Fludarabine-Teva (Concentrate) Instructions for Use

ATC Code

L01BB05 (Fludarabine)

Active Substance

Fludarabine phosphate

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Antitumor drug. Fludarabine phosphate, which is part of the drug, is a water-soluble fluorinated nucleotide analog of the antiviral drug vidarabine, 9-β-D-arabinofuranosyladenine (ara-A), which is relatively resistant to the action of adenosine deaminase.

Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A, which is taken up by cells and then intracellularly phosphorylated by deoxycytidine kinase to the active triphosphate (2-fluoro-ara-ATP). This metabolite inhibits ribonucleotide reductase, DNA polymerase, DNA primase, and DNA ligase, thereby inhibiting DNA synthesis. In addition, RNA polymerase II is partially inhibited, leading to a subsequent decrease in protein synthesis. In vitro studies have shown that exposure of lymphocytes from patients with chronic lymphocytic leukemia to 2-fluoro-ara-A activates a mechanism of intense DNA fragmentation and apoptosis.

Pharmacokinetics

Fludarabine phosphate (2-fluoro-ara-AMP) is a water-soluble precursor of fludarabine (2-fluoro-ara-A). In the human body, 2-fluoro-ara-AMP is rapidly and completely dephosphorylated to the nucleoside 2-fluoro-ara-A.

Absorption

After a single 30-minute infusion of 2-fluoro-ara-AMP at a dose of 25 mg/m² to patients with chronic lymphocytic leukemia, the C_max of 2-fluoro-ara-A is 3.5-3.7 µmol and is reached at the end of the infusion. Determinations of the corresponding level of 2-fluoro-ara-A after 5 administrations of the drug showed moderate accumulation with an average C_max of 4.4-4.8 µmol at the end of the infusion. During the five-day treatment, plasma levels of 2-fluoro-ara-A doubled. However, accumulation of 2-fluoro-ara-A after several cycles of therapy may be insignificant.

Distribution

The binding of 2-fluoro-ara-A to plasma proteins is insignificant.

The C_max of 2-fluoro-ara-ATP in leukemic lymphocytes of patients with CLL was observed on average 4 hours after the infusion and was characterized by significant variation in the average value, approximately 20 µmol. The concentration of 2-fluoro-ara-ATP in leukemic cells was always significantly higher than its maximum concentration in plasma, indicating accumulation of the substance in target cells.

Comparison of the pharmacokinetics of 2-fluoro-ara-A showed that the average total plasma clearance is 79±40 ml/min/m² (2.2±1.2 ml/min/kg), and the average V_d is 83±55 L/m² (2.4±1.61 L/kg). The obtained data indicate high individual variability. After IV administration, the plasma concentration and AUC of 2-fluoro-ara-A increase in a linear dose-dependent manner, while T_1/2, plasma clearance, and V_d remain constant regardless of dose.

Metabolism and Excretion

2-fluoro-ara-A is delivered to leukemic cells by active transport, where 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 T_1/2 of 2-fluoro-ara-ATP from target cells averaged 15 and 23 hours.

After reaching C_max in plasma, the levels of 2-fluoro-ara-A decrease in three phases: the T_1/2 in the alpha phase is approximately 5 min, in the beta phase – 1-2 hours, and in the terminal phase about 20 hours.

2-fluoro-ara-A is excreted primarily by the kidneys (40-60% of the IV dose).

Pharmacokinetics in Special Clinical Cases

No clear correlation between the pharmacokinetics of 2-fluoro-ara-A and the therapeutic effect of the drug in cancer patients has been identified; however, the frequency of neutropenia and changes in hematocrit indicate a dose-dependent nature of the cytotoxic action of fludarabine phosphate in the form of suppression of hematopoiesis.

In individuals with reduced renal function, a decrease in the total clearance of the drug was observed, indicating the need for dose reduction.

Indications

• B-cell lymphocytic leukemia;
• Low-grade non-Hodgkin’s lymphomas.

ICD codes

Dosage Regimen

Concentrate

Only intravenous administration of fludarabine is allowed, and accidental extravascular entry should be avoided.

The recommended dose of fludarabine phosphate for adults is 25 mg/m² of body surface area IV once daily for 5 days every 28 days. The required dose (calculated according to the patient’s body surface area) is drawn into a syringe. For IV bolus administration, the above dose is diluted in 10 ml of 0.9% sodium chloride solution; the required dose can also be diluted in 100 ml of 0.9% sodium chloride solution and administered by drip over 30 minutes. There are no clear data on the optimal duration of treatment. The course of treatment depends on the observed effect and the tolerability of the drug.

