Levofolik

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOFOLIC (LEVOFOLIC)

Composition:

Active substance: sodium leucovorin;

1 ml of solution contains 50 mg of levofolinic acid (leucovorin), equivalent to 54.65 mg of disodium leucovorin;

Excipients: sodium hydroxide, hydrochloric acid, water for injections, nitrogen (for filling the vial with inert atmosphere).

Pharmaceutical form. Solution for injection or infusion.

Main physicochemical characteristics: slightly yellow, clear solution.

Pharmacotherapeutic group.

Agents used to counteract toxic effects of antineoplastic therapy.

ATC code V03AF.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Folinic acid is a formyl derivative of tetrahydrofolic acid, i.e. the active form of folic acid. Leucovorin (levoleucovorin) acid is the biologically active L-isomer of the racemic form of folinic acid. It participates in various metabolic processes, including purine synthesis, pyrimidine nucleotide synthesis, and amino acid metabolism.

Pharmacodynamic properties

Biochemical rationale for the use of sodium leucovorin as a rescue agent in methotrexate therapy

Leucovorin acid is commonly used to reduce the toxicity and counteract the adverse effects of folic acid antagonists such as methotrexate. Leucovorin acid is transported into the cell by the same mechanism as folic acid antagonists and competes with them for this transport, thereby promoting their elimination. It also protects cells from the effects of folic acid antagonists by replenishing the depleted body stores of folic acid. The metabolism of leucovorin acid does not require the participation of the enzyme dihydrofolate reductase. Thus, leucovorin acid serves as a source of H4-folates, can bypass the dihydrofolate reductase blockade induced by folic acid antagonists, and provides a source of various coenzyme forms of folic acid.

Biochemical rationale for combination therapy with sodium leucovorin and 5-fluorouracil

5-Fluorouracil can inhibit DNA synthesis by binding to the enzyme thymidylate synthase. The combination of sodium leucovorin and fluorouracil forms a stable ternary complex comprising thymidylate synthase, 5-fluoro-2'-deoxyuridine monophosphate, and 5,10-methylenetetrahydrofolate.

As a result, thymidylate synthase is blocked, leading to enhanced inhibitory effects on DNA biosynthesis, which in turn increases cytotoxicity compared to monotherapy with fluorouracil.

Pharmacokinetics

Sodium leucovorin is bioequivalent to calcium leucovorin as well as to the racemic mixture of disodium folinate with respect to plasma concentrations of leucovorin acid and its main active metabolite, 5-methyltetrahydrofolate, following intravenous administration of the active isomer at the same molar dose.

Distribution. Approximately 27% of leucovorin acid is protein-bound in the blood. The volume of distribution is approximately 17.5 liters.

Biological transformation. The active isomeric form of leucovorin acid (L-5-formyltetrahydrofolate) is rapidly metabolized in the liver to 5-methyltetrahydrofolate.

This conversion is considered not to be dependent on the presence of dihydrofolate reductase.

Elimination. Approximately 20% of an intravenously administered dose is excreted unchanged (as leucovorin acid) in the urine. The clearance of leucovorin acid is approximately 205 mL/min. After intravenous administration, the elimination half-life of leucovorin acid and its active metabolite, 5-methyltetrahydrofolate, is 0.5 hours and 6.5 hours, respectively.

Clinical characteristics.

Indications.

• To reduce the toxic effects of folic acid antagonists such as methotrexate during cytotoxic therapy and in cases of overdose in adults and children of all age groups.
• In combination with 5-fluorouracil during cytotoxic therapy.

Contraindications.

• Known hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• • Levoleucovorin disodium is not suitable for the treatment of pernicious anemia or other anemias due to vitamin B12 deficiency. Although hematological remissions may occur, neurological manifestations continue to progress.
• The combination of levoleucovorin disodium and fluorouracil is contraindicated in:
  • existing contraindications to the use of fluorouracil;
  • severe diarrhea.

Treatment with levoleucovorin disodium in combination with 5-fluorouracil should not be initiated or continued in patients who have symptoms of gastrointestinal toxicity of any degree of severity until these symptoms have completely resolved. Patients with diarrhea must be under close observation until diarrhea resolves, as rapid clinical deterioration may occur, potentially leading to fatal outcomes.

