Fludarabine-Actavis (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Actavis Group PTC ehf. (Iceland)

Manufactured By

S.C. Sindan-Pharma S.R.L. (Romania)

ATC Code

L01BB05 (Fludarabine)

Active Substance

Fludarabine phosphate

Dosage Form

Fludarabine-Actavis

Lyophilizate for preparation of solution for intravenous administration 50 mg: fl. 1 pc.

Dosage Form, Packaging, and Composition

Lyophilizate for preparation of solution for intravenous administration in the form of a porous mass from white to almost white.

Excipients: mannitol – 50 mg, sodium hydroxide – q.s. to pH of solution 7.7 (7.2-8.2).

100 mg – glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

The drug Fludarabine-Actavis contains Fludarabine phosphate – a fluorinated nucleotide analogue of the antiviral drug 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, after being taken up by cells, is 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 with subsequent reduction in protein synthesis.

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.

After a single infusion to patients with B-cell chronic lymphocytic leukemia (CLL) of 2-fluoro-ara-AMP at a dose of 25 mg/m² over 30 minutes, the C_max of 2-fluoro-ara-A is 3.5-3.7 µmol and is reached by the end of the infusion. Determinations of the corresponding level of 2-fluoro-ara-A after five 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.

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

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

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 volume of distribution is 83±55 L/m² (2.4±1.61 L/kg). The obtained data indicate high individual variability. After intravenous (IV) administration, the plasma concentration of 2-fluoro-ara-A and the area under the concentration-time curve (AUC) increase in a linear dose-dependent manner, whereas T_1/2, plasma clearance, and volumes of distribution remain constant regardless of dose.

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

2-fluoro-ara-A is delivered to leukemia cells by active transport, 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 CLL patients was observed on average 4 hours after the infusion and was characterized by significant fluctuation of the average value, approximately 20 µmol. The concentration of 2-fluoro-ara-ATP in leukemic cells was significantly higher than its maximum concentration 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.

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 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 chronic lymphocytic leukemia;
• Low-grade non-Hodgkin’s lymphomas;

ICD codes

Dosage Regimen

The drug Fludarabine-Actavis should be administered only intravenously.

The recommended dose is 25 mg/m² of body surface area 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.

Duration of treatment

The duration of treatment depends on the effect and tolerability of the drug. In B-cell chronic lymphocytic leukemia, the drug Fludarabine-Actavis should be used until maximum response is achieved (complete or partial remission, usually – 6 cycles), after which treatment should be discontinued.

In low-grade non-Hodgkin’s lymphoma, treatment with Fludarabine-Actavis is recommended until maximum response is achieved (complete or partial remission). After achieving the greatest effect, the need for two consolidation cycles should be considered. In most cases, no more than 8 treatment cycles are required.

Hepatic impairment

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

Renal impairment

With CrCl 30-70 ml/min, it is necessary to reduce the dose by 50%. During therapy in these patients, constant hematological monitoring is necessary.

Adverse Reactions

The frequency of adverse events is indicated based on data from clinical studies, regardless of a causal relationship with the use of the drug Fludarabine-Actavis, according to the following gradation: very common (≥ 10%), common (<10% - ≥1%), uncommon (< 1% - ≥0.1%), rare (< 0.1% - ≥0.01%), very rare (< 0.01%).

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

In patients who received fludarabine before, after, or simultaneously with alkylating cytotoxic agents or radiotherapy, myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) was rarely observed.

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

From the digestive system very common – nausea, vomiting, diarrhea; common – anorexia, stomatitis, mucositis; uncommon – gastrointestinal bleeding, impaired liver and pancreatic enzyme parameters.

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

From the central and peripheral nervous system common – peripheral neuropathy; uncommon – confusion; rare – agitation, seizures, coma, cerebral hemorrhage.

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

From the respiratory system very common – cough; uncommon – dyspnea, pulmonary fibrosis, pneumonitis.

From the cardiovascular system rare – heart failure, arrhythmias.

From the urinary system rare – hemorrhagic cystitis.

From the skin common – skin rash. 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.

Allergic reactions rare – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), anaphylactic shock.

Other very common – fever, increased fatigue, weakness, addition of secondary infections/opportunistic infections (e.g., reactivation of latent viruses, including herpes viruses and Epstein-Barr virus, progressive multifocal leukoencephalopathy), pneumonia; common – chills, malaise, edema; rare – lymphoproliferative disorders (associated with Epstein-Barr virus).

Contraindications

• Renal impairment (CrCl < 30 ml/min);
• Decompensated hemolytic anemia;
• Pregnancy;
• Lactation period (breastfeeding);
• Hypersensitivity to the components of the drug;
• Children under 18 years of age (efficacy and safety have not been established).

With caution: acute infectious diseases of viral, fungal and bacterial nature, severe suppression of bone marrow function (thrombocytopenia, anemia and/or granulocytopenia), debilitated patients, renal failure, hepatic failure, immunodeficiency, in patients over 75 years of age.

