Vero-Fludarabine lyophilisate, 50mg vial 1pc

Composition

Active ingredient:

fludarabine phosphate 50 mg.

Auxiliary substances:

mannitol;

phosphate buffer solution

Pharmacological action

Vero-Fludarabine contains fludarabine phosphate, a fluorinated nucleotide analog of the antiviral agent vidarabine-9-beta-D-arabinofuranosyladenine (ara-A), which is relatively resistant to deamination by adenosine deaminase.

In humans, fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A, which is captured by cells and then intracellularly phosphorylated to active triphosphate (2-fluoro-ara-ATP).

This metabolite inhibits RNA reductase, DNA polymerase (alpha-, delta -, and upsilon -), DNA primase, and DNA ligase, which leads to impaired DNA synthesis. In addition, RNA polymerase II is partially inhibited, followed by a decrease in protein synthesis.

Pharmacokinetics

There was no clear correlation between the pharmacokinetics of fludarabine and its therapeutic effect in cancer patients, and the frequency of detection of neutropenia and changes in hematocrit is dose-dependent. Fludarabine phosphate (2-fluoro-ara-AMP) is a water-soluble precursor of fludarabine (2-fluoro-ara-A) and is rapidly and completely dephosphorylated to the nucleoside 2-fluoro-ara-A.

The association with plasma proteins is insignificant. After a single infusion in patients with chronic lymphocytic leukemia (CLL) of a standard dose of the drug for 30 minutes, Cmax of 2-fluoro-ara-A in plasma, equal to 3.5–3.7 microns, is reached by the end of the infusion. After 5 injections of the drug, a moderate increase in Cmax is detected to 4.4–4.8 microns by the time the infusion ends.

Accumulation of 2-fluoro-ara-A after several cycles of therapy can be excluded. After the end of the infusion, there is a three-phase decrease in the concentration with T1/2 of the initial phase of about 5 minutes, intermediate — 1-2 hours and terminal-about 20 hours. 2-fluoro-ara-A is excreted mainly by the kidneys (from 40 to 60% of the administered intravenous dose).

In individuals with reduced renal function, there is a decrease in total clearance, which indicates the need to reduce the dose. 2-fluoro-ara-A is actively transported to leukemic cells, after which it is refosphorylated to monophosphate and partially to di – and triphosphate.

Triphosphate (2-fluoro-ara-ATP) is the main intracellular metabolite and the only known metabolite with cytotoxic activity.

The maximum level of 2-fluoro-ara-ATP in leukemic lymphocytes of patients with CLL is observed on average by 4 hours and is characterized by significant individual variability.

The concentration of 2-fluoro-ara-ATP in leukemic cells is significantly higher than in plasma, which indicates its accumulation in tumor cells. T1/2 2-fluoro-ara-ATP from target cells is on average from 15 to 23 hours.

Indications

Low-grade non-Hodgkin’s lymphoma (NHL NC);

b-cell lymphocytic leukemia (CLL).

Contraindications

-reduced renal function with creatinine clearance<30 ml / min—

– decompensated hemolytic anemia

— – pregnancy;

– breast-feeding period;

– hypersensitivity to fludarabine or other components of the drug.

The drug should be used with caution after careful assessment of the risk / benefit ratio in patients in a weakened state, with a pronounced decrease in bone marrow function (thrombocytopenia, anemia, and/or granulocytopenia), immunodeficiency, acute viral, fungal or bacterial infection, liver failure (the effectiveness and safety of fludarabine has not been studied), in children and patients over 75 years of age (due to insufficient clinical data on the use of fludarabine).

Side effects

Hematopoietic disorders: very common – neutropenia, thrombocytopenia and anemia; often-myelosuppression.

Immune system disorders: infrequently-autoimmune disorders (including autoimmune hemolytic anemia, thrombocytopenic purpura, pemphigus, Evans syndrome, acquired hemophilia), allergic reactions.

From the digestive system: very often-nausea, vomiting, diarrhea; often-anorexia, stomatitis, mucositis; infrequently-gastrointestinal bleeding, changes in the activity of liver and pancreatic enzymes.

From the side of metabolism: infrequently-as a result of tumor lysis, hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria may develop.

From the nervous system: often-peripheral neuropathy; infrequently-confusion; rarely-agitation, convulsions, coma.

From the side of the visual organ: often-visual disturbances; rarely-optic neuritis, optic neuropathy and blindness.

From the respiratory system: very often – cough; infrequently-shortness of breath, pulmonary fibrosis, pneumonitis.

From the cardiovascular system: rarely-heart failure, arrhythmias.

From the urinary system: rarely-hemorrhagic cystitis.

From the skin and skin appendages: often-skin rash; rarely-Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome).

Rare cases of increased growth of existing skin cancer, as well as skin cancer development, have been reported during or after fludarabine treatment. Other: very often-fever, fatigue, weakness, secondary infections; often-chills, malaise, peripheral edema; rarely-lymphoproliferative disorders (associated with the Epstein-Barr virus).

Myelodysplastic syndrome (MDS)has rarely occurred in patients treated with fludarabine before, after, or simultaneously with alkylating cytotoxic agents or radiotherapy/acute myeloid leukemia (AML).

Interaction

The use of fludarabine in combination with pentostatin (deoxycoformicin) for the treatment of CLL often resulted in death due to high pulmonary toxicity.

The therapeutic efficacy of fludarabine may be reduced by adenosine reuptake inhibitors and dipyridamole. Pharmacokinetic interactions were observed in patients with CLL and AML treated with a combination of fludarabine and cytarabine.

When cytarabine is co-administered with fludarabine, higher intracellular peak concentrations and intracellular AUC of the cytarabine metabolite arabinosyl cytosine triphosphate are shown.

Plasma concentrations of cytarabine and the excretion of arabinosyl cytosine triphosphate did not change. Fludarabine solution for intravenous use should not be mixed with other drugs.

How to take, course of use and dosage

Only intravenous use of fludarabine is allowed, and accidental extravascular ingestion should be avoided.

Adults The recommended dose of fludarabine phosphate is 25 mg / m2 of body surface area IV once a day for 5 days every 28 days.

The required dose (calculated in accordance with the patient’s body surface area) is collected in a syringe.

For intravenous injection of the drug, the above dose is diluted in 10 ml of 0.9% sodium chloride solution, and the required dose can also be diluted in 100 ml of 0.9% sodium chloride solution and administered dropwise for 30 minutes.

There are no clear data on the optimal duration of treatment.

The course of treatment depends on the observed effect and tolerability of the drug.

Treatment with fludarabine is recommended until a therapeutic response is achieved (usually 6 cycles), after which the drug is discontinued.

Overdose

When using high doses of fludarabine, irreversible changes in the central nervous system, vision loss, coma and death may occur, as well as the development of severe thrombocytopenia and neutropenia due to suppression of bone marrow function.

In case of threatening symptoms, the drug should be discontinued immediately and maintenance therapy should be performed.

The specific antidote is not known.

Form of production

Concentrate for preparing a solution for intravenous use

Storage conditions

At a temperature of 2 to 8 °C in a place protected from light. Do not freeze it. Keep out of reach of children.

Shelf

life is 3 years.

Active ingredient

Fludarabine

Conditions of release from pharmacies

By prescription

Dosage form

solution for infusions

Purpose

For adults as directed by your doctor

Indications

Cancer