Fludarabel^® (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

Manufactured By

Institute Of Bioorganic Chemistry Of The National Academy Of Sciences Of Belarus, State Institution (Republic Of Belarus)

ATC Code

L01BB05 (Fludarabine)

Active Substance

Fludarabine phosphate (USAN)

Dosage Form

Fludarabel®

Film-coated tablets 10 mg: 5, 10, 15, 20 or 25 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow in color, round, biconvex, with a white core on the cross-section.

Excipients: lactose monohydrate – 60 mg, corn starch – 9 mg, crospovidone – 3 mg, magnesium stearate – 15 mg, colloidal silicon dioxide – 0.75 mg, microcrystalline cellulose – up to 150 mg.

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

5 pcs. – dark glass bottles (1) – cardboard packs.
5 pcs. – polyethylene terephthalate jars (1) – cardboard packs.
10 pcs. – dark glass bottles (1) – cardboard packs.
10 pcs. – polyethylene terephthalate jars (1) – cardboard packs.
15 pcs. – dark glass bottles (1) – cardboard packs.
15 pcs. – polyethylene terephthalate jars (1) – cardboard packs.
20 pcs. – dark glass bottles (1) – cardboard packs.
20 pcs. – polyethylene terephthalate jars (1) – cardboard packs.
25 pcs. – dark glass bottles (1) – cardboard packs.
25 pcs. – polyethylene terephthalate jars (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Antineoplastic agent. Antimetabolite, purine analog. Fludarabine phosphate is a water-soluble fluorinated nucleotide, an analog of the antiviral agent vidarabine, 9-beta-D-arabinofuranosyladenine (ara-A), which is relatively resistant to deamination by adenosine deaminase. In the human body, Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A, which is taken up by cells and then intracellularly phosphorylated to the active triphosphate (2-fluoro-ara-ATP). This metabolite inhibits RNA reductase, DNA polymerase (alpha, delta, and epsilon), DNA primase, and DNA ligase, leading to disruption of DNA synthesis. Furthermore, RNA polymerase II is partially inhibited, subsequently reducing protein synthesis in malignant cells.

Pharmacokinetics

Fludarabine phosphate (2F-ara-AMP) is a water-soluble prodrug that is rapidly dephosphorylated in the human body to the nucleoside fludarabine (2-fluoro-ara-A). After a single infusion of a standard dose of 25 mg/m² over 30 minutes, the C_max of 2-fluoro-ara-A in plasma equal to 3.5-3.7 µM is reached by the end of the infusion. After five administrations, a moderate increase in C_max to 4.4-4.8 µM is detected by the end of the infusion. No accumulation of 2-fluoro-ara-A was noted after several therapy cycles. After the end of the infusion, a three-phase decrease in concentration is observed with a T_1/2 of the initial phase of about 5 minutes, intermediate – 1-2 hours, and terminal – about 20 hours.

2-fluoro-ara-A is actively transported into leukemia cells, after which it is rephosphorylated to monophosphate and partially to di- and triphosphate. The triphosphate (2-fluoro-ara-ATP) is the main intracellular metabolite and the only known metabolite with cytotoxic activity. The C_max of 2-fluoro-ara-ATP in leukemic lymphocytes of patients with chronic lymphocytic leukemia was observed on average at 4 hours and was characterized by significant variation in the mean peak concentration (on average about 20 µM). The concentration of 2-fluoro-ara-ATP in leukemic cells was also significantly higher than its C_max in plasma, indicating accumulation of the substance in tumor cells. The T_1/2 of 2-fluoro-ara-ATP from target cells averages from 15 to 23 hours.

Indications

Chronic B-cell lymphocytic leukemia (CLL) in patients with adequate bone marrow reserves.

ICD codes

Dosage Regimen

Administer Fludarabel^® tablets orally. Swallow the tablets whole with water; do not chew, split, or crush them.

The standard dosage for adults with chronic lymphocytic leukemia is 40 mg/m² of body surface area once daily for 5 consecutive days. Repeat this 28-day cycle.

Calculate the total daily dose based on the patient’s body surface area. Adjust the dose for patients with renal impairment; reduce the dose by up to 50% for moderate impairment (CrCl 30-70 mL/min). Do not use in patients with severe renal impairment (CrCl less than 30 mL/min).

