Calciumfonilate-Ebwee - instructions for use, dose, side effects, contraindications

1 capsule contains: active substance: calcium folinate pentahydrate 19.06 mg (equivalent to 15.0 mg folinic acid and 16.21 mg calcium folinate); Excipients: lactose monohydrate 23.00 mg; silicon colloidal dioxide 1.50 mg; magnesium stearate 2.00 mg; croscarmellose sodium 20.00 mg; capsule shell: cap: gelatin 1>, 547 mg; purified water 2.784 mg; titanium dioxide (E 171) 0.768 mg; indigo carmine FD&C Blue 2 (El32) 0.005 mg; iron dye oxide yellow (E 172) 0.096 mg; body: gelatin 24.048 mg; titanium dioxide (E 171) 0.576 mg; purified water 4,176 mg.

Description:Hard gelatin capsules No. 3 with a white body and a lid of light green color. The contents of the capsules are a uniform powder from white to light yellow in color.

Pharmacotherapeutic group:Vitamin - antidote of folic acid antagonists (modifier of biological action of fluorouracil)

ATX: & nbsp

V.03.A.F Drugs that reduce the toxicity of cytostatic therapy

Pharmacodynamics:

Calcium folinate is a 5-formylgetrahydrofolate of calcium. Is a restored form of folinic acid and necessary coenzyme for the synthesis of nucleic acids in cytotoxic therapy. Used as an antidote for medicines that act as antagonists of folic acid.

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

Also calcium folinate often used for biochemical modulation of fluorouracil to enhance him cytotoxic action. Fluorouracil inhibits thymidylate synthetase, a key enzyme involved in the biosynthesis of pyrimidine. Calcium folinate enhances the inhibition of thymidine kinase by increasing the intracellular folate pool, thus stabilizing the fluorouracil-thymidine synthetase complex and increasing him activity.

Pharmacokinetics:

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

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

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

The volume of folinic acid distribution is unknown.

The entire half-life of active metabolites with oral intake is 6.0 ± 1.9 hours. When administered 200 mg calcium folinate 20% is displayed kidneys in the first 24 hours (5- and 10-formyltetrahydrofolates as inactive metabolites), 16% in the form of 5-methyltetrahydrofolic acid.

Indications:

Prevention of toxic effects of methotrexate, used in high doses;

intoxication with folic acid antagonists (trimethoprim, pyrimethamine);

megaloblastic anemia caused by a deficiency of folic acid (including against the background of malabsorption syndrome, malnutrition, pregnancy, sprue, in early childhood with congenital Mr.insufficiency of dihydrofolate reductase).

Contraindications:

hypersensitivity to calcium folinate or any other component of the drug;

rare hereditary forms of lactose intolerance, lactase deficiency or impaired absorption of glucose / galactose (because the composition contains lactose);

megaloblastic anemia due to deficiency of cyanocobalamin (vitamin B₁₂);

Children under 3 years old (for this dosage form).

Carefully:

Carefully should be used in patients with epilepsy, chronic renal failure, alcoholism.

Pregnancy and lactation:

Since no controlled studies have been conducted in pregnant women,then use during pregnancy is possible only if the intended benefit to the mother exceeds the potential risk to the fetus and the baby.

It is not known whether the drug is excreted in breast milk, so when the need to use calcium folinate in the lactation period, it is necessary to resolve the issue of stopping breastfeeding.

Dosing and Administration:

Inside.

If a daily dose of more than 50 mg is required, intravenous / intramuscular dosage forms of folinic acid are recommended, since the absorption of calcium folinate in the intestine is saturable.

Prevention of toxic effects of methotrexate

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

The following recommendations can serve as a guide for the determination of doses and the scheme for the protective use of calcium folinate in the elderly, the elderly and children. The dose and duration of calcium folinate, first of all, depend on the type and doses of methotrexate therapy, the appearance of signs of toxicity and the specific features of methotrexate excretion.

When high doses of methotrexate are used, calcium folinate doses up to 120 mg can be administered for 12-24 hours intramuscularly or intravenously, followed by administration of the drug at doses of 12-15 mg intramuscularly or 15 mg orally every 6 hours for a further 48 hours.

When using lower doses of methotrexate calcium folinate It is applied at a dose of 15 mg orally every 6 hours for 48-72 hours.

48 hours after the onset of methotrexate infusion, its residual level should be measured, at which time calcium folinate is assigned as follows:

- at a residual level of methotrexate> 0.5 μmol / l calcium folinate is used in a dose of 15 mg / m²;

- at a residual level of methotrexate> 1.0 μmol / l calcium folinate is applied in a dose of 100 mg / m²;

- at a residual level of methotrexate> 2.0 μmol / l calcium folinate is used in a dose of 200 mg / m²;

Also an integral complement to the use of calcium folinate in the prevention of toxic effects of methotrexate are measures that promote the acceleration of excretion of methotrexate (ensuring the adequacy of urinary function and alkalinization of urine). The kidney function should be monitored daily by measuring the concentration of serum creatinine.

