Fludarabin Hexal50 mg/2 ml

Fludarabin Hexal is a purine analog antineoplastic (chemotherapy) agent used under specialist oncology supervision.

Established / FDA-approved use

• Treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to, or whose disease has progressed during or after treatment with, at least one standard alkylating-agent-containing regimen.

Guideline-supported / adjunct uses (often combination therapy)

• Certain low-grade non-Hodgkin lymphomas, typically used in combination regimens (e.g. with cyclophosphamide and/or rituximab).
• Reduced-intensity conditioning prior to allogeneic hematopoietic stem cell transplantation, as part of a multi-agent conditioning protocol.

Off-label use

• Used off-label in some FLAG/FLAG-IDA type combination regimens for relapsed/refractory acute myeloid leukemia, under specialist protocols only.

Fludarabin Hexal is a specialist chemotherapy medicine; it must only be prescribed, dispensed, and administered by or under the direct supervision of a qualified oncologist/hematologist experienced in cancer chemotherapy.

Each formulation of Fludarabine Phosphate contains fludarabine phosphate as the active pharmaceutical ingredient.

• Lyophilized powder for injection: fludarabine phosphate 50 mg per vial, reconstituted before use.
• Injection concentrate: fludarabine phosphate 25 mg/mL solution for further dilution.

Exact strengths and available presentations of Fludarabine Phosphate may vary by manufacturer; always check the pack label.

Fludarabin Hexal is a fluorinated purine nucleoside analog (a derivative of vidarabine) used as a cytotoxic antineoplastic agent. It is administered intravenously in a hospital or specialist oncology infusion setting, never as a self-administered outpatient medicine.

Fludarabin Hexal is indicated primarily for chronic lymphocytic leukemia and is one of the standard backbone agents in several lymphoid malignancy chemotherapy regimens.

Antineoplastic agent - purine analog / antimetabolite. Fludarabin Hexal belongs to the class of purine nucleoside analog chemotherapy drugs.

Mechanism of action

Fludarabine Phosphate is a prodrug. After intravenous administration it is rapidly dephosphorylated to 2-fluoro-ara-A, which is then taken up by cells and phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate metabolite, 2-fluoro-ara-ATP.

2-fluoro-ara-ATP inhibits DNA polymerase alpha, DNA primase, DNA ligase, and ribonucleotide reductase, and is itself incorporated into DNA, causing chain termination. This inhibits DNA synthesis and induces apoptosis in both actively dividing and quiescent (resting) lymphocytes, which underlies the activity of Fludarabine Phosphate against lymphoid malignancies.

Pharmacokinetics

Following administration of Fludarabine Phosphate, the active metabolite 2-fluoro-ara-A reaches peak plasma concentration shortly after the end of infusion, is eliminated mainly by renal excretion, and has a terminal half-life of approximately 20 hours, supporting once-daily dosing and the need for renal dose adjustment.

Fludarabin Hexal is given only by slow intravenous infusion (typically over about 30 minutes) after reconstitution and dilution, in a hospital or specialist oncology infusion center under direct medical supervision. It is not for oral, intramuscular, subcutaneous, or self-administered use.

Clinically significant interactions with Fludarabin Hexal

• Pentostatin: Concurrent use of Fludarabin Hexal with pentostatin is contraindicated/not recommended because the combination has been associated with severe, sometimes fatal, pulmonary toxicity.
• Live attenuated vaccines: Avoid administering live vaccines during and after treatment with Fludarabin Hexal because of profound immunosuppression; vaccination may result in disseminated infection.
• Cytarabine: Fludarabin Hexal increases intracellular accumulation and activity of cytarabine's active metabolite; this interaction is exploited therapeutically in some combination regimens but increases the risk of additive toxicity.
• Other myelosuppressive or nephrotoxic drugs: Concomitant use with other bone-marrow-suppressing or renally-cleared drugs may increase the risk of additive hematologic or renal toxicity with Fludarabin Hexal.

Common

• Bone marrow suppression: neutropenia, thrombocytopenia, anemia (very common and often dose-limiting with Fludarabin Hexal).
• Fever, chills, and increased susceptibility to infection.
• Nausea, vomiting, diarrhea, and loss of appetite.
• Fatigue, generalized weakness, and malaise.

Serious (require prompt medical attention)

• Severe neurotoxicity (agitation, confusion, visual disturbances, and rarely coma or blindness), particularly at higher-than-recommended doses of Fludarabin Hexal.
• Autoimmune hemolytic anemia (see Precautions and Warnings).
• Pulmonary toxicity/pneumonitis.
• Tumor lysis syndrome in patients with high tumor burden.
• Secondary malignancies (e.g. myelodysplastic syndrome, acute myeloid leukemia) with long-term use of Fludarabin Hexal.

Report any severe or persistent side effect of Fludarabin Hexal to the treating oncologist promptly.

