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

Fludarabine is an antitumor drug that contains fludarabine, which is a water-soluble fluorinated nucleotide analogue of an antiviral agent of the form of arabin, a 9-2-Darabinofuranosyladenine (ara-A), relatively stable to the action of denosine deaminase.

Fludarabine is rapidly dephosphorylated to 2-fluoro-ara-A, which is captured by cells, then intracellularly phosphorylated by deoxycytidine kinase to 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 (2-fluoro-ara-AMP) is a water-soluble precursor of fludarabine (2-fluoro-ara-A). In humans, 2-fluoro-ara-AMP is 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_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_max 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_max in plasma levels of 2-fluoro-ara-A are reduced in three phases: the half-life of the elimination (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 (2.4 ± 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 administration, the concentration of 2-fluoro-ara-A in plasma and the area under the concentration-time curve (AUC) increase linearly with 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, in part, 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 leukemia cells is 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.

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 total clearance of the drug, which indicates the need to reduce the dose.

Indications:

- B-cell chronic 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;

- period of pregnancy;

- lactation period;

- Children's age (lack of sufficient data on effectiveness and safety).

Carefully:

After a thorough assessment of the condition, the risk / benefit fludarabine should be used in weakened patients, with a marked decrease in bone marrow function (thrombocytopenia, anemia and / or granulocytopenia), renal or hepatic insufficiency, immunodeficiency, opportunistic infections in amnesia, in patients older than 75 years.

Pregnancy and lactation:

Contraindicated. The drug may have embryotoxic and teratogenic effects.

For the duration of treatment, breastfeeding should be discontinued.

Dosing and Administration:

It is allowed only intravenous administration of fludarabine, while avoiding its random extravascular exposure.The drug is administered intravenously by drip or jet.

Adults: the recommended dose of fludarabine is 25 mg / m² body surface intravenously 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 jet administration of the drug, this dose is diluted in 10 ml of 0.9% sodium chloride solution. Also, the required dose can be diluted in 100 ml of a 0.9% solution of sodium chloride and injected drip 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 liver 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, impaired renal function and in persons older than 70 years, the definition of creatinine clearance is required. 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 incidence of adverse events is indicated on the basis of clinical trial data, regardless of the cause-and-effect relationship with fludarabine, according to the following gradation: very often (≥10%), often (<10% but ≥1%), infrequently (<1 %, but ≥0.1%), rarely (<0.1%, but ≥0.01%).

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

On the part of the organs of 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 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.

Dermatological reactions: 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.

Allergic reactions: rarely anaphylactic shock.

Overdose:

Symptoms: psychomotor agitation, dizziness, general weakness, lowering blood pressure, tremor, tonic-clonic convulsions, coma, collapse, development of atrioventricular block, central nervous system depression, respiratory arrest.

Treatment: when the first signs of intoxication appear, the drug is discontinued, the patient is transferred to a horizontal position and oxygen therapy is performed.Prescribe symptomatic therapy: anticonvulsants, vasoconstrictors (norepinephrine, mezaton), with bradycardia - holinolitiki (atropine), stimulation of excretion with the help of forced diuresis. If necessary, an artificial ventilation, resuscitation measures. Dialysis is ineffective.

Interaction:

Solution for intravenous administration is incompatible in one syringe with solutions of other medicines.

Incompatible with 2-dezsikokomizitsinom (pentostatin) due to possible severe lung damage up to a lethal outcome.

The therapeutic efficacy of the drug can be reduced by dipyridamole and other inhibitors of adenosine reuptake.

Urikozuric drugs increase the risk of developing nephropathy.

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

Special instructions:

The solution for intravenous administration should not be mixed with other drugs.

The freshly prepared solution of the preparation is stable for 8 hours at room temperature.

Preliminary injection of anti-emetics is optional.

The duration of treatment depends on the effect and tolerability of the drug. In patients with CLL, the treatment is continued until the maximum improvement is achieved (complete or partial remission, usually after 6 cycles), then the drug is withdrawn. Have

patients with NHL treatment should be treated until the maximum response (complete or partial remission) is achieved. After achieving the greatest effect, the need for two consolidation cycles should be discussed. In most cases, no more than 8 treatment cycles are required.

The drug should be administered under the supervision of a qualified physician with experience in antitumor therapy. After careful assessment of the risk / benefit relationship with caution, the drug should be used in weakened patients with a marked decrease in bone marrow function (thrombocytopenia, anemia and / or granulocytopenia), renal or hepatic insufficiency, immunodeficiency, opportunistic infections in the anamnesis, in patients older than 75 years .It is necessary to monitor the concentration of creatinine in the serum and the creatinine clearance.

Treatment should be carried out under careful clinical and hematological control. Since one of the most common side effects of the drug is myelosuppression, periodic peripheral blood testing is recommended to detect the development of neutropenia, anemia and thrombocytopenia in patients. Patients receiving fludarabine treatment should also be carefully observed for symptoms of nonhematological (primarily neurological) toxicity. Effects of prolonged use of fludarabine on the central nervous system 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.

On the background of fludarabine therapy, 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.

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

Careful observation of patients receiving fludarabine treatment should be conducted to determine the signs of hemolytic anemia (a decrease in hemoglobin and a positive Coombs test). 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.

With transfusion of untreated blood, patients receiving fludarabine treatment experienced a "graft-versus-host" reaction in a number of cases, characterized by a high incidence of fatalities. In this regard, patients who need hemotransfusions and who receive or received treatment with fludarabine, only irradiated blood should be transfused.

During and after treatment with the drug, vaccination with live vaccines should be avoided. It should be borne in mind that patients who are resistant to Fludara therapy,in most cases, they show resistance to chlorambucil.

It should be observed rules for the use and destruction of cytotoxic agents: use caution when preparing infusion solutions of the drug, use rubber gloves and goggles, avoid inhaling the drug; if the product gets on the skin, these areas should be washed with soap and water, and after contact with eyes, rinse thoroughly with plenty of water. The remaining drug must be destroyed by burning.

During treatment with the drug, and also within 6 months after its termination, reliable methods of contraception should be used. Pregnant women are not allowed to work with fludarabine (concerns medical personnel).

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

Some of the side effects of fludarabine, such as increased fatigue, weakness, visual impairment, can adversely affect the ability to drive and perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:

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

Packaging:

50 mg per ampoule / vials.

For 5 or 10 ampoules with instructions for use and a scarifier ampullum is placed in a pack of cardboard. When using ampoules with a break ring, it is allowed to pack the ampoules without an ampoule scarifier. Each bottle together with the instruction on is placed in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 5 ° 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:LP-000582

Date of registration:13.09.2011

Date of cancellation:2016-09-13

The owner of the registration certificate:BELMEDPREPARATY, RUP BELMEDPREPARATY, RUP Republic of Belarus

Manufacturer: & nbsp

BELMEDPREPARATY, RUP Republic of Belarus

Information update date: & nbsp26.09.2015

Illustrated instructions

Instructions

Fludarabine (Fludarabine)