Fludarabine-Ebewe (Concentrate) Instructions for Use

Marketing Authorization Holder

Ebewe Pharma Ges.m.b.H.Nfg.KG (Austria)

ATC Code

L01BB05 (Fludarabine)

Active Substance

Fludarabine phosphate

Dosage Form

Fludarabine-Ebewe

Concentrate for preparation of solution for intravenous administration 25 mg/ml: 2 ml fl. 1, 5 or 10 pcs.

Dosage Form, Packaging, and Composition

Concentrate for preparation of solution for intravenous administration in the form of a clear, colorless or light yellow liquid.

Excipients: disodium hydrogen phosphate dihydrate 1.78 mg, sodium hydroxide 5.9 mg, water for injections up to 1 ml.

2 ml – vials (1) – cardboard packs.
2 ml – vials (5) – cardboard packs.
2 ml – vials (10) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Fludarabine (2-fluoro-ara-AMP) is a water-soluble fluorinated nucleotide, an analog of the antiviral agent vidarabine (ara-A, 9-β-D-arabinofuranosyladenine), which is relatively resistant to deamination by the enzyme adenosine deaminase.

In the human body, fludarabine is rapidly dephosphorylated to form 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 (alpha, delta and epsilon), DNA primase, and DNA ligase, thereby inhibiting DNA synthesis. In addition, it partially inhibits RNA polymerase II with subsequent reduction in protein synthesis.

It is believed that the inhibition of cell growth is explained by all three factors – the effect on DNA, RNA, and protein synthesis, however, the effect on DNA synthesis is dominant. Furthermore, in vitro studies have shown that exposure to 2-fluoro-ara-A triggers the process of apoptosis with intense DNA fragmentation in lymphocytes of patients with chronic lymphocytic leukemia.

Patients who have previously responded to fludarabine therapy are highly likely to respond to repeated fludarabine monotherapy.

Pharmacokinetics

The pharmacokinetics of fludarabine (2-fluoro-ara-AMP) were studied in cancer patients following administration of the drug by intravenous bolus injections, as well as short and long intravenous infusions. 2-fluoro-ara-AMP is a water-soluble prodrug that is rapidly and completely dephosphorylated in the human body to form the nucleoside fludarabine (2-fluoro-ara-A). During the first 30-minute intravenous infusion to patients with chronic lymphocytic leukemia at a fludarabine dose of 25 mg/m² body surface area, the mean maximum plasma concentration (C_max) of 2-fluoro-ara-A was 3.5-3.7 μmol by the end of the infusion. After the fifth administration, the corresponding values were 4.4-4.8 μmol by the end of the infusion, indicating moderate accumulation of the drug. During the 5-day treatment course, the minimum plasma concentration of 2-fluoro-ara-A approximately doubled. Accumulation of 2-fluoro-ara-A after several courses of therapy is excluded. The decrease in plasma concentration of 2-fluoro-ara-A is triphasic. The half-life (T_1/2) in the initial phase is about 5 minutes, in the intermediate phase – 1-2 hours, and in the terminal phase – approximately 20 hours.

According to pharmacokinetic study results, the mean total plasma clearance of 2-fluoro-ara-A is 79±40 ml/min/m² body surface area (2.2 ± 1.2 ml/min/kg body weight), and the mean volume of distribution is 83 ± 55 L/m² (2.4 ± 1.6 L/kg). There is significant variability in these parameters among different patients. The plasma concentration of 2-fluoro-ara-A and the area under the pharmacokinetic curve increase linearly with increasing doses, while T_1/2, plasma clearance, and volume of distribution are dose-independent. In vitro studies did not reveal significant binding of 2-fluoro-ara-A to plasma proteins.

2-fluoro-ara-A is excreted primarily by the kidneys. 40-60% of the intravenously administered dose is excreted in the urine.

Since the total clearance of 2-fluoro-ara-A is reduced in patients with impaired renal function, dose reduction is necessary when used in such patients.

Cellular pharmacokinetics of fludarabine triphosphate

2-fluoro-ara-A is actively absorbed by leukemia cells, after which it is rephosphorylated to mono- and diphosphate, and then to triphosphate. Fludarabine triphosphate (2-fluoro-ara-ATP) is the main intracellular metabolite. As far as is known, only it possesses cytotoxic activity. The maximum concentration (C_max) of 2-fluoro-ara-ATP in lymphocytes of patients with chronic lymphocytic leukemia is observed approximately 4 hours after drug administration and is approximately 20 μmol with significant variation among different patients. The concentration of 2-fluoro-ara-ATP in leukemia cells is significantly higher than the C_max of 2-fluoro-ara-A in plasma, indicating accumulation of the drug in target cells. When incubating leukemic lymphocytes in vitro, a linear relationship was found between the extracellular exposure to 2-fluoro-ara-A (which depends on the concentration of 2-fluoro-ara-A and the duration of incubation) and the intracellular concentration of 2-fluoro-ara-ATP. The T_1/2 of 2-fluoro-ara-ATP from target cells averages 15-23 hours.