Treatment with fludarabine is recommended until a therapeutic response is achieved (usually 6 cycles), after which the drug is discontinued.

Data on the efficacy and safety of fludarabine in patients with impaired liver function are limited. In this group of patients, fludarabine should be prescribed with caution after a thorough assessment of the risk/benefit ratio. Treatment of these patients should be carried out under close supervision. If necessary, the dose of the drug should be reduced or treatment discontinued.

In patients with possible impaired renal function and persons over 70 years of age, it is necessary to determine CC. With a CC in the range of 30-70 ml/min, the dose of the drug should be reduced by up to 50% and treatment should be carried out under the control of blood tests to assess toxicity. With a CC of less than 30 ml/min, treatment with fludarabine is contraindicated.

Adverse Reactions

The frequency of adverse reactions is given based on data from clinical studies, regardless of a causal relationship with the use of fludarabine, in accordance with the following frequency gradation: very common (> 10%), common (> 1%, but < 10%), uncommon (> 0.1%, but < 1%), rare (> 0.01%, but < 0.1%).

From the hematopoietic system very common – neutropenia, thrombocytopenia and anemia; common – myelosuppression.

From the immune system: uncommon – autoimmune disorders (including autoimmune hemolytic anemia, thrombocytopenic purpura, pemphigus, Evans syndrome, acquired hemophilia), allergic reactions.

From the digestive system: very common – nausea, vomiting, diarrhea; common – anorexia, stomatitis, mucositis; uncommon – gastrointestinal bleeding, changes in the activity of liver and pancreatic enzymes.

From the metabolism uncommon – as a result of tumor lysis, hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria may develop.

From the nervous system: common – peripheral neuropathy; uncommon – confusion; rare – agitation, seizures, coma.

From the organ of vision: common – visual disturbances; rare – optic neuritis, optic neuropathy and blindness.

From the respiratory system: very common – cough; uncommon – shortness of breath, pulmonary fibrosis, pneumonitis.

From the cardiovascular system: rare – heart failure, arrhythmias.

From the urinary system: rare – hemorrhagic cystitis.

From the skin and its appendages: common – skin rash; rare – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome). Rare cases of increased growth of existing skin cancer, as well as the development of skin cancer during or after treatment with fludarabine have been reported.

Other: very common – fever, increased fatigue, weakness, secondary infections; common – chills, malaise, peripheral edema; rare – lymphoproliferative disorders (associated with Epstein-Barr virus). In patients who received fludarabine before, after, or simultaneously with alkylating cytotoxic agents or radiotherapy, myelodysplastic syndrome/acute myeloid leukemia was rarely observed.

Contraindications

• Hypersensitivity to fludarabine or other components of the drug;
• Impaired renal function (CC less than 30 ml/min);
• Decompensated hemolytic anemia;
• Pregnancy;
• Lactation period (breastfeeding);
• Childhood (lack of sufficient clinical data);

With caution and after a thorough assessment of the risk/benefit ratio, fludarabine should be used in debilitated patients, with severe bone marrow depression (thrombocytopenia, anemia and/or granulocytopenia), with renal or hepatic insufficiency, immunodeficiency, a history of opportunistic infections, in patients over 75 years of age.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and lactation (breastfeeding).

Men and women of childbearing potential should use reliable methods of contraception during (and for 6 months after the end of) treatment with fludarabine.

Fludarabine is toxic; it has teratogenic activity and does not have mutagenic properties.

Use in Hepatic Impairment

With caution: after a thorough assessment of the risk/benefit ratio, fludarabine should be used in hepatic insufficiency.

Use in Renal Impairment

With caution: after a thorough assessment of the risk/benefit ratio, fludarabine should be used in renal insufficiency.

Pediatric Use

Contraindication: childhood (lack of sufficient clinical data).

Geriatric Use

With caution and after a thorough assessment of the risk/benefit ratio, fludarabine should be used in patients over 75 years of age.

Special Precautions

Treatment with fludarabine should be carried out under the supervision of a physician experienced in the use of cytotoxic agents.

During therapy with fludarabine, it is recommended to periodically evaluate peripheral blood counts to detect anemia, neutropenia and thrombocytopenia, carefully monitor serum creatinine concentration and creatinine clearance, and carefully monitor CNS functions to timely identify possible neurological disorders.

