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

Active substance:
Fludarabine phosphate	10.00 mg
Excipients:
Lactose Monohydrate	74.75 mg
Microcrystalline cellulose	60.00 mg
Croscarmellose sodium	3.00 mg
Magnesium stearate	1.50 mg
Silica colloidal dioxide (Aerosil)	0.75 mg
Composition of the film shell:
Film shell Aquarius Prime white [hypromellose - 65%, titanium dioxide - 25%, macrogol - 10%]	5.00 mg

Description:Tablets are round, biconcave, white, covered with a film membrane. The core of the tablet is white or almost white.

Pharmacotherapeutic group:antitumour agent - antimetabolite

ATX: & nbsp

L.01.B.B.05 Fludarabine

Pharmacodynamics:

Fludarabine phosphate (2-fluoro-ara-AMP) is a water-soluble fluorinated nucleotide analogue of an antiviral agent, a species of arabin, 9-β-D-arabinofuranosyladenine (ara-A), which is resistant to deamination by adenosine deaminase. In humans, fludarabine phosphate is rapidly rephosphorylated to 2-fluoro-arabiofuranosyladenine (2-fluoro-ara-A). Inside the cell, it is rephosphorylated by deoxycytidine kinase to the active triphosphate (2-fluoro-ara-ATP), the main metabolite. This metabolite inhibits ribonucleotide reductase, DNA polymerase (alpha, delta and epsilon), DNA primase, DNA ligase and blocks DNA synthesis. Partially binds RNA polymerase II and inhibits protein synthesis (mainly in Sphase of the cell cycle). Activates the mechanism of DNA fragmentation and apoptosis of lymphocytes (shown in the studies in vitro on the lymphocytes of patients with chronic limphlejkozom).

Has cytotoxic, immunosuppressive action, inhibits hemopoiesis. Has teratogenic activity. Mutagenic properties do not.

Pharmacokinetics:

The pharmacokinetics of fludarabine (2-fluoro-ara-A) was studied after intravenous administration and as a bolus injection, a short-term infusion, after a long infusion, and after ingestion of fludarabine phosphate (2-fluoro-ara-AMP).

There was no clear correlation between the pharmacokinetics of fludarabine and its therapeutic effect in oncological patients, with the frequency of neutropenia detection and changes in hematocrit indicating a dose-dependent nature of fludarabine cytotoxicity (in the form of hematopoietic suppression). Linkage to blood plasma proteins is insignificant.

Suction

After oral administration of fludarabine phosphate, the maximum levels of 2-fluoro-ara-A in the plasma are reached after 1-2 hours and are approximately 20-30% of the level determined by the end of the intravenous infusion. The average bioavailability of 2-fluoro-ara-A within 50-65% after a single and repeated administration. After simultaneous reception of 2-fluoro-ara-A with food, there was a slight increase (less than 10%) of bioavailability (AUC), a slight decrease in the maximum plasma concentration (C_max) 2-fluoro-ara-A and an increase in the time to reach the maximum concentration (TC_max) while the half-life of the terminal phase (T_1/2) did not change.

Distribution and Metabolism

2-Fluoro-ara-A is actively transported to leukemic cells, after which it is rephosphorylated to monophosphate and partially to di- and triphosphate. 2-Fluoro-ara-ATP is the main intracellular metabolite and the only known metabolite with cytotoxic activity. The maximum level of 2-fluoro-ara-ATP in leukemic lymphocytes of patients with chronic lymphocytic leukemia (XLL) was observed on average 4 hours after infusion and was characterized by a significant fluctuation from an average value of about 20 μM. The level of 2-fluoro-ara-ATP in leukemic cells was also significantly higher than its maximum level 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.

Excretion

2-Fluoro-ara-A is excreted mostly at night, about 23% unchanged.

Pharmacokinetics in special clinical groups

Patients with severe renal dysfunction there is a decrease in creatinine clearance, so patients with moderate renal failure (creatinine clearance 30-70 ml / min), the dose should be reduced, up to 50%, and these patients should be carefully monitored. The use of fludarabine in patients with a creatinine clearance less than 30 ml / min is contraindicated.

