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

Excipients: lactose monohydrate - 60.0 mg, corn starch - 9.0 mg, crospovidone - 3.0 mg, magnesium stearate - 1.5 mg, silicon dioxide colloid - 0.75 mg, microcrystalline cellulose - up to 150.0 mg;

Shell composition: hypromellose - 1.39 mg, titanium dioxide - 0.72 mg, iron dye oxide yellow - 0.06 mg, macrogol 400 - 0.33 mg.

Description:

Round, biconvex tablets, covered with a film coating of yellow color. On the cross-section the nucleus is white.

Pharmacotherapeutic group:Antitumor agent - antimetabolite

ATX: & nbsp

L.01.B.B.05 Fludarabine

Pharmacodynamics:

The drug Fludarabel^® fludarabine phosphate as active substance, water-soluble fluorinated nucleotide analogue of the antiviral agent vidarabin, 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.

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, and the frequency of detection of neutropenia and changes in hematocrit is dose-dependent.

Fludarabine phosphate (2-fluoro-ara-AMP) in the human body 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 leukemia cells, after which it is re-phosphorylated to monophosphate and partially to di- and triphosphate. Triphosphate (2-fluoro-a-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 oral administration, the maximum concentration (C_mOh) (20-30% of the concentration determined by the end of intravenous infusion) in the blood is observed after 1-2 hours. Bioavailability is 50-65%. Food slightly (less than 10%) increases the area under the concentration-time curve (AUC) and decreases T_mOh (time to reach the maximum concentration) and C_mOh does not change the half-life.

In chronic renal failure, the clearance of 2-fluoro-ara-A decreases.

Indications:

- B-cell chronic lymphocytic leukemia (CLL) (as first-line therapy).

Therapy with Fludarabel® as first-line therapy can be initiated only in patients with progressive disease (stage B of the Binet classification or stage III / IV of the Rai classification), or in A / B stages according to the Binet classification or I / II stages in the Rai classification , when 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 the administration of at least one standard regimen containing alkylating drugs).

- Non-Hodgkin's lymphomas are of low degree of malignancy.

- Follicular B-cell lymphomas.

- Lymphomas from the cells of the mantle zone.

Contraindications:

- Hypersensitivity to the drug or its components;

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

decompensated hemolytic anemia;

- pregnancy;

- the period of breastfeeding;

- children under 18 years of age (lack of sufficient clinical data).

Carefully:

The drug Fludarabel^® should be used with caution (after a thorough assessment of the risk / benefit ratio) in patients:

- elderly (over 75 years),

- with hepatic insufficiency,

- with renal insufficiency (creatinine clearance 30-70 ml / min),

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

- with lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome (since the drug contains lactose).

Pregnancy and lactation:

Pregnancy

Use of the drug Fludarabel® 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 Fludarabel® therapy.

Breastfeeding period

Do not start breastfeeding during treatment with Fludarabel®. If you need to use the drug Fludarabel ®, breastfeeding women should stop breastfeeding.

Dosing and Administration:

Treatment with Fludarabel® should be performed under the supervision of a physician with experience in the use of antitumor therapy.

The recommended dose for oral administration is 40 mg / m² body surface, daily, for 5 days, every 28 days.

The number of tablets to be taken should be determined from Table 1.

Table 1

Body surface area (PPT) [m²]	The total daily dose is calculated according to the PPT (rounded to the nearest integer) [mg / day]	Number of tablets per day (total daily dose)
0,75-0,88	30-35	3 (30 mg)
0,89-1,13	36-45	4 (40 mg)
1,14-1,38	46-55	5 (50 mg)
1,39-1,63	56-65	6 (60 mg)
1,64-1,88	66-75	7 (70 mg)
1,89-2,13	76-85	8 (80 mg)
2,14-2,38	86-95	9 (90 mg)
2,39-2,50	96-100	10 (100 mg)

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

The drug Fludarabe® should be used until the maximum response is achieved (complete or partial remission, usually 6 cycles), after which the treatment should be discontinued.

Patients taking the drug Fludarabel® require strict clinical monitoring to assess response and toxicity.

The individual dose should be carefully adjusted in accordance with the observed hematological toxicity data.

If, at the beginning of the subsequent treatment cycle, the number of blood cells is excessively low for the recommended dose and if there is a probability of suppression of bone marrow function in connection with treatment, the planned treatment cycle should be postponed until the amount of granulocytes reaches a value greater than 1x10⁹/ l, and the number of platelets - more than 100x10⁹/ l.

Treatment can be delayed for a maximum of 2 weeks. If the amount of granulocytes and platelets does not recover within 2 weeks after a pause, the dose should be reduced in accordance with the recommended doses given in Table 2.

table 2

Granulocytes and / or platelets [10⁹/ l]		The dose of fludarabine phosphate
0,5 - 1	50-100	30 mg / m²/day
<0,5	<50	20 mg / m²/day

Do not reduce the dose of the drug if thrombocytopenia is associated with the disease.

