropriate dosing information should be obtained from the methotrexate treatment protocol.

Below are general recommendations for the use of calcium folinate in adults, elderly patients, and children.

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

Calcium folinate rescue is necessary when the administered methotrexate dose exceeds 500 mg/m² body surface area and is advisable at methotrexate doses ranging from 100 to 500 mg/m² body surface area.

The dosage and duration of calcium folinate administration primarily depend on the methotrexate treatment regimen and dose, the occurrence of toxicity symptoms, and individual methotrexate excretion parameters. Generally, an initial dose of calcium folinate 15 mg (6–12 mg/m² body surface area) should be administered 12–24 hours (no later than 24 hours) after the start of methotrexate infusion. Subsequent doses of calcium folinate at the same dosage should then be administered every 6 hours for 72 hours. After several parenteral doses, treatment may be switched to oral administration.

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

Residual methotrexate concentration in blood should be measured 48 hours after the start of methotrexate infusion. If the residual methotrexate concentration is > 0.5 µmol/L, the calcium folinate dose should be adjusted according to the table below.

Residual methotrexate level in blood 48 hours after starting methotrexate administration:	Additional calcium folinate solution to be administered every 6 hours for 48 hours or until methotrexate level falls below 0.05 µmol/L:
≥ 0.5 µmol/L	15 mg/m² body surface area
≥ 1.0 µmol/L	100 mg/m² body surface area
≥ 2.0 µmol/L	200 mg/m² body surface area

In combination with 5-fluorouracil in cytotoxic therapy

Various regimens and dosages are used, none of which has been proven optimal.

Below are described some treatment regimens for adults and elderly patients with advanced or metastatic colorectal cancer. Data on the use of these combinations for treatment of children are lacking.

Regimen repeated every two weeks

Calcium folinate solution 200 mg/m² body surface area should be administered as a two-hour intravenous infusion, followed by 400 mg/m² body surface area 5-fluorouracil as an intravenous bolus injection and 5-fluorouracil 600 mg/m² body surface area via 22-hour intravenous infusion over the next 2 days, repeated every two weeks on days 1 and 2.

Weekly regimen

Calcium folinate solution should be 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 two-hour intravenous infusion; 5-fluorouracil at a dose of 500 mg/m² body surface area should be administered via intravenous bolus injection in the middle or at the end of calcium folinate infusion.

Monthly regimen

Calcium folinate solution should be administered at a dose of 20 mg/m² body surface area via intravenous bolus injection or intravenous infusion at a dose of 200–500 mg/m² body surface area over 2 hours, followed by 5-fluorouracil at a dose of 425 or 370 mg/m² body surface area via intravenous bolus injection for five consecutive days.

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

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

Use of calcium folinate as an antidote to folic acid antagonists trimetrexate, trimethoprim, and pyrimethamine

Trimetrexate toxicity

• Prophylaxis: calcium folinate solution should be administered daily during trimetrexate treatment and for an additional 72 hours after the last dose of trimetrexate. The medicinal product Calcium Folinate-Vista may be administered intravenously at a dose of 20 mg/m² body surface area over 5–10 minutes every 6 hours up to a total daily dose of 80 mg/m² body surface area, or administered orally in four divided doses of 20 mg/m² body surface area per day at equal intervals. Daily doses of calcium folinate should be determined based on the hematological toxicity of trimetrexate.
• Overdose (following administration of trimetrexate exceeding 90 mg/m² body surface area without concomitant calcium folinate): after discontinuation of trimetrexate, intravenous administration of 40 mg/m² body surface area calcium folinate solution every 6 hours for three days is required.

Trimethoprim toxicity

• After discontinuation of trimethoprim, calcium folinate solution should be administered at a dose of 3–10 mg/day until normalization of blood parameters.

Pyrimethamine toxicity

• During high-dose pyrimethamine therapy or prolonged low-dose treatment with pyrimethamine, calcium folinate solution should be co-administered at a dose of 5 to 50 mg/day depending on peripheral blood parameters.

Children

Calcium folinate is indicated for use in children as a protective agent for prevention of methotrexate toxicity, as well as an antidote in cases of overdose and intoxication with methotrexate and other folic acid antagonists.

