Calcium folinate fares

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Calcium Folinate PhaRes (Calcium Folinate PhaRes)

Composition:

Active substance: calcium folinate;

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

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear yellowish solution, free from mechanical inclusions.

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

Pharmacological Properties

Pharmacodynamics

Calcium folinate is the calcium salt of 5-formyltetrahydrofolic acid. 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 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 effects 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 fluorouracil (5-FU). 5-FU inhibits thymidylate synthase (TS), a key enzyme involved in pyrimidine biosynthesis. Calcium folinate enhances the inhibition of TS by increasing intracellular folate pools, thereby stabilizing the 5-FU–TS complex and increasing its inhibitory activity.

In addition, intravenous administration of calcium folinate 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 achieved 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-5-formyltetrahydrofolate, L-5-formyltetrahydrofolate).

The primary metabolite of folinic acid is 5-methyltetrahydrofolate, which is produced predominantly in the liver and intestinal mucosa.

Distribution

The volume of distribution of folinic acid is unknown.

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

After a 25 mg dose, the area under the plasma concentration-time 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 active 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 terminal half-life of active metabolites is approximately 6 hours (following either intravenous or intramuscular administration).

Excretion

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

Clinical characteristics.

Indications.

• For reduction of toxicity and neutralization of the effect of folic acid antagonists, such as methotrexate, during cytotoxic therapy and in cases of overdose in adults and children. This procedure is widely known as "Calcium folinate rescue" when used during cytotoxic therapy.
• As part of combined cytotoxic therapy with 5-fluorouracil.

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 must be administered only intravenously or intramuscularly. Intrathecal administration of the drug is strictly contraindicated.

Fatal cases have been reported following intrathecal administration of folinic acid after intrathecal overdose of methotrexate.

Before administration, calcium folinate should be visually inspected. The injectable solution should be clear and slightly yellow. If turbidity or particulate matter is present, the solution must be discarded. The injectable solution of calcium folinate is intended for single use only. Any unused solution should be destroyed.

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 reduce their antiepileptic activity and potentially increase seizure frequency (this may be due to decreased plasma levels of anticonvulsants 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-fluorouracil; therefore, when used concomitantly, the dose of 5-FU should be reduced.

Special precautions for use.

Calcium folinate must 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 supervision of an experienced oncologist.

Calcium folinate may mask 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 folic acid.

In patients with epilepsy receiving phenobarbital, phenytoin, primidone, or succinimides, the frequency of epileptic seizures may increase during therapy with calcium folinate 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 and dose adjustments during and after calcium folinate treatment.

Use of calcium folinate in combination with methotrexate

Recommendations for prevention of toxic effects during methotrexate therapy are provided in the medical instructions for 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 renal tubules). In patients with delayed elimination of methotrexate in the early phase, there is an increased risk of reversible renal failure and other toxic effects associated with methotrexate use. Renal impairment (whether developed during methotrexate therapy or present before initiation of treatment) is associated with delayed excretion of methotrexate; therefore, in such cases, administration of higher doses of calcium folinate or prolonged treatment may be required.

Administration of excessive doses of calcium folinate should be avoided, as this may reduce the antitumor activity of methotrexate, particularly 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 leads to resistance to calcium folinate, since 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 administration of methotrexate and calcium folinate.

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

Use of calcium folinate in combination with 5-fluorouracil

Calcium folinate may enhance the toxicity of 5-fluorouracil, especially 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 necessary due to toxicity during combined therapy 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 until complete resolution of gastrointestinal toxicity symptoms, regardless of their severity.

Since diarrhea may be a sign of gastrointestinal toxicity (which can rapidly lead to clinical deterioration and even fatal outcome), patients with diarrhea must be closely monitored until complete resolution of symptoms. Particular caution is required when treating debilitated patients and elderly individuals.

Lower initial doses of 5-fluorouracil are recommended for elderly patients and those previously treated with radiotherapy.

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

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

This medicinal product contains sodium. This should be taken into account when prescribing the drug to 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 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 reactions or neutralization of methotrexate toxicity.

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

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

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. If treatment is required, breastfeeding should be discontinued.

Ability to affect reaction rate when driving or operating machinery.

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

Dosage and Administration

Calcium folinate is intended for intravenous or intramuscular use only. The rate of intravenous administration should not exceed 160 mg/min, taking into account the calcium content in the solution.

Infusion solutions for intravenous administration are 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 administration schedules of calcium folinate depend on the dosing and regimens of intermediate- and high-dose methotrexate therapy, appropriate dosing information should be obtained from the methotrexate treatment protocol.

