Universal reference book for medicines
Product name: NATRIOFOLINE MEDAC (NATRIOFOLINE MEDAC)

Active substance: disodium folinate

Type: Antidote antagonists of folic acid

Manufacturer: medac (Germany) produced by HAUPT PHARMA WOLFRATSHAUSEN (Germany)
Composition, form of production and packaging
The solution for intravenous administration is
clear, from light yellow to yellow or greenish-yellow in color.

1 ml of 1 fl.

disodium folinate 54.65 mg 546.5 mg,

which corresponds to the content of folinic acid 50 mg 500 mg

Auxiliary substances: sodium hydroxide, hydrochloric acid, water d / u.

10 ml - bottles (1) - packs of cardboard.

The solution for intravenous administration is clear, from light yellow to yellow or greenish-yellow in color.

1 ml of 1 fl.

disodium folinate 54.65 mg 983.7 mg,

which corresponds to the content of folinic acid 50 mg 900 mg

Auxiliary substances: sodium hydroxide, hydrochloric acid, water d / u.

18 ml - bottles (1) - packs of cardboard.

The solution for intravenous administration is clear, from light yellow to yellow or greenish-yellow in color.

1 ml of 1 fl.

disodium folinate 54.65 mg 109.3 mg,

which corresponds to the content of folinic acid 50 mg of 100 mg

Auxiliary substances: sodium hydroxide, hydrochloric acid, water d / u.

2 ml - bottles (1) - packs of cardboard.

The solution for intravenous administration is clear, from light yellow to yellow or greenish-yellow in color.

1 ml of 1 fl.

disodium folinate 54.65 mg 218.6 mg,

which corresponds to the content of folinic acid 50 mg 200 mg

Auxiliary substances: sodium hydroxide, hydrochloric acid, water d / u.

4 ml - vials (1) - packs cardboard.

The solution for intravenous administration is clear, from light yellow to yellow or greenish-yellow in color.

1 ml of 1 fl.

disodium folinate 54.65 mg 327.9 mg,

which corresponds to the content of folinic acid 50 mg 300 mg

Auxiliary substances: sodium hydroxide, hydrochloric acid, water d / u.

6 ml - bottles (1) - packs of cardboard.

The solution for intravenous administration is clear, from light yellow to yellow or greenish-yellow in color.

1 ml of 1 fl.

disodium folinate 54.65 mg 382.55 mg,

which corresponds to the content of folinic acid 50 mg 350 mg

Auxiliary substances: sodium hydroxide, hydrochloric acid, water d / u.

7 ml - bottles (1) - packs of cardboard.

The solution for intravenous administration is clear, from light yellow to yellow or greenish-yellow in color.

1 ml of 1 fl.

disodium folinate 54.65 mg 437.2 mg,

which corresponds to the content of folinic acid 50 mg 400 mg

Auxiliary substances: sodium hydroxide, hydrochloric acid, water d / u.

8 ml - bottles (1) - packs of cardboard.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2012.

PHARMACHOLOGIC EFFECT

Folinic acid is a formyl derivative of tetrahydrofolic acid and is an active form of folic acid.
Folinic acid is involved in a number of metabolic processes, including the synthesis of purines, the synthesis of pyrimidine nucleotides and the metabolism of amino acids. Folinic acid is used as an antidote for medicines that act as antagonists of folic acid.
There is a biochemical justification for the desirability of a combination of disodium folinate with fluorouracil: fluorouracil inhibits DNA synthesis by binding to thymidylate synthetase.
The combined action of disodium folinate with fluorouracil is the formation of a stable three-component complex consisting of thymidylate synthetase, 5-fluorodeoxyuridine monophosphate and 5,10-methylenetetrahydrofolate. This results in a more intense block of thymidylate synthetase with increased inhibition of DNA synthesis, resulting in an increase in cytotoxicity compared to that of monotherapy with fluorouracil.
PHARMACOKINETICS

