Flugarda^® (Tablets, Lyophilisate) Instructions for Use

ATC Code

L01BB05 (Fludarabine)

Active Substance

Fludarabine phosphate

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Flugarda^® contains Fludarabine phosphate, a fluorinated nucleotide analogue of the antiviral agent vidarabine, 9-β-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, after being taken up by cells, is 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 vitro studies have shown that exposure of lymphocytes from patients with chronic lymphocytic leukemia (CLL) to 2-fluoro-ara-A activates a mechanism of intense DNA fragmentation and apoptosis.

It is toxic. It has teratogenic activity. It does not possess mutagenic properties.

Pharmacokinetics

No clear correlation has been identified between the pharmacokinetics of fludarabine and its therapeutic effect in cancer patients, while the frequency of neutropenia detection and changes in hematocrit are dose-dependent.

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. Plasma protein binding is insignificant.

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 concentration of 2-fluoro-ara-ATP in leukemia 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.

After oral administration, C_max (20-30% of the concentration determined at the end of IV infusion) in blood is observed after 1-2 hours.

Bioavailability is 50-65%.

Food slightly (less than 10%) increases AUC and reduces T_max (time to reach C_max) and C_max, but does not change T_1/2.

In chronic renal failure, its clearance is reduced.

Indications

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

ICD codes

Dosage Regimen

Lyophilisate

Flugarda should be administered only intravenously, and accidental extravascular entry should be avoided.

The recommended dose of fludarabine phosphate is 25 mg/m² body surface area IV once daily for 5 days every 28 days.

The contents of each vial should be dissolved in 2 ml of water for injections.

1 ml of the prepared solution contains 25 mg of fludarabine phosphate.

The required dose (calculated based on the patient’s body surface area) is drawn into a syringe.

This dose is then diluted in 10 ml of 0.9% sodium chloride solution and administered IV bolus, or diluted in 100 ml of 0.9% sodium chloride solution and administered IV drip over approximately 30 minutes.

The duration of treatment depends on the effect and tolerability of the drug.

In CLL patients, Flugarda^® should be prescribed until maximum response is achieved (complete or partial remission, usually 6 cycles), after which treatment should be discontinued.

In patients with low-grade NHL, treatment with Flugarda is recommended until maximum response is achieved (complete or partial remission).

After achieving the greatest effect, the need for two consolidation cycles should be discussed.

According to clinical trials in low-grade NHL, most patients received no more than 8 treatment cycles.

Data on the efficacy and safety of fludarabine in patients with impaired liver function are limited.

Patients in this group should be prescribed fludarabine 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, creatinine clearance should be determined.

For creatinine clearance from 30 to 70 ml/min, the dose should be reduced to 50%, and constant hematological monitoring is necessary to assess toxicity.

Treatment with Flugarda is contraindicated with creatinine clearance <30 ml/min.

Tablets

The recommended oral dose is 40 mg/m² body surface area daily for 5 days every 28 days.

The table provides recommendations for determining the number of tablets to take, depending on the body surface area (BSA).

The tablets can be taken on an empty stomach or with food.

The tablets should be swallowed whole (not chewed, not broken), with water.

The duration of treatment depends on the effect and tolerability of the drug.

The drug Flugarda^® should be used until maximum response is achieved (complete or partial remission, usually 6 cycles), after which treatment should be discontinued.

Dosage regimen adjustment

Patients with impaired renal function

If CrCl is from 30 to 70 ml/min, the dose should be reduced by 50%.

During therapy in such patients, constant hematological monitoring is necessary.

Patients with impaired liver function

The safety and efficacy of fludarabine have not been studied in patients with impaired liver function.

Caution should be exercised in this category of patients.

Hematological toxicity

If at the beginning of the subsequent cycle a pronounced decrease in the absolute neutrophil count and/or platelet count is observed, the planned treatment cycle should be postponed until the neutrophil count reaches 1.0×10⁹/L and platelets reach 100×10⁹/L or higher.

Treatment can be delayed for a maximum of two weeks.

If the absolute neutrophil count and platelet count have not reached the specified values after two weeks, treatment should be continued using a reduced dose according to the table below.

If thrombocytopenia is associated with the underlying disease, dose adjustment of the drug is not required.

Use in special patient groups

Children

Efficacy and safety in children have not been studied.

Elderly patients

Since there are limited data on the use of fludarabine in elderly patients (over 75 years), the drug should be used with caution in this category of patients.

