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Composition:


active ingredient: fludarabine phosphate;


1 bottle contains fludarabine phosphate 50 mg;


excipient: mannitol (E 421).


Dosage form. Powder for preparing a solution for injection or infusion.


Basic physical and chemical properties: lyophilized powder of white or almost white color.


Pharmacotherapeutic group. Antitumor drugs. Structural analogues of purine. Fludarabine. ATX code L01B B05.


Pharmacological properties.


Pharmacodynamics.


Fludarabine Vista contains fludarabine phosphate, a water-soluble fluorinated nucleotide analog of the antiviral agent vidarabine, 9-β-D-arabinofuranosyladenin (Ara-A), which is relatively resistant to deamination by adenosine deaminase.


Fludarabine phosphate is rapidly dephosphorylated to 2p-Ara-A, which is absorbed by cells and then phosphorylated inside cells by deoxycytidine kinase to the active triphosphate, 2p-Ara-ATP. This metabolite has been shown to inhibit ribonucleotide reductase, DNA polymerase, α -, δ-and ε - DNA primase, and DNA ligase, thus inhibiting DNA synthesis. In addition, there is a partial inhibition of RNA polymerase II and, as a result, a decrease in protein synthesis.


Although some aspects of the mechanism of action of 2P-Ara-ATP are still unclear, it is believed that the action on DNA, RNA and protein synthesis contributes to the inhibition of cell growth and inhibition of DNA synthesis is the dominant factor in this process. In addition, in vitro studies have shown that the action of 2F-Ara-a on CLL lymphocytes causes large-scale DNA fragmentation and increases the proportion of cells that die due to apoptosis.


In the 3rd phase of the study, which was conducted with patients with previously untreated B-Cell Chronic Lymphocytic Leukemia, which compared treatment with fludarabine with treatment with chlorambucil (40 mg/m2 every 4 weeks) in 195 and 199 patients, respectively, the following result was obtained: statistically significantly higher overall response to treatment (effectiveness of therapy) and the rate of complete response to treatment after first-line therapy with fludarabine compared with treatment with chlorambucil (61.1% vs 37.6% and 14.9% vs 3.4% respectively); statistically significantly longer response time to treatment (19 vs 12.2 months).) and time to disease progression (17 vs. 13.2 months.) in patients from the group where fludarabine was treated. The median survival of patients in both groups was 56.1 months for the fludarabine group and 55.1 months for the chlorambucil Group; a small difference was also demonstrated in relation to the overall condition of patients. The percentage of patients who developed toxic reactions was comparable to that of patients treated with fludarabine (89.7%) and patients treated with chlorambucil (89.9 %). While the difference in the total percentage of hematological toxicity was not significant between the two groups, a significantly higher percentage of patients treated with fludarabine experienced white blood cell (p=0.0054) and lymphocyte (p=0.0240) toxicity compared to patients in the chlorambucil group. The percentage of patients who experienced adverse reactions such as nausea, vomiting, and diarrhea was significantly lower in the fludarabine group (p, 0001, p, 0001,and p=0.0489, respectively) than in the chlorambucil group. A significantly lower percentage of toxic liver damage (p=0.0487) was also reported in patients in the fludarabine group compared to the chlorambucil group.


Patients who initially responded well to fludarabine treatment are likely to respond well to fludarabine monotherapy in the future.


In a randomized trial of fludarabine compared to cyclophosphamide, Adriamycin and prednisone (DAC) involving 208 patients with CLL (chronic lymphocytic leukemia) in Stage B or C according to Binet in a subgroup of 103 patients who were previously treated, the following results were obtained: the overall response to treatment (effectiveness of therapy) and the complete response to treatment was higher when using fludarabine compared to DAC (45% vs 26% and 13% vs 6%, respectively); the duration of response to treatment and overall survival were similar with fludarabine and DAC. Within the predicted treatment period of 6 months, the number of deaths was 9 (fludarabine) vs. 4 (DAC).


According to the analysis of the results obtained (post-hoc), which used only data for 6 months after the start of treatment, a difference was found between the survival curves in the group with fludarabine and the group with DAC in favor of the group with DAC − in the subgroup of patients with Stage C according to Binet who had previously received treatment.