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

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

Intoxication with folic acid antagonists (trimethoprim, pyrimethamine)

Toxicity of trimethoprim

After stopping the administration of trimethoprim, calcium folinate in a dose of 3-10 mg / day until the recovery of peripheral blood.

The toxicity of pyrimethamine

In the case of high doses of pyrimethamine or long-term treatment with low doses, calcium folinate in a dose of 5-50 mg / day, depending on the parameters of peripheral blood.

With megaloblastic anemia, caused by a deficiency of folic acid, calcium folinate prescribe a dose of up to 5 mg (maximum to 15 mg) per day.

Have elderly patients correction of the dose is not required.

Have patients with impaired hepatic and / or renal function correction of the dose is not required.

Side effects:

According to the World Health Organization (WHO), adverse reactions are classified according to their frequency of development as follows: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, < 1/100), rarely (> 1/10000, <1/1000) and very rarely (<1/10000); frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

Immune system disorders

rarely: allergic reactions, including anaphylactic shock and hives.

Disorders of the psyche

rarely: insomnia, anxiety, depression when applying high doses.

Disorders from the gastrointestinal tract

rarely: nausea, dyspepsia (when applying high doses).

Disturbances from the nervous system

rarely: increased frequency of epileptic seizures.

General disorders and disorders at the site of administration

infrequently: fever.

There are data on the occurrence of such undesirable phenomena as Stevens-Johnson syndrome, toxic epidermal necrolysis, sometimes fatal, in the development of which the role of calcium folinate can not be ruled out.

Overdose:

The effect of taking significantly higher doses than recommended calcium doses of folate was not reported.However, high doses of calcium folinate can neutralize the chemotherapeutic effect of folic acid antagonists.

Interaction:

With the simultaneous use of calcium folinate with antagonists of folic acid (eg, co-trimoxazole, pyrimethamine), the efficacy of folic acid antagonists can be reduced or completely eliminated.

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

When combined use of calcium folinate and fluorouracil The efficacy and toxicity of the latter are increased.

Special instructions:

Treatment of methotrexate and the preparation of Calciumfonilate-Ebwe® should be performed by a qualified oncologist in the hospital, provided that the necessary controls are available.

Application of the preparation Calciumfonolate-Ebwe^® can mask a clinical picture of a pernicious or other type of anemia caused by vitamin B deficiency₁₂.

Many cytotoxic drugs cause the development of macrocytosis (in particular, direct and indirect inhibitors of the synthesis of deoxyribonucleic acid - 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, primidon, phenytoin, or succinimides, there is a risk of an increased incidence of epileptic seizures due to a decrease in plasma concentrations of antiepileptic drugs. In this case, it is recommended to conduct clinical monitoring, control of plasma concentrations of drugs and, if necessary, dose adjustment of antiepileptic drugs during the use of the Calciumfolinate-Ebevé® and after the course of therapy.

Calciumfonolate-Ebove® does not protect against non-hematologic toxic effects during methotrexate therapy (for example, from nephrotoxic effects due to precipitation of methotrexate and its metabolites in the renal tubules).The presence of a previous or methotrexate-induced renal failure that is associated with delayed excretion of methotrexate may require higher doses or a longer course of therapy with the drug Calciumfonolate-Ebove®.

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

In case of accidental overdose with a folic acid antagonist, such as methotrexate, it is necessary to provide emergency medical care, since an increase in the time interval between the use of methotrexate and the preparation Calciumfonolate-Ebove® leads to a decrease in the effectiveness of the latter.

Due to the occurrence of clinical manifestations of toxicity or deviations in laboratory tests, the likelihood of the patient using other drugs that interact with methotrexate (for example, drugs that may affect the elimination of methotrexate or bind to blood plasma proteins) should always be considered.

Effect on the ability to drive transp. cf. and fur:

With the use of the preparation Kalciumfolinate-Ebove®, there was no effect on the ability to drive vehicles and to engage in other activities requiring concentration of attention and speed of psychomotor reactions.

Form release / dosage:Capsules 15 mg.

Packaging:

Primary packaging

For 20 capsules in a white polypropylene bottle, closed with a cork of low density polyethylene.

Secondary packaging

One bottle together with instructions for use in a cardboard box.

Storage conditions:

In a dry, protected from light place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Special precautions for unused medicinal product

Not applicable.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N014892 / 01

Date of registration:21.04.2008

The owner of the registration certificate:Ebewe Pharma Gesmb.b. Nfg. KGEbewe Pharma Gesmb.b. Nfg. KG Austria

Manufacturer: & nbsp

HAUPT PHARMA AMAREG, GmbH Germany

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp11.09.2015

Illustrated instructions

Instructions

Calcium Phosphinate-Ebove® (Calciumfolinat-Ebewe®)