Interaction with other medicinal products and other forms of interaction.

Levoleucovorin disodium is an antidote to folic acid antagonists, such as methotrexate. Overdosing levoleucovorin disodium after methotrexate administration may result in loss of methotrexate therapeutic efficacy (so-called "rescue overdose").

If levoleucovorin disodium is administered concomitantly with a folic acid antagonist (e.g., co-trimoxazole, pyrimethamine), the efficacy of the folic acid antagonist may be reduced or completely neutralized.

Levoleucovorin disodium may reduce or completely neutralize the effect of folic acid antagonists (e.g., co-trimoxazole, pyrimethamine).

Concomitant administration of levoleucovorin disodium with 5-fluorouracil enhances the effect and toxicity of fluorouracil.

Life-threatening diarrhea has occurred when fluorouracil was administered at a dose of 600 mg/m² (intravenous bolus injection once weekly) in combination with levoleucovorin disodium. When levoleucovorin disodium is used in combination with fluorouracil, the dose of fluorouracil must be significantly lower than that used in fluorouracil monotherapy.

Levoleucovorin disodium may reduce the efficacy of antiepileptic drugs (phenobarbital, phenytoin, primidone, succinimides), potentially increasing the frequency of epileptic seizures (since folates are one of the cofactors enhancing hepatic metabolism, plasma levels of enzyme-inducing anticonvulsants may decrease).

Special precautions for use.

Dinatrium leucovorin should be administered intravenously only: either undiluted by injection or by infusion after dilution. Intrathecal administration is not recommended. Fatal outcomes have been reported following intrathecal administration of folic acid after intrathecal methotrexate overdose.

General

Treatment with dinatrium leucovorin in combination with methotrexate or 5-fluorouracil must be carried out under the supervision of an experienced oncologist.

Dinatrium leucovorin may mask the symptoms of pernicious anemia and other anemias caused by vitamin B12 deficiency.

Many cytotoxic agents, which are direct or indirect inhibitors of DNA synthesis, may cause macrocytosis (e.g., hydroxyurea, cytarabine, mercaptopurine, thioguanine). Such macrocytosis should not be treated with dinatrium leucovorin.

Patients with epilepsy

In patients with epilepsy receiving phenobarbital, phenytoin, primidone, or succinimides, seizure frequency may increase due to reduced plasma concentrations of antiepileptic drugs. Clinical monitoring, and possibly plasma concentration monitoring, is required, with dose adjustment of antiepileptic drugs as needed during and after dinatrium leucovorin therapy.

Use of dinatrium leucovorin in combination with 5-fluorouracil

When used in combination with 5-fluorouracil, dinatrium leucovorin may alter or enhance the toxicity of 5-fluorouracil, particularly in elderly or debilitated patients. The most common toxic effects are leukopenia, mucositis, stomatitis, and/or diarrhea. These adverse effects may be dose-limiting. When dose reductions are required due to toxicity during combination therapy with 5-fluorouracil and dinatrium leucovorin, the dose of 5-fluorouracil should be reduced more than during monotherapy with 5-fluorouracil.

Gastrointestinal toxicity is the most frequent and may be very severe, even life-threatening (particularly stomatitis and diarrhea). In severe cases, treatment with 5-fluorouracil and dinatrium leucovorin should be discontinued and symptomatic intravenous therapy initiated. Treatment with 5-fluorouracil in combination with dinatrium leucovorin should not be initiated or continued until gastrointestinal toxicity symptoms have completely resolved, regardless of severity.

Since diarrhea may be a sign of gastrointestinal toxicity, patients with diarrhea should be closely monitored until symptoms fully resolve, as rapid clinical deterioration may lead to fatal outcomes. If diarrhea and/or stomatitis occur, a reduction in the dose of 5-fluorouracil is recommended until symptoms have completely resolved. Particular caution is required when treating elderly patients and patients with poor performance status due to their disease, as they are more prone to toxicity. Therefore, special attention should be given to treatment of these patients.

All patients should be instructed to contact their physician immediately if stomatitis (formation of small or medium-sized ulcers) and/or diarrhea (watery stools or increased bowel motility occurring twice daily) develops.

