Leukovorin-mili

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEUCOVORIN-MILI (LEUCOVORIN-MILI)

Composition:

active substance: calcium folinate;

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

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

* - calcium leucovorin, corresponding to leucovorin.

Pharmaceutical form. Solution for injection.

Basic physicochemical properties: yellowish solution.

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

Pharmacological Properties

Pharmacodynamics

Calcium folinate is one of several biologically active, chemically reduced derivatives of folic acid. It is useful as an antidote to drugs that act as folic acid antagonists. Administration of calcium folinate can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase.

In contrast, calcium folinate may enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy, such as 5-fluorouracil. Concurrent administration of calcium folinate is unlikely to alter the pharmacokinetics of 5-fluorouracil in blood plasma. 5-Fluorouracil is metabolized to fluorodeoxyuridylic acid, which binds to the enzyme thymidylate synthase (an enzyme essential for DNA repair and replication) and inhibits it.

Calcium folinate is readily converted into another reduced folate, 5,10-methylenetetrahydrofolate, which stabilizes the binding of fluorodeoxyuridylic acid to thymidylate synthase, thereby enhancing the inhibition of this enzyme.

Pharmacokinetics

The pharmacokinetics after intravenous, intramuscular, and oral administration of 25 mg of calcium folinate were studied in male volunteers. After intravenous administration, total reduced folate in serum (measured by Lactobacillus casei assay) reached a mean peak of 1259 ng/mL (range: 897–1625 ng/mL). The mean time to peak was 10 minutes. This initial increase in total reduced folate was primarily due to the parent compound, 5-formyl-THF (measured by Streptococcus faecalis assay), which rose to 1206 ng/mL at 10 minutes. This was followed by a sharp decline in the parent compound, coinciding with the appearance of the active metabolite 5-methyl-THF, which became the predominant circulating form of the drug. The mean peak concentration of 5-methyl-THF was 258 ng/mL, observed at 1.3 hours. The terminal half-life of total reduced folate was 6.2 hours. The area under the concentration-time curve (AUC) for l-leucovorin, d-leucovorin, and 5-methyltetrahydrofolate was 28.4 ± 3.5, 956 ± 97, and 129 ± 12 (mg·min/L ± standard deviation), respectively. Similar results were obtained with higher doses of d,l-leucovorin (200 mg/m²). The d-isomer remained in plasma at concentrations significantly exceeding those of the l-isomer.

Indications

As a protective agent to prevent the toxic effects of methotrexate when administered in high doses for osteosarcoma.

Reduction of toxicity in cases of methotrexate overdose or intoxication and other folic acid antagonists.

Treatment of megaloblastic anemia caused by folic acid deficiency when oral administration of folic acid is not feasible.

Leucovorin-Mili is also indicated for use in combination with 5-fluorouracil to prolong survival in palliative treatment of patients with advanced colorectal cancer. Leucovorin should not be mixed in the same infusion with 5-fluorouracil, as precipitation may occur.

Contraindications

Pernicious anemia and other types of megaloblastic anemias caused by vitamin B12 deficiency. Hematological remission may occur, while neurological manifestations continue to progress.

Interaction with Other Medicinal Products and Other Forms of Interaction

High-dose folic acid may reduce the anticonvulsant effect of phenobarbital, phenytoin, and primidone, and may also increase the frequency of seizures in predisposed children.

Preclinical studies in animals and humans have shown that small amounts of systemically administered leucovorin enter the cerebrospinal fluid primarily as 5-methyltetrahydrofolate and remain 1–3 orders of magnitude lower than typical methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate.

The medicinal product Leucovorin-Mili may enhance the toxic effects of 5-fluorouracil, necessitating dose adjustment of the latter (see section "Dosage and Administration").

Special precautions for use

In cases of overdose with folic acid antagonists, treatment with Leucovorin-Mili should be initiated as early as possible, since the antidotal efficacy of the drug decreases when administered late after the overdose.

