Fludarabine accord

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUDARABINE ACCORD

Composition:

Active substance: fludarabine phosphate;

1 ml of concentrate contains 25 mg fludarabine phosphate;

2 ml vial contains 50 mg fludarabine phosphate;

Excipients: mannitol (E 421), disodium phosphate dihydrate, water for injections.

Pharmaceutical form. Concentrate for solution for injection or infusion.

Main physicochemical properties: clear, colorless or slightly brownish-yellow solution in a clear glass vial. The solution should be practically free from particles.

Pharmacotherapeutic group. Antineoplastic agents. Purine analogues. ATC code L01B B05.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

The medicinal product Fludarabine Accord contains fludarabine phosphate, a water-soluble fluorinated nucleotide analogue of the antiviral agent vidarabine, 9-β-D-arabinofuranosyladenine (ara-A), which is relatively resistant to deamination by adenosine deaminase.

Fludarabine phosphate is rapidly dephosphorylated to 2F-ara-A, which is taken up by cells and subsequently phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2F-ara-ATP. This metabolite has been shown to inhibit ribonucleotide reductase, DNA polymerase, DNA primase α, δ, and ε, and DNA ligase, thereby inhibiting DNA synthesis. Additionally, partial inhibition of RNA polymerase II occurs, resulting in reduced protein synthesis.

Although some aspects of the mechanism of action of 2F-ara-ATP remain unclear, it is believed that effects on DNA, RNA, and protein synthesis contribute to inhibition of cell growth, with inhibition of DNA synthesis being the dominant factor in this process. Furthermore, in vitro studies have demonstrated that the action of 2F-ara-A on CLL lymphocytes causes extensive DNA fragmentation and increases the proportion of cells undergoing apoptosis.

Clinical Efficacy and Safety

In a phase III study involving patients with previously untreated B-cell chronic lymphocytic leukemia, treatment with Fludarabine Accord was compared to chlorambucil (40 mg/m² every 4 weeks) in 195 and 199 patients, respectively. The results showed a statistically significantly higher overall response rate (treatment efficacy) and complete response rate with Fludarabine Accord compared to chlorambucil (61.1% vs. 37.6%, and 14.9% vs. 3.4%, respectively). A statistically significantly longer duration of response (19 vs. 12.2 months) and time to disease progression (17 vs. 13.2 months) was observed in the group receiving fludarabine. Median survival was 56.1 months in the fludarabine group and 55.1 months in the chlorambucil group; a non-significant difference was also observed in overall patient status. The percentage of patients experiencing toxic reactions was comparable between the fludarabine group (89.7%) and the chlorambucil group (89.9%). While the overall incidence of hematological toxicity was not significantly different between the two groups, a significantly higher percentage of patients receiving fludarabine experienced leukocyte (p = 0.0054) and lymphocyte (p = 0.0240) toxicity compared to the chlorambucil group. The incidence of adverse reactions such as nausea, vomiting, and diarrhea was significantly lower in the fludarabine group (p < 0.0001, p < 0.0001, and p = 0.0489, respectively) than in the chlorambucil group. A significantly lower incidence of hepatic toxicity (p = 0.0487) was also reported in the fludarabine phosphate group compared to the chlorambucil group.

Patients who initially responded well to fludarabine therapy are likely to maintain a favorable response to monotherapy with Fludarabine Accord.

In a randomized study comparing fludarabine to cyclophosphamide, doxorubicin, and prednisone (CAP) in 208 patients with chronic lymphocytic leukemia (CLL) at Binet stage B or C, subgroup analysis of 103 previously treated patients showed the following results: the overall response rate (treatment efficacy) and complete response rate were higher with fludarabine compared to CAP (45% vs. 26%, and 13% vs. 6%, respectively); duration of response and overall survival were similar between fludarabine and CAP. During the planned 6-month treatment period, the number of deaths was 9 (fludarabine) vs. 4 (CAP).

