Calciumfolinate "ebewe"

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CALCIUMFOLINATE «EBEWE»

Composition:

Active substance: calcium folinate;

1 ml of solution contains 10.8 mg of calcium folinate (calculated as anhydrous substance, corresponding to 10 mg of free folinic acid);

Excipients: sodium chloride, sodium hydroxide, hydrochloric acid diluted, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear yellowish solution.

Pharmacotherapeutic group.

Agents used to counteract toxic effects of anticancer therapy.

ATC code V03A F03.

Pharmacological Properties

Pharmacodynamics

Calcium folinate is the calcium salt of 5-formyltetrahydrofolic acid. It is an active metabolite of folic acid and an important cofactor required for the synthesis of nucleic acids.

Calcium folinate is commonly used to prevent or counteract the toxic effects of folic acid antagonists (particularly methotrexate). Calcium folinate and folic acid antagonists compete for the same membrane transporter, thereby promoting the efflux of folic acid antagonists. Calcium folinate also protects cells from the effects of folic acid antagonists by replenishing depleted folate stores in the body. It serves as a source of reduced tetrahydrofolate, allowing it to bypass the blockade caused by folate antagonists and to provide various cofactor forms, similar to folic acid.

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

Pharmacokinetics

Absorption

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

Metabolism

Calcium folinate is a racemate. The active enantiomer is the L-form (L-formyltetrahydrofolate, L-5-formyltetrahydrofolate). The main metabolite of folic acid is 5-methyltetrahydrofolate, with transformation occurring primarily in the liver and gastrointestinal mucosa.

Distribution

The volume of distribution of calcium folinate is unknown. The maximum plasma concentration of the parent compound (folic acid, D/L-formyltetrahydrofolate) 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 ± 11 mg·min/L, respectively. The inactive D-isomer is present at higher concentrations than L-5-formyltetrahydrofolate.

Elimination

The elimination half-life is 32–35 minutes for the active L-form and 352–485 minutes for the inactive D-form.

The half-life of active metabolites is approximately 6 hours (after both intravenous and intramuscular administration).

Excretion

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

Clinical characteristics.

Indications.

• To reduce toxicity and counteract folic acid antagonists such as methotrexate in cytotoxic therapy and in cases of overdose in adults and children. In cytotoxic therapy, this procedure is commonly known as "calcium folinate rescue".
• As part of combined cytotoxic therapy with 5-fluorouracil.

Contraindications.

• Hypersensitivity to calcium folinate or to any of the excipients of the medicinal product.
• Pernicious anemia or other types of anemia caused by vitamin B12 deficiency.

Special precautions.

Calcium folinate "Ebewe" must be administered only intravenously or intramuscularly. Intrathecal administration of the drug is strictly prohibited!

There have been reports of death following intrathecal administration of folic acid after intrathecal overdose of methotrexate.

Only a single withdrawal of the drug from the vial is permitted.

The solution should be visually inspected prior to use. It should be clear and yellowish. If the solution is cloudy or contains visible particulate matter, the product must not be used.

Interaction with other medicinal products and other forms of interaction.

Calcium folinate may reduce or completely neutralize the effect of folic acid antagonists (e.g., co-trimoxazole, pyrimethamine).

Calcium folinate may reduce the efficacy of antiepileptic drugs (phenobarbital, phenytoin, primidone, succinimides), potentially increasing the frequency of epileptic seizures (since folates act as cofactors enhancing hepatic metabolism, plasma levels of enzyme-inducing anticonvulsants may decrease).

When calcium folinate is used concomitantly with 5-fluorouracil, both the therapeutic and toxic effects of 5-fluorouracil are enhanced.

Special precautions for use.

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 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, treatment with calcium folinate may increase the frequency of epileptic seizures due to reduced plasma concentrations of antiepileptic drugs. Therefore, close clinical monitoring is required in such cases, and, if necessary, monitoring of plasma concentrations of antiepileptic drugs, with dose adjustments during and after calcium folinate therapy.