Pharmacokinetics.


Pharmacokinetic parameters of fludarabine (2f-Ara-A) in plasma and urine


The pharmacokinetics of fludarabine (2f-Ara-A) were studied after intravenous administration by rapid bolus injection, short-term infusion and subsequent continuous infusion, as well as after oral administration of fludarabine phosphate (fludarabine, 2f-Ara-amp).


No clear correlation has been established between the pharmacokinetics of 2F-Ara-A and the effectiveness of treatment in cancer patients.


However, the development of neutropenia and changes in hematocrit indicate dose-dependent inhibition of hematopoiesis due to the cytotoxicity of fludarabine phosphate.


Distribution and metabolism


2F-Ara-AMP is a water-soluble prodrug of fludarabine (2f-Ara-A), which is rapidly and quantitatively dephosphorylated in the human body to the nucleoside fludarabine (2f-Ara-a).


Another metabolite, 2f-Ara-hypoxanthine, which is the main metabolite of the substance in dogs, was observed in humans only in small amounts.


After the infusion of a single dose of 2F-Ara-AMP, which was 25 mg/m2 in patients with CLL, for 30 minutes, the average value of the maximum concentration of 2F-Ara-a in plasma was 3.5-3.7 microns at the end of the infusion. The corresponding levels of 2F-Ara-A after the fifth dose showed moderate accumulation with an average maximum level of 4.4-4.8 µm at the end of the infusion. During five-day treatment, the lowest plasma levels of 2F-Ara-A are approximately doubled. Accumulation of 2F-Ara-A does not occur after several treatment cycles. Post-maximum levels decrease during three pharmacokinetic phases with an initial half – life of approximately 5 minutes, an intermediate half – life of 1-2 hours, and a final half-life of approximately 20 hours.


Comparison of the pharmacokinetic data of 2F-Ara-a obtained during various studies made it possible to determine the average rate of total plasma clearance, which is 79±40 mL/min/M2 (2.2±1.2 mL/min/kg) and the average volume of distribution, which is 83±55 L/m2 (2.4±1.6 l/kg).


The data show high individual variability. After intravenous and oral administration of fludarabine phosphate, plasma 2f-Ara-A levels and the area under the pharmacokinetic curve of plasma time dependence (AVC) increase linearly with the dose, while the Half-Life, plasma clearance, and volume of distribution remain constant regardless of the dose, which indicates the linear nature of the dose dependence.


After oral administration of fludarabine phosphate, the maximum plasma level of 2F-Ara-a increases by approximately 20-30% from the corresponding intravenous level at the end of the infusion and persists for 1-2 hours after administration. The average systemic availability of 2F-Ara-a ranges from 50% to 60% after single and repeated doses and is similar after the use of an immediate-release solution or tablet. After oral administration of 2F-Ara-amp during food intake, there was a slight increase (max) and a delay in reaching Cmax; the final half-life did not change.


Elimination from the body


Elimination of 2F-Ara-a from the body occurs mainly by renal excretion.


40-60% of the intravenous dose is excreted in the urine. The results of studies of the mass ratio in laboratory animals using 3H-2f-Ara-amp indicate complete elimination of radioactively labeled substances in the urine.


Features in some patients


In individuals with impaired renal function, total clearance in the body is reduced, which indicates the need to reduce the dose. The results of studies of human plasma proteins in vitro did not reveal a clear trend of Binding of 2F-Ara-a to proteins.

Pharmacokinetic parameters of fludarabine triphosphate in the cell


2F-Ara – A is actively transported to leukemia cells, where it is refosphorylated to monophosphate, and then to DI - and triphosphate. Triphosphate 2p-Ara-ATP is the main intracellular metabolite and the only metabolite known to have cytotoxic activity. The maximum level of 2F-Ara-ATP in the leukemic lymphocytes of CLL patients was observed on average after 4 hours and significantly differed at an average peak concentration of approximately 20 microns. The level of 2F-Ara-ATP in leukemia cells was always significantly higher than the maximum level of 2F-Ara-a in plasma, which indicates accumulation at Target sites. When incubating leukemic lymphocytes in vitro, a linear relationship was observed between the extracellular action of 2F-Ara-a (due to the concentration of 2F-Ara-A and the duration of incubation) and intracellular enrichment of 2F-Ara-ATP. Elimination of 2p-Ara-ATP from target cells occurs with an average Half-Life of 15 and 23 hours.