Overdose

No adverse effects have been observed in patients receiving calcium folinate at doses significantly higher than recommended. Excessive amounts of calcium folinate may neutralize the chemotherapeutic effect of folic acid antagonists. In case of overdose with 5-fluorouracil in combination with calcium folinate, measures recommended for 5-fluorouracil overdose should be implemented.

Side effects

Adverse reactions are listed by organ systems and frequency: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, ≤1/100); rare (≥1/10,000, ≤1/1,000); very rare (≤1/10,000); frequency not known (based on available data, the frequency of occurrence cannot be determined).

When used for all indications

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

Psychiatric disorders: rare – insomnia, excitation, and depression after high doses.

Nervous system disorders: rare – increased frequency of seizures in patients with epilepsy (see section "Interaction with other medicinal products and other forms of interaction").

Gastrointestinal disorders: rare – gastrointestinal disturbances after administration of high doses.

Skin and subcutaneous tissue disorders: frequency not known – Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

In patients receiving calcium folinate in combination with other agents known to be associated with these conditions; some cases may be fatal. It cannot be excluded that calcium folinate contributed to the occurrence of SJS/TEN.

General disorders and administration site conditions: uncommon – hyperthermia.

Combination therapy with 5-fluorouracil

Generally, the safety profile depends on the 5-fluorouracil regimen due to enhanced toxicity induced by 5-fluorouracil.

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

Metabolism and nutrition disorders: frequency not known – hyperammonemia.

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

General disorders and administration site conditions: mucositis, including stomatitis and cheilitis. Fatal cases due to mucositis have been observed.

Adverse effects with monthly treatment regimen

Gastrointestinal disorders: very common – nausea, vomiting, and diarrhea.

Absence of increased other toxic effects caused by 5-fluorouracil (e.g., neurotoxicity).

Adverse effects with weekly treatment regimen

Gastrointestinal disorders: very common – diarrhea with high-grade toxic effects and dehydration requiring hospitalization, sometimes even with fatal outcome.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

2 years.

Do not use after the expiry date stated on the packaging.

After opening the vial: the product should be used immediately.

Shelf life after dilution

Chemical and physical stability has been demonstrated for 4 days at 25°C (in a light-protected environment) and at temperatures from 2°C to 8°C when diluted with 9 mg/mL (0.9%) sodium chloride injection solution.

From a microbiological standpoint, the solution should be used immediately. If the product is not used immediately, the storage conditions and duration of the prepared solution prior to use are the responsibility of the user. Normally, storage should not exceed 24 hours at 2–8°C, unless the solution was prepared under controlled and validated aseptic conditions.

Chemical and physical stability has been demonstrated for 24 hours at 2–8°C after dilution with 50 mg/mL (5%) glucose injection solution.

Due to the potential for microbiological contamination, the product should be used immediately if the method of opening/dilution does not eliminate the risk of microbial contamination. If the product is not used immediately, the storage conditions and duration of the prepared product prior to use are the responsibility of the user.

Storage conditions

Store in a refrigerator in the original packaging at 2–8°C in a light-protected place.

Keep out of reach of children.

Incompatibilities

Incompatibility has been observed when calcium folinate injection solutions are mixed with injection solutions of droperidol, 5-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, precipitation occurred.
• When 2.5 mg/0.5 mL droperidol was mixed with 10 mg/0.5 mL calcium folinate, precipitation occurred immediately after sequential addition of the drugs 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 has been demonstrated between 5-fluorouracil at 50 mg/mL and calcium folinate at 20 mg/mL, with or without 5% dextrose in water, 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.

This medicinal product must not be mixed with other medicinal products except those specified in the section "Instructions for use and dosage."

Packaging

5 mL or 10 mL in a vial. 10 vials per cardboard box.

Prescription status

Prescription only.

Manufacturer

Manufacturer responsible for batch release:

JSC "Kalceks", Latvia.

Manufacturer's address and location of operations

71E Krustpils Street, Riga, LV-1057, Latvia.

Marketing Authorization Holder

JSC "Kalceks", Latvia.

Address of Marketing Authorization Holder

71E Krustpils Street, Riga, LV-1057, Latvia.