Leucovorin-Teva (Solution) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Pharmachemie, B.V. (Netherlands)

ATC Code

V03AF03 (Calcium folinate)

Active Substance

Calcium folinate (Rec.INN registered by WHO)

Dosage Form

Leucovorin-Teva

Solution for intravenous and intramuscular administration 10 mg/1 ml: fl. 5 ml, 10 ml, 30 ml or 50 ml

Dosage Form, Packaging, and Composition

Solution for intravenous and intramuscular administration transparent, from colorless to yellow.

* theoretical amount of 100% calcium folinate calculated as the anhydrous substance.

Excipients : sodium chloride – 8 mg, sodium hydroxide 1N solution – sufficient quantity (used to adjust pH), hydrochloric acid 1N solution – sufficient quantity (used to adjust pH), water for injections – up to 1 ml.

5 ml – vials (1) – cardboard packs^×.
10 ml – vials (1) – cardboard packs^×.
30 ml – vials (1) – cardboard packs^×.
50 ml – vials (1) – cardboard packs^×.

^× protective stickers may additionally be applied.

Clinical-Pharmacological Group

Folic acid antagonists antidote

Pharmacotherapeutic Group

Other therapeutic agents; agents for reducing the toxicity of anticancer therapy

Pharmacological Action

Calcium folinate is a reduced form of folic acid and is used as an antidote for drugs that act as folic acid antagonists.

Folic acid antagonists, such as methotrexate, inhibit dihydrofolate reductase and thereby prevent the formation of tetrahydrofolate from folic acid, which is a co-factor for the transfer of one-carbon residues in nucleic acid biosynthesis. As a result, the synthesis of nucleic acids and cell division is blocked. Unlike folic acid, Calcium folinate does not require reduction by dihydrofolate reductase to be converted into tetrahydrofolate, which allows for the restoration of the impaired biosynthesis of DNA, RNA, and proteins when it is used. The protective effect of calcium folinate is manifested only in healthy cells. Due to these properties, Calcium folinate prevents the toxic effect of methotrexate on bone marrow and gastrointestinal tract cells but does not significantly affect the already developed nephrotoxic effect of methotrexate.

The drug helps to replenish the deficiency of folic acid in the body.

Calcium folinate can also enhance the antitumor effect of fluorouracil. When these two drugs interact, a stable complex of components is formed, containing thymidylate synthase, which inhibits and suppresses DNA synthesis.

The onset of action of the drug after intramuscular administration is within 10-20 minutes, after intravenous administration – less than 5 minutes. The duration of action is about 3-6 hours regardless of the route of administration.

Pharmacokinetics

C_max of reduced folate in blood serum after intramuscular administration is reached on average in 40 minutes, after intravenous administration – in 10 minutes, and after oral administration in 1 hour 40 minutes. Penetrates the blood-brain barrier in moderate amounts; accumulates to a greater extent in the liver. Metabolized in the liver and intestinal mucosa mainly into the active metabolite 5-methyltetrahydrofolate. Half-life – 6.2 hours regardless of the route of administration.

Excreted by the kidneys 80-90%, by the intestines – 5-8%.

Indications

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

ICD codes

Dosage Regimen

The solution is administered intramuscularly or intravenously.

When choosing doses and the administration regimen of the drug in each individual case, one should refer to specialized literature.

Usually, when prescribing the drug in combination with high doses of methotrexate (12-15 mg/m²⁾, administration begins 24 hours after the end of methotrexate treatment at a dose: 10 mg/m² every 6 hours for 72 hours or until the plasma concentration of methotrexate is less than 5×10^{-8 M}.

In patients with acidic urine, exudative effusions, impaired renal function, intestinal obstruction, a higher dose of calcium folinate and/or a longer duration of treatment may be required, as the elimination of methotrexate in this group of patients may be slowed. The use of Leucovorin-Teva in these cases is recommended to be based on the mandatory determination of the plasma concentration of methotrexate.

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

In case of accidental overdose of methotrexate, Leucovorin-Teva is administered at a dose equal to or exceeding the dose of the administered methotrexate no later than 1 hour after the methotrexate injection, then the drug is administered every 3 hours at 10 mg/m² until signs of toxicity disappear.

When combined with fluorouracil, Leucovorin-Teva is administered

• At a dose of 200 mg/m² intravenously slowly (not less than 3 minutes) or by intravenous drip followed by intravenous administration of fluorouracil at a dose of 370 mg/m²or
• At a dose of 20 mg/m² intravenously followed by intravenous administration of fluorouracil at a dose of 425 mg/m².

The drugs are administered daily for 5 days with an interval of 4-5 weeks for repeated courses.

In the treatment of megaloblastic anemia caused by folic acid deficiency, Leucovorin-Teva is prescribed at 1 mg/day intramuscularly or intravenously.

Preparation of the drug for injection

The drug Leucovorin-Teva is diluted in Ringer’s solution; Ringer’s solution with lactate; 10% dextrose solution in water; 5% dextrose solution in water; 0.9% sodium chloride solution to a concentration from 0.06 mg/ml to 1 mg/ml. The resulting solution remains stable for 24 hours. Do not use the solution remaining after injection.

Adverse Reactions

The adverse events listed below, noted with the use of the drug Leucovorin-Teva, are distributed by frequency of occurrence according to the following gradation: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000).

Immune system disorders: very rare – allergic reactions: skin rash, urticaria, itching, anaphylactic shock.

Nervous system disorders: rare – insomnia, agitation, depression, excitation, increased frequency of epileptic seizures.

Gastrointestinal disorders: rare – dyspeptic phenomena (when using high doses of calcium folinate).

Other: uncommon – fever.

Contraindications

• Hypersensitivity to calcium folinate or any other component included in the drug;
• Megaloblastic anemia due to cyanocobalamin (vitamin B₁₂) deficiency;
• Pregnancy and breastfeeding period.

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

Use in Pregnancy and Lactation

Prohibited to take during pregnancy and lactation.

Use in Renal Impairment

Use with caution in chronic renal failure (CRF), in case of impaired renal function.

Pediatric Use

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

Special Precautions

The use of calcium folinate in pernicious and other megaloblastic anemias due to cyanocobalamin (vitamin B₁₂) deficiency may lead to hematological remission with simultaneous progression of neurological disorders.

May increase the frequency of epileptic seizures in predisposed children due to a reduction in the effect of antiepileptic drugs – hydantoin and primidone (hexamidine) derivatives.

Calcium folinate is used with caution in acidic urine, ascites, dehydration, exudative pleurisy, impaired renal function.

Before starting and during therapy, renal function and urine pH should be monitored.

In case of accidental overdose of methotrexate, calcium folinate should be started as soon as possible.

Overdose

Calcium folinate is slightly toxic. Even when using high doses, no signs of overdose are observed.

Drug Interactions

Calcium folinate, when used concomitantly, reduces the effectiveness of folic acid antagonists.

Reduces the anticonvulsant activity of phenobarbital, phenytoin, and primidone. Its use may lead to an increase in both the therapeutic and toxic effects of fluorouracil, which is why when used together, the doses of fluorouracil should be reduced.

Storage Conditions

List B.

The drug should be stored at a temperature from 2 to 8°C (46.4°F), in a place protected from light.

Keep out of reach of children.

Shelf Life

Shelf life 2 years.

Do not use after the expiration date indicated on the packaging.

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.