No clear correlation was found between the pharmacokinetics of fludarabine and its therapeutic effect in cancer patients, while the development of neutropenia and a decrease in hematocrit indicate that the cytotoxic effect of fludarabine causes dose-dependent suppression of hematopoiesis.

Indications

• B-cell chronic lymphocytic leukemia (CLL);
• Low-grade non-Hodgkin’s lymphomas (LG NHL).

ICD codes

Dosage Regimen

The dose and treatment regimen are determined individually depending on the patient’s condition, as well as whether fludarabine is used as monotherapy or in combination with other drugs. Treatment with Fludarabine-Ebewe should be carried out under the supervision of a qualified oncologist.

The drug must be administered only intravenously. Although no local irritation has been reported with paravenous administration of fludarabine, all measures should be taken to prevent extravasation.

Treatment of adults

The usual initial dose of Fludarabine-Ebewe is 25 mg/m² body surface area per day. The drug is administered intravenously daily for 5 days (1 course). Courses are repeated at 28-day intervals.

The required amount of the drug (calculated based on body surface area) is drawn into a syringe. In the case of administration by intravenous bolus injection, the concentrate in the syringe is diluted with 10 ml of 0.9% sodium chloride solution. Alternatively, the drug may be diluted with 100 ml of 0.9% sodium chloride solution and administered by intravenous infusion over approximately 30 minutes.

The optimal duration of treatment has not been precisely established. It depends on the therapeutic efficacy and tolerability of the therapy.

For patients with CLL, treatment with Fludarabine-Ebewe is recommended until remission is achieved (usually 6 courses are required), after which the drug is discontinued.

For patients with LG NHL, treatment with Fludarabine-Ebewe is recommended until the maximum response (complete or partial remission) is achieved. After achieving the greatest effect, the need for two consolidation cycles (up to a maximum of 8 treatment cycles) should be considered.

Treatment of patients with hepatic impairment

There is no information on the use of Fludarabine-Ebewe for the treatment of patients with hepatic impairment. The drug should be prescribed to such patients with caution and only when the expected benefit of treatment outweighs the potential risk.

Treatment of patients with renal impairment

If serum creatinine clearance is 30-70 ml/min, the dose of Fludarabine-Ebewe must be reduced by 50% and hematological parameters should be carefully monitored for timely detection of toxic effects. If creatinine clearance is below 30 ml/min, the use of Fludarabine-Ebewe is contraindicated.

Adverse Reactions

The most common side effects of fludarabine treatment are bone marrow suppression (with manifestations such as neutropenia, thrombocytopenia, and anemia), infections (particularly pneumonia), fever, nausea, vomiting, and diarrhea. Side effects such as fatigue, weakness, stomatitis, malaise, anorexia, edema, chills, peripheral neuropathy, visual disturbances, and skin rashes are also frequently reported. Cases of severe opportunistic infections have been noted in patients receiving fludarabine. Sometimes severe adverse reactions have resulted in death.

According to the World Health Organization (WHO), adverse effects are classified according to their frequency of occurrence as follows: very common (> 1/10), common (> 1/100, <1/10), uncommon (> 1/1000, <1/100), rare (>1/10000, <1/1000) and very rare (<1/10000); frequency unknown (frequency of occurrence cannot be estimated from the available data).

Infections and infestations

Very common: infections/opportunistic infections (activation of latent viral carriage including progression of multifocal leukoencephalopathy, infection caused by Herpes zoster virus, Epstein-Barr virus), pneumonia;

Rare: lymphoproliferative disorders (associated with Epstein-Barr virus).

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Common: myelodysplastic syndrome, acute myeloid leukemia.

Blood and lymphatic system disorders

Very common: neutropenia, anemia, thrombocytopenia;

Common: myelosuppression.

Immune system disorders

Uncommon: autoimmune diseases (including autoimmune hemolytic anemia, Evans syndrome, thrombocytopenic purpura, acquired hemophilia, pemphigus).

Metabolism and nutrition disorders

Common: anorexia;

Uncommon: tumor lysis syndrome (with manifestations such as renal failure, metabolic acidosis, hyperkalemia, hypocalcemia, hyperuricemia, hematuria, urate salts in urine. At the initial stage of development of this syndrome, pain in the hip and flank may also occur).

