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

Fludarabine-Teva is an antitumor drug containing 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.

Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A, which is captured by cells, then intracellularly phosphorylated by deoxycytidine kinase to the active triphosphate (2-fluoro-ara-ATP). This metabolite inhibits ribonucleotide reductase, DNA polymerase, DNA primase, and DNA ligase, thereby inhibiting DNA synthesis. In addition, RNA polymerase II is partially inhibited, followed by a decrease in protein synthesis. 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 precursorfludarabine (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 of patients with CLL 2-fluoro-ara-AMP in a dose of 25 mg / m² within 30 minutes the maximum concentration (C_mOh) 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 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 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 plasma levels of 2-fluoro-ara-A are reduced in three phases: the half-life (T_1/2) in the alpha phase is about 5 minutes, the beta phase is 1-2 hours and in the terminal stage 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 - 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.

2-Fluoro-ara-A is excreted mainly by the kidneys (40-60% of the administered IV dose). 2-Fluoro-ara-A is delivered to leukemic cells by active transport, 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 known metabolite with cytotoxic activity. The maximum concentration of 2-fluoro-ara-ATP in leukemic lymphocytes in patients with CLL was observed on average about 4 hours after 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 always significantly higher than its maximum concentration in the plasma, indicating a cumulation of the substance in the target cells. T_1/22-fluoro-ara-ATP from the target cells averaged 15 and 23 hours.

A clear correlation between the pharmacokinetics of 2-fluoro-ara-A and the therapeutic effect of the drug in cancer patients was not revealed,however, the frequency of neutropenia and changes in hematocrit indicate a dose-dependent nature of the cytotoxic effect of fludarabine phosphate 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 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 less than 30 ml / min);

- decompensated hemolytic anemia;

- pregnancy and the period of breastfeeding;

- children's age (lack of sufficient clinical data).

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 or hepatic insufficiency, immunodeficiency, opportunistic infections in the anamnesis, in patients older than 75 years.

Dosing and Administration:

It is allowed only in / in the administration of fludarabine, while avoiding its random extravascular exposure.

Adults

The recommended dose of fludarabine phosphate is 25 mg / m² body surface in / once a day for 5 days every 28 days. The required dose (calculated in accordance with the patient's body surface area) is collected in a syringe. For intravenous administration of the drug, the above dose is diluted in 10 ml of 0.9% sodium chloride solution, also the required dose can be diluted in 100 ml of 0.9% sodium chloride solution and injected for 30 minutes. Clear data on the optimal duration of treatment is not available. The course of treatment depends on the observed effect and tolerability of the drug.

It is recommended to perform fludarabine treatment before reaching a therapeutic response (usually 6 cycles), after the drug is canceled.

Use in 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.

Use in 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. In case of creatinine clearance within 30-70 ml / min the dose of the drug should be reduced up to 50% and the treatment under the control of blood tests to assess toxicity. When creatinine clearance is less than 30 ml / min, treatment with fludarabine is contraindicated.

Side effects:

The frequency of adverse events is indicated on the basis of clinical trials, regardless of the causal relationship with fludarabine, according to the following frequency gradation: very often (more than 10%), often (more than 1% but less than 10%), infrequently (more 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, 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 can develop.

From the nervous system: often peripheral neuropathy; infrequently - confusion of consciousness; rarely excitation, convulsions, coma.

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 and skin appendages: often - skin rash; rarely Stevens-Johnson syndrome, 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 - an increase in body temperature, increased fatigue, weakness, attachment of secondary infections; 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:

When using high doses of fludarabine, it is possible to develop irreversible changes in the central nervous system, loss of vision, coma and death, as well as the development of severe thrombocytopenia and neutropenia due to 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:

The use of fludarabine in combination with pentostatin (deoxycoformylin) for the treatment of CLL has often led to death due to high pulmonary toxicity.

The therapeutic efficacy of fludarabine can be reduced by adenosine reuptake inhibitors and dipyridamole.

When treated with a combination of fludarabine and cytarabine in patients with CLL and AML, pharmacokinetic interaction was observed.

When co-administration of cytarabine with fludarabine is combined, higher intracellular peak 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 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 is used, it is recommended that peripheral blood levels be periodically assessed for anemia, neutropenia and thrombocytopenia, carefully monitor serum creatinine and creatinine clearance, and closely monitor CNS functions to identify possible neurological disorders in a timely manner.

