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

The preparation Fludara® contains fludarabine phosphate, a fluorinated nucleotide analogue of the antiviral agent vidarabine, a 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 is captured by cells, then intracellularly phosphorylated to 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.

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:

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

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. Binding to blood plasma proteins is negligible.

2-Fluoro-ara-A is excreted mainly by the kidneys.

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 concentration of 2-fluoro-ara-ATP in leukemia cells was significantly higher than its maximum concentration in the plasma, indicating a cumulation of the substance in the tumor cells. The half-life of 2-fluoro-ara-ATP from the target cells averages from 15 to 23 hours.

After a single intravenous infusion of patients with CLL 2-fluoro-ara-AMP in a dose of 25 mg / m² within 30 minutes the maximum concentration (C_max) in the blood plasma of 2-fluoro-ara-A is 3.5-3.7 μmol / l 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 / L by the end of infusion. During the 5-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. After the end of the infusion, a three-phase decrease in concentration with a half-life (T₁_/₂) of the initial phase of 5 min, T1/2 an intermediate phase of 1-2 h and T₁_/₂The study 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 the blood plasma and the area under the concentration-time curve (AUC) increase in linear dependence on the dose, whereas T₁_/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 intravenously administered dose).

In patients 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 (as first-line therapy). Therapy with Fludara®as first-line therapy can be initiated only in patients with progressive disease (stage C by classification Binet or steps III/IV by classification Rai), or in stages A/ B by classification Binet or stages I/II by classification Raiwhen symptoms and signs of disease progression are observed;

- B-cell chronic lymphocytic leukemia (in patients who are resistant to therapy with alkylating agents, or who have progression of the disease during or after using at least one standard regimen containing alkylating drugs);

- low-grade non-Hodgkin's lymphomas (for treatment of patients who are resistant to alkylating drugs or who have progression of the disease during or after treatment with at least one standard regimen containing alkylating drugs).

Contraindications:

- Hypersensitivity to fludarabine or other components of the drug;

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

- decompensated hemolytic anemia;

- pregnancy (see section "Application during pregnancy and during breast-feeding");

- the period of breastfeeding;

- children's age (lack of sufficient clinical data on efficacy and safety).

Carefully:

The drug Fludara® should be used with caution after a thorough assessment of the risk / benefit ratio:

- in patients in a weakened state (especially in patients with severe impairment of bone marrow function [thrombocytopenia, anemia and / or granulocytopenia], patients with immunodeficiency or with opportunistic infections in the anamnesis);

- in elderly patients over the age of 75;

- in patients with renal insufficiency (creatinine clearance 30-70 ml / min);

- in patients with hepatic insufficiency.

Pregnancy and lactation:

Pregnancy

The use of the drug Fludara® is contraindicated during pregnancy. Women of childbearing age should avoid conception and use reliable contraceptive methods during treatment and at least 6 months after the end of Fludara® therapy.

Breastfeeding period

Do not start breastfeeding while taking Fludara®. If it is necessary to use the drug, breastfeeding women should stop breastfeeding.

Dosing and Administration:

Treatment with Fludara^® should be conducted under the supervision of a doctor who has experience in the use of antitumor therapy.

The drug Fludara^® should be administered only intravenously. There were no reports of the occurrence of severe local adverse reactions with the administration of the preparation Fludara^® extravagantly. However, it is necessary to avoid accidental extravascular administration of the drug.

The recommended dose of fludarabine phosphate is 25 mg / m² 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 0.9% sodium chloride solution and injected intravenously bolus. Alternatively, for intravenous infusion, the required dose collected in the syringe is diluted in 100 ml of 0.9% sodium chloride solution and injected intravenously for about 30 minutes.

The drug does not contain antimicrobial preservatives.Therefore, from a microbiological point of view, the solution should be used immediately after preparation. If it was not used immediately after preparation, the user is responsible for the terms and conditions of storage. Normally, do not store the prepared solution for more than 24 hours at a temperature of 2 ° C to 8 ° C or 8 hours at room temperature.

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

Patients with chronic lymphocytic leukemia Fludara^® should be applied until the maximum response is achieved (complete or partial remission, usually 6 cycles), after which the treatment should be discontinued.