Adverse Reactions

The frequency of adverse events is indicated based on clinical trial data, regardless of a causal relationship with the use of fludarabine, according to the following gradation: very common (>10%), common (<10->1%), uncommon (<1%->0.1%), rare (<0.1%->0.01%), frequency unknown.

Infections and infestations

Very common – addition of secondary infections/opportunistic infections (e.g., reactivation of latent viruses, including herpes viruses and Epstein-Barr virus, progressive multifocal leukoencephalopathy), pneumonia; rare – lymphoproliferative disorders (associated with Epstein-Barr virus).

Blood and lymphatic system disorders

Very common – neutropenia, thrombocytopenia, and anemia; common – myelosuppression.

Immune system disorders

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

Gastrointestinal disorders

Very common – nausea, vomiting, diarrhea; common – anorexia, stomatitis, mucositis; uncommon – gastrointestinal bleeding, changes in liver and pancreatic enzyme activity.

Metabolism and nutrition disorders

Uncommon – as a result of tumor lysis, hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria, and renal failure may develop.

Nervous system disorders

Common – peripheral neuropathy; uncommon – confusion; rare – agitation, seizures, coma.

Eye disorders

Common – visual impairment; rare – optic neuritis, optic neuropathy, and blindness.

Respiratory, thoracic and mediastinal disorders

Very common – cough; uncommon – dyspnea, pulmonary fibrosis, pneumonitis.

Cardiac disorders

Rare – heart failure, arrhythmias.

Renal and urinary disorders

Rare – hemorrhagic cystitis.

Skin and subcutaneous tissue disorders

Common – skin rash; rare – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome). Rare cases of exacerbation of existing skin cancer, as well as development of skin cancer during or after treatment with fludarabine have been reported.

General disorders and administration site conditions

Very common – fever, increased fatigue, weakness; common – chills, malaise, edema.

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

In patients who received fludarabine before, after, or simultaneously with alkylating cytotoxic agents, topoisomerase inhibitors, or radiotherapy, rare cases of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) were observed.

Post-marketing data

Nervous system disorders

Frequency unknown – leukoencephalopathy, acute toxic leukoencephalopathy, posterior reversible encephalopathy syndrome (PRES).

Vascular disorders

Frequency unknown – bleeding (including cerebral hemorrhage, pulmonary hemorrhage).

Contraindications

• Hypersensitivity to fludarabine or other components of the drug;
• Impaired renal function with CrCl<30 ml/min;
• Decompensated hemolytic anemia;
• Pregnancy and breastfeeding period;
• Childhood (insufficient clinical data).

With caution

Flugarda^® should be used with caution after a thorough assessment of the risk/benefit ratio in debilitated patients, patients with severe bone marrow function depression (thrombocytopenia, anemia, and/or granulocytopenia), immunodeficiency or a history of opportunistic infections, patients over 75 years of age, patients with renal failure (CrCl – 30-70 ml/min), patients with hepatic failure, patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

Use in Pregnancy and Lactation

Use in pregnant women and during lactation is contraindicated. Pregnant women are also prohibited from working with the drug.

Use in Hepatic Impairment

The safety and efficacy of fludarabine have not been studied in patients with impaired liver function. Caution should be exercised in this category of patients.

Use in Renal Impairment

The drug should be used with caution in patients with renal failure (CrCl – 30-70 ml/min).

If CrCl is from 30 to 70 ml/min, the dose should be reduced by 50%. During therapy in such patients, constant hematological monitoring is necessary.

Pediatric Use

Use of the drug in children is contraindicated (efficacy and safety in children have not been studied).

Geriatric Use

Since there are limited data on the use of fludarabine in elderly patients (over 75 years), the drug should be used with caution in this category of patients.

Special Precautions

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

During therapy with Flugarda^®, it is recommended to periodically evaluate peripheral blood counts to detect anemia, neutropenia, and thrombocytopenia, carefully monitor serum creatinine concentration and CrCl, and also carry out careful monitoring of CNS function in order to timely identify possible neurological disorders.

Bone marrow suppression is usually reversible.

During therapy of solid tumors in adults with fludarabine, the greatest decrease in neutrophil count is observed on average on day 13 (range 3-25 days) from the start of treatment, and platelets on average on day 16 (range 2-23 days).

Myelosuppression can be severe and have a cumulative nature.

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.

The effects of long-term use of fludarabine on the CNS are unknown.

During therapy with Flugarda^®, it is recommended to monitor CNS parameters due to the possible neurotoxicity of the drug, which has been described during therapy with fludarabine in high doses.

