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

Core: active substance: fludarabine phosphate 10,000 mg; Excipients: microcrystalline cellulose 60,000 mg, lactose monohydrate 74.750 mg, carmellose sodium (sodium carboxymethylcellulose) 3,000 mg, silicon dioxide colloidal 0.750 mg, magnesium stearate 1,500 mg.

Casing of the tablet: hypromellose (hydroxypropylmethylcellulose 2910) 2,250 mg, talc 0,450 mg, titanium dioxide 1,187 mg, iron (II) oxide 0.077 mg, iron (III) oxide 0.036 mg.

Description:

Tablets capsular shaped, covered with a film membrane, from orange-pink to pink with engraving "LN"in the right hexagon on one side.

Pharmacotherapeutic group:antitumour agent - antimetabolite

ATX: & nbsp

L.01.B.B.05 Fludarabine

Pharmacodynamics:

The drug Floodar contains fludarabine phosphate, a fluorinated nucleotide analogue of the antiviral agent vidarabin, 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, and 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-a-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 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 fludarabine decreases.

Indications:

- B-cell chronic lymphocytic leukemia (as first-line therapy). Therapy with Fludara® as a first-line therapy can only be initiated in patients with progressive disease (stage C according to 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 the application of at least one standard regimen,containing alkylating agents);

- non-Hodgkin's lymphoma of a low degree of malignancy;

- follicular B-cell lymphomas;

- lymphoma from the cells of the mantle zone.

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).

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 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 older than 75 years;

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

- in patients with hepatic insufficiency;

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

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 Fludara®, women who breastfeed should stop breastfeeding.

Dosing and Administration:

Treatment with Fludara® should be performed under the supervision of a doctor who has experience with antitumor therapy.

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

The number of tablets to be taken should be determined according to the following table.

Surface area body (PPT), [m²]	The calculated total daily dose, based on PPT (rounded to the whole value), [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 effectiveness and tolerability of the drug.

The drug Fludara® 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 Fludara® 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 cycle, the number of blood cells is excessively low for the recommended dose and if there is a possibility 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 1.0 × 10⁹/ 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 recommendations in the following table.

Granulocytes (10⁹/ l ) and / or platelets (10⁹/ l )

Dose

fludarabine phosphate

0,5-1,0

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 increasing dose of Fludara® in subsequent cycles of treatment can be considered.

Tablets can be taken as an empty stomach, or at the same time as eating. Tablets should be swallowed whole (do not chew, do not break), washing down with water.

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 (see the section "Contraindications").

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, the dose should be reduced by 50% and thorough hematologic testing should be performed to assess the toxicity.sections "With care" and "Special instructions").

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

Patients with impaired hepatic function

The safety and efficacy of using Fludara® have not been studied in patients with impaired hepatic function. 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 cause-and-effect relationship with the use of the preparation Fludara®, and 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 the available data it is impossible to estimate the incidence of side effects).

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

Disorders 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 - a tumor lysis syndrome (as a result of tumor lysis, hyperuricemia, hyperphosphataemia,hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria and renal failure).

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:

When used in doses exceeding the recommended levels, the preparation of Fludara® causes the development of leukoencephalopathy, acute toxic leukoencephalopathy, or a syndrome of reversible posterior encephalopathy. Symptoms may include headache, nausea, vomiting, convulsions, visual impairment (such as loss of vision), sensitivity disorder and focal neurological symptoms, 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 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.

The specific antidote for an overdose of Fludara® is unknown. Treatment consists in stopping the drug and holding 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 of ara-CTF (the active metabolite of cytarabine) in leukemia cells. The concentration of cytarabine in the blood plasma and the rate of its excretion remained unchanged.

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 Fludara® 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 / m body surface / day for 5-7 days). In patients taking Fludara® in a range of doses recommended for the treatment of chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphoma, severe toxic symptoms from the CNS were rare (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 in 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 / quadriparesis, 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 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 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 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 treatment the Fludara® preparation. 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 "With caution" and "Dosing and Administration"). 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 in whom primary therapy with Fludara® was effective,Have a good chance 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 contraceptive methods during treatment and at least 6 months after the end of Fludara® therapy.

Rules for handling Fludara®

When handling Fludara®, all instructions adopted for the use and destruction of cytotoxic drugs should be followed. 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, agitation can adversely affect the ability to drive and perform potentially dangerous activities requiring increased concentration 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 each.

Packaging:

5 tablets per blister of aluminum foil.

2, 3, 4 or 5 blisters are placed in a plastic case with a screw cap.

The pencil case together with the instruction for use is placed in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

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 / 02

Date of registration:19.11.2007

Date of cancellation:2017-06-23

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

Manufacturer: & nbsp

BAYER SCHERING PHARMA, AG Germany

Representation: & nbspJENZAIM RUS LLCJENZAIM RUS LLCRussia

Information update date: & nbsp23.06.2017

Illustrated instructions

Instructions

Fludara® (Fludara®)