The bioequivalence of disodium folinate versus licensed calcium folinate preparations was studied in the framework of pharmacokinetic studies and was evaluated on the basis of compliance of pharmacokinetic parameters for D- and L-folinic acids and for metabolite 5-methyltetrahydrofolic acid.
Studies have shown that calcium folinate and disodium folinate are bioequivalent. The volume of folinic acid distribution is not established. When intravenously administered, the peak concentration of D / L-Formyltetrahydrofolic acid, folinic acid in blood plasma is reached after 10 minutes.
The active isomer, L-5-formyltetrahydrofolic acid, in the liver is rapidly converted to 5-methyltetrahydrofolic acid.
It is assumed that this conversion is not associated with the presence of dehydrofolate reductase and occurs most rapidly and completely when ingested than with parenteral administration. The inactive isomer, D-5-formyltetrahydrofolic acid, is excreted unchanged by the kidneys. The active isomer, L-5-formyltetrahydrofolic acid, is partially excreted by the kidneys, but is mainly metabolized to folic acid.
INDICATIONS

- intoxication with folic acid antagonists (methotrexate, trimethoprim and pyrimethamine);

- prevention of toxic effects of methotrexate when used in high and high doses;

- colorectal cancer (as part of combination therapy with fluorouracil).

DOSING MODE

Intravenously sprayed or infused.
Do not enter intrathecally.
When choosing a dose and mode of administration in each individual case should be guided by special medical literature.

The administration of antidotes of folic acid antagonists is recommended after the application of methotrexate in a dose of? 100 mg / m 2 of the body surface of the patient.
It should be borne in mind that disodium folinate is used in the same dosages as calcium folinate. After intravenous infusion of high doses of methotrexate (from 500 mg / m 2 to 12-15 g / m 2 ), the administration of Natriopholin medac is commenced, usually 24 hours after the end of methotrexate administration and is continued for 72 hours or until the plasma methotrexate concentration is reached blood levels of less than 0.5 μmol / l. Unified recommendations for the use of Natriopholin medak does not exist. The use of Natriopholin medac in these cases is recommended to be based on the mandatory determination of the concentration of methotrexate (MTX) in blood plasma (see Table 1 as an example).
Table 1

Levels of MTX in the serum 24-30 hours after the onset of MTX administration Disodium folinate dose (mg / m body surface) Calculation of folic acid dose and intervals of drug administration (in hours) Duration of treatment

From 1.0 x 10 -8 mol / l to 1.5 x 10 -6 mol / l from 10 to 15 mg / m 2 every 6 hours 48 hours

From 1.5 x 10 -6 mol / l to 5.0 x 10 -6 mol / l 30 mg / m 2 every 6 hours Up to the MTX level in the serum <5 x 10 -8 mol / l

> 5.0 x 10 -6 mol / l from 60 to 100 mg / m 2 every 6 hours Up to the MTX level in the serum <5 x 10 -8 mol / l

To prevent the development of chronic renal failure, hydration (3 L / day) is performed and sodium carbonate is introduced to maintain urine pH at 7 or higher.

In patients with acid urine reaction, exudative effusions, impaired renal function, intestinal obstruction , a higher dose of Natriopholin medac and / or longer duration of treatment may be required, since excretion of methotrexate in this group of patients may be delayed.
When combined with fluorouracil, Natriopholin medac is administered:
- in a dose of 500 mg / m intravenously drip for 1-2 hours in combination with intravenous jet fluorouracil administration at a dose of 600 mg / m 2 after 1 hour after the onset of infusion of Natriopholin medak or subsequent intravenous 24 hour infusion of fluorouracide at a dose of 2600 mg / m 2 , 1 time per week for 6 weeks with an interval between repeated courses of 2 weeks.

- at a dose of 200 mg / m 2, intravenously slowly (at least 3 minutes) or intravenously drip followed by intravenous fluorouracil at a dose of 370 mg / m 2 daily for 5 days at intervals of 4-5 weeks between repeated courses.

- at a dose of 20 mg / m 2 intravenously followed by intravenous fluorouracil at a dose of 425 mg / m 2 daily for 5 days at intervals of 4-5 weeks between repeated courses.

