FLUDARABINE 50 Teva

Indications

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma
• Acute lymphoblastic leukemia

Dosage

Children: Refer to BNF for Children for appropriate dosing information.

Adults: Refer to BNF for specific dosing guidelines based on the condition treated and patient characteristics.

Mechanism of action

Fludarabine phosphate is rapidly converted to 2-fluoro-ara-A and subsequently phosphorylated to 2-fluoro-ara-ATP by deoxycytidine kinase. The active triphosphate inhibits DNA polymerase alpha, ribonucleotide reductase, and DNA primase, leading to inhibition of DNA synthesis, particularly during the S-phase of the cell cycle. Additionally, it may interfere with RNA synthesis by reducing the incorporation of uridine and leucine into RNA and proteins, respectively.

Pharmacodynamics

Fludarabine exerts cytotoxic effects primarily by inhibiting DNA synthesis in cancer cells, resulting in cell death. It is particularly effective against rapidly dividing cells but also shows activity against non-proliferating cells. The drug's mechanism of action is multifaceted, involving interference with both DNA and RNA metabolism.

Pharmacokinetics

Fludarabine is administered intravenously and is rapidly dephosphorylated to its active form. It is then phosphorylated intracellularly by deoxycytidine kinase. Its pharmacokinetics are characterized by a short half-life and the need for cellular uptake for therapeutic activity. The pharmacokinetic profile does not fully reflect its therapeutic effects, as the active metabolites are responsible for its cytotoxicity.

Adverse effects

• Increased risk of infections
• Bone marrow suppression
• Nausea
• Vomiting
• Fatigue
• Diarrhea
• Fever
• Headache

Interactions

• Live vaccines: Unknown interaction, but may increase the risk of generalized infection, possibly life-threatening

Pregnancy

Fludarabine is contraindicated during pregnancy due to potential harm to the fetus.

Breast-feeding

Fludarabine is excreted in breast milk; breastfeeding is not recommended during treatment.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Fludarabine phosphate

Indications

• Advanced B-cell chronic lymphocytic leukemia (CLL)
• Acute myeloid leukemia (AML) in patients over 65 years of age who are not candidates for standard induction chemotherapy

Dosage

Children: Paediatric dosing should be consulted in the BNF for Children as specific dosing guidelines may differ based on age and weight.

Adults: For adults, the typical dosage is 25 mg/m² body surface area by intravenous infusion for 5 consecutive days, repeated every 28 days. Specific dosing may vary based on clinical protocols and patient factors.

Mechanism of action

Fludarabine phosphate is phosphorylated intracellularly to its active form, fludarabine triphosphate, which interferes with DNA synthesis. It inhibits DNA polymerase, leading to the inhibition of DNA replication and repair. This action ultimately results in apoptosis of malignant cells, particularly in lymphoid tissues.

Pharmacodynamics

The drug's cytotoxic effects are primarily due to its ability to incorporate into DNA and inhibit key enzymes involved in DNA synthesis and repair. This leads to cell cycle arrest and apoptosis in rapidly dividing cells, including malignant B lymphocytes. Fludarabine exhibits a high affinity for lymphoid tissues, making it particularly effective in treating B-cell malignancies.

Pharmacokinetics

Fludarabine phosphate is administered intravenously, with rapid distribution in the body. It has a half-life of approximately 20 to 30 minutes after intravenous administration. The drug is predominantly eliminated via renal excretion, necessitating dose adjustments in patients with renal impairment. Its metabolites are primarily excreted in urine, and it has minimal hepatic metabolism.

