Fludarabine-TL (Tablets) Instructions for Use

Marketing Authorization Holder

Technology Lekarstv LLC (Russia)

ATC Code

L01BB05 (Fludarabine)

Active Substance

Fludarabine phosphate (USAN)

Dosage Form

Fludarabine-TL

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

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex; the tablet core is white or almost white.

Excipients : lactose monohydrate – 74.75 mg, microcrystalline cellulose – 60 mg, carmellose sodium – 3 mg, magnesium stearate – 1.5 mg, colloidal silicon dioxide (aerosil) – 0.75 mg.

Shell composition film coating Aquarius Prime white – 5 mg (hypromellose – 65%, titanium dioxide – 25%, macrogol – 3%).

5 pcs. – contour cell packaging (3) – cardboard packs.
5 pcs. – contour cell packaging (4) – cardboard packs.
15 pcs. – bottles (1) – cardboard packs.
20 pcs. – bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Antitumor 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 ribonucleotide 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 triphasic concentration decline is observed with an initial phase T_1/2 of about 5 minutes, an intermediate phase of 1-2 hours, and a terminal phase of about 20 hours.

2-fluoro-ara-A is actively transported into leukemia cells, after which it is rephosphorylated to the monophosphate and partially to the 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 Fludarabine-TL tablets orally for the treatment of chronic B-cell lymphocytic leukemia (CLL).

The recommended dosage is 40 mg/m² of body surface area administered once daily for 5 consecutive days.

Repeat this 5-day cycle every 28 days.

Continue treatment until a maximal response is achieved or until unacceptable toxicity occurs.

Calculate the dose based on actual body surface area at the start of each treatment cycle.

Adjust the dosage for patients with renal impairment.

For patients with creatinine clearance (CrCl) of 30-70 mL/min, reduce the dose by 20%.

Do not administer to patients with CrCl less than 30 mL/min.

Monitor hematological parameters closely before and during therapy.

Delay treatment if significant hematological toxicity is present.

Swallow tablets whole with water; do not chew or crush.

Take tablets at approximately the same time each day.

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 lactation (breastfeeding).

Special Precautions

As a first-line therapy, it should be used 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 of solid tumors in adults with fludarabine phosphate, 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 blood transfusions, 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 blood transfusions 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 operate machinery

Since there is a risk of such side effects as fatigue, weakness, and 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 a fatal outcome 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.