Continue treatment until a maximum response is achieved, typically for a minimum of 6 cycles. Base the decision for continued therapy on periodic clinical and hematological assessments.

Administer subsequent cycles only after adequate recovery of hematological parameters. Withhold therapy if severe hematological toxicity (neutropenia, thrombocytopenia) or significant non-hematological toxicity occurs.

Initiate therapy only in patients with adequate bone marrow function. Monitor complete blood counts regularly, before each cycle and more frequently if indicated. Monitor for signs of hemolytic anemia and tumor lysis syndrome, especially during the initial cycles.

Use with extreme caution in patients with a history of immunodeficiency or opportunistic infections. Consider prophylactic therapy for patients at high risk of infection. Avoid concurrent use with live vaccines during and after treatment.

Adverse Reactions

From the hematopoietic system neutropenia, thrombocytopenia, anemia.

From the digestive system anorexia, nausea, vomiting, changes in the activity of liver and pancreatic enzymes.

From metabolism in tumor lysis syndrome – hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia.

From the urinary system in tumor lysis syndrome – hematuria, urate crystalluria, renal failure, edema; rarely – hemorrhagic cystitis.

From the respiratory system dyspnea, cough, interstitial pulmonary infiltration, pneumonia.

From the CNS and peripheral nervous system rarely – weakness, agitation, consciousness disorders, vision disorders; in isolated cases – peripheral neuropathy, coma.

From the reproductive system azoospermia, amenorrhea.

Allergic reactions skin rash, Lyell’s syndrome.

Other development of infectious complications, fever, chills, fatigue.

Contraindications

Severe renal impairment (CrCl <30 ml/min); decompensated hemolytic anemia; pregnancy; lactation period, hypersensitivity to fludarabine phosphate.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and during the lactation (breastfeeding) period.

Special Precautions

Should be used as first-line therapy only in patients with advanced disease, stage III/IV radiation sickness (Binet, stage C), or stage I/II radiation sickness (Binet, stage A/B), when the patient has symptoms or evidence of disease progression.

Use with caution and only after careful assessment of the risk/benefit ratio in debilitated patients, patients with severe bone marrow function depression (thrombocytopenia, anemia and/or granulocytopenia), with a history of immunodeficiency or opportunistic infections. Patients at increased risk of developing opportunistic infections are recommended to receive prophylactic therapy.

During treatment, peripheral blood counts should be periodically assessed to detect anemia, neutropenia, and thrombocytopenia, serum creatinine concentration and CrCl should be carefully monitored, and careful monitoring of CNS function should be carried out for the timely detection of possible neurological disorders.

Bone marrow suppression is usually reversible. During therapy with fludarabine phosphate for solid tumors in adults, the greatest decrease in the number of granulocytes is observed on average on day 13 (range 3-25 days) from the start of treatment, and platelets – on average on day 16 (range 2-32 days). Myelosuppression can be severe and cumulative.

Patients receiving treatment with fludarabine phosphate require careful monitoring for signs of hemolytic anemia. In case of hemolysis development, discontinuation of therapy is recommended. The most common therapeutic measures for hemolytic anemia are transfusions of irradiated blood and corticosteroid therapy.

Graft-versus-host disease (reaction of transfused immunocompetent lymphocytes against the host), resulting from hemotransfusions, has been observed after transfusion of non-irradiated blood to patients treated with fludarabine phosphate. A high frequency of fatal outcomes has been reported as a consequence of these procedures. Therefore, patients who require hemotransfusions and who are receiving or have received treatment with fludarabine should be transfused only with irradiated blood.

Tumor lysis syndrome, occurring during treatment with fludarabine phosphate, especially with large tumor sizes, can manifest as early as the first week of therapy.

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

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

Use in pediatrics

Fludarabine is not recommended for use in children due to lack of safety and/or efficacy data.

Effect on ability to drive vehicles and mechanisms

Since there is a risk of such side effects as fatigue, weakness, visual impairment, it may affect the ability to drive a car and perform work requiring increased concentration and speed of psychomotor reactions.

Drug Interactions

The use of fludarabine phosphate in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia often led to fatal outcomes due to high pulmonary toxicity. Therefore, this combination is not recommended.

The therapeutic efficacy of fludarabine phosphate may be reduced by dipyridamole or other inhibitors of adenosine uptake.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.