Calciumfolinat-Ebewe (Capsules) Instructions for Use

Marketing Authorization Holder

Ebewe Pharma Ges.m.b.H.Nfg.KG (Austria)

ATC Code

V03AF03 (Calcium folinate)

Active Substance

Calcium folinate

Dosage Form

Calciumfolinat-Ebewe

Capsules 15 mg: 20 pcs.

Dosage Form, Packaging, and Composition

Capsules are hard gelatin, the body is white, the cap is green; the capsule contents are a white or light yellow powder.

Excipients: microcrystalline cellulose, silicon dioxide, magnesium stearate, titanium dioxide, iron oxide, indigotine, gelatin.

20 pcs. – polypropylene bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Folic acid antagonists antidote

Pharmacotherapeutic Group

Vitamin, antidote to folic acid antagonists, biological response modifier of fluorouracil

Pharmacological Action

Antidote to folic acid antagonists. Calcium folinate is calcium 5-formyltetrahydrofolate. It is a reduced form of folinic acid and a necessary coenzyme for the synthesis of nucleic acids in cytotoxic therapy.

Calcium folinate is often used to reduce the toxicity and neutralize the action of folic acid antagonists, such as methotrexate. Calcium folinate and folate antagonists are transported by the same carrier agents and compete with each other for transport into the cell, which causes the efflux of folate antagonists. This also protects cells from the action of the latter by reducing the folate pool. Calcium folinate serves as a source of H4 folate, so it can bypass the folate antagonist block and provide a source for various coenzyme forms as folic acid.

Calcium folinate is also often used for the biochemical modulation of fluorouracil to enhance its cytotoxic action. Fluorouracil suppresses thymidylate synthase, a key enzyme involved in pyrimidine biosynthesis. Calcium folinate enhances the inhibition of thymidylate synthase by increasing the intracellular folate pool, thus stabilizing the fluorouracil-thymidylate synthase complex and increasing its activity.

Pharmacokinetics

Absorption

When taken orally as a single 20 mg dose of calcium folinate, 98% is absorbed from the gastrointestinal tract. When taking 60 mg and 100 mg, bioavailability decreases from 62% to 42%, since the process of calcium folinate absorption in the gastrointestinal tract is saturable.

Calcium folinate is a racemate, where the active enantiomer is the levorotatory form (L-5-formyltetrahydrofolate).

Distribution

The V_d of folinic acid is unknown.

Metabolism

The main metabolite of calcium folinate is 5-methyltetrahydrofolic acid, which is predominantly formed in the intestinal mucosa and liver.

Excretion

The total T_1/2 of active metabolites after oral administration is 6.0±1.9 h. After oral administration of 200 mg of calcium folinate, 20% is excreted in the urine within the first 24 h (5- and 10-formyltetrahydrofolates as inactive metabolites), 16% as 5-methyltetrahydrofolic acid.

Indications

• Prevention of the toxic effects of methotrexate used in high doses;
• Intoxication with folic acid antagonists (trimethoprim, pyrimethamine);
• Megaloblastic anemia caused by folic acid deficiency (including against the background of malabsorption syndrome, malnutrition, pregnancy, sprue, in early childhood with congenital dihydrofolate reductase deficiency).

ICD codes

Dosage Regimen

Capsules are taken orally. Doses greater than 50 mg are recommended to be administered intravenously or intramuscularly, since the process of calcium folinate absorption in the intestine is saturable.

Prevention of the toxic effects of methotrexate

The regimens for prescribing calcium folinate depend on the therapy regimens with medium and high doses of methotrexate, therefore, for relevant information, it is advisable to refer to the corresponding methotrexate treatment protocol.

The following recommendations can serve as a guide for determining the doses and regimens of protective use of calcium folinate in adults, the elderly and children. The dose and duration of calcium folinate use primarily depend on the doses and type of methotrexate therapy, the occurrence of signs of toxicity and individual characteristics of methotrexate excretion.

As a rule, the first dose of calcium folinate is 15 mg (6-12 mg/m²), applied no later than 12-24 hours after the start of the methotrexate infusion. When using high doses of methotrexate, doses of calcium folinate up to 120 mg can be administered by intramuscular or intravenous injection or infusion, and then 15 mg orally every 6 hours for the next 48 hours.

When using lower doses of methotrexate, the administration of 15 mg of calcium folinate for 48-72 hours after methotrexate administration may be sufficient.

An integral addition to the use of calcium folinate in the prevention of the toxic effects of methotrexate are measures that accelerate the excretion of methotrexate (ensuring adequate urinary function and alkalinization of urine). Kidney function should be monitored daily by measuring serum creatinine concentration.

It is recommended to measure the serum methotrexate concentration 48 hours after the start of the infusion.

Prevention of the toxic effects of methotrexate with calcium folinate in patients with malabsorption syndrome or other gastrointestinal disorders (vomiting, diarrhea, etc.), when enteral absorption is reduced, should be carried out by parenteral administration.

Intoxication with folic acid antagonists (trimethoprim, pyrimethamine)

After discontinuation of trimethoprim administration, Calcium folinate is used at a dose of 3-10 mg/day until peripheral blood counts are restored.