Particular attention should be paid to treatment of elderly patients, debilitated patients, and patients previously treated with radiotherapy, as these patient groups have an increased risk of severe toxicity. Lower initial doses of 5-fluorouracil are recommended for such patients.

Use of dinatrium leucovorin in combination with methotrexate

Dinatrium leucovorin should not be administered simultaneously with antineoplastic agents that are folic acid antagonists (such as methotrexate) for the purpose of modifying or eliminating clinical signs of toxicity, as the therapeutic effect of the antagonists may be nullified, except in cases of overdose of folic acid antagonists.

Detailed information on methotrexate toxicity reduction can be found in the medical instructions for methotrexate.

Accidental overdose with folic acid antagonists, such as methotrexate, should be treated immediately as a medical emergency. The effectiveness of dinatrium leucovorin in reversing toxicity decreases as the time interval between methotrexate and dinatrium leucovorin administration increases. Monitoring of serum methotrexate concentrations is important for determining the optimal dose and duration of dinatrium leucovorin therapy. Delayed methotrexate excretion may be caused by fluid accumulation in the interstitium (ascites, pleuritis), renal impairment, inadequate hydration, or concomitant use of nonsteroidal anti-inflammatory drugs or salicylates. In such cases, higher doses or prolonged administration of dinatrium leucovorin may be indicated.

Dinatrium leucovorin 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). Patients with delayed methotrexate elimination are at higher risk of developing reversible renal failure and other methotrexate-related toxic effects early in treatment. Renal impairment (whether pre-existing or developing during methotrexate therapy) is potentially associated with delayed methotrexate excretion; therefore, higher doses or prolonged administration of dinatrium leucovorin may be necessary in such cases.

Excessive doses of dinatrium leucovorin should be avoided, as they may reduce the antitumor activity of methotrexate, particularly in central nervous system tumors where accumulation of dinatrium leucovorin may occur after multiple treatment cycles.

Resistance to methotrexate due to impaired membrane transport also leads to resistance to folic acid, since both substances are transported by the same transport system.

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

Excipients

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

There are no adequate and well-controlled clinical studies in pregnant or breastfeeding women. No official reproductive toxicity studies of dinatrium leucovorin have been conducted in animals.

There is no evidence that dinatrium leucovorin may have harmful effects when used during pregnancy.

Methotrexate should be administered during pregnancy only under strict indications, when the benefit of the drug to the mother must be weighed against the potential risk to the fetus.

If a patient is receiving methotrexate or other folic acid antagonists, there are no restrictions on the use of dinatrium leucovorin for prevention of adverse effects or neutralization of methotrexate toxicity.

The use of 5-fluorouracil during pregnancy or breastfeeding is contraindicated. The same applies to combination therapy with 5-fluorouracil and dinatrium leucovorin.

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

It is unknown whether dinatrium leucovorin passes into breast milk. Dinatrium leucovorin may be used during breastfeeding if clinically indicated.

However, methotrexate and 5-fluorouracil are known to pass into breast milk; therefore, both agents are contraindicated during breastfeeding. Women should discontinue breastfeeding before starting such therapy.

Fertility
There is no information available on the effect of folic acid itself on fertility and general reproductive function.

Ability to influence the reaction rate while driving or operating machinery.

Dinatrium leucovorin has no or negligible effect on the ability to drive or operate machinery. The patient's general condition will be more relevant than any effect caused by this medicinal product.

Administration and Dosage

Combination therapy with 5-fluorouracil

Combination therapy with sodium leucovorin and 5-fluorouracil should be prescribed by a physician experienced in combining folinate with 5-fluorouracil in cytotoxic therapy.

Various treatment regimens with different drug dosages are used; however, superiority of any particular regimen has not been established.

Below are described some treatment regimens for adults and elderly patients with advanced or metastatic colorectal cancer.

Bi-weekly regimen (treatment cycles repeated every two weeks)

Administer leucovoric acid at a dose of 100 mg/m² body surface area (equivalent to 109.3 mg/m² body surface area of dinatrium leucovorin) as a two-hour intravenous infusion, followed by
5-fluorouracil at a dose of 400 mg/m² body surface area as an intravenous bolus injection and 5-fluorouracil at a dose of 600 mg/m² body surface area as a 22-hour intravenous infusion on each of the next 2 days, repeated every 2 weeks on Day 1 and Day 2.

