Vero-fludarabine

Vero-Fludarabine is an antineoplastic medicine that is a structural purine analogue. The drug contains fludarabine phosphate. It is a fluorinated form of a nucleotide analogue of the antiviral substance vidarabine (element 9-β-D-ara-A), which is relatively resistant to the deamination of the component ADA.

Inside the human body, the active element of a drug at high speed is dephosphorylated to form 2-fluoro-ara-A, absorbed by the cells. Further, it is intracellularly phosphorylated under the action of deoxycytidine kinase relative to 3-phosphate (element 2-fluoro-ara-ATP).

Indications Vero-fludarabine

It is used in patients with B-cell lymphocytic leukemia in the chronic stage, as well as in NHL with a low level of malignancy.

Release form

The release of the component is in the form of an injection powder for intravenous injections. Lyophilisate contains 50 mg of active ingredient and is sold inside glass vials.

[1], [2]

Pharmacodynamics

This metabolic component slows down the DNA polymerase with ribonucleotide reductase, and in addition, α-, δ- with ε-DNA primase, as well as DNA ligase, which results in slowing down of DNA binding. Along with this, partial inhibition of RNA polymerase 2 is carried out, as well as, as a result, a decrease in protein binding.

There is no confirmed information regarding a clear relationship between the pharmacokinetic parameters of 2-fluoro-ara-A, as well as the effectiveness of cancer therapy. But a change in hematocrit and the emergence of neutropenia confirm the dose-dependent inhibition of hematopoiesis due to the cytotoxic properties of fludarabine phosphate.

[3], [4], [5], [6]

Pharmacokinetics

Fludarabine is a prodrug of a water-soluble character (2-fluoro-ara-A), which is dephosphorylated at a high rate inside the human body, transforming into a nucleoside (2-fluoro-ara-A). Intlasma protein binding is rather weak.

With a 1-time infusion of a 2-fluoro-ara-AMP element in a 25 mg / m ² dose to people with CLL for half an hour, plasma Cmax values of 2F-ara-A are 3.5–3.7 μm by the end of the infusion procedure. The corresponding values of 2-fluoro-ara-A after the 5th portion moderately accumulate; average Cmax values by the end of the infusion are 4.4-4.8 microns. With 5-day therapy, low plasma values of 2-fluoro-ara-A are approximately doubled. Cumulation 2F-ara-A after a few treatment courses does not develop.

Post-maximal indices decrease in the period of 3 pharmacokinetic stages with an initial half-life term of approximately 5 minutes. The intermediate term half-life is about 1-2 hours; final - about 20 hours.

Excretion of 2-fluoro-ara-A is implemented mainly through the kidneys. With urine, 40-60% of the portion applied through IV injection is excreted.

In people with weakened kidney function, the systemic clearance is lowered, which is why the dosage of the drug should be reduced.

The 2-fluoro-ara-A component actively moves inside the leukemic cells, undergoing refractorylation there to monophosphate, and then to 2- and 3-phosphate. The latter is the main intracellular metabolic element (it is the only one that has a cytotoxic effect).

The Cmax values of 2-fluoro-ara-ATP inside the altered lymphocytes of people with CLL are on average observed after 4 hours and are characterized by significant personal variability. Indicators of 2-fluoro-ara-ATP inside leukemic cells on a permanent basis substantially exceed the plasma level Cmax of the component 2-fluoro-ara-A, from which it can be concluded that the accumulation is specific.

Excretion of 2-fluoro-ara-ATP from the sites of target cells is realized with an average half-life term of 15 and 23 hours.

[7], [8]

Dosing and administration

The drug is administered through an IV drip for half an hour. Therapy is performed under the supervision of an experienced and qualified physician who has previously performed antitumor treatment.

It is required to use 25 mg / m ^{2 of}  medication - every day for 5 days; such courses should be conducted with 28-day intervals. Lyophilisate vials are diluted in injection water (2 ml). Each 1 ml of the resulting liquid contains 25 mg of the component fludarabine phosphate.

The required portion (it is calculated taking into account the size of the human body surface) is drawn inside the syringe. For bolus injections, this medicinal portion is dissolved in 0.9% NaCl (10 ml). To complete the infusion, the dosage entered into the syringe should be diluted in 0.1 L of the above solution.

The duration of the therapeutic cycle is determined by the effectiveness of treatment and the development of tolerance regarding Vero-Fludarabina.

Persons with CLL need to use the medication until the maximum response is obtained (partial or full remission is noted after 6 courses). After that, the use of drugs is canceled.