Preclinical safety data


Systemic toxicity


When conducting acute toxicity studies, the use of single doses of fludarabine phosphate, which were twice the therapeutic dose, led to the appearance of symptoms of severe intoxication or death. As expected with the use of a cytotoxic compound, the use of this drug negatively affects the bone marrow, lymphoid organs, gastrointestinal mucosa, kidneys and sex glands of men. Severe adverse reactions in patients were observed when using a dose approaching the recommended therapeutic dose (factor 3-4) and included severe neurotoxicity, in some cases fatal (see the section "overdose").


Studies of systemic toxicity after repeated administration of fludarabine phosphate also demonstrated the expected reactions with rapid tissue proliferation when using a dose exceeding the threshold dose. The severity of morphological manifestations increased with increasing dose and duration of Use, and the observed changes were generally considered reversible. Experience with the therapeutic use of fludarabine indicates a similar toxicological profile in humans, although they have experienced additional adverse reactions, such as neurotoxicity (see the section "adverse reactions").


Embryotoxicity


The results of studies of embryotoxicity with intravenous administration to animals showed the embryoletal and teratogenic effects of fludarabine phosphate, which was manifested in skeletal malformations, fetal weight loss and post-implantation death of the embryo (miscarriage). In view of the small safety margin between teratogenic doses in animals and therapeutic doses in humans, and in accordance with the analogy with other antimetabolites that are thought to interfere with the differentiation process, the Therapeutic Use of fludarabine Vista is associated with a significant risk of teratogenic effects in humans (see below). (see the section "use during pregnancy or lactation").


Genotoxic effect, oncogenicity


Fludarabine phosphate was found to cause DNA damage during sister chromatic exchange studies, cause chromosomal aberrations during in vitro cytogenetic studies, and lead to an increase in the number of micronuclei in an in vivo micronuclei test in mice. The mutagenic effect of fludarabine phosphate was not detected in gene mutation studies, as well as in the test of dominant lethality in male mice. Thus, the mutagenic effect was demonstrated in somatic cells, but not detected in germ cells.


The activity of fludarabine phosphate at the DNA level is known, and the results of mutagenicity studies underlie the suspicion of oncogenicity of the drug. No animal studies that would be directly aimed at determining the oncogenicity of the drug have been conducted, since the suspicion of a greater risk of other tumors due to fludarabine phosphate therapy can be verified (verified) exclusively with the help of epidemiological data.


Local portability


According to the results obtained in animal studies with intravenous administration of fludarabine phosphate, no significant irritation at the injection site is expected. Even in the case of inappropriate administration, no relevant local irritations were observed after paravenous, intra-arterial, or intramuscular administration of an aqueous solution containing 7.5 mg of fludarabine phosphate/ML.


The similarity of the nature of lesions observed in the gastrointestinal tract after intravenous or intragastric administration in animal studies supports the assumption that fludarabine phosphate-induced enteritis is a systemic effect.


Clinical characteristics.


Indications.


Treatment of B-Cell Chronic Lymphocytic Leukemia (CLL) in patients with sufficient bone marrow Reserve.


First-line therapy with fludarabine should only be performed in patients with advanced disease, stage III/IV according to Raya (stage C according to Binet) or stage I/II according to Raya (stage a/B according to Binet), in which the patient has symptoms associated with the disease or signs of progressive disease.


Contraindications.


Hypersensitivity to the active substance or to any of the components of the drug.


Renal failure with creatinine clearance


Decompensated hemolytic anemia.


Breast-feeding period.


Special security measures.


Fludarabine should only be used in departments that specialize in the use of potentially toxic cancer drugs, under the supervision of a qualified doctor who has experience in chemotherapy in the treatment of cancer.


Handling this potentially toxic substance requires medical personnel to take all precautions to ensure that the employee and their environment are protected.