In patients with non-Hodgkin's lymphoma a low degree of malignancy, treatment with Fludara® is recommended until the maximum response is achieved (complete or partial remission). After achieving the greatest effect, consideration should be given to the need for two consolidation cycles. According to clinical trials with low-grade non-Hodgkin's lymphoma, most patients received no more than 8 treatment cycles.

Children

The drug Fludara® is not recommended for use in children under the age of 18 because there is insufficient data on the effectiveness and safety of its use in this category of patients.

Elderly patients

Since there are limited data on the use of Fludara® in elderly patients (over 75 years of age), the drug should be used with caution in this category of patients (see the sections "With caution" and "Special instructions").

Patients with impaired renal function

In patients with impaired renal function, dose adjustment is necessary. When creatinine is cleared from 30 to 70 ml / min, a dose of 50% should be reduced and thorough hematological control should be performed to assess toxicity (see "With caution" and "Special instructions").

When creatinine clearance <30 ml / min, the use of the drug Fludara ® is contraindicated.

Patients with hepatic impairment

The safety and efficacy of Fludara® have not been studied in patients with hepatic impairment. Caution should be exercised when using fludarabine in this group of patients (see "With caution").

Side effects:

The incidence of adverse reactions is indicated on the basis of clinical trial data, regardless of the causal relationship with the use of the preparation Fludara®, according to the classification recommended by the World Health Organization: very often (≥10%), often (<10% - ≥1%) , infrequently (<1% - ≥0.1%), rarely (<0.1% - ≥ 0.01%), the frequency is unknown (based on available data it is impossible to estimate the incidence of side effects).

Infectious and parasitic diseases: very often - infections / opportunistic infections (eg, reactivation of latent viral infections, including those caused by the virus Herpes zoster, Epstein-Barr virus, as well as progressive multifocal leukoencephalopathy), pneumonia; rare-lymphoproliferative disorders (associated with the Epstein-Barr virus).

Benign, malignant and unspecified neoplasms (including cysts and polyps): often - myelodysplastic syndrome and acute myelogenous leukemia (mainly associated with preliminary, concomitant or subsequent treatment with alkylating agents, topoisomerase inhibitors or radiation therapy).

Violations of the blood and lymphatic system: very often - neutropenia, thrombocytopenia, anemia; often - myelosuppression.

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

Disorders from the gastrointestinal tract: very often - nausea, vomiting, diarrhea; often - stomatitis; infrequently - the deviation from the norm of indicators of the activity of pancreatic enzymes.

Disturbances from the liver and bile ducts: infrequently - the deviation from the norm of liver enzymes activity.

Disorders from the metabolism and nutrition: often - anorexia; infrequently, tumor lysis syndrome (as a result of tumor lysis hyperuricemia, hyperphosphataemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria and renal failure may develop).

Disturbances from the nervous system: often peripheral neuropathy; infrequently - confusion of consciousness; rarely - agitation, convulsions, coma.

Disturbances on the part of the organ of sight: often - visual impairment; rarely - optic neuritis, optic nerve neuropathy, blindness.

Disturbances from the respiratory system: very often - cough; infrequent - pulmonary toxicity (including dyspnea, pulmonary fibrosis, pneumonitis).

Heart Disease: rarely - heart failure, arrhythmia.

Vascular disorders: infrequently, gastrointestinal bleeding.

Disturbances from the skin and subcutaneous tissues: often - skin rash; rarely - skin cancer, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

General disorders: very often - an increase in body temperature,

increased fatigue, weakness; often - chills, malaise, swelling, mucositis.

Post-registration data

Impaired nervous system: frequency unknown - leukoencephalopathy, acute toxic leukoencephalopathy, reversible back leukoencephalopathy syndrome (SWDD) (see "With caution" and "Special instructions").

Vascular disorders: frequency unknown - bleeding (including cerebral hemorrhage, pulmonary hemorrhage, hemorrhagic cystitis).

Overdose:

Application in doses exceeding recommended, the drug Floodar® causes the development of leukoencephalopathy, acute toxic leukoencephalopathy or a syndrome of reversible posterior encephalopathy. Symptoms may include headache, nausea, vomiting, seizures, visual impairment (such as loss of vision), sensitivity disorder and focal neurological gypsy symptom, as well as optic neuritis and papillitis, confusion, drowsiness, agitation, paraparesis / quadrupause, muscle spasticity and incontinence, irreversible changes in the central nervous system, including blindness, coma and death. The use in doses exceeding the recommended ones is also associated with the development of severe thrombocytopenia and neutropenia due to the suppression of bone marrow function.