According to a post-hoc analysis using only data from the first 6 months after treatment initiation, a difference in survival curves was observed between the fludarabine and CAP groups, favoring the CAP group in the subgroup of previously treated patients with Binet stage C disease.

Pharmacokinetics

Pharmacokinetic Parameters of Fludarabine (2F-ara-A) in Plasma and Urine

The pharmacokinetics of fludarabine (2F-ara-A) were studied after intravenous administration via rapid bolus injection, short-term infusion, continuous infusion, and after oral administration of fludarabine phosphate (fludarabine, 2F-ara-AMP).

No clear correlation has been established between the pharmacokinetics of 2F-ara-A and treatment efficacy in cancer patients.

However, the development of neutropenia and changes in hematocrit indicate dose-dependent suppression of hematopoiesis due to the cytotoxicity of fludarabine phosphate.

Distribution and Metabolism

2F-ara-AMP are water-soluble prodrugs of fludarabine (2F-ara-A), which are rapidly and quantitatively dephosphorylated in the human body to the nucleoside fludarabine (2F-ara-A).

Another metabolite, 2F-ara-hypoxanthine, which is the major metabolite in dogs, was observed in humans only in negligible amounts.

After a 30-minute infusion of a single dose of 2F-ara-AMP at 25 mg/m² in patients with CLL, the mean peak plasma concentration of 2F-ara-A was 3.5–3.7 µM at the end of the infusion. Plasma levels after the fifth dose showed moderate accumulation, with mean peak levels of 4.4–4.8 µM at the end of the infusion. During five-day treatment cycles, the trough plasma level of 2F-ara-A approximately doubles. Accumulation of 2F-ara-A does not occur over multiple treatment cycles. The post-peak decline occurs in three pharmacokinetic phases, with an initial half-life of approximately 5 minutes, an intermediate half-life of 1–2 hours, and a terminal half-life of approximately 20 hours.

Comparison of pharmacokinetic data for 2F-ara-A from various studies determined a mean total plasma clearance of 79±40 mL/min/m² (2.2±1.2 mL/min/kg) and a mean volume of distribution of 83±55 L/m² (2.4±1.6 L/kg). These data indicate high individual variability. After both intravenous and oral administration of fludarabine phosphate, plasma levels of 2F-ara-A and the area under the plasma concentration-time curve (AUC) increase linearly with dose, while half-life, plasma clearance, and volume of distribution remain constant regardless of dose, indicating dose-linear pharmacokinetics.

Excretion

Elimination of 2F-ara-A occurs predominantly via renal excretion. 40–60% of the intravenously administered dose is excreted in urine. Studies using radiolabeled 3H-2F-ara-AMP in laboratory animals indicate complete urinary excretion of radioactivity.

Special Populations

In individuals with impaired renal function, total body clearance is reduced, indicating the need for dose reduction. In vitro studies with human plasma proteins did not reveal a significant tendency for 2F-ara-A to bind to proteins.

Pharmacokinetic Parameters of Fludarabine Triphosphate in Cells

2F-ara-A is actively transported into leukemic cells, where it is rephosphorylated to the monophosphate, then to di- and triphosphate. The triphosphate 2F-ara-ATP is the major intracellular metabolite and the only known metabolite with cytotoxic activity. The maximum level of 2F-ara-ATP in leukemic lymphocytes of CLL patients was observed on average at 4 hours and varied significantly, with a mean peak concentration of approximately 20 µM. The level of 2F-ara-AT6 in leukemic cells was consistently much higher than the peak plasma level of 2F-ara-A, indicating accumulation at target sites. In vitro incubation of leukemic lymphocytes showed a linear relationship between extracellular exposure to 2F-ara-A (due to 2F-ara-A concentration and incubation time) and intracellular accumulation of 2F-ara-ATP. Elimination of 2F-ara-ATP from target cells occurs with a mean half-life of 15 and 23 hours.