Indications:

- B-cell chronic lymphocytic leukemia (as first-line therapy). Ludarabine therapy as first-line therapy can be saline 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 steps I/II but the 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);

- Mr.echodkinskaya lymphoma of low degree of malignancy (NHL NZ);

- folicicular B-cell lymphomas;

- lImpham from the cells of the mantle zone.

Contraindications:

- Hypersensitivity to fludarabine or other components of the drug;

- Mr.Abnormal kidney function with creatinine clearance <30 mL / min;

- dCompensated hemolytic anemia;

- bVariability;

- PThe period of breastfeeding;

- d(lack of sufficient clinical data).

Carefully:

Fludarabine should be administered with caution after a thorough assessment of the risk / benefit ratio for patients in a weakened state, patients with a marked decrease in bone marrow function (thrombocytopenia, anemia and / or granulocytopenia), immunodeficiency, opportunistic infections in the anamnesis, patients at the start of 75 years (efficacy and safety not patients with renal insufficiency (creatinine clearance 30-70 ml / min), patients with hepatic insufficiency, patients with lactase deficiency, lactose intolerance, indromom glucose-galactose malabsorption.

Pregnancy and lactation:

Fludarabine is contraindicated in pregnancy, its metabolites penetrate the placenta and have teratogenic properties. Women of childbearing age who are appointed fludarabine, should be informed of the dangers to the fetus, especially in the first trimester of pregnancy.

During treatment, and also within 6 months after its termination, contraceptive preparations should be used to prevent the onset of pregnancy.

Fludarabine and its metabolites penetrate into the mother's milk. To avoid severe adverse reactions during treatment, breastfeeding should be discontinued.

Dosing and Administration:

For oral administration.

Tablets should be taken in full, regardless of the reception of the nurse, not chewing and not breaking, washing down with water.

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

The following table is a guide for determining the amount of tablets taken depending on the surface of the body.

Body surface area (PPT), m²	Estimated total daily dose, based on PPT, 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 success of the treatment and the tolerability of the drug. The individual dose should be carefully adjusted in accordance with the observed data on hematological toxicity.

Adjusting the dose of fludarabine in the first cycle of treatment is not required (except for patients with renal insufficiency).

In patients receiving fludarabine we can expect the development of anemia, neutropenia, thrombocytopenia and myelosuppression. It is necessary to carefully monitor blood counts. When the blood values change, the course of treatment should be postponed until the amount of granulocytes reaches a value of more than 1.0х10⁹/ l, and the number of platelets is 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, the dose should be reduced in accordance with the recommendations in the following table:

Granulocytes (10⁹/ l)	Platelets (10⁹/ l)	The dose of fludarabine phosphate
0,5-1,0	150-100	30 mg / m²/ day
<0,5	<50	20 mg / m²/ day

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

If the patient's condition does not change after 2 weeks of treatment, a very low degree of hematologic toxicity will not be detected, careful dose correction with an increase in the dose of fludarabine in subsequent cycles of treatment can be considered.

With CLL treatment is continued until the maximum effect is achieved (complete or partial remission, usually 6 cycles), after which the therapy should be discontinued.

With NHL NZ treatment with fludarabine is performed until complete or partial remission is achieved (and an average of 6 cycles). After achieving the greatest effect, it is necessary to evaluate the need for two cycles of consolidation therapy. According to clinical studies, most patients with NH NHL received no more than 8 cycles of treatment.

Children safety and efficacy of the drug have not been established.

Special Groups

Patients with renal insufficiency and the clearance of creatinine (CK) from 30 to 70 ml / min dose of the drug is reduced by 50%. In this case, a permanent hematologic control for toxicity assessment. When creatinine clearance is less than 30 ml / min fludarabine is contraindicated.

Patients with insufficient liver function

Patients with liver disease should be prescribed fludarabine, only if the potential benefit exceeds the potential risk.

Elderly patients

There is insufficient data on the use of fludarabine in elderly people over 75 years of age. However, taking into account such age-related features as decreased renal function, changes in blood counts, the appointment of the drug in this age group should be carried out with caution.