If the patient's condition does not change after 2 weeks of treatment, there is no detectable or very low hematological toxicity, careful dose adjustment with an increase in the dose of Fludarabel® in subsequent cycles of treatment can be considered.

Tablets Fludarabel ® can be taken as an empty stomach, and at the same time with food intake.

Tablets should be swallowed whole (do not chew, do not break), washing down with water.

Special patient groups

Patients with impaired renal function

In patients with impaired renal function, dose adjustment is necessary. In case of creatinine clearance from 30-70 ml / min, the dose of the drug should be reduced by 50% and thorough hematological control should be performed to assess toxicity (see sections "Precautions for Use" and "Special Instructions").

When creatinine clearance <30 ml / min, the use of the drug Fludarabel ® is contraindicated (see the section "Contraindications").

Patients with impaired hepatic function

The safety and effectiveness of the use of the drug Fludarabel® have not been studied in patients with impaired liver function. Caution should be exercised when using Fludarabe ® in this group of patients (see section "Precautions for Use").

Elderly patients

Since data on the use of the drug Fludarabe® in elderly patients (> 75 years) are limited, care should be taken with the drug Fludarabel® in this category of patients.

In patients over 65 years of age, creatinine clearance should be measured.section "Special instructions").

Side effects:

Possible side effects are given below for the body systems and frequency of occurrence: very often (≥1 / 10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, <1/100), rarely (≥ 1/10000, <1/1000), very rarely (<1/10000), the frequency is unknown (can not be estimated from available data).

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;

rarely - 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 previous, 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 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;

frequency unknown - leukoencephalopathy, acute toxic leukoencephalopathy, reversible leukoencephalopathy syndrome (COPD), cerebral hemorrhage.

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;

frequency unknown - bleeding (including cerebral hemorrhage, pulmonary hemorrhage, haemorrhagic cystitis).

Disorders from the gastrointestinal tract:

very often - nausea, vomiting, diarrhea; often - stomatitis, mucositis;

infrequently - gastrointestinal bleeding, deviation from the norm of the activity indices of pancreatic enzymes.

Disturbances from the liver and bile ducts:

infrequently - the deviation from the norm of liver enzymes activity.

Disturbances from the skin and subcutaneous tissues:

often - skin rash;

rarely - skin cancer, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

General disorders and disorders at the site of administration:

very often - an increase in body temperature, increased fatigue, weakness;

often - chills, malaise, swelling, mucositis.

Overdose:

When used in doses exceeding the recommended levels, fludarabine causes the development of leukoencephalopathy, acute toxic leukoencephalopathy or a syndrome of reversible posterior encephalopathy. Symptoms may include headache, nausea, vomiting, convulsions,visual disturbances (such as loss of vision), impaired sensitivity and focal neurological symptoms and optic neuritis and papillitis, confusion, drowsiness, agitation, paraparesis / kvadroparez, spasticity and incontinence, irreversible changes in the central nervous system, which include blindness, to whom and death. The use of the drug 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.

A specific antidote overdose fludarabine unknown. Treatment consists in stopping the drug or maintenance therapy.

Interaction:

With peptostatin

Use in combination with fludarabine pentostatin (dezoksikoformitsinom) for the treatment of chronic lymphocytic leukemia (CLL) often leads to death due to high pulmonary toxicity. Therefore, the use Fludarabel® drug 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 of ara-CTF (the active metabolite of cytarabine) in leukemia cells. The concentration of cytarabine in plasma and the rate of its excretion remained unchanged.

Special instructions:

When treating with Fludarabel®, periodic evaluation of peripheral blood parameters is recommended to detect anemia, neutropenia and thrombocytopenia, carefully monitor serum creatinine and creatinine clearance, and monitor closely 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, fludarabine 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 intravenous fludarabine at doses approximately four times the recommended dose (96 mg /m² body surface / day for 5-7 days).In patients receiving fludarabine in a dosage range recommended for the treatment of chronic lymphocytic leukemia and non-Hodgkin's lymphoma, low-grade, heavy toxic lesions of the central nervous system were observed rarely (> 1/10000 - <1/1000) (coma, seizures and agitation) or infrequently (> 1 / 1000 - <1/100) (confusion) (see "Side effects").. The effect of prolonged use of fludarabine on the CNS is unknown. However, it was in some studies have shown that at relatively prolonged use (up to 26 treatments) fludarabine was tolerated satisfactorily by patients. Patients should be closely monitored for neurological symptoms.

Application fludarabine may be associated with the development leukoencephalopathy, leukoencephalopathy or acute toxic syndrome reversible rear leukoencephalopathy (SLDF).