Leucovorin should not be administered intrathecally in the treatment of accidental intrathecal overdose of folic acid antagonists.

LEUCOVORIN CAN BE HARMFUL OR FATAL IF ADMINISTERED INTRATHECALLY.

Monitoring serum methotrexate concentrations is essential for determining the optimal dose and duration of leucovorin treatment. Delayed elimination of methotrexate may be associated with fluid retention (edema, ascites, pleural effusion), renal impairment, or inadequate hydration during therapy. In such cases, prolonged administration of Leucovorin-Mili at high doses is indicated. When administering Leucovorin-Mili at doses exceeding those recommended for oral use, the drug should be given intravenously.

Due to the calcium content in the leucovorin solution, no more than 160 mg of leucovorin should be administered intravenously per minute (16 mL of a 10 mg/mL solution or 8 mL of a 20 mg/mL solution per minute).

Leucovorin enhances the toxicity of 5-fluorouracil. When these drugs are used concomitantly in palliative treatment of advanced colorectal cancer, the dosage of 5-fluorouracil should be lower than usual. Although the toxicity observed in patients receiving the combination of leucovorin and 5-fluorouracil is qualitatively similar to that seen in patients receiving 5-fluorouracil alone, gastrointestinal toxicity (particularly stomatitis and diarrhea) occurs more frequently and may be more severe and prolonged in patients receiving the combination.

In the first controlled Mayo/NCCTG study, gastrointestinal toxicity predominantly led to hospitalization in 7% of patients treated with 5-fluorouracil alone or in combination with 200 mg/m² leucovorin, and in 20% of patients treated with 5-fluorouracil in combination with 20 mg/m² leucovorin. In the second Mayo/NCCTG study, hospitalization due to treatment-related toxicity also occurred more frequently in patients receiving the low-dose combination of leucovorin/5-fluorouracil compared to those receiving the high-dose combination—11% versus 3%. Therapy with leucovorin and 5-fluorouracil should not be initiated or continued in patients who have symptoms of gastrointestinal toxicity of any severity until these symptoms have completely resolved.

Patients with diarrhea require particularly careful monitoring until diarrhea resolves, as rapid clinical deterioration may occur, potentially leading to death. In an additional study using higher weekly doses of 5-fluorouracil and leucovorin, elderly patients and/or debilitated patients were found to have an increased risk of developing severe gastrointestinal toxicity.

Seizures and/or loss of consciousness have been rarely observed in oncology patients receiving leucovorin, usually in conjunction with fluoropyrimidine administration, most frequently in patients with CNS metastases or other predisposing factors; however, a causal relationship has not been established.

Concomitant use of leucovorin with trimethoprim-sulfamethoxazole for acute treatment of Pneumocystis carinii-induced pneumonia in HIV-infected patients was associated with increased rates of treatment failure and morbidity in a placebo-controlled study.

This medicinal product contains 3.14 mg of sodium per milliliter of solution, which should be taken into account when treating patients on a sodium-restricted diet.

WARNINGS

Parenteral administration is preferred over oral administration if there is a risk that the patient may vomit and leucovorin will not be absorbed. Leucovorin does not counteract non-hematological toxicities of methotrexate, such as nephrotoxicity resulting from drug and/or metabolite precipitation in the kidneys.

Since leucovorin enhances the toxicity of fluorouracil, combined therapy with leucovorin/5-fluorouracil for the treatment of advanced colorectal cancer should be administered only under the direct supervision of a physician experienced in the use of oncologic chemotherapeutic agents.

Particular caution is required when treating elderly or debilitated patients with colorectal cancer, as these patients may have an increased risk of severe toxicity.