Use of calcium folinate in combination with 5-fluorouracil

Calcium folinate may enhance the toxic effects of 5-fluorouracil, particularly in elderly and debilitated patients. The most common toxic effects include leukopenia, mucositis, stomatitis, and diarrhea. These adverse effects may be dose-limiting. When dose reductions are required due to toxicity during combined treatment with 5-fluorouracil and calcium folinate, the dose of 5-fluorouracil should be reduced more than during monotherapy with 5-fluorouracil.

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 (which can rapidly lead to clinical deterioration and even fatal outcomes), patients with diarrhea must be closely monitored until symptoms have fully resolved. If diarrhea and/or stomatitis occur, it is recommended to reduce the dose of 5-fluorouracil until symptoms have completely disappeared. Particular caution is required when treating debilitated patients and elderly patients.

Lower initial doses of 5-fluorouracil are recommended for elderly patients and those who have previously undergone radiotherapy.

Calcium folinate and 5-fluorouracil should be administered separately.

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

Use of calcium folinate in combination with methotrexate

Recommendations for preventing toxic effects during methotrexate therapy are provided in the methotrexate medical instructions.

Calcium folinate does not protect against non-hematological toxic effects during methotrexate therapy (e.g., nephrotoxicity due to precipitation of methotrexate and/or its metabolites in renal tubules). Patients with delayed methotrexate elimination are at higher risk of developing reversible renal failure and other methotrexate-related toxic effects in the early phase. Renal impairment (either present before treatment initiation or developing during methotrexate therapy) is potentially associated with delayed methotrexate excretion; therefore, in such cases, higher doses or prolonged administration of calcium folinate may be required.

Excessive doses of calcium folinate should be avoided, as they may reduce the antitumor activity of methotrexate, particularly in central nervous system tumors, where calcium folinate accumulation has been observed after several treatment cycles.

Resistance to methotrexate due to impaired membrane transport also leads to 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 always verify whether the patient is taking other medications that interact with methotrexate (e.g., those affecting methotrexate elimination or its plasma protein binding).

Infusion solutions prepared by diluting the product with 0.9% sodium chloride solution 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 must be monitored by medical personnel. Generally, storage should not exceed 24 hours at 2–8°C, unless the solution was prepared under controlled and validated aseptic conditions.

The medicinal product contains sodium, which should be taken into account when treating patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

There is no evidence that calcium folinate causes harmful effects when used during pregnancy; however, adequate data on the use of calcium folinate for treating pregnant women are lacking.

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

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

Further information on this subject is provided in the medical instructions for methotrexate, other folic acid antagonists, and 5-fluorouracil.

It is unknown whether calcium folinate is excreted in breast milk. If necessary, calcium folinate may be used during breastfeeding according to therapeutic indications.

Ability to affect reaction speed when driving or operating machinery.

No data available.

Method of Administration and Dosage

Calcium folinate "Ebewe" may be administered only intravenously or intramuscularly.

Intrathecal administration of the drug is strictly contraindicated!

All dosages specified below are expressed in terms of folic acid.

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

Infusion solutions should be prepared by diluting the drug with 0.9% sodium chloride solution or 5% glucose solution.

Calcium Folinate Rescue in Methotrexate Therapy

Since the doses and regimens of calcium folinate depend on the doses and treatment protocols involving medium- or high-dose methotrexate, appropriate 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 is not assured. 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 doses of 100–500 mg/m² body surface area.

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

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

Methotrexate plasma concentration should be measured 48 hours after the start 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 another 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-Fluorouracil

Various regimens combining 5-fluorouracil with calcium folinate have been used, but superiority of any particular 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, administer calcium folinate at 200 mg/m² body surface area via a 2-hour intravenous infusion, followed by 5-fluorouracil at 400 mg/m² body surface area as an intravenous bolus injection, and then 5-fluorouracil at 600 mg/m² body surface area via a 22-hour intravenous infusion, repeated every two weeks on days 1 and 2.

Weekly regimen: Calcium folinate is administered at 20 mg/m² body surface area as an intravenous bolus injection or at 200–500 mg/m² body surface area via a 2-hour intravenous infusion; 5-fluorouracil at 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 the cycle, administer calcium folinate daily at 20 mg/m² body surface area as an intravenous bolus injection or at 200–500 mg/m² body surface area via a 2-hour intravenous infusion, immediately followed by 5-fluorouracil at 425 or 370 mg/m² body surface area as an intravenous bolus injection.

