Vero-Fludarabine - instructions for use, dose, side effects, contraindications

Vero-fludarabine is an antitumor drug containing fludarabine phosphate, which is a water-soluble fluorinated nucleotide analogue antiviral agent vidarabin, 9-beta-D-arabinofuranosyladenine (ara-A), relatively resistant to the action of adenosine deaminase.

In humans, fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A, which, captured by cells, is then intracellularly phosphorylated to the active triphosphate (2-fluoro-ara-ATP) with deoxycytidine kinase. This metabolite inhibits DNA polymerase (alpha, delta and ipsylon), DNA primase and DNA ligase, ribonucleotide reductase and is inserted into DNA and RNA, which leads to termination of DNA replication, RNA disruption, processing and translation of mRNA.

Research in vitro showed that the effect of 2-fluoro-ara-A on the lymphocytes of patients with chronic lymphocytic leukemia (CLL) activates the mechanism of intensive DNA fragmentation and apoptosis. Toxic. Has teratogenic activity.

Pharmacokinetics:

There was no clear correlation between the pharmacokinetics of fludarabine and its therapeutic effect in cancer patients, with the frequency of detection of neutropenia and changes in hematocrit dose-dependent.

Fludarabine phosphate (2-fluoro-ara-AMP) is a water soluble precursor of fludarabine (2-fluoro-ara-A), in the human body, 2-fluoro-ara-AMP is rapidly and completely dephosphorylated to the nucleoside of 2-fluoro-ara-A. Linkage to blood plasma proteins is insignificant.

After a single infusion of CLL patients with a standard dose of the drug for 30 minutes, the maximum concentration of 2-fluoro-ara-A in plasma equal to 3.5-3.7 μM is reached by the end of the infusion. After five administrations of the drug, a moderate increase in the maximum concentration to 4.4-4.8 μM is revealed by the end of the infusion. Cumulation of 2-fluoro-ara-A after several cycles of therapy can be ruled out. After the end of the infusion, there is a three-phase decrease in concentration with a half-life of the initial phase of about 5 minutes, an intermediate phase of 1-2 hours and a terminal phase of about 20 hours.

According to the results of pharmacokinetic studies, the average total plasma clearance of 2-fluoro-ara-A is 79 ± 40 ml / min / m² body surface area (2.2 ± 1.2 ml / min / kg body weight), and the mean distribution volume is 83 ± 55 l / m² (2.4 ± 1.6 l / kg). Characteristic significant individual variability of indicators. The concentration of 2-fluoro-ara-A in the blood plasma and the area under the pharmacokinetic curve linearly increase with increasing dose, and the half-life,plasma clearance and volume of distribution do not depend on the dose.

2-Fluoro-ara-A is excreted mainly by the kidneys (from 40 to 60% of the intravenously administered dose). In individuals with reduced renal function, there is a decrease in overall clearance, indicating a need for dose reduction.

2-Fluoro-ara-A is actively transported to leukemic cells, after which it is rephosphorylated 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 much higher than in plasma, indicating its accumulation in tumor cells. The half-life of 2-fluoro-ara-ATP from the target cells averages from 15 to 23 hours.

Indications:

- Chronic B-cell lymphocytic leukemia (CLL);

- Non-Hodgkin's lymphomas of low degree of malignancy (NHL NZ).

Contraindications:

- Hypersensitivity to fludarabine or other components of the drug;

- decreased renal function with creatinine clearance <30 ml / min;

decompensated hemolytic anemia;

- Pregnancy and the period of breastfeeding.

Carefully:

Vero-fludarabine should be administered with caution after a thorough assessment of the risk / benefit ratio for patients in a weakened state, patients with a marked decrease in bone marrow function (thrombocytopenia, anemia and / or granulocytopenia), immunodeficiency or with acute viral, fungal or bacterial infection, children and patients with liver failure (the efficacy and safety of fludarabine in children, as well as in patients with hepatic insufficiency is not studied), patients older than 75 years (due to an insufficient number of clinics FIR data on the use of fludarabine in elderly patients).