Preclinical Safety Data

Systemic Toxicity

Acute toxicity studies with single doses of fludarabine phosphate twice the therapeutic dose resulted in symptoms of severe intoxication or lethal outcomes. As expected with a cytotoxic compound, administration of this drug negatively affects bone marrow, lymphoid organs, gastrointestinal mucosa, kidneys, and male reproductive glands. Severe adverse reactions in patients occurred at doses approaching the recommended therapeutic dose (factor 3–4) and included severe neurotoxicity, sometimes fatal (see section "Overdose").

Repeated-dose systemic toxicity studies with fludarabine phosphate also demonstrated expected effects on rapidly proliferating tissues at doses exceeding the threshold. The severity of morphological changes increased with higher doses and longer duration of administration; observed changes were generally considered reversible. Therapeutic experience with fludarabine indicates a similar toxicological profile in humans, although additional adverse reactions such as neurotoxicity have been observed (see section "Adverse Reactions").

Embryotoxicity

Embryotoxicity studies with intravenous administration in animals (rats and rabbits) showed embryolethal and teratogenic effects of fludarabine phosphate, manifested as skeletal malformations, reduced fetal weight, and post-implantation embryonic death (abortion). Given the narrow safety margin between teratogenic doses in animals and therapeutic doses in humans, and by analogy with other antimetabolites believed to interfere with differentiation processes, therapeutic use of Fludarabine Accord is associated with a relevant risk of teratogenic effects in humans (see section "Use During Pregnancy or Breastfeeding").

Genotoxicity, Carcinogenicity

Fludarabine phosphate was found to cause DNA damage in sister chromatid exchange assays, induce chromosomal aberrations in in vitro cytogenetic tests, and increase micronuclei frequency in the in vivo micronucleus test in mice. Mutagenic activity of fludarabine phosphate was not observed in gene mutation studies or in the dominant lethal test in male mice. Thus, mutagenic activity was demonstrated in somatic cells but not in germ cells.

The known activity of fludarabine phosphate at the DNA level and mutagenicity test results form the basis for suspicion of carcinogenicity. No animal studies directly aimed at determining carcinogenicity have been conducted, as the increased risk of secondary malignancies following fludarabine phosphate therapy can only be verified through epidemiological data.

Local Tolerance

Based on results from animal studies with intravenous administration of fludarabine phosphate, significant irritation at the injection site is not expected. Even with improper administration, no relevant local irritation was observed after paravenous, intra-arterial, or intramuscular injection of an aqueous solution containing 7.5 mg of fludarabine phosphate/mL.

The similarity of lesions observed in the gastrointestinal tract after intravenous or intragastric administration in animal studies suggests that enteritis caused by fludarabine phosphate is a systemic effect.

Clinical characteristics.

Indications.

Treatment of B-cell chronic lymphocytic leukemia (CLL) in adult patients with adequate bone marrow reserve.

First-line therapy with Fludarabine Accord should be administered only to adult patients with progressive disease, stage III/IV according to Rai (stage C according to Binet) or stage I/II according to Rai (stage A/B according to Binet), in whom the patient has disease-related symptoms or signs of progressive disease.

Contraindications.

Hypersensitivity to the active substance or to any of the components of the medicinal product.

Renal impairment with creatinine clearance < 30 mL/min.

Decompensated hemolytic anemia.

Breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

During clinical studies, when fludarabine was used in combination with pentostatin (deoxycoformycin) for the treatment of chronic lymphocytic leukemia (CLL), an unacceptably high incidence of fatal pulmonary toxicity was observed. Therefore, the use of Fludarabine Accord in combination with pentostatin is not recommended.

The therapeutic efficacy of fludarabine may be reduced when administered with dipyridamole and other adenosine uptake inhibitors.

Results from clinical studies and in vitro experiments have demonstrated that the use of fludarabine in combination with cytarabine may increase the intracellular concentration and intracellular exposure of Ara-CTP (the active metabolite of cytarabine) in leukemic cells. No effect was observed on plasma concentrations of Ara-C or on the elimination rate of Ara-CTP.

Special precautions for use.

