Fludarabin-Aktavis - instructions for use, dose, side effects, contraindications

The drug Fludarabin-Aktavis contains a fludarabine phosphate-fluorinated nucleotide analogue of the antiviral drug vidrabine, 9-β-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, captured by cells, is then intracellularly phosphorylated to the active triphosphate (2-fluoro-ara-ATP). This metabolite inhibits RNA reductase, DNA polymerase (alpha, delta, and ipsylon), DNA primase and DNA ligase, which leads to a disruption in DNA synthesis. In addition, RNA polymerase II is partially inhibited, followed by a decrease in protein synthesis.

Pharmacokinetics:

Fludarabine phosphate (2-fluoro-ara-AMP) is a water-soluble precursor of fludarabine (2-fluoro-ara-A). In humans, 2-fluoro-ara-AMP is rapidly and completely dephosphorylated to the nucleoside of 2-fluoro-ara-A.

After a single infusion, patients with 13-cell chronic lymphocytic leukemia (CLL) 2-fluoro-ara-AMP in a dose of 25 mg / m² within 30 minutes the maximum concentration (C_max) 2-fluoro-ara-A is 3.5-3.7 μmol and is reached by the end of the infusion.The determinations of the corresponding level of 2-fluoro-ara-A after five injections of the drug showed moderate cumulation with an average value of C_mOh equal to 4.4-4.8 μmol by the end of infusion. During the five-day treatment, the levels of 2-fluoro-ara-A in blood plasma increased 2-fold. The cumulation of 2-fluoro-ara-A after several cycles of therapy may be insignificant. The association of 2-fluoro-ara-A with plasma proteins is insignificant.

After reaching C_mOh in blood plasma levels of 2-fluoro-ara-A are reduced in three phases: half-life (T_1/2) in the initial phase is approximately 5 minutes, the intermediate phase - 1-2 hours and in the final phase - about 20 hours.

A comparison 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 the blood 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.

2-Fluoro-ara-A is excreted mainly by the kidneys (from 40% to 60% of the administered IV dose). 2-fluoro-ara-A is delivered to leukemic cells by active transport, then 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. FROM_mOh 2-fluoro-ara-ATP in leukemic lymphocytes of patients with CLL was observed on average 4 hours after the infusion and was characterized by a significant fluctuation in the mean value of approximately 20 μmol. The concentration of 2-fluoro-ara-ATP in leukemic cells was significantly higher than its maximum concentration in the blood plasma, indicating a cumulation of the substance in the tumor cells.

T_1/22-fluoro-ara-ATP from the target cells averages from 15 to 23 hours.

There was no clear correlation between the pharmacokinetics of 2-fluoro-ara-A and the therapeutic effect of the drug in cancer patients, however, the frequency of neutropenia and changes in hematocrit indicate a dose-dependent nature of the cytotoxic effect of fludarabine in the form of inhibition of hemopoiesis.

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

Indications:

- B-cell chronic lymphocytic leukemia;

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

Contraindications:

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

- decompensated hemolytic anemia;

- pregnancy;

- lactation period (breastfeeding);

- hypersensitivity to the components of the drug;

- children under 18 years of age (efficacy and safety not established).

Carefully:

Acute infectious diseases of viral, fungal and bacterial nature, marked depression of bone marrow function (thrombocytopenia, anemia and / or granulocytopenia), weakened patients, renal insufficiency, hepatic insufficiency, immunodeficiency, in patients older than 75 years.

Pregnancy and lactation:

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

Women and men of childbearing age should use reliable contraceptive methods during and for at least 6 months after the end of therapy.

Dosing and Administration:

The drug Fludarabine-Aktavis should be administered only intravenously.

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

The contents of each vial should be dissolved in 2 ml of water for injection. In 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 a 0.9% solution of sodium chloride and injected in / in a jet or diluted in 100 ml of 0.9% sodium chloride solution and injected / dripped in about 30 minutes.

Duration of treatment

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

With B-cell chronic lymphocytic leukemia the drug Fludarabine-Actavis should be used until the maximum response is achieved (complete or partial remission, usually 6 cycles), after which treatment should be discontinued.

With non-Hodgkin's lymphoma low degree of malignancy treatment with Fludarabine-Aktavis is recommended before the maximum response (complete or partial remission) is achieved. After achieving the greatest effect, consideration should be given to the need for two consolidation cycles.In most cases, no more than 8 treatment cycles are required.

Impaired liver 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.

Impaired renal function

With QA 30-70 ml / min it is necessary to reduce the dose by 50%. When performing therapy in these patients, continuous hematological control is necessary.

Side effects:

The incidence of adverse events is indicated on the basis of clinical trial data, regardless of the causal relationship with the use of the drug Fludarabine-Actavis, according to the following gradation: very often (≥10%), often (<10% - ≥1%) infrequently <1% - ≥0,1%), rarely (<0,1% - ≥0,01%), very rarely (<0,01%).

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

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.

From the immune system: infrequently - autoimmune disorders (including autoimmune hemolytic anemia, thrombocytopenic purpura, pemphigus, Evans syndrome, acquired hemophilia).

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

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 central and peripheral nervous system: often peripheral neuropathy; infrequently - confusion of consciousness; rarely - agitation, convulsions, coma, cerebral hemorrhage.