These diseases can develop:

- when used at recommended doses;

when fludarabine It used after or in combination with drugs whose use also leads to the development leukoencephalopathy, acute toxic SLDF or leukoencephalopathy;
or when fludarabine is used in patients with risk factors, such as: cranial irradiation or total (total) whole-body 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 / quadroparesis, muscle spasticity and incontinence.

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

If suspected of leukoencephalopathy, acute toxic leukoencephalopathy or COPD, fludarabine treatment 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 in a weakened state fludarabine 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. 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.

Myelosuppression

In patients receiving fludarabine treatment, severe inhibition of bone marrow function, severe anemia, thrombocytopenia and neutropenia were noted. In fludarabine therapy of solid tumors in adults, the largest decrease in the number of neutrophils was observed on average on the 13th day (3-25 days) from the start of treatment, platelets on the 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 myelosuppressure induced by chemotherapy is often reversible, the use 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 2 months to 1 year. These episodes manifested themselves in previously 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"

Reaction "graft versus host" (reaction transfuziruemyh immunocompetent lymphocytes against the "host"), resulting from blood transfusions, observed after transfusion of blood components unirradiated patients treated with fludarabine. A high incidence of fatalities has been reported as a consequence of this disease.In this regard, patients who require blood transfusion and which is prepared or treated fludarabine, only irradiated blood components to be transfused.

Skin cancer

In patients during or after treatment with fludarabine marked deterioration or exacerbation of pre-existing tumor lesions, as well as the development of new skin cancer.

Tumor lysis syndrome

The development of tumor lysis syndrome has been reported, especially with a large tumor mass. As 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.

Autoimmune phenomena

Is independent of the presence or absence of a history of autoimmune processes, and results Coombs, it described the occurrence of life-threatening, and sometimes fatal autoimmune disease (e.g., autoimmune hemolytic anemia, autoimmune thrombocytopenia, thrombocytopenic purpura, pemphigus, Evans' syndrome). In most patients with hemolytic anemia, recurrent hemolysis was noted after repeated use of fludarabine.

Patients receiving fludarabine treatment should be carefully observed to identify hemolysis symptoms. In the case of hemolysis, it is recommended to stop treatment. The most common therapeutic measures for hemolytic anemia are transfusion of irradiated blood and glucocorticoid therapy.

Renal impairment

There are limited clinical data on the use of fludarabine for the treatment of patients with impaired renal function (creatinine clearance <70 mL / min).

The drug Fludarabel^® should be used with caution in patients with renal insufficiency. In patients with impaired renal function of moderate severity (creatinine clearance is in the range of 30 to 70 ml / min), the dose should be reduced by 50%, and careful monitoring of patients (see "Precautions for Use" and "Method of Use and dose "). Treatment with Fludarabe® is contraindicated if creatinine clearance <30 mL / min.

Elderly patients

Due to limited data on the use of fludarabine in elderly patients (over 75 years of age), the drug should be used with caution in this category of patients.Patients aged 65 years and over should be monitored for creatinine clearance before starting treatment.

Vaccination

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

Repeated treatment after initial treatment with Fludarabel®

Patients in whom primary therapy with fludarabine has a good chance of a second response with monotherapy with fludarabine.

Avoid switching from initial fludarabine therapy to chlorambucil in patients who did not respond to fludarabine therapy, as patients resistant to fludarabine therapy in most cases show resistance to chlorambucil.

Other Warnings

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

Rules for handling Fludarabel®

When handling Fludarabel®, all instructions adopted for the use and destruction of cytotoxic drugs should be followed. Pregnant women should not work with the drug Fludarabel®.

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

Some of the side effects of Fludarabel®, such as fatigue, weakness, visual impairment, confusion, agitation, can adversely affect the ability to drive and perform potentially dangerous activities requiring increased attention and speed of psychomotor reactions. When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:Tablets, film-coated, 10 mg.

Packaging:

To 5, 10, 15, 20 or 25 tablets in a bottle of dark glass with a polymeric cover with a corrugated tube and a control of the first opening or a can of polyethylene terephthalate with corrugation for sealing tablets and capsules with a polymer screw cap.

Each bottle or jar, together with instructions for medical use, is placed in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

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:LP-004028

Date of registration:22.12.2016

Expiration Date:22.12.2021

The owner of the registration certificate:FARMSINTEZ, PAO FARMSINTEZ, PAO Russia

Manufacturer: & nbsp

INSTITUTE OF BIOORGANIC CHEMISTRY OF THE NATIONAL ACADEMY OF SCIENCES OF BELARUS, GNU Republic of Belarus

Representation: & nbspFARMSINTEZ, PAO FARMSINTEZ, PAO Russia

Information update date: & nbsp20.01.2017

Illustrated instructions

Instructions

Fludarabel® (Fludarabel)