Specific antidote for an overdose of the drug Fludara^® is unknown. Treatment consists in stopping the administration of the drug and conducting maintenance therapy.

Interaction:

- With pentostatin

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

- With dipyridamole

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

- With cytarabine

Clinical studies and research in vitro showed that the use of fludarabine in combination with cytarabine may increase the concentration ara-CTF (an active metabolite of cytarabine) in leukemia cells. The concentration of cytarabine in the blood plasma and the rate of its excretion remained unchanged.

Compatibility

A solution of Fludara® for intravenous use should not be mixed with other drugs.

Special instructions:

When treating with Fludara®, periodic evaluation of peripheral blood parameters is recommended to detect anemia, neutropenia and thrombocytopenia, carefully monitor serum creatinine and creatinine clearance, and closely monitor the central nervous system (CNS) function in order to identify possible neurological disorders in a timely manner .

Neurotoxicity

When high doses were used in studies to determine the optimal doses in patients with acute lymphocytic leukemia, the use of Fludar's drug was associated with the development of severe neurologic symptoms, including blindness, coma, and death. These symptoms developed within 21 to 60 days after the last dose and were observed in approximately 36% of patients with Fludara® intravenously at doses about 4 times the recommended dose (96 mg / m² body surface / day for 5-7 days). In patients taking Fludara® in the dose range recommended for the treatment of chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphoma, severe toxic symptoms from the central nervous system were rarely observed (coma, agitation and convulsions) or infrequent (confusion) (see "Side act").

The effect of prolonged use of the drug Fludara® on the CNS is unknown. However, in some studies, it has been shown that, with a relatively long-term use (up to 26 courses of therapy), the preparation of Fludara® was tolerated satisfactorily by patients.Patients should be closely monitored for neurological symptoms. The use of the preparation Fludara® may be associated with the development of leukoencephalopathy, acute toxic leukoencephalopathy or reversible reversible leukoencephalopathy syndrome (COPD).

These diseases can develop:

- when administered at the recommended doses:

a) when Fludara® is used after or in combination with drugs, the use of which also leads to the development of leukoencephalopathy, acute toxic leukoencephalopathy or COPD;

b) or when the Fludara® drug is used in patients with risk factors such as cranial irradiation or total body total irradiation, hematopoietic cell transplantation, graft versus host, kidney failure, or hepatic encephalopathy.

- when administered at doses exceeding the recommended dose.

Symptoms of leukoencephalopathy, acute toxic leukoencephalopathy or COPD may include headache, nausea and vomiting, convulsions, visual disturbances (such as loss of vision), impaired sensation, focal neurological symptoms,as well as optic neuritis and papillitis, confusion, drowsiness, agitation, paraparesis / quadraparesis, muscle spasticity and incontinence.

Leukoencephalopathy, acute toxic leukoencephalopathy and COPD can be irreversible, life-threatening or fatal.

If there is a suspicion of leukoencephalopathy, acute toxic leukoencephalopathy or COPD, treatment with fludarabine should be discontinued. Patients should be under the supervision of medical personnel, they need to do a brain imaging, preferably an MRI. If the diagnosis is confirmed, then fludarabine therapy should be discontinued forever.

Patients in a weakened state

In patients with a weakened condition, the Fludara® preparation should be used with caution and after a thorough assessment of the risk / benefit ratio. This is especially important for patients with severe impairment of bone marrow function (thrombocytopenia, anemia and / or granulocytopenia), immunodeficiency or opportunistic infections in the anamnesis.

Against the background of therapy with the drug Fludara®, 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.

Myelosuppression

Patients receiving treatment with Fludara® showed severe oppression of bone marrow function, severe anemia, thrombocytopenia and neutropenia. When treatment with Fludara ® solid tumors in adults, the largest decrease in the number of neutrophils was observed on average on the 13th day (day 3-25) from the start of treatment, platelets - on average on the 16th day (2-32 days) . Most patients had hematologic disorders that were associated with either the disease or previous mielosupressivnoy therapy. Cumulative myelosuppression may be observed. Although myelosuppression, induced by chemotherapy, is often reversible, the administration of fludarabine requires careful hematological control.

