Flugarda - instructions for use, dose, side effects, contraindications

Flugard® is an antitumor drug that contains fludarabine phosphate, which is a water-soluble fluorinated nucleotide analogue of the antiviral drug vidrabine, 9-β-D-arabinofuranosyladenine (ara-A), relatively stable to the action of adenosine deaminase.

In humans, fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A, which is captured by cells, then is intracellularly phosphorylated to the active triphosphate (2-fluoro-ara-ATP) with deoxycytidine kinase. This metabolite inhibits DNA polymerase (alpha, delta and ipsylon), DNA primase, 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. Mutagenic properties do not.

Pharmacokinetics:

Fludarabine phosphate (2-fluoro-ara-AMP) is a water-soluble precursor of fludarabine (2-fluoro-ara-A).After intravenous administration, 2-fluoro-ara-AMP is rapidly dephosphorylated in the body to the nucleoside 2-fluoro-ara-A. After a single intravenous infusion for 30 min, the maximum plasma concentration (C_mOh) 2-Fluoro-ara-A is 3.5-3.7 μmol / L and is reached by the end of the infusion. After five administrations of the drug, a moderate increase in C_mOh up to 4.4-4.8 μmol / l at the end of infusion. The cumulation of 2-fluoro-ara-A after several cycles of therapy may be insignificant. The connection with blood plasma proteins is negligible.

After the end of the infusion, a three-phase decrease in concentration with a half-life (T_1/2) of the initial phase of 5 min, T_1/2an intermediate phase of 1-2 h and T_1/2terminal phase - about 20 hours.

A study of the pharmacokinetics of 2-fluoro-ara-A showed that, on average, the total plasma clearance is 79 ± 40 ml / min / m² (2.2 ± 1.2 ml / min / kg), and the average volume of distribution is 83 ± 55 l / m² (2.4 ± 1.61 l / kg). The data obtained indicate a high individual variability. After intravenous (iv) administration, the concentration of 2-fluoro-ara-A in plasma and the area under the concentration-time curve (AUC) increase in linear dependence on the dose, whereas T_1/2, plasma clearance and volume distribution remain constant regardless of dose.

It is excreted mainly by the kidneys (40-60% of the dose administered intravenously). 2-Fluoro-ara-A is actively transported to leukemia cells, where it is rephosphorylated to monophosphate and partially to di- and triphosphate. Triphosphate (2-fluoro-ara-ATP) is the main intracellular metabolite and the only metabolite that has cytotoxic activity. The maximum concentration of 2-fluoro-ara-ATP in tumor cells was observed on average after 4 hours, with significant fluctuations in the mean peak concentration (on average about 20 μmol / L). The concentration of 2-fluoro-ara-ATP in tumor cells was also significantly higher than its maximum concentration in the plasma, indicating a cumulation of the substance in the tumor cells. T_1/22-fluoro-ara-ATP from the target cells is 15-23 hours. There was no clear correlation between the pharmacokinetics of 2-fluoro-ara-A and the therapeutic effect of the drug in oncological patients, however, the frequency of neutropenia and changes in hematocrit indicate the dose-dependent nature of the cytotoxic effect (in the form of inhibition of hemopoiesis) of fludarabine phosphate.

In individuals with reduced renal function, there was a decrease in the overall clearance of the drug, indicating a need for dose reduction.

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;

- impaired renal function (creatinine clearance <30 mL / min);

- decompensated hemolytic anemia;

- pregnancy and the period of breastfeeding.

Carefully:

After a thorough assessment of the risk / benefit ratio fludarabine should be used in weakened patients, with a marked decrease in bone marrow function (thrombocytopenia, anemia and / or granulocytopenia), in renal (KK 30-70 ml / min) or liver failure, immunodeficiency, opportunistic infections in the anamnesis, in patients older than 75 years.

The available data on the safety and effectiveness of fludarabine in children do not allow one to give unambiguous recommendations for its relative use in pediatric practice.

Dosing and Administration:

Flugard® should only be administered intravenously, and its accidental extravascular course should be avoided.

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

The contents of each vial should be dissolved in 2 ml of water for injection. 1 ml of the prepared solution contains 25 mg of fludarabine phosphate. The required dose (calculated from the patient's body surface) is collected in a syringe. Then this dose is diluted in 10 ml of 0.9% sodium chloride solution and injected intravenously or diluted in 100 ml of 0.9% sodium chloride solution and injected intravenously for about 30 minutes.

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

Patients with CLL Flugard® should be administered until the maximum response is achieved (complete or partial remission, usually 6 cycles), after which the treatment should be discontinued.

In patients with NHL NC Flugardoy® treatment is recommended to be performed until the maximum response is achieved (complete or partial remission). After achieving the greatest effect, the need for two consolidation cycles should be discussed. According to clinical trials with NHL NZ, most patients received no more than 8 cycles of treatment.

Patients with impaired hepatic function. Data on the efficacy and safety of fludarabine in patients with impaired hepatic function are limited.Patients in this group fludarabine prescribe with caution after a thorough assessment of the risk / benefit ratio. The treatment of these patients should be closely monitored. If necessary, reduce the dose of the drug or cancel treatment.

Patients with impaired renal function. In patients with possible impairment of renal function and in persons older than 70 years, a determination of creatinine clearance is necessary. With a creatinine clearance of 30 to 70 ml / min, the dose should be reduced to 50%, and a permanent hematologic control is necessary to assess toxicity. Treatment Flugardoy® is contraindicated in the clearance of creatinine <30 ml / min.

Side effects:

The frequency of side effects is given below in accordance with the following gradation: very often (more than 10%), often (more than 1% but less than 10%), infrequently (more than 0.1% but less than 1%), rarely (more than 0, 01%, but less than 0.1%).