Side effects:

Adverse reactions are given according to the classification of MedDRAnd according to the frequency of development: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1/10000, <1 / 1000), very rarely, including individual messages (<1/10000), the frequency is unknown.

Infectious and parasitic diseases: very often - infections, including opportunistic (for example, reactivation of latent viruses: progressive multifocal leukoencephalopathy, herpes, Epstein-Barr virus); rarely lymphoproliferative disease (associated with the Epstein-Barr virus).

Benign, malignant and unspecified neoplasms (including cysts and polyps): often - myelodysplastic syndrome and acute myeloid leukemia (mainly associated with the preceding one,concomitant or subsequent treatment with alkylating drugs, topoisomerase inhibitors or radiation).

Violations of the blood and lymphatic system: very often - neutropenia, thrombocytopenia and anemia; often - myelosuppression (can be expressed and have a cumulative character).

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 (including hyperuricemia, hyperphosphataemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria, and renal failure). The first signs of this syndrome can be acute pain in the lumbar region and hematuria.

Impaired nervous system: often peripheral neuropathy; infrequently - confusion of consciousness; rarely - coma, cramps, agitation; very rarely - cerebral hemorrhage; frequency unknown - leukoencephalopathy, acute toxic leukoencephalopathy, reversible leukoencephalopathy syndrome (COPD).

Disorders from the side of the organ of vision: often - impaired vision; rarely - optic neuritis, optic nerve neuropathy, blindness.

Disturbances from the respiratory system, organs of the chest and mediastinum: very often - cough; infrequently - pulmonary toxicity (including pulmonary fibrosis, pneumonia, dyspnea); very rarely - pulmonary hemorrhage.

Heart Disease: rarely - heart failure, arrhythmia.

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

Disorders from the liver and bile ducts: infrequently - a deviation from the norm of indicators of hepatic enzymes.

Disorders from the kidneys and urinary tract: very rarely - hemorrhagic cystitis.

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

General disorders and disorders at the site of administration: very often - fever, fatigue, weakness; often - swelling, mucositis, chills, malaise.

If any of the side effects listed in the manual are aggravated or you notice any other undesirable side effects not listed in the instructions, report on this doctor.

Overdose:

When used in doses exceeding the recommended levels, fludarabine causes the development of leukoencephalopathy, acute toxic leukoencephalopathy, or a syndrome of reversible posterior leukoencephalopathy.

Symptoms may include headache, nausea, vomiting, convulsions, visual disturbances, impaired sensation and focal neurological symptoms, as well as optic neuritis and papillitis, confusion, drowsiness, agitation, paraparesis / quadriparesis, muscle spasticity and incontinence, irreversible changes in the central nervous system, including blindness, to whom and death.

The use of fludarabine in doses exceeding the recommended levels is also associated with the development of severe thrombocytopenia and neutropenia due to the suppression of bone marrow function.

Specific antidotes with an overdose of fludarabine are unknown.

Treatment is to stop the introduction of the drug and support maintenance therapy.

Interaction:

Use of fludarabine in combination with pentostatin (Dezoksikoformitsinom) for the treatment of refractory XLL may lead to death due to high pulmonary toxicity. Therefore, the use of fludarabine in combination with pentastatin is not recommended.

In patients who received fludarabine before or after alkylating cytotoxic agents, topoisomerase inhibitors or radiotherapy, myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML) was observed.

The therapeutic efficacy of fludarabine can be reduced dipyridamole or other inhibitors of adenosine capture.

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

Special instructions:

The drug should be administered under the supervision of a qualified physician with experience in antitumor therapy.

MIelosuppression

When fludarabine therapy is recommended, periodic evaluation of peripheral blood parameters for the detection of anemia, neutropenia and thrombocytopenia, carefully monitor serum creatinine and creatinine clearance, and monitor closely the function of the central nervous system (CNS) in order to identify possible neurological disorders in a timely manner. Oppression of the bone marrow is usually reversible. In fludarabine therapy of solid tumors in adults, the largest 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 g. These episodes were detected in both treated and untreated patients.

In rare cases, patients who received fludarabine before, after or simultaneously with alkylating cytotoxic agents or radiotherapy, there was an MDS / AML.