From the side of the organ of vision: often - visual impairment; rarely - optic neuritis, optic nerve 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: often - skin rash. 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.

Allergic reactions: rarely Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), anaphylactic shock.

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, swelling; rarely lymphoproliferative disorders (associated with the Epstein-Barr virus).

Overdose:

Symptoms: fludarabine in high doses causes irreversible changes in the central nervous system (CNS), including blindness, coma and death. When using fludarabine in doses 4 times higher than recommended (96 mg / m²/ day for 5-7 days), neurotoxicity was observed in about 36% of patients, with neurotoxicity symptoms appearing 21-60 days after the last dose.The use in high doses is also associated with the development of severe thrombocytopenia and neutropenia due to the suppression of bone marrow function.

Treatment: discontinuation of the drug and maintenance therapy, a specific antidote is unknown.

Interaction:

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

Dipyridamole or other inhibitors of adenosine reuptake may decrease the therapeutic efficacy of fludarabine.

When treated with a combination of fludarabine and cytarabine in patients with CLL and AML, pharmacokinetic interaction was observed. When cytarabine is combined with fludarabine, higher intracellular maximal concentrations and intracellular AUC metabolite of cytarabine - arabinosyl cytosine triphosphate. Plasma concentrations of cytarabine and excretion of arabinosyl cytosine triphosphate remained unchanged.

A solution of fludarabine for intravenous administration should not be mixed with other drugs.

Special instructions:

Women and men of childbearing age should use reliable contraceptive methods during and for at least 6 months after the end of therapy.

With caution, after careful assessment of the risk / benefit ratio, it should be used in weakened patients with a marked decrease in bone marrow function (thrombocytopenia, anemia and / or granulocytopenia), renal insufficiency, hepatic insufficiency, immunodeficiency, opportunistic infections in the anamnesis and patients older than 75 years.

Treatment with the drug Fludarabin-Aktavis should be carried out under the supervision of a doctor with experience in the use of cytotoxic drugs.

The drug Fludarabin-Aktavis should be administered only IV. There have been no reports of significant local adverse reactions when the drug is administered extravasively. However, it is necessary to avoid accidental extravascular administration. When treating with Fludarabine-Aktavis, periodic evaluation of peripheral blood parameters is recommended to detect anemia, neutropenia and thrombocytopenia, carefully monitor serum creatinine and QC levels, and monitor closely the function of the central nervous system in order to detect possible neurological disorders in a timely manner.

Oppression of the bone marrow is usually reversible. When therapy with Fludarabine-Aktavis solid tumors in adults, 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 previously treated and untreated patients.

Effects of prolonged use of the drug Fludarabine-Actavis on the CNS are unknown. However, in some studies it was shown that with a relatively long-term use (up to 26 courses of therapy) fludarabine satisfactorily tolerated by patients.

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

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 drug treatment Fludarabine-Aktavis. Most patients with hemolytic anemia experienced recurrence of hemolysis after a provocative test with fludarabine. Patients receiving treatment with the drug Fludarabine-Aktavis should be carefully observed for signs of hemolytic anemia. In the case of hemolysis, discontinuation of therapy with the drug is recommended. The most common therapeutic measures for hemolytic anemia are transfusion of irradiated blood and glucocorticosteroid therapy.

In rare cases, patients who received fludarabine before, after or simultaneously with alkylating cytotoxic agents or radiotherapy, MDS / AML was observed. No monotherapy with Fludarabine-Actavis MDS / AML 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 the drug Fludarabin-Aktavis. A high incidence of fatalities has been reported as a consequence of this disease. In this regard, patients who need hemotransfusions and who receive or received treatment with the drug Fludarabin-Aktavis, it is necessary to transfuse only the irradiated blood.

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

It should be borne in mind that patients who are resistant to therapy with the drug Fludarabine-Actavis, in most cases, show resistance to chlorambucil.

During and after treatment with Fludarabine-Aktavis, vaccination with live vaccines should be avoided.

When handling the drug, you should follow all instructions adopted to use and destroy cytotoxic drugs. Avoid inhalation of the drug.It is recommended to use protective glasses and latex gloves. 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. Pregnant women should not work with the drug.

Pediatric Use

The effectiveness and safety of the use of the drug Fludarabine-Aktavis in children under 18 years of age have not been established.

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

Some of the side effects of the drug, such as fatigue, weakness, visual impairment, confusion, agitation and convulsions, can adversely affect the ability to drive and perform potentially dangerous activities requiring increased concentration and speed of psychomotor reactions.

Form release / dosage:

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

Packaging:

For 100 mg of the drug in a glass bottle (type I) with a capacity of 5 ml, sealed with a rubber stopper (type I) and rinsed with an aluminum cap with a polypropylene disc.

1 bottle with instructions for use in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

4 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001990

Date of registration:30.01.2013

Date of cancellation:2018-01-30

The owner of the registration certificate:Actavis PTS ehf GroupActavis PTS ehf Group Iceland

Manufacturer: & nbsp

SINDAN-PHARMA S.C. S.r.L. Romania

Representation: & nbspAktavis, Open Company Aktavis, Open Company

Information update date: & nbsp26.09.2015

Illustrated instructions

Instructions

Fludarabin-Aktavis (Fludarabine-Actavis)