Myelosuppression

Severe myelosuppression, particularly anaemia, thrombocytopenia, and neutropenia, has been reported in patients treated with fludarabine. In early studies of intravenous administration of the drug to adult patients with solid tumours, the median time to nadir granulocyte count was 13 days (range 3 to 25 days), and for platelets it was 16 days (range 2 to 32 days). Most patients had pre-existing haematological abnormalities at the start of treatment due to the disease or prior therapy causing myelosuppression.

Cumulative myelosuppression may occur. Although chemotherapy-induced myelosuppression is often reversible, treatment with fludarabine phosphate requires careful monitoring of haematological parameters.

Fludarabine phosphate is a potent antineoplastic agent with potentially severe toxic side effects. Patients receiving Fludarabine Accord must be closely monitored for signs of haematological and non-haematological toxicity.

Periodic complete blood counts are recommended to detect the development of anaemia, neutropenia, and thrombocytopenia.

There have been several reports of trilineage hypoplasia or aplasia of the bone marrow in adult patients, resulting in pancytopenia, which occasionally led to fatal outcomes. The duration of clinically significant cytopenic episodes reported ranged from 2 months to 1 year. Such episodes have been observed in both previously treated and untreated patients.

As with other cytotoxic agents, caution should be exercised regarding the continued collection of haematopoietic stem cell samples.

Autoimmune phenomena

Life-threatening, sometimes fatal, autoimmune phenomena (see section "Side effects") have been reported during or after treatment with Fludarabine Accord, regardless of any prior history of autoimmune disorders or a positive Coombs test. In most patients who developed haemolytic anaemia, re-exposure to Fludarabine Accord resulted in recurrence of haemolysis.

If haemolysis is detected, fludarabine phosphate should be discontinued. The main treatment for autoimmune haemolytic anaemia includes transfusion of blood (irradiated, see below) and administration of adrenocorticosteroid drugs.

Hepatic impairment

Fludarabine phosphate should be used with caution in patients with hepatic dysfunction due to the risk of hepatotoxicity. Fludarabine phosphate should only be administered if the anticipated benefit outweighs any potential risk. These patients should be closely monitored for signs of increased toxicity, and dosage adjustments or discontinuation of treatment should be considered if indicated (see section "Dosage and administration").

Neurotoxicity

The long-term impact of fludarabine phosphate on the central nervous system is unknown. However, in some studies, patients tolerated the recommended dose for relatively prolonged treatment periods (up to 26 treatment cycles).

Patients should be carefully monitored for signs of neurological effects.

When administered at high doses in dose-ranging studies in patients with acute leukaemia, intravenous fludarabine was associated with severe neurological effects, including blindness, coma, and death. Symptoms appeared 21 to 60 days after the last dose. Severe toxic central nervous system effects were observed in 36% of patients receiving intravenous doses approximately four times higher than the recommended dose (96 mg/m²/day for 5–7 days) for CLL. In patients receiving doses recommended for CLL treatment, severe central nervous system toxicity occurred rarely (coma, seizures, and anxious agitation) or infrequently (confusion) (see section "Side effects").

Post-marketing experience with fludarabine indicates cases of neurotoxicity occurring earlier or later than those observed during clinical trials.

Administration of fludarabine may be associated with leukoencephalopathy, acute toxic leukoencephalopathy, or reversible posterior leukoencephalopathy syndrome.

This may occur:

• at the recommended dose:
  • when fludarabine is administered after or in combination with agents known to be associated with leukoencephalopathy, acute toxic leukoencephalopathy, or reversible posterior leukoencephalopathy syndrome;
  • when fludarabine is administered to patients with other risk factors such as cranial or total body irradiation, haematopoietic cell transplantation, graft-versus-host disease, renal impairment, or hepatic encephalopathy;
• at doses higher than the recommended dose.

Symptoms of leukoencephalopathy, acute toxic leukoencephalopathy, or reversible posterior leukoencephalopathy syndrome may include headache, nausea and vomiting, seizures, visual disturbances such as vision loss, sensory changes, and focal neurological deficits. Additional effects include optic neuritis, confusion, somnolence, agitation, paraparesis/quadriparesis, muscle spasticity, and urinary incontinence.

