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Indications
Fludarabine Phosphate Injection is a nucleotide metabolic inhibitor indicated for: The treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen. Benefit in treatment-naïve or non-refractory CLL patients is not established. ( 1.1 )
1.1Indication Fludarabine Phosphate
Injection is indicated for the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen. The safety and effectiveness of Fludarabine Phosphate Injection in previously untreated or non-refractory patients with CLL have not been established.
Contraindications
None None
Warnings and precautions
( see BOXED WARNINGS ) Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia. Monitor blood counts before and during treatment. ( 5.2 ) Transfusion-associated graft-versus-host disease. Use only irradiated blood products for transfusions. ( 5.4 ) Infections. Monitor for infection. ( 5.2 ) Renal Insufficiency. Reduce dose for moderate renal impairment and monitor closely. Do not administer to patients with severe renal impairment.
( 5.9 ) Tumor lysis syndrome (TLS). Take precautions for patients at high risk for TLS. ( 5.8 ) Can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant. ( 5.6 )
5.1Dose Dependent Neurologic Toxicities
There are clear dose dependent toxic effects seen with fludarabine phosphate. Dose levels approximately 4 times greater (96 mg/m 2 /day for 5 to 7 days) than that recommended for CLL (25 mg/m 2 /day for 5 days) were associated with a syndrome characterized by delayed blindness, coma and death. Symptoms appeared from 21 to 60 days following the last dose. Thirteen of 36 patients (36%) who received fludarabine phosphate at high doses (96 mg/m 2 /day for 5 to 7 days) developed this severe neurotoxicity.
Similar severe central nervous system toxicity, including coma, seizures, agitation and confusion, has been reported in patients treated at doses in the range of the dose recommended for chronic lymphocytic leukemia. In post-marketing experience neurotoxicity has been reported to occur either earlier or later than in clinical trials (range 7 to 225 days). The effect of chronic administration of fludarabine phosphate on the central nervous system is unknown; however, patients have received the recommended dose for up to 15 courses of therapy.
Fludarabine phosphate may reduce the ability to drive or use mechanical equipment, since fatigue, weakness, visual disturbances, confusion, agitation and seizures have been observed.
5.2Bone Marrow Suppression
Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia, has been reported in patients treated with fludarabine phosphate. In a Phase I study in adult solid tumor patients, the median time to nadir counts was 13 days (range, 3 to 25 days) for granulocytes and 16 days (range, 2 to 32 days) for platelets. Most patients had hematologic impairment at baseline either as a result of disease or as a result of prior myelosuppressive therapy.
Cumulative myelosuppression may be seen. While chemotherapy-induced myelosuppression is often reversible, administration of Fludarabine Phosphate Injection requires careful hematologic monitoring. Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in adult patients. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year.
These episodes have occurred both in previously treated or untreated patients.
5.3Autoimmune Reactions Instances
of life-threatening and sometimes fatal autoimmune phenomena such as hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia have been reported to occur after one or more cycles of treatment with fludarabine phosphate in patients with or without a previous history of autoimmune hemolytic anemia or a positive Coombs' test and who may or may not be in remission from their disease.
Steroids may or may not be effective in controlling these hemolytic episodes. The majority of patients rechallenged with fludarabine phosphate developed a recurrence in the hemolytic process. The mechanism(s) which predispose patients to the development of this complication has not been identified. Patients undergoing treatment with Fludarabine Phosphate Injection should be evaluated and closely monitored for hemolysis.
Discontinuation of therapy with Fludarabine Phosphate Injection is recommended in case of hemolysis.
Transfusion-associated graft-versus-host disease has been observed after transfusion of non-irradiated blood in fludarabine phosphate treated patients. Fatal outcome as a consequence of this disease has been reported. Therefore, to minimize the risk of transfusion-associated graft-versus-host disease, patients who require blood transfusion and who are undergoing, or who have received, treatment with Fludarabine Phosphate Injection should receive irradiated blood only.
5.5 Pulmonary Toxicity In a clinical investigation using fludarabine phosphate in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL) in adults, there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of Fludarabine Phosphate Injection in combination with pentostatin is not recommended.
5.6Pregnancy Based
on its mechanism of action, fludarabine phosphate can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Fludarabine Phosphate Injection in pregnant women. Fludarabine phosphate was embryolethal and teratogenic in rats and rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Women of childbearing potential should be advised to avoid becoming pregnant [see Use in Specific Populations ( 8.1 )].
5.7Male Fertility and Reproductive Outcomes Males
with female sexual partners of childbearing potential should use contraception during and after cessation of fludarabine phosphate therapy. Fludarabine phosphate may damage testicular tissue and spermatozoa. Possible sperm DNA damage raises concerns about loss of fertility and genetic abnormalities in fetuses. The duration of this effect is uncertain [see Nonclinical Toxicology ( 13.1 )].