Weekly regimen

Leucovoric acid is administered at a dose of 10 mg/m² body surface area (equivalent to 10.93 mg/m² body surface area of dinatrium leucovorin) as an intravenous bolus injection, or at a dose of
100–250 mg/m² body surface area (equivalent to 109.3–273.25 mg/m² body surface area of dinatrium leucovorin) as a two-hour intravenous infusion; 5-fluorouracil at a dose of 500 mg/m² body surface area is administered as an intravenous bolus injection during or at the end of the dinatrium leucovorin infusion.

Monthly regimen:
For the first 5 days of the cycle, administer dinatrium leucovorin daily at a dose of 10 mg/m² body surface area (equivalent to 10.93 mg/m² body surface area of dinatrium leucovorin) as an intravenous bolus injection, or at a dose of 100–250 mg/m² body surface area (equivalent to 109.3–273.25 mg/m² body surface area of dinatrium leucovorin) as a two-hour intravenous infusion, followed immediately by 5-fluorouracil at a dose of 425 or 370 mg/m² body surface area as an intravenous bolus injection.

During combination therapy with 5-fluorouracil and dinatrium leucovorin, dose adjustments of 5-fluorouracil and intervals between administrations may be necessary depending on the patient's condition, clinical response to therapy, and dose-limiting toxic effects. Appropriate recommendations are provided in the medical instructions for 5-fluorouracil. Dose reduction of dinatrium leucovorin is not required.

The required number of treatment cycles is determined by the physician.

Children

Data on the use of this combination in children are lacking.

Dinatrium leucovorin as rescue therapy in methotrexate treatment

Since the treatment regimen with dinatrium leucovorin largely depends on the doses and protocols of intermediate- or high-dose methotrexate therapy, it is advisable to refer to the methotrexate treatment protocol, which will dictate the dosing schedule for dinatrium leucovorin. Therefore, it is best to consult the applicable intermediate- or high-dose methotrexate protocol for guidance on dosing and administration of dinatrium leucovorin.

Below are general recommendations for the use of dinatrium leucovorin in adults, elderly patients, and children.

Dinatrium leucovorin should be administered parenterally to patients with malabsorption syndrome or other gastrointestinal disorders where intestinal absorption of the drug cannot be assured.

Leucovoric acid doses exceeding 12.5–25 mg should be administered parenterally due to saturation effects in gastrointestinal absorption of dinatrium leucovorin.

Rescue with dinatrium leucovorin 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 dosage and duration of dinatrium leucovorin therapy should be determined primarily based on the methotrexate dose and regimen, presence of signs of toxicity, and individual parameters of methotrexate excretion. Typically, leucovoric acid should be administered at a dose of 7.5 mg (3–6 mg/m² body surface area) 12–24 hours (no later than 24 hours) after the start of methotrexate infusion. Subsequently, the same doses of dinatrium leucovorin should be administered every 6 hours for 72 hours. After several parenteral doses, transition to oral administration may be considered.

In addition to dinatrium leucovorin therapy, measures to accelerate methotrexate excretion are necessary.

These measures include:

• Alkalinization of urine with pH increased above 7.0 prior to methotrexate infusion (to increase solubility of methotrexate and its metabolites).
• Maintenance of diuresis at 1800–2000 cm³/m²/24 hours by increasing intravenous or intravenous fluid administration on Day 2, 3, and 4 after methotrexate therapy.
• Plasma methotrexate concentration, blood urea nitrogen, and creatinine levels should be monitored on Day 2, 3, and 4.

These measures should be continued until the plasma methotrexate level falls below
10⁻⁷ mol (0.1 μmol).

In some patients, delayed methotrexate elimination may occur. This may be due to third-space accumulation (e.g., ascites or pleural effusion), renal impairment, or inadequate hydration. Under such circumstances, higher doses or prolonged administration of dinatrium leucovorin may be indicated. Patients with delayed early methotrexate elimination are at risk of developing reversible renal impairment.