Neurotoxicity

The effects of prolonged therapy with fludarabine on the CNS are unknown. When using Fludarabine-TL, it is recommended that the CNS indices are monitored, at connection with the possible neurotoxicity of the drug, which is described in fludarabine therapy in high doses. As part of the postgraduate experience with the use of fludarabine, cases of leukoencephalopathy, acute toxic leukoencephalopathy and reversible leukoencephalopathy syndrome (COPD) have been documented.

However, in some studies, it has been shown that prolonged use of fludarabine (up to 26 courses of therapy) is tolerated satisfactorily by patients.

Opportunistic infections

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.

Autoimmune disorders

Regardless of the presence or absence of autoimmune processes in the anamnesis, as well as the results of the Coombs test, the occurrence of life-threatening,and sometimes fatal autoimmune reactions (autoimmune hemolytic anemia, autoimmune thrombocytopenia, thrombocytopenic purpura, pemphigus, Evans syndrome) during or after fludarabine treatment. Most patients with hemolytic anemia experienced recurrence of hemolysis after a provocative test with fludarabine. Patients receiving fludarabine treatment should be carefully observed for signs of hemolytic anemia. In the case of hemolysis, discontinuation of fludarabine therapy is recommended. The most common therapeutic measures for hemolytic anemia are the transfusion of irradiated blood and glucocorticosteroid therapy (GCS).

The "graft versus host"

The reaction of transfused immunocompetent lymphocytes against the host, resulting from blood transfusions, was observed after transfusion of unirradiated blood to patients treated with fludarabine. A high incidence of fatalities has been reported as a consequence of this reaction. In this regard, patients who need hemotransfusions and who receive or received treatment with fludarabine, only irradiated blood should be transfused.

Skin cancer

Single cases of skin cancer have been reported in patients in a weakened state, with the progression of the disease, and also the growth of existing skin cancer during or after treatment with fludarabine.

Tumor Lysis

Due to fludarabine may cause tumor lysis in the first week of therapy, care should be taken in treating patients at risk of developing this syndrome (especially with a large tumor mass).

Renal insufficiency

Patients with renal insufficiency with creatinine clearance <70 ml / min dose should be reduced by 50%. At the same time, a permanent hematological control is necessary to assess the toxicity. When creatinine clearance is less than 30 ml / min, treatment with fludarabine is contraindicated.

Elderly patients

Due to the lack of clinical data on the use of fludarabine in elderly patients (> 75 years), treatment with fludarabine at this age should be administered with caution. In patients aged 65 years and older, the clearance of creatinine should be measured before treatment begins.

Resistance

It should be borne in mind that patients resistant to fludarabine therapy, in most cases, show resistance to chlorambucil.

Vaccination

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

Contraception

Women and men should use reliable methods of contraception during treatment, and also within 6 months after its termination.

Treatment of medical personnel with the drug

Medical personnel when handling fludarabine should comply with all instructions adopted for the use and destruction of cytotoxic drugs.

Pregnant women work with fludarabine is prohibited.

Children

Children safety and efficacy have not been established.

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

Based on the pharmacological properties of the drug, some side effects of the drug, such as increased fatigue, weakness, visual impairment can adversely affect the ability to manage vehicles, mechanisms. When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:

Tablets, film-coated, 10 mg.

Packaging:

5 tablets in a contour mesh box of aluminum foil printed lacquered and aluminum foil.

For 15 or 20 tablets in a vial for medicines from plastic with a desiccant in the lid.

Each vial or 3 or 4 contour mesh packs together with the instruction for use are placed in a pack of cardboard box.

Storage conditions:

In a dry, protected from light place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003052

Date of registration:19.06.2015

Date of cancellation:2020-06-19

The owner of the registration certificate:TECHNOLOGY OF DRUGS, LTD. TECHNOLOGY OF DRUGS, LTD. Russia

Manufacturer: & nbsp

TECHNOLOGY OF DRUGS, LTD. Russia

Information update date: & nbsp25.09.2015

Illustrated instructions

Instructions

Fludarabine-TL (Fludarabine-TL)