Leukoencephalopathy/acute toxic leukoencephalopathy/reversible posterior leukoencephalopathy syndrome may be irreversible, life-threatening, or fatal. If these conditions are suspected, Fludarabine Accord should be discontinued.

Patients should be monitored by brain scanning, preferably using MRI. If diagnosis is confirmed, fludarabine therapy should be discontinued.

Tumour lysis syndrome

Tumour lysis syndrome has been reported in CLL patients with a large tumour burden. Since fludarabine administration may trigger this reaction as early as the first week of treatment, preventive measures should be taken when treating patients at risk of this complication, and hospitalization may be recommended during the first treatment cycle.

Graft-versus-host reaction

Graft-versus-host reaction (reaction of transfused immunocompetent lymphocytes against the "host" organism) has been observed after transfusion of non-irradiated blood to patients treated with fludarabine. This reaction has frequently been reported as fatal. Therefore, to minimize the risk of graft-versus-host reaction, patients requiring blood transfusions who are undergoing or have undergone fludarabine treatment should receive only irradiated blood.

Skin cancer

Exacerbation or sudden worsening of existing skin cancers, as well as newly diagnosed skin cancers, have been reported in some patients during or after treatment with Fludarabine Accord.

Impaired health status

Fludarabine should be administered with caution and only after careful risk-benefit assessment in patients with impaired health status. This is particularly relevant for patients with severe bone marrow dysfunction (thrombocytopenia, anaemia and/or granulocytopenia), immunodeficiency, or a history of opportunistic infections.

Renal impairment

The total plasma clearance of the main metabolite 2-F-ara-A correlates with creatinine clearance, indicating the importance of renal excretion in eliminating this compound. Greater systemic exposure (AUC of 2-F-ara-A) has been observed in patients with reduced renal function. Clinical data in patients with renal impairment (creatinine clearance < 70 ml/min) are limited.

Fludarabine should be used with caution in patients with renal insufficiency. In patients with moderate renal impairment (creatinine clearance 30–70 ml/min), the dose should be reduced by 50%, and close monitoring is required. Treatment with Fludarabine Accord is contraindicated if creatinine clearance is < 30 ml/min.

Elderly patients

Due to limited data on fludarabine use in elderly patients (>75 years), the drug should be used with caution in this patient group.

Creatinine clearance should be measured in patients aged 65 years or older before starting treatment (see section "Dosage and administration", subsection "Patients with renal impairment").

Pregnancy

Fludarabine should not be used during pregnancy unless its use is necessary (e.g., life-threatening situation, no alternative safe treatment possible without compromising therapeutic benefit, treatment cannot be avoided). Fludarabine has potential adverse effects on the foetus (see sections "Pharmacological properties" and "Pregnancy and breastfeeding"). Fludarabine may be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the foetus.

Women should avoid pregnancy during fludarabine therapy.

Women of childbearing potential should be informed about the potential adverse effects of the drug on the foetus.

Contraception

Women and men of reproductive potential must use effective contraception during treatment and for at least 6 months after treatment ends (see section "Pregnancy and breastfeeding").

Vaccination

Live vaccines should be avoided during and after fludarabine treatment.

Re-treatment after initial fludarabine therapy

Switching from initial Fludarabine Accord therapy to chlorambucil treatment should be avoided in case of non-response to fludarabine therapy, as most patients resistant to fludarabine have also shown resistance to chlorambucil.

Excipients

Each vial of Fludarabine Accord contains less than 1 mmol of sodium (23 mg), i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Reproductive function

Patients of reproductive potential should be informed about the potential adverse effects of the drug on the foetus.

Women and men of reproductive potential must use effective contraception during treatment and for at least 6 months after treatment ends (see section "Special precautions for use").

Pregnancy

Preclinical studies in rats demonstrated that fludarabine phosphate and its metabolites cross the placental barrier.

Embryo-toxicity studies following intravenous administration in rats and rabbits indicate embryolethal and teratogenic effects of the drug at recommended therapeutic doses (see section "Pharmacological properties").