Use in Pregnancy and Lactation

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

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

Use in Hepatic Impairment

With caution: hepatic failure.

Use in Renal Impairment

With caution: renal failure.

Pediatric Use

Contraindicated in children under 18 years of age (efficacy and safety have not been established).

Geriatric Use

With caution in patients over 75 years of age.

Special Precautions

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

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

Treatment with the drug Fludarabine-Actavis should be carried out under the supervision of a physician experienced in the use of cytotoxic agents.

The drug Fludarabine-Actavis should be administered only IV. There have been no reports of severe local adverse reactions when the drug was administered extravasally. However, accidental extravascular administration should be avoided.

During therapy with Fludarabine-Actavis, it is recommended to periodically evaluate peripheral blood counts to detect anemia, neutropenia and thrombocytopenia, carefully monitor serum creatinine concentration and CrCl, and also carefully monitor CNS function for the timely detection of possible neurological disorders.

Bone marrow suppression is usually reversible. During therapy with Fludarabine-Actavis for solid tumors in adults, 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 2-32 days). Myelosuppression can be severe and cumulative. Several cases of bone marrow hypoplasia or aplasia in adults, manifested by pancytopenia, sometimes with a fatal outcome, have been described. The duration of clinically significant pancytopenia ranged from 2 months to 1 year. These episodes were identified in both previously treated and untreated patients.

The effects of long-term use of the drug Fludarabine-Actavis on the CNS are unknown. However, some studies have shown that with relatively long-term use (up to 26 courses of therapy), fludarabine is well tolerated by patients.

During therapy with Fludarabine-Actavis, the development of serious opportunistic infections, in some cases leading to death, has been noted. 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 history, as well as the results of the Coombs test, life-threatening, and sometimes fatal, autoimmune reactions (autoimmune hemolytic anemia, autoimmune thrombocytopenia, thrombocytopenic purpura, pemphigus, Evans syndrome) have been described during or after treatment with Fludarabine-Actavis. In most patients with hemolytic anemia, a recurrence of hemolysis was noted after a provocative test with fludarabine. Patients receiving treatment with Fludarabine-Actavis should be carefully monitored for signs of hemolytic anemia. In case of hemolysis development, discontinuation of therapy with the drug is recommended.

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

In rare cases, in patients who received fludarabine before, after, or simultaneously with alkylating cytotoxic agents or radiotherapy, MDS/AML were observed. With monotherapy with Fludarabine-Actavis, MDS/AML were not observed.

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

Since fludarabine 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).

It should be borne in mind that patients resistant to therapy with Fludarabine-Actavis in most cases also show resistance to chlorambucil.

During and after treatment with Fludarabine-Actavis, vaccination with live vaccines should be avoided.

When handling the drug, all instructions adopted for the use and disposal of cytotoxic drugs should be observed. Inhalation of the drug should be avoided. The use of protective goggles and latex gloves is recommended. If the solution comes into contact with the skin or mucous membranes, these areas should be thoroughly washed with water and soap. If it gets into the eyes, the eyes should be thoroughly rinsed with plenty of water.

Pregnant women are prohibited from working with the drug.

Use in pediatrics

The efficacy and safety of the use of the drug Fludarabine-Actavis in children under 18 years of age have not been established.

Effect on ability to drive vehicles and mechanisms

Some side effects of the drug, such as increased fatigue, weakness, visual disturbances, confusion, agitation and seizures, may adversely affect the ability to drive a car and perform potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms Fludarabine in high doses causes irreversible changes in the CNS, including blindness, coma and death. When using fludarabine in doses 4 times higher than recommended (96 mg/m²/day for 5-7 days), neurotoxicity was observed in approximately 36% of patients, with symptoms of neurotoxicity appearing on days 21-60 after the last dose administration. Use in high doses is also associated with the development of severe thrombocytopenia and neutropenia due to suppression of bone marrow function.

Treatment discontinuation of drug administration and supportive therapy, specific antidote is unknown.

Drug Interactions

The use of fludarabine in combination with pentostatin (deoxycoformycin) for the treatment of CLL often led to death due to high pulmonary toxicity, therefore it is not recommended to use fludarabine in combination with pentostatin. Dipyridamole or other inhibitors of adenosine reuptake may reduce the therapeutic efficacy of fludarabine.

During treatment with a combination of fludarabine and cytarabine in patients with CLL and AML, a pharmacokinetic interaction was observed. When cytarabine is used concomitantly with fludarabine, higher intracellular maximum concentrations and intracellular AUC of the cytarabine metabolite – cytarabine triphosphate are shown. Plasma concentrations of cytarabine and the elimination of cytarabine triphosphate were not changed.

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

Storage Conditions

Store at a temperature not exceeding 25°C (77°F). Keep out of reach of children!

Shelf Life

Shelf life – 4 years.

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.