Below are 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 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 methotrexate doses of 100–500 mg/m² body surface area.

The doses and duration of calcium folinate therapy should be determined based on the methotrexate dosing regimen, presence of signs of toxicity, and individual methotrexate excretion parameters. 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 the start of methotrexate infusion. Subsequent doses of calcium folinate should be given every 6 hours for 72 hours. After several parenteral administrations, a switch to oral administration 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 an additional 48 hours or until methotrexate concentration falls 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 enhance 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 are used, but no single regimen has been proven superior. Below are some treatment regimens for adults and elderly patients with advanced or metastatic colorectal cancer. Data on the use of these combinations in children are lacking.

Biweekly regimen: On days 1 and 2 of each cycle, calcium folinate is administered 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 5-fluorouracil at 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 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 is administered at 500 mg/m² body surface area 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 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, followed immediately by 5-fluorouracil at 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 necessary 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 folate antagonist drugs trimetrexate, trimethoprim, and pyrimethamine

Prevention of trimetrexate toxicity: Calcium folinate should be administered daily during trimetrexate therapy and for an additional 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), trimetrexate therapy should be discontinued and calcium folinate administered intravenously at 40 mg/m² body surface area every 6 hours for three days.

Prevention of trimethoprim toxicity: After discontinuation of trimethoprim therapy, calcium folinate should be administered at 3–10 mg daily 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 of 5 to 50 mg daily, depending on the peripheral blood cell counts.

The injectable form of calcium folinate is indicated for the treatment of megaloblastic anemia due to folic acid deficiency, and 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).

Stability after dilution

From a microbiological standpoint, the prepared medicinal product should be used immediately. If not used immediately, the user is responsible for the storage duration and conditions. If dilution is performed under controlled and validated aseptic conditions, the storage time of the ready-to-use medicinal product should not exceed 24 hours at room temperature (not above 25°C), protected from light.

Children.

Calcium folinate is indicated for use in children as a protective agent to prevent methotrexate toxicity, and as an antidote in cases of overdose or intoxication with methotrexate and other folate antagonists.

Overdose.

No adverse effects 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 folate antagonists.

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

Side effects

The frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

When used for all indications

Immune system disorders

Very rare: allergic reactions, including anaphylactoid reactions and urticaria.

Psychiatric disorders

Rare: insomnia, excited state, and depression after administration of high doses.

Gastrointestinal disorders

Rare: gastrointestinal disturbances after administration of high doses.

Nervous system disorders

Rare: increased frequency of epileptic seizures in patients with epilepsy.

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 above-mentioned syndromes, fatal cases have been reported. It cannot be excluded that folic acid contributed to the occurrence of these syndromes.

General disorders and administration site reactions

Uncommon: increase in body temperature after administration of calcium folinate as an injection solution.

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.

Metabolism and nutrition disorders

Frequency not known: hyperammonaemia.

Blood and lymphatic system disorders

Very common: bone marrow failure, including fatal cases.

General disorders and administration site reactions

Uncommon: mucositis, including stomatitis and cheilitis. Fatal cases due to mucositis have occurred.

Skin and subcutaneous tissue disorders

Common: palmar-plantar erythrodysesthesia.

Fatal cases have occurred due to gastrointestinal toxicity (mainly mucositis and diarrhoea) and myelosuppression. In patients with diarrhoea, rapid clinical deterioration with fatal outcome may occur.

Monthly treatment regimen with repeated cycles

Gastrointestinal disorders

Very common: vomiting and nausea.

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

Weekly treatment regimen with repeated cycles

Gastrointestinal disorders

Very common: diarrhoea with high degree of toxicity and dehydration requiring hospitalization of the patient, in individual cases even with fatal outcome.

Shelf life.

30 months.

Storage conditions.

Store in the original packaging at 2–8 °C, protected from light and out of reach of children.

Incompatibilities.

Calcium folinate solutions 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.

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

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

The medicinal product must be visually inspected prior to use. It should be clear, colourless or slightly yellow. If the solution is cloudy or contains visible mechanical particles, the medicinal product must not be used.

Packaging.

5 ml, 10 ml, 20 ml, 35 ml, 50 ml, and 100 ml of solution in glass vials. 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Haupt Pharma Wolfrausen GmbH.

Manufacturer's address and place of business.

Pfaffenrieder Strasse 5, Wolfratshausen, Bavaria, 82515, Germany.