Residual methotrexate concentration in blood should be measured 48 hours after the start of methotrexate infusion. If methotrexate concentration exceeds
0.5 μmol/L, the dose of dinatrium leucovorin should be adjusted according to the table:

Residual concentration of methotrexate in blood 48 hours after initiation of methotrexate infusion	Dose of leucovorin acid administered every 6 hours for 48 hours or until methotrexate levels decrease below 0.05 µmol/L
≥ 0.5 µmol/L	7.5 mg/m² body surface area
≥ 1.0 µmol/L	50 mg/m² body surface area
≥ 2.0 µmol/L	100 mg/m² body surface area

Rescue therapy should be continued and intensified. Dinatrium leucovorin should be administered at the doses indicated below every 6 hours for another 48 hours or until methotrexate concentration reaches < 0.05 µmol/L:

• at methotrexate concentration ≥ 0.5 µmol/L – at a dose of 15 mg/m² body surface area;
• at methotrexate concentration ≥ 1.0 µmol/L – at a dose of 100 mg/m² body surface area;
• at methotrexate concentration ≥ 2.0 µmol/L – at a dose of 200 mg/m² body surface area.

In addition to therapy with dinatrium leucovorin, measures to accelerate methotrexate excretion (maintaining high diuresis, urine alkalinization) should be taken, and serum creatinine levels should be determined daily to monitor renal function.

Administration method

Dinatrium leucovorin should be administered intravenously: either undiluted by injection or diluted for infusion. Dinatrium leucovorin must not be administered intrathecally.

Children.

Dinatrium leucovorin may be used in children of all age groups as a rescue agent to prevent methotrexate toxicity, as well as an antidote in cases of methotrexate overdose and intoxication with other folic acid antagonists.

Overdose.

When dinatrium leucovorin is administered in doses significantly higher than recommended, no adverse effects have been reported.

In methotrexate treatment, overdose of dinatrium leucovorin may lead to reduced therapeutic effect of methotrexate.

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

Side effects.

Side effects when used for all indications

From the nervous system

Rare: Increased frequency of epileptic seizures.

From the gastrointestinal tract

Rare: Gastrointestinal disorders when high doses of sodium leucovorin are used.

General and local reactions

Uncommon: Fever has been observed after administration of sodium leucovorin as an injection solution.

From the immune system

Very rare: Allergic reactions, including urticaria, anaphylactoid/anaphylactic reactions.

Psychiatric disorders

Rare: Insomnia, agitation, and depression when high doses of sodium leucovorin are used.

Side effects during combination therapy with 5-fluorouracil

Overall safety profile depends on the 5-fluorouracil treatment regimen, as combined use enhances the toxicity of 5-fluorouracil.

From the blood and lymphatic system

Very common: Bone marrow suppression, including fatal cases.

Metabolism and nutrition disorders

Unknown: Hyperammonemia.

From the skin and subcutaneous tissues

Common: Hand-foot syndrome (palmar-plantar erythrodysesthesia).

General and local reactions

Very common: Mucositis, including stomatitis and cheilitis. Fatal cases have been reported due to mucositis.

Side effects with a monthly drug administration regimen

From the gastrointestinal tract

Very common: Nausea and vomiting.

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

Side effects with a weekly drug administration regimen

From the gastrointestinal tract

Very common: Diarrhea with higher grades of toxicity and dehydration requiring hospitalization; in isolated cases, even with fatal outcome.

Shelf life. 3 years.

After mixing with fluorouracil solution or dilution with 0.9% sodium chloride solution or 5% glucose solution, chemical and physical stability is maintained for 72 hours at 20–25 °C.

From a microbiological standpoint, the solution should be used immediately. If not used immediately, the user is responsible for the storage duration and conditions, which should not exceed 24 hours at 2–8 °C, unless dilution was performed under controlled and validated aseptic conditions.

Storage conditions.

Store in a refrigerator at 2–8 °C. Keep the vial in its cardboard packaging to protect from exposure to sunlight.

Incompatibility.

Do not mix with other solutions. For dilution, use only the solutions specified in the section "Administration and dosage."

Packaging. 1 ml, 4 ml, 9 ml in colorless glass vials (type I), closed with bromobutyl rubber stoppers and aluminum caps № 1 and № 5, packed in cardboard boxes.

Prescription status. Prescription only.

Manufacturer.

Medac Gesellschaft für klinische Spezialpräparate mbH.

Manufacturer's address and location of operations.

Theaterstraße 6, 22880 Wedel, Germany.