Nervous system disorders

Common: peripheral neuropathy;

Uncommon: confusion;

Rare: agitation, seizures, coma;

Very rare: cerebral hemorrhage.

Eye disorders

Common: visual disturbances;

Rare: optic neuritis, optic neuropathy, blindness.

Cardiac disorders

Rare: heart failure, arrhythmia.

Respiratory, thoracic and mediastinal disorders

Very common: cough;

Uncommon: toxic lung damage (including pulmonary fibrosis, pneumonitis, dyspnea);

Very rare: pulmonary hemorrhage.

Gastrointestinal disorders

Very common: nausea, diarrhea, vomiting;

Common: stomatitis, mucositis (inflammatory, erythematous and erosive-ulcerative lesions of the oral mucosa, pharynx, esophagus and the entire gastrointestinal tract);

Uncommon: gastrointestinal bleeding (mainly associated with thrombocytopenia), increased plasma concentration of pancreatic enzymes.

Hepatobiliary disorders

Uncommon: increased activity of “liver” transaminases.

Renal and urinary disorders

Very rare: hemorrhagic cystitis.

Skin and subcutaneous tissue disorders

Common: skin rashes;

Rare: Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome).

General disorders and administration site conditions

Very common: fever, fatigue, weakness;

Common: malaise, chills, peripheral edema.

Contraindications

• Hypersensitivity to fludarabine or other components of the drug;
• Severe renal failure (creatinine clearance less than 30 ml/min);
• Decompensated hemolytic anemia;
• Childhood (lack of safety data);
• Breastfeeding period;
• Pregnancy.

With caution after a thorough assessment of the risk/benefit ratio, it should be prescribed to debilitated patients, patients with renal failure, impaired liver function, severe bone marrow suppression (thrombocytopenia, anemia and/or granulocytopenia), immunodeficiency or a history of opportunistic infections, elderly patients over 75 years of age (insufficient clinical data on use), in acute infectious diseases of viral, fungal and bacterial nature.

Use in Pregnancy and Lactation

The use of the drug during pregnancy is contraindicated.

It is not known whether fludarabine is excreted in breast milk, therefore breastfeeding must be discontinued during treatment with the drug.

Use in Hepatic Impairment

There is no information on the use of Fludarabine-Ebewe for the treatment of patients with hepatic impairment. The drug should be prescribed to such patients with caution and only when the expected benefit of treatment outweighs the potential risk.

Use in Renal Impairment

If serum creatinine clearance is 30-70 ml/min, the dose of Fludarabine-Ebewe must be reduced by 50% and hematological parameters should be carefully monitored for timely detection of toxic effects. If creatinine clearance is below 30 ml/min, the use of Fludarabine-Ebewe is contraindicated.

Pediatric Use

Due to the lack of safety data, use in children is contraindicated.

Geriatric Use

Caution should be exercised when prescribing to elderly patients over 75 years of age (insufficient clinical data on use).

Special Precautions

The use of Fludarabine-Ebewe should be carried out under the supervision of a qualified physician experienced in the use of antineoplastic chemotherapeutic drugs. The dose and regimen of the drug are selected individually.

Caution must be exercised when handling Fludarabine-Ebewe. The drug should be diluted under aseptic conditions in a designated area. This should be done by trained personnel. All measures must be taken to prevent fludarabine solution from coming into contact with the skin and mucous membranes, in particular, protective clothing (gown, cap, mask, goggles, and disposable gloves) should be used. If fludarabine comes into contact with the skin or mucous membranes, it must be thoroughly washed with soap and water or (eyes) with plenty of water.

When treating acute leukemia with high doses of fludarabine, severe neurological effects, including blindness, coma, and death, have been observed. Toxic lesions of the central nervous system were observed in 36% of patients who received intravenous doses approximately 4 times higher than those recommended for chronic lymphocytic leukemia (96 mg/m² body surface area per day for 5-7 days). During therapy with fludarabine at the doses recommended for chronic lymphocytic leukemia, severe neurological effects are rare (coma, seizures, agitation) or occur occasionally (confusion). Patients should be closely monitored for signs of neurological side effects.

The effect of fludarabine on the central nervous system with long-term use has not been studied. However, in some studies, patients who tolerated therapy at recommended doses normally received up to 26 courses.

Fludarabine should be prescribed to debilitated patients with caution and only after a thorough assessment of the risk/benefit ratio. This applies especially to patients with severe bone marrow dysfunction (thrombocytopenia, anemia and/or granulocytopenia), immunodeficiency, or a history of opportunistic infections.