Contra-indications

• Haemolytic anaemia
• History of severe congestive heart failure
• History of unstable cardiac disease

Adverse effects

• Anaemia
• Diarrhoea
• Epistaxis
• Neutropenia
• Oedema
• Stomatitis
• Thrombocytopenia
• Malaise
• Nausea
• Vomiting
• Increased risk of infection
• Acute febrile neutrophilic dermatosis syndrome
• Pancytopenia
• Progressive multifocal leukoencephalopathy (PML)
• Skin reactions
• Viral infection reactivation
• Severe cutaneous adverse reactions
• Interstitial lung disease
• Agitation
• Arrhythmia
• Coma
• Heart failure
• Seizure

Interactions

• Caution with other cytotoxic drugs due to additive effects on bone marrow suppression
• Increased risk of infections when used with immunosuppressants
• Avoid live vaccines in patients receiving fludarabine

Precautions

• Immunosuppression may lead to serious infections
• Caution in patients with hepatic impairment
• Monitor for signs of tumour lysis syndrome
• Prophylactic antibiotics may be necessary

Pregnancy

Fludarabine phosphate is not recommended during pregnancy due to potential harm to the fetus.

Breast-feeding

Breastfeeding is not recommended during treatment with fludarabine as it may be excreted in breast milk.

Storage

Store in a refrigerator (2-8°C). Protect from light. Do not freeze.

Formulations

• Powder for solution for infusion
• Solution for injection

Mechanism of action

Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted. Fluorinated adenine analog causes inhibition of DNA synthesis by inhibiting ribonucleotide reductase & DNA polymerase. Fludarabine is a purine antimetabolite. Activity occurs as the result of activation to 2-fluoro-ara-ATP and includes inhibition of DNA synthesis (primarily in the S-phase of cell division by inhibition of ribonucleotide reductase and the DNA polymerases. It is also postulated that fludarabine interferes with RNA by decreased incorporation of uridine and leucine into RNA and protein, respectively. Fludarabine is also active against non-proliferating cells. This review establishes the pharmacokinetic characteristics of the major nucleoside analogs with cytotoxic activity. Cytarabine, pentostatin, fludarabine, cladribine & gemcitabine are all prodrugs whose plasma pharmacokinetics do not fully reflect their therapeutic activity; after cellular uptake, these compounds undergo phosphorylation by deoxycytidine kinase before their incorporation into DNA results in cell death. Cytarabine is principally active in the S phase of the cell cycle & is most toxic to replicating cells, whereas pentostatin, fludarabine & cladribine are incorporated into DNA during the process in which strand breaks are repaired & are therefore cytotoxic to slowly replicating cells (although the action of pentostatin results from its inhibition of adenosine deaminase). Gemcitabine is unusual in being highly metabolized in solid tumor cells. The cytotoxic activity of pentostatin, fludarabine and cladribine against the clonal cells of lymphoproliferative disorders is accompanied by damage to normal lymphoid cells, which results in significant & long-lasting immunosuppression. Useful interactions between nucleoside analogs have been defined. Cells that are primed by exposure to fludarabine or cladribine exhibit enhanced accumulation of cytarabine triphosphate (the cytotoxic nucleotide of cytarabine) & an improved therapeutic effect against acute myeloid leukemia & chronic lymphocytic leukemia can be achieved by clinical schedules that exploit this effect. Combinations of alkylating agents & fludarabine or cladribine are also synergistic in producing significantly enhanced activity against refractory lymphoid malignancies, but at the cost of increased hematological toxicity. Developments in the clinical admin of gemcitabine are concentrating on efforts to extend the duration of exposure to the drug as a means of counteracting its rapid catabolism in the circulation. Future developments with this group of agents will further explore the use of fludarabine-based combination therapies to produce a transient period of myelosuppression & immunosuppression that is sufficient to permit the engraftment of allogeneic hemopoietic stem cells & also exploit the immunological benefits of graft-versus-tumor reactions. In addition, the clinical spectrum of activity of gemcitabine is also being extended by combining the drug with other active chemotherapeutic agents, such as cisplatin, & by early studies of its role as a radiosensitiser.

Pharmacodynamics

Fludarabine is a chemotherapy drug used in the treatment of chronic lymphocytic leukemia. It acts at DNA polymerase alpha, ribonucleotide reductase and DNA primase, results in the inhibition of DNA synthesis, and destroys the cancer cells.