Natriopholin medak can be used undiluted in the case of injections, or diluted in the case of infusions.
Preparation of a solution for infusion should be carried out while observing the rules of aseptic. The drug can be diluted with 0.9% sodium chloride solution.
You can use only a clean solution, with no visible foreign particles and impurities.
The drug is intended for single use only. Unused medication is subject to destruction.
SIDE EFFECT

Adverse reactions are rare.
When parenteral administration, there were cases of hyperthermia. There were individual cases of allergic reactions, including anaphylactic reactions and rash. Dyspeptic disorders are possible with high doses.
CONTRAINDICATIONS

- hypersensitivity to disodium folinate or any other component included in the preparation;

- pernicious anemia or other anemia caused by a deficiency of cyanocobalamin (vitamin B12);

- Pregnancy and the period of breastfeeding.

With caution: alcoholism, epilepsy, chronic renal failure (CRF), children under 2 years of age (safety and efficacy for children not established).

PREGNANCY AND LACTATION

Contraindicated in pregnancy and during lactation.

APPLICATION FOR FUNCTIONS OF THE LIVER

With caution: chronic renal failure (CRF).

APPLICATION FOR CHILDREN

With caution: children under 2 years of age (safety and efficacy for children not established).

SPECIAL INSTRUCTIONS

Disodium folinate must be used only under the supervision of physicians with experience in the use of antitumor chemotherapeutic drugs.

Except for cases of overdose with folic acid antagonists, disodium folinate should not be used concomitantly with antitumor drugs such as folate (eg, methotrexate) to compensate for or reduce toxicity, since the therapeutic effect of antagonists can be leveled.

The concomitant use of disodium folinate does not reduce the antibacterial activity of folic acid antagonists such as trimethoprim and pyrimethamine.
In the combined use with fluorouracil, the toxicity profile of fluorouracil may be enhanced or altered by disodium folinate. The most common manifestations in this case are leukopenia, mucositis, stomatitis and / or diarrhea, which can cause a dose restriction. In the treatment of disintegration with folinate and fluorouracil, the dose of fluorouracil in case of toxic effects should be reduced more than in the case of fluorouracil in the monotherapy regimen.
In the treatment of accidental overdose with folic acid antagonists, disodium folinate should be given as soon as possible.
With an increase in the time interval between the appointment of antifolate (methotrexate) and the initiation of disinfection by folinate, the effectiveness of counteracting toxic manifestations decreases. To determine the optimal dose and duration of disodium folinate therapy, it is necessary to monitor the concentration of methotrexate in the blood serum. The delay in excretion of methotrexate can be caused by its delay in places of accumulation of pathological fluids (such as ascites, pleural effusion), renal insufficiency, unbalanced hydration, the use of nonsteroidal anti-inflammatory drugs or salicylates. In such cases, the purpose of disodium folinate may be indicated at higher doses or prolonged. Disodium folinate does not affect the non-hematologic toxicity of methotrexate, such as nephrotoxicity caused by precipitation of the drug and / or its metabolites in the kidneys.
In patients with epilepsy receiving phenobarbital, phenytoin, primidone, there is a risk of an increased incidence of seizures due to a decrease in the concentration of antiepileptic drugs in the blood.
During therapy with disodium folinate and after its discontinuation it is recommended to carry out clinical observation, control the concentration of antiepileptic drugs in plasma, and, if necessary, adjust their doses.
The use of disodium folinate in pernicious and other megaloblastic anemias caused by a deficiency of cyanocobalamin (vitamin B12) can lead to hematological remission with simultaneous progression of neurological disorders.

OVERDOSE

Disodium folinate is not toxic.
Even with very high doses of signs of overdose is not observed.
DRUG INTERACTION

Disodium folinate with simultaneous application reduces the effectiveness of folic acid antagonists.

Reduces anticonvulsant activity of phenobarbital, phenytoin and primidone.
May lead to an increase in both the therapeutic and toxic effects of fluorouracil, and therefore, when combined, fluorouracil doses should be reduced.
Natriopholin medak is compatible with fluorouracil.
With other drugs, it is impossible to mix Natriopholin medak.
TERMS OF RELEASE FROM PHARMACY

On prescription.

TERMS AND CONDITIONS OF STORAGE

Store in a place protected from light and inaccessible to children at a temperature of 2-8 ° C.
Do not freeze!
Shelf life - 2 years.

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

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