Preparation of solutions of potentially toxic substances should be carried out by an experienced specialist who is familiar with the use of these medicines, in compliance with conditions that guarantee environmental protection and, above all, the personnel working with these medicines. It is necessary to have a specially designated place for performing preparatory operations, where it is forbidden to smoke, eat or drink.


Personnel should be provided with appropriate protective equipment, such as sterile disposable gloves, containers and waste collection bags.


Pregnant health workers should not work with fludarabine.


Special care should be taken in contact with the patient's excrement and vomit.


Pregnant women should be warned about the need to avoid working with the drug.


Any damaged packaging must be handled in compliance with these warnings and treated as contaminated waste.


If fludarabine comes into contact with the prepared solution for infusions or injections on the skin or mucous membranes, immediately thoroughly wash the affected area with soap and water. In case of contact with eyes, rinse thoroughly with plenty of water. Inhalation of fludarabine should be avoided.


Recycling


The medicinal product is intended for single use only.


Any residues of the drug and all items that were used to dissolve and administer fludarabine must be disposed of in accordance with the standard procedure for the disposal of potentially toxic waste, in accordance with the current regulations for the disposal of toxic waste.


Interactions with other drugs and other types of interactions.


In clinical trials, an unacceptably high percentage of fatal pulmonary toxicity was observed when fludarabine was used together with pentostatin (deoxycoformicin) for the treatment of chronic lymphocytic leukemia (CLL). In view of this, it is not recommended to use fludarabine in combination with pentostatin.


The therapeutic efficacy of fludarabine may decrease with the use of Dipyridamole and other adenosine uptake inhibitors.


The results of clinical studies and in vitro experiments have shown that the use of fludarabine in combination with cytarabine can increase the intracellular concentration and intracellular exposure of Ara-CTP (the active metabolite of cytarabine) in leukemia cells. There was no effect on the plasma concentration of Ara-C and the rate of elimination of Ara-PP.

Application features.


Myelosuppression


Severe myelosuppression, especially anemia, thrombocytopenia, and neutropenia, has been reported in patients treated with fludarabine. In the Phase 1 study of intravenous administration of the drug to adult patients with solid tumors, the average time to reach the lowest number of granulocytes was 13 days (in the range from 3 to 25 days), platelets – 16 days (in the range from 2 to 32 days). Most patients had hematological abnormalities at the beginning of treatment, as a result of a disease or as a result of previous treatment that caused myelosuppression.


Cumulative myelosuppression may occur. Although chemotherapy-induced myelosuppression is often reversible, the use of fludarabine phosphate requires careful monitoring of hematological parameters.


Fludarabine phosphate is a powerful antitumor agent with possible severe toxic adverse reactions. Patients treated with fludarabine should be carefully examined for signs of hematological and non-hematological toxicity.


To detect the development of anemia, neutropenia and thrombocytopenia, it is recommended to periodically perform a general analysis of peripheral blood.


Several cases of bone marrow hypoplasia or aplasia have been reported in adult patients, causing pancytopenia, which is sometimes fatal. The duration of clinically significant episodes of cytopenia in the reported cases ranged from 2 months to 1 year. Such episodes were observed in both patients who had previously received treatment and those who had not previously received treatment.


As with other cytotoxic drugs, the issue of further sampling of hematopoietic stem cells should be carefully considered.


Autoimmune phenomena


Regardless of any history of autoimmune processes or the outcome of the Coombs reaction, life-threatening, sometimes fatal autoimmune events have been reported during or after treatment with fludarabine. In most patients who developed hemolytic anemia, a relapse of the hemolytic process was observed after a provocative test with fludarabine.


If hemolysis is detected, it is recommended to discontinue treatment with fludarabine. The most common treatment for autoimmune hemolytic anemia is blood transfusions (irradiated, see below) and the use of adrenocorticoid drugs. 


Neurotoxicity


The effect of long-term use of fludarabine on the central nervous system is unknown. However, in some studies, patients maintained the recommended dose for relatively long treatment periods (up to 26 courses of therapy).


Patients should be carefully examined for signs of neurological effects.