Pregnancy and lactation:

The drug is contraindicated for use in pregnancy and lactation (breastfeeding).

Women and men of childbearing age should use reliable methods contraception during and not less than 6 months after the end of therapy.

Dosing and Administration:

Intravenously spray or drip for 30 minutes.

The recommended dose is 25 mg / m² the body surface daily for 5 days every 28 days.

Before administration, the contents of the vial are dissolved in 2 ml of water for injection.

For intravenous jet administration, the required dose (calculated from the body surface of the patient) is diluted in 10 ml of 0.9% sodium chloride solution for intravenous fluid administration and in 100 ml of 0.9% sodium chloride solution for infusion administration.

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

CLL patients Vero-fludarabine is prescribed until the maximum response is achieved (complete or partial remission, usually 6 cycles), after which the treatment should be discontinued.

In patients with NHL, treatment with Vero-fludarabine is recommended before the maximum response (complete or partial remission) is obtained. After achieving the greatest effect, the need to conduct two cycles of consolidation (usually 8 cycles) should be discussed.

Children

The effectiveness and safety of Vero-fludarabine in children have not been studied.

Decreased kidney function

When creatinine is cleared from 30 to 70 ml / min, Vero-fludarabine is administered in a 50% reduced dose, with the treatment being conducted under a constant blood test.At clearance of creatinine <30 ml / min, treatment with Vero-fludarabine is contraindicated.

Side effects:

The frequency of side effects is given below-in accordance with the following gradation: typical (≥ 1%), rare (≥0.1% and <1%), very rare events (0.1%).

From the hematopoiesis: neutropenia, thrombocytopenia and anemia. The greatest decrease in the number of neutrophils is observed on average 13 days (from 3 to 25 days) from the start of treatment, platelets - on average on day 16 (from 2 to 32 days). Myelosuppression can be expressed and have a cumulative character.

Decrease in the number of T-lymphocytes, which is observed with prolonged treatment fludarabine may lead to an increased risk of opportunistic infections, including infections resulting from the reactivation of latent viral infections, for example, progressive multifocal leukoencephalopathy.

Metabolic disorders: as a result of tumor lysis, hyperuricemia, hyperphosphataemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria and renal dysfunction may develop. The first sign of tumor lysis syndrome can be acute pain and hematuria.

From the central and peripheral nervous system: peripheral neuropathy. Rarely - a coma or an excited state, epileptiform seizures, confusion.

From the sense organs: visual impairment, rarely - optic neuritis, visual neuropathy and blindness.

From the respiratory system: pneumonia; rarely - pulmonary infiltrates, pneumonitis, pulmonary fibrosis, accompanied by dyspnoea and cough.

On the part of the digestive system: nausea, vomiting, anorexia, diarrhea and stomatitis; rarely - gastrointestinal bleeding against thrombocytopenia, an increase in the activity of liver and pancreatic enzymes.

From the cardiovascular system: rarely - the development of heart failure and arrhythmia.

From the genitourinary system: rarely - hemorrhagic cystitis.

From the skin and skin appendages: skin rash; rarely - the development of Stevens-Johnson syndrome or toxic epidermal necrolysis (Lyell's syndrome).

Autoimmune reactions: regardless of the presence or absence of autoimmune processes in the anamnesis, as well as the results of the Coombs test, the emergence of life-threatening,and sometimes fatal autoimmune reactions (autoimmune hemolytic anemia, autoimmune thrombocytopenia, thrombocytopenic purpura, pemphigus, Evans syndrome) during or after fludarabine treatment.

Other: fever, chills, infection, malaise, fatigue and fatigue, peripheral edema are typical.

Overdose:

High doses of fludarabine cause irreversible changes in the central nervous system, including blindness, coma and death. The use of high doses is also associated with the development of severe thrombocytopenia and neutropenia due to the suppression of bone marrow function.

Specific antidotes with fludarabine overdose are unknown.