In case of using high doses of pyrimethamine or during long-term treatment with low doses, Calcium folinate should be used simultaneously at a dose of 5-50 mg/day, depending on peripheral blood counts.

For megaloblastic anemia caused by folic acid deficiency, Calcium folinate is prescribed at a dose of up to 5 mg/day (maximum up to 15 mg/day).

Adverse Reactions

According to WHO, adverse effects are classified according to their frequency of occurrence as follows: very common (≥10%), common (≥1%, <10%), uncommon (≥0.1%, <1%), rare (≥0.01%, <0.1%), very rare (<0.01%, including isolated cases).

From the immune system: very rarely – allergic reactions, including anaphylactic shock and urticaria.

From the central nervous system: rarely – insomnia, anxiety, depression when taking high doses, increased frequency of epileptic seizures.

From the digestive system: rarely – nausea, dyspepsia (when using high doses).

Other: uncommon – fever.

Contraindications

• Megaloblastic anemia due to cyanocobalamin (vitamin B₁₂) deficiency;
• Rare hereditary forms of lactose intolerance, lactase deficiency or glucose/galactose malabsorption (the drug contains lactose);
• Children under 3 years of age (for this dosage form).
• Hypersensitivity to calcium folinate or any other component of the drug.

Use with caution in patients with epilepsy, chronic renal failure, alcoholism.

Use in Pregnancy and Lactation

Since controlled studies in pregnant women have not been conducted, the drug can be prescribed during pregnancy only if the intended benefit to the mother outweighs the potential risk to the fetus and child.

It is not known whether the drug is excreted in breast milk, so if it is necessary to use calcium folinate during lactation, the issue of stopping breastfeeding should be decided.

Use in Renal Impairment

The presence of pre-existing or methotrexate-induced renal failure, which is associated with delayed methotrexate excretion, may require the use of higher doses or a longer course of therapy with Calciumfolinat-Ebewe.

Pediatric Use

The drug in capsule form is contraindicated for use in children under 3 years of age.

Special Precautions

Treatment with methotrexate and Calciumfolinat-Ebewe should be carried out by a qualified oncologist in a hospital, with the necessary means of control.

The use of Calciumfolinat-Ebewe may mask the clinical picture of pernicious or other types of anemia caused by vitamin B₁₂ deficiency.

Many cytotoxic drugs cause the development of macrocytosis (in particular, direct and indirect inhibitors of DNA synthesis – hydroxycarbamide, cytarabine, mercaptopurine, thioguanine). It is believed that such macrocytosis does not require treatment with folic acid.

In patients with epilepsy receiving treatment with phenobarbital, primidone, phenytoin or succinimides, there is a risk of increased frequency of epileptic seizures due to a decrease in the plasma concentration of antiepileptic drugs. In this case, clinical monitoring, monitoring of drug concentrations in plasma and, if necessary, dose adjustment of antiepileptic drugs during the use of Calciumfolinat-Ebewe and after the end of the course of therapy is recommended.

Calciumfolinat-Ebewe does not protect against toxic effects of a non-hematological nature during methotrexate therapy (for example, from nephrotoxic effects due to the precipitation of methotrexate or its metabolites in the renal tubules). The presence of pre-existing or methotrexate-induced renal failure, which is associated with delayed methotrexate excretion, may require the use of higher doses or a longer course of therapy with Calciumfolinat-Ebewe.

In case of development of resistance to methotrexate due to deterioration of membrane transport function, resistance to calcium folinate also develops, since both drugs are transported by the same transport system.

In case of accidental overdose of a folic acid antagonist, such as methotrexate, emergency medical care should be provided, since an increase in the time interval between the use of methotrexate and Calciumfolinat-Ebewe reduces the effectiveness of the latter.

When clinical manifestations of toxicity occur or laboratory parameters change, the possibility of the patient using other drugs that interact with methotrexate (for example, drugs that can affect the elimination of methotrexate or bind to plasma proteins) should always be considered.

Effect on the ability to drive vehicles and mechanisms

No effect on the ability to drive vehicles and engage in other activities requiring concentration and speed of psychomotor reactions was observed when using Calciumfolinat-Ebewe.

Overdose

No reports of consequences from taking a dose significantly larger than the recommended dose of calcium folinate have been reported. However, high doses of calcium folinate may negate the chemotherapeutic effect of folic acid antagonists.

Drug Interactions

With simultaneous use of calcium folinate with folic acid antagonists (for example, with co-trimoxazole, pyrimethamine), the effectiveness of folic acid antagonists may decrease or be completely eliminated.

Calcium folinate may reduce the effectiveness of antiepileptic drugs (phenobarbital, primidone and phenytoin, succinimides) and increase the frequency of epileptic seizures (due to a decrease in the concentration of enzyme inducers of antiepileptic drugs in plasma due to the acceleration of metabolic processes in the liver, since folates are one of the co-factors).

With the combined use of calcium folinate and fluorouracil, the effectiveness and toxicity of the latter are increased.

Storage Conditions

The drug should be stored in a dry, light-protected place, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.