When using high doses during studies with different doses in patients with acute leukemia, intravenous administration of fludarabine was accompanied by serious neurological effects, including blindness, coma, and death. Symptoms appeared 21-60 days after the last dose was administered. Such severe toxic damage to the central nervous system occurred in 36% of patients who received intravenous doses approximately four times higher than the dose (96 mg/m2/day for 5-7 days) recommended for CLL. In patients who were given the recommended doses of CLL, severe toxic lesions of the central nervous system were rare (coma, convulsions, and agitation) or infrequent (confusion).


Post-marketing experience with fludarabine indicates cases of neurotoxicity that occurred earlier or later compared to cases reported during clinical trials.


Administration of fludarabine may be associated with the occurrence of leukoencephalopathy, acute toxic leukoencephalopathy, or reversible posterior leukoencephalopathy syndrome.


This can happen:


- if the recommended dose is observed:


* when fludarabine is administered after or in combination with drugs that are known to be associated with the occurrence of leukoencephalopathy, acute toxic leukoencephalopathy, or reversible posterior leukoencephalopathy syndrome;


* when fludarabine is administered to patients with other risk factors, such as radiation exposure to the skull or body as a whole, hematopoietic cell transplantation, graft-versus-host disease, kidney failure, or hepatic encephalopathy;


- at doses higher than the recommended dose.


Symptoms of leukoencephalopathy, acute toxic leukoencephalopathy, or reversible posterior leukoencephalopathy syndrome may include headache, nausea and vomiting, seizures, and visual disturbances (vision loss, altered light perception, and neurological disorders). Additional effects include optic neuritis, confusion, drowsiness, agitation, paraparesis, muscle spasticity, and urinary incontinence.


Leukoencephalopathy, acute toxic leukoencephalopathy, or reversible posterior leukoencephalopathy syndrome can be irreversible, life-threatening, or fatal. If these diseases are suspected, treatment with fludarabine should be discontinued.


Patients should be monitored by brain scans, preferably using MRI. If the diagnosis is confirmed, fludarabine therapy should be discontinued.


Tumor lysis syndrome


Tumor lysis syndrome has been reported in CLL patients with large tumor mass. Since the use of fludarabine can cause such a reaction as early as the first week of treatment, it is necessary to take precautions when treating patients at risk of developing this complication, and during the first course of treatment, such patients can be recommended hospitalization.


Graft-versus-host reaction»


The graft-versus-host reaction (the reaction of transfused immunocompetent lymphocytes to the host's body) was observed after transfusion of unirradiated blood to patients treated with fludarabine. A fatal outcome of this reaction has often been reported. Therefore, in order to minimize the risk of developing a graft-versus-host reaction, patients who require blood transfusions and are undergoing or have been treated with fludarabine should only receive irradiated blood transfusions.


Skin cancer


Increased or sudden exacerbation of pre-existing skin cancers has been reported, as well as newly detected skin cancer in some patients during or after treatment with fludarabine.


Weakened state of Health


Patients with impaired health should be prescribed fludarabine with caution and after careful assessment of the risk/benefit ratio. This is especially true in patients with severe bone marrow disorders (thrombocytopenia, anemia, and/or granulocytopenia), immunodeficiency, or a history of opportunistic infection.


Impaired renal function


Total clearance of the main plasma metabolite 2-F-Ara-A from the body correlates with creatinine clearance, which indicates the importance of the renal excretion pathway for the elimination of this compound. Patients with reduced renal function had a greater overall effect on the body (AUC 2f-Ara-a). There are limited clinical data available for patients with impaired renal function (creatinine clearance


Patients with renal insufficiency should use fludarabine with caution. In patients with moderate renal insufficiency (creatinine clearance is in the range of 30-70 mL/min), the dose of the drug should be reduced to 50% and the patient's condition should be carefully monitored. Treatment with fludarabine is contraindicated if creatinine clearance is


Elderly patients


Since data on the use of fludarabine in elderly patients (> 75 years) are limited, the drug should be used with caution in this category of patients.


In patients over 65 years of age, creatinine clearance should be measured before starting treatment (see Section "dosage and administration", subsection "patients with impaired renal function").