Bone marrow suppression is usually reversible. During therapy with fludarabine, the greatest decrease in the number of neutrophils 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. Several cases of bone marrow hypoplasia or aplasia in adults, manifested by pancytopenia, sometimes fatal, have been described. The duration of clinically significant pancytopenia ranged from 2 months to 1 year. These episodes were identified in both pre-treated and untreated patients.

Patients at increased risk of developing opportunistic infections are recommended to receive prophylactic therapy. Serious opportunistic infections, sometimes fatal, have been observed during therapy with fludarabine.

If hematopoietic stem cell transplantation is planned in the future, caution should be exercised when prescribing fludarabine, which belongs to cytotoxic substances.

Transfusion of non-irradiated blood to patients receiving fludarabine treatment has been observed to lead to the development of graft-versus-host disease (reaction of transfused immunocompetent lymphocytes against the host), which is associated with a high frequency of fatal outcomes. Patients requiring blood transfusions and receiving or having received fludarabine should be transfused only with irradiated blood.

Tumor lysis syndrome occurring during treatment with fludarabine has been observed in patients with CLL who have a large tumor mass. Since fludarabine may have a therapeutic effect as early as the first week of therapy, precautions should be taken in patients at probable risk of developing this complication.

Regardless of the presence or absence of a history of autoimmune processes, as well as the results of the Coombs test, there is a risk of life-threatening autoimmune reactions (autoimmune hemolytic anemia, autoimmune thrombocytopenia, thrombocytopenic purpura, pemphigus, Evans syndrome) during or after treatment with fludarabine. Recurrent hemolytic process after resumption of fludarabine treatment is possible. Patients receiving fludarabine should be closely monitored for hemolysis. If hemolysis develops, discontinuation of therapy is recommended. The most commonly used therapeutic measures for the treatment of autoimmune hemolytic anemia are blood transfusion (irradiated) and corticosteroids.

Vaccination with live vaccines should be avoided during and after treatment with fludarabine.

Most patients who are insensitive to fludarabine are also insensitive to chlorambucil.

Use only a clear and colorless solution that does not contain visible solid particles. If the container is damaged, the drug should not be used.

The chemical and physical stability of the solution prepared for injection or infusion is maintained for 3 days at a temperature of 25°C (77°F) or in a refrigerator (from 2°C (35.6°F) to 8°C (46.4°F)) when the concentrate is diluted with 0.9% sodium chloride solution for infusion or 5% dextrose solution for infusion. From the point of view of microbiological purity, the diluted solution should be used immediately; storage of the diluted solution in a refrigerator (from 2°C (35.6°F) to 8°C (46.4°F)) for no more than 24 hours is allowed.

When working with fludarabine, the rules for handling cytotoxic drugs should be observed, and contact with the solution should be avoided! If the solution gets on the skin, mucous membranes or in the eyes, they should be thoroughly rinsed with plenty of water.

Effect on ability to drive vehicles and operate machinery

Some side effects of the drugs, such as increased fatigue, weakness, blurred vision, may adversely affect the ability to drive vehicles and engage in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms when using fludarabine in high doses, irreversible changes in the central nervous system, loss of vision, coma and death, as well as the development of a severe form of thrombocytopenia and neutropenia due to suppression of bone marrow function are possible.

Treatment if threatening symptoms appear, the drug should be discontinued immediately and supportive therapy should be carried out. A specific antidote is not known.

Drug Interactions

The use of fludarabine in combination with pentostatin (deoxycoformycin) for the treatment of chronic lymphocytic leukemia often led to death due to high pulmonary toxicity.

The therapeutic efficacy of fludarabine may be reduced by adenosine reuptake inhibitors and dipyridamole.

Pharmacokinetic interaction was observed during treatment with a combination of fludarabine and cytarabine in patients with chronic lymphocytic leukemia and acute myeloid leukemia.

With the combined use of cytarabine with fludarabine, higher intracellular peak concentrations and intracellular AUC of the cytarabine metabolite, cytosine arabinoside triphosphate, were shown. Plasma concentrations of cytarabine and the excretion of cytosine arabinoside triphosphate did not change.

Fludarabine solution for intravenous administration should not be mixed with other drugs.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature of 2°C (35.6°F) to 8°C (46.4°F). Do not freeze.

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.