Within the post-marketing experience of fludarabine use, cases of leukoencephalopathy, acute toxic leukoencephalopathy, and posterior reversible encephalopathy syndrome have been registered.

However, some studies have shown that with relatively long-term use (up to 26 therapy courses), fludarabine is well tolerated by patients.

During therapy with fludarabine, the development of serious opportunistic infections has been noted, in some cases leading to death.

Patients at increased risk of developing opportunistic infections are recommended to receive prophylactic therapy.

Regardless of the presence or absence of autoimmune processes in the medical history, as well as the results of the Coombs test, the occurrence of life-threatening, and sometimes fatal, autoimmune reactions (autoimmune hemolytic anemia, autoimmune thrombocytopenia, thrombocytopenic purpura, pemphigus, Evans syndrome) during or after treatment with fludarabine has been described.

In most patients with hemolytic anemia, a recurrence of hemolysis was noted after a provocative test with fludarabine.

Patients receiving treatment with fludarabine should be carefully monitored for signs of hemolytic anemia.

In case of hemolysis development, discontinuation of fludarabine therapy is recommended.

The most common therapeutic measures for hemolytic anemia are transfusions of irradiated blood and glucocorticoid therapy.

In rare cases, in patients who received fludarabine before, after, or simultaneously with alkylating cytotoxic agents, topoisomerase inhibitors, or radiotherapy, myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) were observed.

MDS/AML were not observed during fludarabine monotherapy.

Graft-versus-host disease (reaction of transfused immunocompetent lymphocytes against the host), occurring as a result of blood transfusions, was observed after transfusion of non-irradiated blood to patients receiving treatment with fludarabine.

A high frequency of fatal outcomes as a consequence of this disease has been reported.

Therefore, patients who require blood transfusions and who are receiving or have received treatment with fludarabine should be transfused only with irradiated blood.

Isolated cases of skin cancer development, as well as exacerbation of pre-existing skin cancer, during or after treatment with fludarabine have been reported.

Since Flugarda^® can cause tumor lysis as early as the first week of therapy, caution should be exercised when treating patients at risk of developing this syndrome (especially with a large tumor mass).

Due to insufficient clinical data on the use of fludarabine in elderly patients (over 75 years), fludarabine should be used with caution in this age group.

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

Women and men of reproductive potential should use reliable methods of contraception during treatment and for at least 6 months after the end of therapy.

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

Precautions for Use

All guidelines adopted for the handling and disposal of cytotoxic drugs must be observed when handling fludarabine. Inhalation of the drug should be avoided. The use of protective glasses and latex gloves is recommended. If the solution comes into contact with the skin or mucous membranes, these areas should be washed thoroughly with soap and water. If it gets into the eyes, the eyes should be rinsed thoroughly with plenty of water. Pregnant women are prohibited from working with fludarabine.

Effect on the Ability to Drive Vehicles and Operate Machinery

Some side effects of the drug, such as increased fatigue, weakness, and visual disturbances, may adversely affect the ability to drive a car and perform potentially hazardous activities requiring increased concentration and speed of psychomotor reactions. If the described adverse events occur, one should refrain from performing these activities.

Overdose

High doses of fludarabine cause irreversible changes in the central nervous system, including blindness, coma, and death. When using fludarabine at doses 4 times higher than recommended (95 mg/m²/day for 5-7 days), neurotoxicity was observed in approximately 36% of patients, with symptoms of neurotoxicity appearing 21-60 days after the last dose administration.

Use of doses exceeding the recommended ones is also associated with the development of severe thrombocytopenia and neutropenia due to suppression of bone marrow function.

Specific antidotes for fludarabine overdose are unknown. Treatment involves discontinuing the drug and providing supportive therapy.

Drug Interactions

The use of fludarabine in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL) often led to a fatal outcome due to high pulmonary toxicity; therefore, the use of Flugarda^® in combination with pentostatin is not recommended.

Dipyridamole or other inhibitors of adenosine reuptake may reduce the therapeutic efficacy of fludarabine.

Pharmacokinetic interaction was observed during treatment with a combination of fludarabine and cytarabine in patients with chronic lymphocytic leukemia and acute myeloid leukemia. When cytarabine is used concomitantly with fludarabine, higher intracellular peak concentrations and intracellular AUC of the cytarabine metabolite, cytarabine triphosphate, are observed. Plasma concentrations of cytarabine and the elimination of cytarabine triphosphate were not changed.

Storage Conditions

The drug should be stored in a dry place, protected from light, and out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years.

Do not use after the expiration date printed on the packaging.

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.