Dosage and administration.


Adults.


The recommended dose is 25 mg of fludarabine phosphate per 1 m2 of body surface area and is administered intravenously daily for 5 consecutive days every 28 days. The contents of 1 bottle are dissolved in 2 ml of water for injection. 1 ml of the resulting solution contains 25 mg of fludarabine phosphate.


The required dose of the solution (calculated in accordance with the patient's body surface area) is collected in a syringe. For intravenous bolus administration, this dose is then diluted in 10 ml of 0.9% sodium chloride solution.


Alternatively, the required infusion dose collected in a syringe is diluted in 100 ml of 0.9% sodium chloride solution and administered for approximately 30 minutes.


The duration of treatment depends on the tolerability of the drug and the effectiveness of treatment.


In patients with CLL, fludarabine Vista should be used until the maximum response to treatment is achieved (complete or partial remission, which is usually achieved after 6 courses), after which the drug should be discontinued.


Special patient groups


Patients with impaired renal function


When using fludarabine in patients with renal insufficiency, the dose of the drug should be adjusted. If creatinine clearance is in the range of 30-70 mL/min, the dose of the drug should be reduced to 50 %, and to assess toxicity, it is necessary to carefully monitor hematological parameters (see the section "application features").


Treatment with fludarabine is contraindicated if the creatinine clearance is 30 mL/min (see the section "contraindications").


Patients with impaired liver function


There are no data on the use of fludarabine in patients with impaired liver function, so the drug should be used with caution in this group of patients.


Elderly patients


Since data on the use of fludarabine in elderly patients (> 75 years) are limited, the drug should be used with caution in this category of patients.


Creatinine clearance should be determined in patients over 65 years of age (see the section "application features", subsection "patients with impaired renal function").


Method of application


Prescribe fludarabine should be a qualified doctor who has experience in antitumor therapy.


It is strongly recommended to use fludarabine Vista only intravenously.


No cases have been reported that would lead to severe local adverse reactions when using fludarabine paravenically. However, it is necessary to prevent accidental paravenous administration of the drug.


Dissolution


To prepare a solution of fludarabine-Vista for parenteral use, 2 ml of sterile water for injection is added to the bottle, following the rules of asepsis. The contents of the bottle should completely dissolve within 1 minute. 1 ml of the resulting solution contains 25 mg of fludarabine phosphate, 25 mg of mannitol and sodium hydroxide (to adjust the PH). The pH value of the finished solution is from 7.2 to 8.2.


Breeding


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


For intravenous bolus administration, this dose is then diluted in 10 ml of 0.9% sodium chloride solution. Alternatively, for infusion, the required dose can be diluted in 100 ml of 0.9% sodium chloride solution and administered for about 30 minutes.


In clinical trials, the drug was diluted in 100 ml or 125 ml of 5% dextrose solution or 0.9% sodium chloride solution.


Pre-application verification


Just like other drugs for parenteral administration, the resulting solution should be visually examined before use. The solution should be transparent and colorless, without visible mechanical inclusions. A solution that does not meet the specified requirements or in which sediment is detected must be destroyed.


Do not use the drug if it was stored in a damaged container.


Children.


The safety and efficacy of fludarabine in children have not been established, so the drug should not be prescribed to this category of patients.


Overdose.


The use of high doses of the drug was accompanied by leukoencephalopathy, acute toxic leukoencephalopathy, or reversible posterior leukoencephalopathy syndrome. Symptoms may include headache, nausea and vomiting, seizures, visual disturbances such as vision loss, sensory changes, and focal neurological deficits. Additional effects may include optic neuritis, papillitis, confusion, drowsiness, agitation, paraparesis/quadriparesis, muscle spasticity, and urinary incontinence.


The use of high doses of fludarabine was accompanied by irreversible toxic damage to the central nervous system, which caused delayed blindness, coma and death.


High doses of the drug can also lead to severe thrombocytopenia and neutropenia caused by bone marrow damage.


The specific antidote to fludarabine is still unknown.


Treatment consists of stopping the use of the drug and conducting maintenance therapy.

Tags: Fludarabine phosphate