There are very limited data on fludarabine use in pregnant women during the first trimester.

Fludarabine phosphate should not be used during pregnancy unless its use is necessary (e.g., life-threatening situation, no alternative safe treatment possible without compromising therapeutic benefit, treatment cannot be avoided). Fludarabine has potential adverse effects on the foetus (see sections "Pharmacological properties" and "Pregnancy and breastfeeding"). Fludarabine may be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the foetus.

Lactation

It is unknown whether the drug or its metabolites are excreted in human breast milk.

However, preclinical data indicate that fludarabine phosphate and/or its metabolites pass from maternal blood into breast milk.

Due to the potential for serious adverse reactions in breastfed newborns, fludarabine is contraindicated in women who are breastfeeding.

Ability to affect driving and use of machinery.

Fludarabine may impair the ability to drive or operate machinery, as side effects such as fatigue, weakness, visual disturbances, confusion, anxious agitation, and seizures have been observed during its use.

Method of Administration and Dosage

Dosage

The recommended dose is 25 mg of fludarabine phosphate per m² of body surface area, administered intravenously daily for 5 consecutive days every 28 days.

The required dose (calculated according to the patient's body surface area) is drawn into a syringe. For intravenous bolus injection, this dose is then diluted in 10 mL of 0.9% sodium chloride solution.

Alternatively, the required dose drawn into a syringe for infusion may be diluted in 100 mL of 0.9% sodium chloride solution and administered over approximately 30 minutes.

The duration of treatment depends on treatment efficacy and tolerability.

For patients with CLL, fludarabine should be administered until maximum response is achieved (complete or partial remission, typically reached after 6 cycles), after which treatment should be discontinued.

Special Patient Groups

Patients with Renal Impairment

Dose adjustment is required when administering fludarabine to patients with renal impairment. If creatinine clearance is between 30–70 mL/min, the dose should be reduced to 50% of the standard dose, and careful monitoring of hematological parameters is necessary to assess toxicity (see section "Special Warnings and Precautions for Use").

Fludarabine treatment is contraindicated if creatinine clearance is < 30 mL/min (see section "Contraindications").

Patients with Hepatic Impairment

There is no data available on the use of Fludarabine Accord in patients with hepatic impairment. Therefore, caution should be exercised when administering the drug to this patient group (see also section "Special Warnings and Precautions for Use").

Pediatric Patients

The safety and efficacy of fludarabine in children under 18 years of age have not been established. Therefore, Fludarabine Accord is not recommended for use in pediatric patients.

Method of Administration

Fludarabine should be prescribed only by a qualified physician experienced in antineoplastic therapy.

Fludarabine Accord should be administered strictly by intravenous route.

Although no cases of severe local adverse reactions following accidental para-venous administration of fludarabine have been reported, accidental para-venous injection must be avoided.

Precautions to be Taken When Handling the Medicinal Product

Reconstitution

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

For intravenous bolus injection, this dose is then diluted in 10 mL of 0.9% sodium chloride solution. Alternatively, for infusion, the required dose may be diluted in 100 mL of 0.9% sodium chloride solution and administered over approximately 30 minutes.

In clinical studies, the drug was diluted in 100 mL or 125 mL of 5% dextrose solution or 0.9% sodium chloride solution.

Visual Inspection Prior to Administration

The diluted solution is clear, colorless, or slightly brownish-yellow. It should be inspected visually before use.

Only clear, colorless, or slightly brownish-yellow solutions free from particles should be used.

Fludarabine Accord must not be used if it has been stored in a damaged container.

Handling and Disposal

Fludarabine should not be handled by pregnant personnel.

Appropriate handling procedures in accordance with local regulations for cytotoxic agents must be followed.

Extreme care should be taken when handling and preparing fludarabine phosphate solution. The use of latex gloves and protective goggles is recommended to prevent exposure in case of vial breakage or accidental spillage. If the solution comes into contact with skin or mucous membranes, the affected area should be thoroughly washed with soap and water. In case of eye contact, eyes should be rinsed thoroughly with copious amounts of water. Inhalation exposure should be avoided.