Laboratory tests

Patients receiving combination therapy with leucovorin and 5-fluorouracil should have a complete blood count with differential and platelet count performed before each treatment. During the first two cycles, complete blood counts with differential and platelet counts should be repeated weekly, and thereafter once per cycle at the time of expected nadir leukocyte count. Electrolyte and liver function tests should be performed before each treatment during the first three cycles, and then before each subsequent cycle. Dose modification of 5-fluorouracil should be performed (see Table 1) based on the most severe toxicity observed:

Table 1

Dose modification of 5-fluorouracil

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If toxicity does not occur, the dose of fluorouracil may be increased by 10%. Treatment should be postponed until the white blood cell count reaches 4000/mm³ and platelets reach 130000/mm³. If blood counts do not reach these levels within two weeks, treatment should be discontinued. Patients should be examined before each treatment cycle, and appropriate radiological evaluation should be performed when necessary. Treatment should be discontinued when there are clear signs of tumor progression.

Use during pregnancy or breastfeeding

Pregnancy

Adequate reproductive studies with leucovorin in animals have not been conducted.

It is also not known whether leucovorin can cause fetal harm when administered to pregnant women or whether it can affect reproductive capacity. Leucovorin should be administered to pregnant women only if clearly needed.

Period of breastfeeding

Currently, there is no information on whether calcium folinate is excreted in human milk. Since many drugs are excreted in breast milk, caution should be exercised when administering leucovorin to a nursing mother.

Ability to influence reaction rate while driving or operating machinery

There is no information regarding the ability of calcium folinate to affect the ability to drive or operate machinery.

Method of Administration and Dosage

Metastatic Colorectal Cancer

One of the following two treatment regimens is recommended:

1. Leucovorin is administered at a dose of 200 mg/m² by slow intravenous injection over at least 3 minutes, followed by 5-fluorouracil 370 mg/m² administered intravenously.
2. Leucovorin is administered at a dose of 20 mg/m² by intravenous injection, followed by 5-fluorouracil 425 mg/m² administered intravenously.

5-Fluorouracil and leucovorin should be administered separately to avoid precipitation.

Treatment is repeated daily for five consecutive days. This five-day treatment cycle may be repeated every 4 weeks (28 days) for up to 2 cycles, then repeated every 4–5 weeks (28–35 days), provided the patient has fully recovered from the toxic effects of the previous treatment cycle.

In subsequent treatment cycles, the dosage of 5-fluorouracil should be adjusted according to the patient's tolerance of the previous cycle. The daily dose of 5-fluorouracil should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity during the previous cycle, and by 30% for patients who experienced severe toxicity (see section "Special Warnings and Precautions for Use"). For patients who experienced no toxicity during the previous cycle, the dose of 5-fluorouracil may be increased by 10%. Leucovorin doses are not adjusted based on toxicity.

Reduction of Toxicity in Methotrexate Overdose and Intoxication

The dose and regimen of calcium folinate depend directly on the dose and route of methotrexate administration—12 to 15 grams/m² administered intravenously over 4 hours (the calcium folinate regimen is established according to the methotrexate treatment protocol).

Generally, the first dose of calcium folinate 15 mg (approximately 10 mg/m²) should be administered within 12–24 hours (no later than 24 hours) after the start of methotrexate infusion.

The same dose should be repeated every 6 hours for 72 hours. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally. Do not administer leucovorin intrathecally.

Serum creatinine and methotrexate levels should be determined at least once daily.

Administration of leucovorin, hydration, and alkalinization of urine (pH 7.0 or higher) should be continued until serum methotrexate levels fall below 5 x 10⁻⁶ M (0.05 micromolar). In patients with delayed early elimination of methotrexate, reversible renal insufficiency is likely to develop. In addition to appropriate leucovorin therapy, these patients require continuous hydration and urinary alkalinization, as well as careful monitoring of fluid and electrolyte status, until serum methotrexate levels decrease below 0.05 micromolar and renal insufficiency resolves.

In some patients, after methotrexate administration, disturbances in methotrexate excretion or renal function may occur that are significant but less severe than those described in the table above. These disturbances may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, rescue therapy with leucovorin should be extended for an additional 24 hours (a total of 14 doses over 84 hours) in subsequent treatment cycles. The possibility that the patient is taking other medications that interact with methotrexate (e.g., drugs that may interfere with methotrexate excretion or binding to serum albumin) should always be considered when laboratory abnormalities or clinical toxicity are observed.