From the hematopoiesis: very often - neutropenia, thrombocytopenia and anemia; often - myelosuppression.

From the immune system: infrequently - autoimmune disorders (including autoimmune hemolytic anemia, thrombocytopenic purpura, pemphigus, Fisher-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, hyperphosphataemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria and kidney failure may develop.

From the nervous system: often - peripheral neuropathy, infrequently - confusion; rarely comatose or excited state, epileptiform seizures.

From the side of the organ of vision: often - visual impairment. Rarely, neuritis or neuropathy of the optic nerve, blindness were observed.

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 a skin rash, rarely Stevens-Johnson syndrome or toxic epidermal necrolysis (Lyell's syndrome). There have been reports of rare cases of increased growth of existing skin cancer, as well as the development of skin cancer during or after treatment with fludarabine.

Other: very often - increased body temperature, fatigue, weakness, attachment of secondary infections / opportunistic infections (for example, reactivation of latent viruses, including herpes and Epstein-Barr viruses, progressive multifocal leukoencephalopathy, pneumonia); often - chills, malaise, peripheral edema; rarely - lymphoproliferative disorders (associated with the Epstein-Barr virus).

In patients who received fludarabine Before, after or simultaneously with alkylating cytotoxic agents or radiotherapy, in rare cases, myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML) was observed.

Overdose:

With an overdose of fludarabine, it is possible to develop irreversible changes in the central nervous system, late blindness, coma and death, as well as the development of severe thrombocytopenia and neutropenia due to the suppression of bone marrow function. In case of appearance of threatening symptoms, the drug should be immediately discontinued and supportive therapy should be provided. The specific antidote is not known.

Interaction:

Use of fludarabine in combination with pentostatin for treatmentrefractory chronic lymphocytic leukemia often resulted in death due to high pulmonary toxicity.

The therapeutic efficacy of fludarabine may decrease with simultaneous use with dipyridamole.

When a combination of fludarabine and cytarabine was used, a pharmacokinetic interaction was observed. When co-administration of cytarabine with fludarabine is combined, higher intracellular maximum concentrations and area under the time-concentration curve (AUC) metabolite of cytarabine - arabinosyl cytosine triphosphate. Plasma concentrations of cytarabine and excretion of arabinosyl cytosine triphosphate remained unchanged.

Pharmaceutical interaction. A solution of fludarabine for intravenous use should not be mixed with other drugs.

Special instructions:

Treatment with fludarabine should be performed under the supervision of a physician experienced in the use of cytotoxic agents.

When fludarabine therapy is recommended, periodic evaluation of peripheral blood parameters for the detection of anemia, neutropenia and thrombocytopenia, carefully monitor the serum creatinine concentration and creatinine clearance,and also to carry out careful monitoring of the CNS function with the purpose of timely detection of possible neurological disorders.

Oppression of the bone marrow is usually reversible. In fludarabine therapy, the greatest decrease in the number of neutrophils is observed on average 13 days (3-25 days) from the start of treatment, platelets - on average on day 16 (2-32 days). Myelosuppression can be expressed and have a cumulative character. Several cases of bone marrow hypoplasia or aplasia in adults with pancytopenia, sometimes fatal, have been described. The duration of clinically significant pancytopenia ranged from 2 months to 1 year. These episodes were detected in both treated and untreated patients.

Patients with an increased risk of developing opportunistic infections are recommended to conduct preventive therapy. On the background of fludarabine therapy, development of serious opportunistic infections, in some cases leading to death, was noted.

Caution should be exercised when administering fludarabine to patients who are later to be transplanted to hematopoietic stem cells.

When transfusion of non-irradiated blood, patients who received fludarabine treatment developed a "graft versus host" reaction (the reaction of transplanted immunocompetent lymphocytes against the host). A high incidence of fatalities has been reported as a result of this reaction. In this regard, patients who need hemotransfusions and who receive or received treatment with fludarabine, only irradiated blood should be transfused.

The tumor lysis syndrome that occurs with fludarabine treatment has been observed in patients with CLL who have a large tumor mass. As fludarabine can have a therapeutic effect at the first week of therapy, it is necessary to take precautions in patients with probable risk of developing this complication.

Regardless of the presence or absence of autoimmune processes in the anamnesis, as well as the results of the Coombs test, there is a risk of life-threatening autoimmune reactions (autoimmune hemolytic anemia, autoimmune thrombocytopenia, thrombocytopenic purpura, pemphigus, Fisher-Evans syndrome) during or after fludarabine treatment.A repeated hemolytic process is possible after the resumption of treatment with fludarabine. If hemolysis develops, discontinuation of therapy is recommended. Treatment for hemolytic anemia is the transfusion of irradiated blood and the introduction of glucocorticosteroids.

Men and women who have sex should take reliable methods of contraception during (and within 6 months after the end of) fludarabine treatment. During and after treatment with fludarabine, vaccination with live vaccines should be avoided.

Most fludarabine-insensitive patients are also insensitive to chlorambucil.

The rules for the use and destruction of cytostatic agents should be observed. Avoid contact with solution! 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 fludarabine may adversely affect the ability to drive and engage in potentially hazardous activities,requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

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

Packaging:

For 50 mg of fludarabine phosphate in bottles of colorless neutral glass, hermetically sealed with rubber stoppers with the rolling off of aluminum caps.

For 1 or 5 bottles with instructions for use in a pack of cardboard.

Storage conditions:

Store in a dry place protected from light at a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LSR-002967/10

Date of registration:08.04.2010

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia

Manufacturer: & nbsp

BIOCAD, CJSC Russia

Representation: & nbspBIOCAD CJSC BIOCAD CJSC Russia

Information update date: & nbsp26.09.2015

Illustrated instructions

Instructions

Flugard® (Fluguarda®)