The medicinal product is intended for single use only. Any unused product, spilled solution, or waste must be disposed of in accordance with local regulations.

Pediatric Patients

The safety and efficacy of fludarabine in children under 18 years of age have not been established. Therefore, Fludarabine Accord is not recommended for use in pediatric patients.

Overdose

High-dose administration of the medicinal product has been associated with leukoencephalopathy, acute toxic leukoencephalopathy, or reversible posterior leukoencephalopathy syndrome. Symptoms may include headache, nausea and vomiting, seizures, visual disturbances such as vision loss, sensory disturbances, and focal neurological deficits. Additional effects may include optic neuritis, papillitis, confusion, somnolence, agitation, paraparesis/quadriparesis, muscle spasticity, and urinary incontinence.

High-dose fludarabine administration has resulted in irreversible toxic damage to the central nervous system, leading to delayed blindness, coma, and fatal outcome.

High doses of the drug may also cause severe thrombocytopenia and neutropenia due to bone marrow suppression.

There is currently no known specific antidote for fludarabine.

Management consists of discontinuation of the drug and provision of supportive care.

Adverse Reactions

Summary of safety profile

Based on the experience with fludarabine, the most commonly reported adverse reactions are myelosuppression (neutropenia, thrombocytopenia, and anemia), infectious disorders including pneumonia, cough, fever, fatigue, weakness, nausea, vomiting, and diarrhea. Other commonly reported adverse reactions include cold-like symptoms, edema, malaise, peripheral neuropathy, visual disturbances, anorexia, mucositis, stomatitis, and skin rash. Opportunistic infections of severe nature have occurred in patients treated with fludarabine. Fatal outcomes have been reported following the development of serious adverse reactions.

Tabulated list of adverse reactions

The adverse reactions listed below in the table are classified by MedDRA system organ class (MedDRA SOC).

Frequencies are based on data from clinical trials, regardless of causal relationship to fludarabine. Rare adverse reactions were primarily identified from post-marketing experience.

The most relevant MedDRA terms have been used to describe a specific adverse reaction. Synonyms or related conditions are not listed but should also be considered. The presentation of adverse reaction terms is based on MedDRA version 16.1.

Within each frequency category, adverse reactions are presented in order of decreasing severity.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System of Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Chemical and physical stability of the solution during use has been demonstrated at concentrations of 0.2 mg/mL and 6.0 mg/mL after dilution with 0.9% sodium chloride solution for up to 7 days at 2–8°C and 5 days at 20–25°C in non-PVC bags and glass vials.

From a microbiological standpoint, the product should be used immediately after dilution. If not used immediately, the responsibility for storage conditions and duration lies with the user. The diluted product should not be stored for longer than 24 hours at 2–8°C, unless dilution has been carried out under controlled and validated aseptic conditions.

Storage conditions.

Store in a refrigerator (2–8°C). Do not freeze.

Keep out of the reach of children.

Packaging.

2 mL (50 mg/2 mL) in a vial, 1 vial per carton.

Prescription status.

Prescription only.

Manufacturer.

Accord Healthcare Polska Sp. z o.o. Importer's Warehouse/Accord Healthcare Polska Sp. z o.o. Magazyn Importera.

Manufacturer's address and place of business.

ul. Lutomierska 50, Pabianice, 95-200, Poland / ul. Lutomierska 50, Pabianice, 95-200, Poland.

Marketing Authorization Holder. Accord Healthcare Polska Sp. z o.o. / Accord Healthcare Polska Sp. z o.o.

Inquiries regarding substandard quality of the medicinal product, safety concerns, improper use, or complaints are accepted 24/7 (24 hours a day, 7 days a week) via phone at +380993100335 or by email at [email protected].

Address of the Marketing Authorization Holder. 7 Tasmowa St., Warsaw, 02-677, Poland / 7 Tasmowa St., Warsaw, 02-677, Poland.