Severe bone marrow suppression (anemia, thrombocytopenia, neutropenia) may be observed during treatment with fludarabine. In patients with solid tumors, the minimum number of granulocytes is observed on average at 13 days (range 3-25 days), and platelets – at 16 days (range 2-32 days). Most patients had hematological abnormalities prior to the start of fludarabine treatment (as a result of the underlying disease or previous therapy with myelosuppressive drugs). Cumulative myelosuppression may be observed. Although chemotherapy-induced bone marrow suppression is often reversible, careful monitoring of hematological parameters is necessary during fludarabine treatment.

Fludarabine is a potent antineoplastic agent that can have significant toxic side effects. Patients receiving the drug should be under close medical supervision for signs of hematological and non-hematological toxic effects. Regular monitoring of peripheral blood cell counts is recommended to detect the development of anemia, neutropenia, and thrombocytopenia.

As with the use of other cytotoxic agents, caution is required when treating with fludarabine if stem cell harvesting followed by autotransplantation is planned during further treatment.

Cases of post-transfusion graft-versus-host disease (caused by immunocompetent donor lymphocytes) have been reported after transfusion of non-irradiated blood to patients receiving fludarabine. This reaction is very often fatal, so patients requiring blood transfusion before or after treatment with fludarabine should receive only irradiated blood.

Isolated cases of reversible exacerbation of existing skin cancer during or after treatment with fludarabine have been reported.

In patients with chronic lymphocytic leukemia and large tumor masses, treatment with fludarabine may cause tumor lysis syndrome as early as the first week of therapy. Therefore, appropriate measures must be taken to prevent the development of this complication in at-risk patients.

Regardless of the presence or absence of a history of autoimmune processes, as well as Coombs test results, life-threatening and even fatal autoimmune reactions sometimes develop during or after treatment with fludarabine (in particular, autoimmune hemolytic anemia, autoimmune thrombocytopenia, thrombocytopenic purpura, pemphigus, Evans syndrome). In most patients who developed hemolytic anemia during treatment with fludarabine, a recurrence of hemolysis was noted after resumption of fludarabine treatment. It is necessary to carefully monitor for signs of possible development of autoimmune hemolytic anemia (such as a decrease in hemoglobin level and a positive Coombs test) in patients receiving Fludarabine-Ebewe. In case of hemolysis development, discontinuation of fludarabine therapy is recommended. The most common therapeutic measures for autoimmune hemolytic anemia are transfusions of irradiated blood and adrenocorticoid therapy.

Men and women of reproductive potential should use reliable methods of contraception during and for 6 months after the end of fludarabine therapy.

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

Effect on ability to drive vehicles, operate machinery

Due to the possibility of side effects such as visual disturbances, seizures, and confusion, caution should be exercised when engaging in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Overdose

Symptoms high doses of fludarabine cause irreversible damage to the central nervous system with manifestations such as blindness, coma, and death. Overdose can also cause severe thrombocytopenia and neutropenia due to bone marrow function suppression.

Treatment a specific antidote for fludarabine is unknown. In case of overdose, the drug should be discontinued and supportive treatment instituted.

Drug Interactions

The use of fludarabine 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, it is not recommended to prescribe fludarabine in combination with pentostatin.

Dipyridamole and other adenosine uptake inhibitors may reduce the therapeutic efficacy of fludarabine.

Pharmacokinetic interaction was observed during combined chemotherapy with fludarabine and cytarabine in patients with chronic lymphocytic leukemia and acute myeloid leukemia. Clinical studies and in vitro experiments on cancer cell lines revealed an increase in intracellular levels of arabinosylcytidine triphosphate (Ara-CTP) in leukemia cells when cytarabine was administered after fludarabine. This applies to both the maximum intracellular concentration and the total intracellular exposure. The plasma concentration of cytarabine and the elimination rate of Ara-CTP do not change in this case.

Due to the development of cross-resistance to chlorambucil, it should not be prescribed to patients with resistance to fludarabine.

Must not be mixed with other solutions.

Storage Conditions

Store protected from light at a temperature of 2 to 8°C (46.4°F). Keep out of reach of children.

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the packaging!

Special precautions for disposal of unused medicinal products

Residues of the drug and all instruments and materials that were used for preparing infusion solutions of Fludarabine-Ebewe must be disposed of in accordance with the standard hospital procedure for the disposal of cytotoxic waste, taking into account the current regulations for the disposal of hazardous waste.

Dispensing Status

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.