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.

If further transplantation of hematopoietic stem cells is envisaged, caution should be exercised in the administration of fludarabine, which refers to cytotoxic substances.

Transfusion of non-irradiated blood to patients receiving fludarabine treatment, the development of the "graft versus host" reaction (the reaction of transfused immunocompetent lymphocytes against the host) was observed, which is associated with a high incidence of lethal outcomes. Patients in need of blood transfusion and receiving or receiving fludarabine, only irradiated blood should be transfused.

decay Syndrome tumor arising in the treatment fludarabine, was observed in patients with CLL, having 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 a history of autoimmune processes, and also from the results of sample Coombs exists the risk of life-threatening autoimmune reactions (autoimmune hemolytic anemia, autoimmune thrombocytopenia, thrombocytopenic purpura, pemphigus, Evans' syndrome) during or after treatment with fludarabine. A repeated hemolytic process is possible after the resumption of treatment with fludarabine. Patients receiving fludarabineshould be carefully observed for hemolysis. With the development of hemolysis, discontinuation of therapy is recommended. The most commonly used therapeutic measures for the treatment of autoimmune hemolytic anemia - Blood transfusion (irradiated) and 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.

Use only a clear and colorless solution that does not contain any visible solid particles. In case of damage to the container, the drug is not used.

The chemical and physical stability of the solution prepared for injection or infusion is maintained for 3 days at 25 ° C or in a refrigerator (2-8 ° C) when the concentrate is diluted with 0.9% sodium chloride solution for infusion or 5% dextrose solution for infusion. From the point of view of microbiological purity, the diluted solution should be used immediately, it is allowed to store dilute solution in the refrigerator (2-8 ° C) for no more than 24 hours.

When working with fludarabine, the rules for handling cytotoxic drugs should be observed. Avoid contact with solution! If the solution comes into contact with the skin, mucous membranes or 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:

Concentrate for the preparation of a solution of the day of intravenous administration, 25 mg / ml.

Packaging:

2.0 ml of clear colorless vials of glass type I (Eur. Pharm.) With bromobutyl rubber stoppers and aluminum caps provided with a protective cover made of colored polypropylene. 1 bottle, covered with a film of transparent PVC / polietiyaeva, together with instructions for use in a cardboard package.

When packing kit # 1

LLC MC "Ellara" or SIO "Ellara"

2.0 ml of clear colorless vials of glass type I (Eur Pharm..) With bromobutyl rubber stoppers and aluminum caps provided with a protective cover made of colored polypropylene; 1 bottle, covered with a transparent film of PVC / polyethylene, together with instructions for use in a cardboard bundle.

1 cardboard pack and device elements for infusion systems and syringes for breeding andintroduction of medicinal products "Tevadaptor" (adapter to the bottle, adapter to the syringe, connecting device, instructions for using the device) in a cardboard box with a corrugated cardboard box sealer, boxed or without it. Control of the first opening of the cardboard box is a transparent oval sticker with the TEVA logo.

When packing kit number 2

Open Company MC "Ellara" or Open Company "Ellara"

By 2.0 ml in bottles of transparent colorless glass type I (Hev.Pharm.) With plugs of bromobutyl rubber and aluminum collapses, protected with a lid of colored polypropylene; 1 bottle, covered with a transparent film of PVC / polyethylene, together with instructions for use in a cardboard bundle.

1 carton pack and elements of the device for infusion systems and syringes for the dilution and administration of medicinal products "Tevadaltor" (adapter to the bottle, adapter for the syringe, adapter for the injection of the syringe, instruction for the use of the device) in a cardboard box with corrugated cardboard box sealer or without him. Control of the first opening of the cardboard box is a transparent oval sticker with the TEVA logo.

Storage conditions:

Store at a temperature of 2 to 8 ° C in a dark place. Do not freeze.

Keep out of the reach of 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:LSR-007033/09

Date of registration:04.09.2009

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

PHARMACHEMIE, B.V. Netherlands

Representation: & nbspTeva Teva Israel

Information update date: & nbsp26.09.2015

Illustrated instructions

Instructions

Fludarabine-Teva (Fludarabine-Teva)