In 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, and dose-limiting toxic effects. Appropriate recommendations are provided in the 5-fluorouracil product information. 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 Folic Acid Antagonists: Trimetrexate, Trimethoprim, and Pyrimethamine

Prevention of trimetrexate toxicity: 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 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 case of overdose (possible with trimetrexate doses exceeding 90 mg/m² body surface area without concomitant calcium folinate), discontinue trimetrexate therapy and administer intravenous calcium folinate at 40 mg/m² body surface area every 6 hours for three days.

Prevention of trimethoprim toxicity: After discontinuation of trimethoprim therapy, administer calcium folinate at 3–10 mg/day until hematological parameters normalize.

Prevention of pyrimethamine toxicity: 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.

Children.

Calcium folinate should be used 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.

No adverse consequences have been observed with calcium folinate doses significantly higher than recommended. However, excessive doses of calcium folinate may neutralize the chemotherapeutic effect of folic acid antagonists.

In case of 5-fluorouracil overdose 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 (≥ 1/1000, < 1/100); rare (≥ 1/10 000, < 1/1000); very rare (< 1/10 000); frequency not known (cannot be estimated from available data).

When used for all indications

Central nervous system: rare – increased frequency of epileptic seizures.

Gastrointestinal disorders: rare – gastrointestinal disturbances when calcium folinate is used at high doses.

General disorders and administration site conditions: uncommon – fever.

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

Psychiatric disorders: rare – insomnia, agitation and depression when calcium folinate is used at high doses.

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 – mucosal inflammation, including stomatitis and cheilitis. Fatal cases due to mucosal inflammation have been reported.

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

Side effects with monthly treatment regimen

Gastrointestinal disorders: very common – nausea and vomiting.

General disorders and administration site conditions: very common – (severe) mucosal inflammation.

Side effects with weekly treatment regimen

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

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at 2–8 °C.

Keep out of the reach and sight of children.

Incompatibilities.

Incompatibility (precipitation) has been observed when solutions of calcium folinate are mixed with solutions of 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, precipitation was observed.
• When 2.5 mg/0.5 mL droperidol was mixed with 10 mg/0.5 mL calcium folinate, precipitation occurred immediately after sequential injection into a Y-type connector without flushing the side port of the Y-connector between injections.

Fluorouracil

Calcium folinate and 5-fluorouracil should be administered separately, as mixing may result in precipitation. 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, turbid yellow discoloration of the solution was observed.

Calcium folinate "Ebewe" should not be mixed with other medicinal products.

Packaging.

3 mL (30 mg), 5 mL (50 mg), 10 mL (100 mg), or 20 mL (200 mg) in a brown glass vial stoppered with a rubber plug and sealed with an aluminium crimp cap; 1 vial per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

EBEWE Pharma Ges.m.b.H. Nfg. KG
EBEWE Pharma Ges.m.b.H. Nfg. KG
(batch release authorization)

Manufacturer's location and address of place of business.

Mondseestrasse 11, 4866 Unterach am Attersee, Austria
Mondseestrasse 11, 4866 Unterach am Attersee, Austria

or

Manufacturer.

Sandoz GmbH – Manufacturing Site Anti Infectives & Chemical Operations FDF Kundl (AICO FDF Kundl)
Sandoz GmbH – Manufacturing Site Anti Infectives & Chemical Operations FDF Kundl (AICO FDF Kundl) (batch release authorization)

Manufacturer's location and address of place of business.

Biochemiestrasse 10, 6250 Kundl, Austria
Biochemiestrasse 10, 6250 Kundl, Austria

or

Manufacturer.

Salutas Pharma GmbH / Salutas Pharma GmbH (batch release authorization)

Manufacturer's location and address of place of business.

Otto-von-Guericke-Allee 1, 39179 Barleben, Germany / Otto-von-Guericke-Allee 1, 39179 Barleben, Germany.