Methotrexate Excretion Impairment or Accidental Overdose

Rescue therapy with leucovorin should be initiated as soon as possible after accidental overdose and within 24 hours of methotrexate administration if delayed excretion is observed (see section "Special Warnings and Precautions for Use"). Leucovorin 10 mg/m² should be administered intramuscularly, intravenously, or orally every 6 hours until serum methotrexate levels fall below 10⁻⁸ M. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally. Do not administer leucovorin intrathecally.

Serum creatinine and methotrexate levels should be determined at 24-hour intervals. If the 24-hour serum creatinine level increases by 50% compared to baseline, or if the 24-hour methotrexate level exceeds 5 x 10⁻⁶ M, or if the 48-hour level exceeds 9 x 10⁻⁷ M, the leucovorin dose should be increased to 100 mg/m² intravenously every 3 hours until serum methotrexate levels fall below 10⁻⁸ M.

Concurrent hydration (3 L/day) and urinary alkalinization with sodium bicarbonate solution should be administered. The bicarbonate dose should be adjusted to maintain urine pH at 7.0 or higher.

Megaloblastic Anemia due to Folic Acid Deficiency

Dosage up to 1 mg daily. There is no evidence that doses exceeding 1 mg daily are more effective than 1 mg; furthermore, urinary folate excretion becomes approximately logarithmic as the administered amount exceeds 1 mg.

Due to the calcium content in leucovorin solution, intravenous administration of more than 160 mg leucovorin per minute (16 mL of 10 mg/mL solution or 8 mL of 20 mg/mL solution per minute) should not be performed.

Parenteral medicinal products should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit.

Leucovorin should not be mixed in the same infusion with 5-fluorouracil, as this may lead to precipitation.

Children

Calcium folinate is indicated for use in children as a protective agent to prevent the toxic effects of methotrexate, as well as an antidote in cases of overdose and intoxication with methotrexate and other folic acid antagonists.

Overdose

Excessive amounts of calcium folinate may negate the effects of chemotherapy with folic acid antagonists.

Adverse Reactions

Following oral and parenteral administration of leucovorin, allergic sensitization has been reported, including anaphylactoid reactions and urticaria. Anaphylactic reactions, including shock, have not been reported. No other adverse reactions related to the use of leucovorin have been reported.

Table 2 summarizes significant adverse reactions occurring in 316 patients receiving leucovorin/5-fluorouracil combinations compared to 70 patients receiving 5-fluorouracil alone for the treatment of advanced colorectal carcinoma. These data are from a large multicenter prospective study (Mayo/NCCTG) evaluating the efficacy and safety of the combination regimen.

Table 2

Percentage of patients treated with leucovorin/fluorouracil for advanced colorectal carcinoma

High LV = Leucovorin 200 mg/m², Low LV = Leucovorin 20 mg/m².

Any grade = percentage of patients reporting toxicity of any severity grade.

Grade 3+ = percentage of patients reporting toxicity of grade 3 or higher.

Leucovorin dose should be adjusted or leucovorin therapy continued according to the recommendations below (see Table 3).

Table 3

Recommendations for leucovorin dosing and administration

DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY

Reporting of adverse reactions after drug registration is highly important. It enables continuous monitoring of the benefit-risk balance associated with the use of this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at 2–8 °C, in a place inaccessible to children.

Packaging. 5 mL (50 mg), or 10 mL (100 mg), or 30 mL (300 mg) in a vial. One vial per cardboard box.

Prescription status. Prescription only.

Manufacturer

Venus Remedies Limited.

Manufacturer's address and location of operations

Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn.), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh, 173205, India.

Marketing Authorization Holder

Mili Healthcare Limited.

Address of the Marketing Authorization Holder and/or its representative

2nd Floor, Office Premises, 4 Charterfield House, Castle Street, Taunton, Somerset, England, TA1 4AS, United Kingdom.