Pregnancy: Fludarabin Hexal is contraindicated in pregnancy. Animal studies have shown embryo-fetal toxicity, and Fludarabin Hexal may cause fetal harm. Women of childbearing potential should use effective contraception during and for a period after treatment with Fludarabin Hexal; if pregnancy occurs, seek immediate medical advice.

Lactation: It is not known whether Fludarabin Hexal or its metabolites are excreted in human breast milk. Because of the potential for serious adverse effects in a nursing infant, breastfeeding should be discontinued before starting Fludarabin Hexal and should not resume unless specifically advised by the treating physician.

Boxed warnings

• Severe bone marrow suppression: Fludarabin Hexal can cause severe, sometimes fatal, neutropenia, thrombocytopenia, and anemia; monitor blood counts regularly.
• Neurotoxicity: Severe neurologic effects, including blindness and coma, have occurred, particularly at doses higher than recommended; discontinue Fludarabin Hexal promptly if such toxicity develops.
• Autoimmune hemolytic anemia: Life-threatening autoimmune hemolytic anemia, sometimes fatal, has occurred during and after treatment with Fludarabin Hexal.
• Pulmonary toxicity with pentostatin: Do not combine Fludarabin Hexal with pentostatin because of the risk of severe pulmonary toxicity.

Other important precautions

• Fludarabin Hexal must be prescribed and administered only by, or under the direct supervision of, a specialist experienced in cancer chemotherapy; it is not intended for general-practice or self-administered use.
• If blood transfusion is required during treatment with Fludarabin Hexal, only irradiated blood products should be used, due to the risk of transfusion-associated graft-versus-host disease.
• Monitor renal function, complete blood counts, and for signs of infection, hemolysis, or tumor lysis syndrome throughout treatment.
• Avoid live vaccines during and after therapy with Fludarabin Hexal (see Interactions).

Overdose of Fludarabin Hexal has been associated with severe and sometimes irreversible toxicity, including profound bone marrow suppression and severe neurotoxicity (visual loss, confusion, and coma) at doses well above the recommended dose.

There is no specific antidote for Fludarabin Hexal overdose. If overdose is suspected, seek immediate medical attention or contact emergency services/a poison control center right away. Management is supportive, with close monitoring of blood counts, neurologic status, and organ function in a hospital setting.

Store unreconstituted Fludarabin Hexal powder/vials in a refrigerator (2°C to 8°C), protected from light, unless the specific product labeling states otherwise. Keep out of reach of children. Reconstituted/diluted solutions should be used within the time specified on the product label and handled as cytotoxic waste.

• Renal impairment: Dose reduction of Fludarabin Hexal is required for moderate renal impairment; it is contraindicated in severe renal impairment (see Dosage and Administration, Contraindications).
• Hepatic impairment: Limited data; use Fludarabin Hexal with caution and close monitoring.
• Elderly patients: Use Fludarabin Hexal with caution given the higher likelihood of decreased renal function and greater sensitivity to bone marrow suppression; assess renal function before and during treatment.
• Pregnancy and lactation: See Pregnancy and Lactation section.
• Pediatric patients: See Pediatric Uses section.

Treatment with Fludarabin Hexal is given in cycles (typically 5 consecutive days of infusion every 28 days) for up to approximately 6 cycles, or as otherwise directed by the treating oncologist based on response, blood counts, and tolerability. Duration is individualized and must not be extended or shortened without specialist guidance.

Lyophilized Fludarabin Hexal powder for injection should be reconstituted with the volume of Sterile Water for Injection specified on the product label (commonly to a concentration of 25 mg/mL). The reconstituted solution is then further diluted, typically in 5% Dextrose Injection or 0.9% Sodium Chloride Injection, before slow intravenous infusion. Reconstitution and handling must follow institutional cytotoxic-drug handling procedures and be performed by trained personnel.

Antineoplastic agents; Purine analogs; Antimetabolites. Fludarabine Phosphate is classified within this pharmacologic group.

Fludarabine Phosphate is dephosphorylated to 2-fluoro-ara-A and then converted intracellularly to its active triphosphate, 2-fluoro-ara-ATP, which inhibits DNA polymerase alpha, DNA primase, and ribonucleotide reductase, and is incorporated into DNA to cause chain termination. This blocks DNA synthesis and repair and triggers apoptosis in malignant and normal lymphocytes, both dividing and resting, accounting for the antileukemic/antilymphoma activity of Fludarabine Phosphate.

D

The safety and efficacy of Fludarabin Hexal have not been established for routine use in children with chronic lymphocytic leukemia, which is exceedingly rare in the pediatric population. Fludarabin Hexal has been used in children only within specialized protocols, such as certain conditioning regimens prior to allogeneic hematopoietic stem cell transplantation, and only under the direct supervision of a pediatric oncology/transplant specialist. It should not be used in children outside such specialist settings.