Fludarabine

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Antineoplastic and immunomodulating agents -> Antineoplastic agents

Breast Feeding; Lactation; Milk, Human; Antineoplastic Agents

Cytotoxic medicines

Warning

H302 (95.5%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 44 reports by companies from 6 notifications to the ECHA C&L Inventory.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Fludarabine may raise the concentration of blood uric acid as part of a tumor lysis syndrome; dosage adjustment of antigout agents /allopurinol, colchicine, probenecid, sulfinpyrazone/ may be necessary to control hyperuricemia and gout; allopurinol may be preferred to prevent or reverse fludarabine-induced hyperuricemia because of risk of uric acid nephropathy with uricosuric antigout agents.

Leukopenic and/or thrombocytopenic effects of fludarabine may be increased with concurrent or recent therapy if these medications /blood dyscrasia causing medications/ cause the same effects; dosage adjustment of fludarabine, if necessary, should be based on blood counts.

Additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively.

Concurrent use with fludarabine is not recommended because of a possible increased risk of fatal pulmonary toxicity. /Pentostatin/

For more Interactions (Complete) data for FLUDARABINE (10 total), please visit the HSDB record page.

In clinical trials, serum enzymes elevations occurred in only a small proportion of patients treated with fludarabine for leukemia. The role of fludarabine as opposed to other antineoplastics used in antileukemic regimens was not always clear from these studies. Cases of clinically apparent liver injury due to fludarabine have been reported to occur, but few details were available and most patients were receiving other cancer chemotherapeutic agents.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

fludarabine

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

Dose-related adverse effects on the male reproductive system have been demonstrated in mice, rats, and dogs; effects consisted of a decrease in mean testicular weights in mice and rats with a trend toward decreased testicular weights in dogs, and degeneration and necrosis of spermatogenic epithelium of the testes in mice, rats, and dogs.

Studies in rats at intravenous doses of 0, 1, 10, or 30 mg per kg of body weight (mg/kg) per day on days 6 to 15 of gestation found an increased incidence of skeletal malformations. Studies in rabbits at doses of 5 and 8 mg/kg per day found dose-related teratogenic effects (external deformities and skeletal malformations).

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

L01BB05

L - Antineoplastic and immunomodulating agents

L01BB05

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.

P2K93U8740

FLUDARABINE

Mechanisms of Action [MoA] - Nucleic Acid Synthesis Inhibitors

Established Pharmacologic Class [EPC] - Nucleoside Metabolic Inhibitor

Fludarabine is a Nucleoside Metabolic Inhibitor. The mechanism of action of fludarabine is as a Nucleic Acid Synthesis Inhibitor.

Bioavailability is 55% following oral administration.

117-145 mL/min [patients with B-cell CLL receiving IV administration of a single dose of 40 mg/m^2.

... To compare the pharmacokinetics of sc & iv fludarabine in patients with lupus nephritis. ... Open-label, randomized, crossover trial conducted with a phase I-II trial. ... Government research hospital. ... Five patients with lupus nephritis. ... Fludarabine 30 mg/m2/day was administered either sc or as a 0.5-hr iv infusion for 3 consecutive days. All patients received oral cyclophosphamide 0.5 g/m2 on the first day of each cycle. ... Plasma samples were collected before & 0.5, 1, 1.5, 2, 4, 8, & 24 hrs after the first dose. Urine was collected at 6-hr intervals for 24 hrs. Plasma & urine were analyzed for fluoro-arabinofuranosyladenine (F-ara-A), fludarabine's main metabolite, using high-performance liquid chromatography. Compartmental techniques were used to determine the pharmacokinetics of F-ara-A; a linear two-compartment model best described them. Comparison of the pharmacokinetics between sc & iv admin was done by using a Wilcoxon signed rank test. No significant differences were found between sc & iv admin in median (interquartile range) maximum concns of 0.51 (0.38-0.56) & 0.75 (0.52-0.91) mg/L, respectively, or in fitted area under the concn-time curves from 0-24 hrs of 4.65 (4.17-4.98) & 4.55 (3.5-4.94) mg x hr/L, respectively. Bioavailability of F-ara-A after sc dosing was approx 105% of the bioavailability after iv admin. Differences in renal clearance & % of dose excreted in urine for sc & iv admin were nonsignificant. No injection site reactions were seen with subcutaneous dosing. ... Sc & iv admin of fludarabine appear to have similar pharmacokinetics in patients with lupus nephritis. Sc injection may offer a convenient alternative to iv admin.