Treatment is to stop the introduction of the drug and support maintenance therapy.

Interaction:

The use of fludarabine in combination with pentostatin (deoxycoformylin) for the treatment of refractory chronic lymphocytic leukemia (CLL) has often led to death due to high pulmonary toxicity. Therefore, the use of fludarabine in combination with pentostatin is not recommended.

The therapeutic efficacy of fludarabine can be reduced by dipyridamole or other inhibitors of adenosine capture.

The solution of Vero-fludarabine for intravenous use should not be mixed with other drugs.

Special instructions:

Precautions for use

Treatment Vero-fludarabine should be administered under the supervision of a physician experienced in the use of cytotoxic agents.

Patients treated with Vero-fludarabine should be carefully monitored for timely detection of hematologic and non-hematologic (primarily neurological) toxicity. Periodic evaluation of peripheral blood indicators is recommended to detect anemia, neutropenia and thrombocytopenia, as well as careful monitoring of serum creatinine and the determination of creatinine clearance.

In rare cases, patients who received fludarabine before, after or simultaneously with alkylating cytotoxic agents or radiotherapy, myelodysplastic syndrome (MDS) was observed. When monotherapy with fludarabine MDS is not was observed.

The "graft versus host" reaction (the reaction of transfused immunocompetent lymphocytes against the host) resulting from blood transfusions was observed after transfusion of unirradiated blood to patients treated with fludarabine. Reported a high incidence of fatalities as a consequence of this disease. In this regard, patients who need blood transfusions and who receive or received treatment with Vero-fludarabine, only irradiated blood should be transfused. There have been reports of occasional increases in the growth of existing skin cancer during or after treatment with fludarabine.

As fludarabine may cause tumor lysis as early as the first week of therapy, caution should be observed in the treatment of patients at risk of developing this syndrome (especially with a large tumor mass).

Patients treated with Vero-fludarabine should be carefully observed for signs of hemolytic anemia (decreased hemoglobin and positive Coombs test). In the case of hemolysis, discontinuation of Vero-fludarabine therapy is recommended. The most common therapeutic measures for hemolytic anemia are transfusion of irradiated blood and glucocorticosteroid therapy.

Fertile women and men should use contraceptives during and for at least 6 months after the end of therapy.

During and after treatment with Vero-fludarabine, vaccination with live vaccines should be avoided.

Pregnant women are not allowed to work with Vero-fludarabine.

The rules for the use and destruction of cytostatic agents should be observed.

It is recommended to use latex gloves and goggles. Avoid inhalation of the drug. In case of contact with the skin or mucous membranes, these areas should be thoroughly rinsed with soap and water. In case of contact with eyes, rinse thoroughly with plenty of water.

Effect on the ability to drive transp. cf. and fur:

Some side effects of drugs, such as increased fatigue, weakness, blurred vision, may adversely affect the ability to drive and engage in potentially hazardous activities that require high concentration and psychomotor speed reactions.

Form release / dosage:

Lyophilizate for the preparation of a solution for intravenous administration, 50 mg.

Packaging:

50 mg of the active substance in the bottles of colorless glass I or II hydrolytic class, hermetically sealed with stoppers / rubber, with the capping of the caps aluminum or alumoplastikovymi.

One bottle with instructions for use in a pack of cardboard. For 3 or 5 bottles together with instructions for use in a pack with partitions or special cardboard sockets. By 25, 35 or 50 bottles with instructions for use, based on one instruction for ten bottles, in a box of cardboard (for hospitals).

Storage conditions:

At a temperature of no higher than 30 ° C in a place protected from light and inaccessible to children.

Shelf life:3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:P N003887 / 01

Date of registration:03.12.2009 / 12.08.2016

Expiration Date:Unlimited

The owner of the registration certificate:VEROPHARM SA VEROPHARM SA Russia

Manufacturer: & nbsp

VEROPHARM SA Russia

Information update date: & nbsp02.02.2017

Illustrated instructions

Instructions

Vero-Fludarabine (Vero-Fludarabin)