There have been reports of several cases of development in adult patients of trilinear hypoplasia or bone marrow aplasia, manifested by pancytopenia, sometimes fatal. The duration of clinically significant cytopenia in these cases ranged from approximately 2 months to 1 year.These episodes manifested itself in pre-treated patients, as well as in untreated patients.

Progression of the disease

Progression of the disease and its transformation (eg, Richter's syndrome) were usually observed in patients with chronic lymphocytic leukemia.

The "graft versus host"

The "graft versus host" reaction (the reaction of the transfused immunocompetent lymphocytes against the host) resulting from blood transfusions was observed after transfusion of the unirradiated blood components to patients treated with the Fludara® preparation. 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 have received treatment with the drug Fludara®, only irradiated blood components should be transfused.

Skin cancer

In patients during or after therapy with Fludara®, there was a worsening or aggravation of already existing tumor lesions of the skin, as well as the development of new malignant skin tumors.

Tumor lysis syndrome

The development of tumor lysis syndrome has been reported, especially with a large tumor mass.Since the preparation of Fludara® can cause tumor lysis in the first week of therapy, care should be taken in treating patients at risk of developing this syndrome.

Autoimmune diseases

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 diseases (autoimmune hemolytic anemia, autoimmune thrombocytopenia, thrombocytopenic purpura, pemphigus, Evans syndrome) during or after drug treatment Fludara®. Most patients with hemolytic anemia experienced recurrence of hemolysis after repeated use of the preparation Fludara®.

Patients treated with Fludara® should be carefully observed to identify hemolysis symptoms. If hemolysis develops, discontinuation of Fludara® therapy is recommended. The most common therapeutic measures for hemolytic anemia are transfusion of irradiated blood and glucocorticosteroid therapy.

Renal impairment

There are limited clinical data on the use of the preparation Fludara for the treatment of patients with impaired renal function (creatinine clearance <70 ml / min). The drug Fludara® should be used with caution in patients with renal insufficiency. In patients with impaired renal function of moderate severity (creatinine clearance 30-70 ml / min), the dose should be reduced by 50% and careful monitoring of patients (see section "Method of administration and dose"). Treatment with Fludara® is contraindicated if creatinine clearance <30 mL / min.

Elderly patients

Due to limited data on the use of Fludara® in elderly patients (> 75 years), the drug should be used with caution in this category of patients. In patients 65 years of age and older, it is necessary to control the clearance of creatinine before starting treatment.

Vaccination

During and after treatment with Fludara®, vaccination with live vaccines should be avoided.

Repeated course of treatment after initial therapy with Fludara®

Patients who have primary therapy with Fludara^® was effective, have good chances of a second response with monotherapy with Fludara®.

The transition from initial Fludara® therapy to chlorambucil in patients who did not respond to Fludara® therapy, as patients resistant to Fludara® therapy in most cases show resistance to chlorambucil.

Other Warnings

Fertile women and men should use reliable methods of contraception during treatment and at least 6 months after the end of therapy.

Rules for handling Fludara®

When handling Fludara®, all instructions adopted for the use and destruction of cytotoxic drugs should be followed. Avoid inhalation of the drug. Use of goggles and latex gloves is recommended to avoid contact in the event of damage to the vial or other accidental loss 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.

Pregnant women should not work with Fludara®.

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,Excitement can adversely affect the ability to drive and perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions. When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:

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

Packaging:

50 mg in a bottle sealed with a stopper, covered with an aluminum cap with a colored plastic cover.

5 bottles placed in pallets (cardboard inserts), along with the instruction is placed in a cardboard box.

Storage conditions:Store at temperature not higher than 30 ° С.

Keep out of the reach of children.

Shelf life:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:П N013522 / 01

Date of registration:07.08.2007

Date of cancellation:2017-06-23

The owner of the registration certificate:Genzyme Europe BVGenzyme Europe BV Netherlands

Manufacturer: & nbsp

BAYER PHARMA, AG Germany

GENZYME, Ltd. United Kingdom

Representation: & nbspJENZAIM RUS LLCJENZAIM RUS LLCRussia

Information update date: & nbsp23.06.2017

Illustrated instructions

Instructions

Fludara® (Fludara®)