People with low-grade NHL are required to continue therapy until they get the maximum response (partial or full remission). When the desired effect is obtained, the option of performing another 2 courses of consolidated treatment is considered. In clinical testing of individuals with the above pathology, most of them underwent a maximum of 8 treatment courses.

Patients with kidney disorders need to adjust the dosage of drugs. When the level of QC in the range of 30-70 ml per minute, the portion is reduced to 50%. To assess the toxicity indicators, careful hematologic monitoring should be performed.

Vero-Fludarabine should not be administered with QA values below 30 ml per minute.

[11], [12]

Use Vero-fludarabine during pregnancy

During pregnancy and breastfeeding medication is not prescribed.

Contraindications

The main contraindications:

• strong personal sensitivity regarding the drug and its constituent elements;
• renal impairment (CC values below 30 ml per minute);
• anemia of hemolytic nature in decompensated phase.

[9]

Side effects Vero-fludarabine

Among the main side effects:

• lesions of the blood-forming organs: thrombocyto- or neutropenia, as well as anemia. The number of neutrophils decreases to an average of 13 days (within the 3-25th day) since the start of therapy, and platelet count - on the 16th day (in the range of the 2-32th day). In this case, myelosuppression may be of high intensity and cumulative form. A decrease in the number of T-lymphocytes, noted in the case of prolonged use of fludarabine, may increase the likelihood of opportunistic infections, including latent viral lesions developing due to reactivation (for example, a multifocal leukoencephalopathy, which has a progressive character);
• metabolic disorders: due to lysis of the neoplasm, hyperphosphatemia,,kalemia or uriuricemia may occur, and in addition hypocalcemia, metabolic acidosis, urate-type crystalluria, hematuria and kidney disorders. The first symptom of neoplasm lysis is considered to be hematuria and the appearance of acute pain;
• damage to the PNS and CNS function: polyneuropathy. Excitement or coma is rarely observed, as well as confusion and epileptoform seizures;
• problems with the work of the sense organs: the development of neuritis affecting the optic nerve, visual disorders or neuropathy, as well as blindness;
• respiratory infection: the appearance of pneumonia. Occasionally there is pneumonitis, pulmonary infiltration or pulmonary fibrosis, against the background of which there is cough and dyspnea;
• disorders of digestive activity: anorexia, stomatitis, nausea, diarrhea or vomiting. Occasionally, thrombocytopenia causes bleeding in the gastrointestinal area, and also increases the activity of pancreatic and liver enzymes;
• disorders of the CVS function: arrhythmias or insufficiency of the CVS are rarely observed;
• problems with the work of the urogenital tract: occasionally hemorrhagic cystitis occurs;
• lesions of the subcutaneous tissue with the epidermis: rash. Occasionally TEN or SSD appears;
• autoimmune manifestations: regardless of the presence or absence of a history of autoimmune processes, and in addition to this data from the Coombs test, there are reports of life threatening, and in some cases, the development of deadly autoimmune symptoms (autoimmune varieties of thrombocytopenia or anemia of hemolytic nature, vesicle, thrombocytopenic purpura and Evans syndrome) with fludarabine therapy or after its completion;
• other symptoms: chills, malaise, fever and fatigue, infection, weakness, and peripheral edema (typical symptoms).

[10]

Overdose

With the introduction of too high portions of Vero-Fludarabina, an incurable CNS damage occurs, leading to blindness and coma. Also observed platelet and neutropenia in severe.

The antidote is missing. It is required to cancel the use of drugs and perform symptomatic procedures.

Interactions with other drugs

The use of fludarabine in combination with the substance pentostatin in the treatment of refractory CLL often causes death (because this combination has a high degree of toxicity to the lungs). Because of this, prescribe these drugs together is prohibited.

Drug effectiveness of fludarabine may be impaired with the administration of dipyridamole or other adenosine seizure inhibitors.

Intravenous fluid Vero-Fludarabina prohibited from mixing with other medicines.

[13], [14], [15], [16], [17]

Storage conditions

Vero-Fludarabin must be kept in a dark, closed from children and moisture penetration place. Temperature values are in the range of 25 ° С.

[18], [19], [20], [21], [22]

Shelf life

Vero-Fludarabine is allowed to apply for a 2-year period from the time of production of the drug.

[23], [24]

Application for children

Safety and drug efficacy of fludarabine in pediatrics has not been studied.

[25], [26], [27], [28]

Analogs

Analogues of drugs are the substances Darbines, Flutothera, Flidarin with Fludarabel, Flugard and Fludarabine with Fludara.

[29], [30]