5.8Tumor Lysis
Tumor lysis syndrome has been associated with fludarabine phosphate treatment. This syndrome has been reported in CLL patients with large tumor burdens. Since fludarabine phosphate can induce a response as early as the first week of treatment, precautions should be taken in those patients at risk of developing this complication.
5.9Renal Impairment Fludarabine Phosphate
Injection must be administered cautiously in patients with renal impairment. The total body clearance of 2-fluoro-ara-A has been shown to be directly correlated with creatinine clearance. Patients with creatinine clearance 30 to 79 mL/min should have their fludarabine phosphate dose reduced and be monitored closely for excessive toxicity. Fludarabine phosphate should not be administered to patients with creatinine clearance less than 30 mL/min [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )].
In patients aged 65 years or older, creatinine clearance should be measured before start of treatment.
5.10 Vaccination During and after treatment with Fludarabine Phosphate Injection, vaccination with live vaccines should be avoided.
Interactions
Fludarabine phosphate injection in combination with pentostatin is not recommended due to the risk of severe pulmonary toxicity ( 5.5 and 7.1 ).
7.1Pentostatin
The use of Fludarabine Phosphate Injection in combination with pentostatin is not recommended due to the risk of fatal pulmonary toxicity [see Warnings and Precautions ( 5.5 )].
Pregnancy and breastfeeding
5.6Pregnancy Based
on its mechanism of action, fludarabine phosphate can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Fludarabine Phosphate Injection in pregnant women. Fludarabine phosphate was embryolethal and teratogenic in rats and rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Women of childbearing potential should be advised to avoid becoming pregnant [see Use in Specific Populations ( 8.1 )].
8.1 Pregnancy [See Warnings and Precautions ( 5.6 )]. Based on its mechanism of action, fludarabine phosphate can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Fludarabine Phosphate Injection in pregnant women. In rats, repeated intravenous doses of fludarabine phosphate at 2.4 times and 7.2 times the recommended human intravenous dose (25 mg/m 2 ) administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations (cleft palate, exencephaly, and fetal vertebrae deformities) and decreased fetal body weights.
Maternal toxicity was not apparent at 2.4 times the human intravenous dose, and was limited to slight body weight decreases at 7.2 times the human intravenous dose. In rabbits, repeated intravenous doses of fludarabine phosphate at 3.8 times the human intravenous dose administered during organogenesis increased embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in malformations including cleft palate, hydrocephaly, adactyly, brachydactyly, fusions of the digits, diaphragmatic hernia, heart/great vessel defects, and vertebrae/rib anomalies were seen in all dose levels (≥ 0.5 times the human intravenous dose).
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
17.3Pregnancy
Fludarabine phosphate can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant [see Warnings and Precautions ( 5.6 )]. Distributed by: Lannett Company, Inc. Philadelphia, PA 19136 Made in Italy L7324 Rev. 05/2022
Adverse reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Very common adverse reactions include myelosuppression (neutropenia, thrombocytopenia and anemia), fever and chills, fatigue, weakness, infection, pneumonia, cough, nausea, vomiting and diarrhea.
Other commonly reported events include malaise, mucositis, and anorexia. Serious opportunistic infections have occurred in CLL patients treated with fludarabine phosphate. The most frequently reported adverse reactions and those reactions which are more clearly related to the drug are arranged below according to body system. Most common adverse reactions (incidence > 30%) include myelosuppression (neutropenia, thrombocytopenia and anemia), fever, infection, nausea and vomiting, fatigue, anorexia, cough and weakness ( 6 ).
To report SUSPECTED ADVERSE REACTIONS, contact Areva at 1-855-853-4760 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Hematopoietic Systems
Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of CLL patients treated with fludarabine phosphate. During fludarabine phosphate treatment of 133 patients with CLL, the absolute neutrophil count decreased to less than 500/mm 3 in 59% of patients, hemoglobin decreased from pretreatment values by at least 2 grams percent in 60%, and platelet count decreased from pretreatment values by at least 50% in 55%.
Myelosuppression may be severe, cumulative, and may affect multiple cell lines. Bone marrow fibrosis occurred in one CLL patient treated with fludarabine phosphate. Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in post-marketing surveillance. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year.
These episodes have occurred both in previously treated or untreated patients. Life-threatening and sometimes fatal autoimmune phenomena such as hemolytic anemias, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia have been reported to occur in patients receiving fludarabine phosphate [see Warnings and Precautions ( 5.3 )]. The majority of patients rechallenged with fludarabine phosphate developed a recurrence in the hemolytic process.
In post-marketing experience, cases of myelodysplastic syndrome and acute myeloid leukemia, mainly associated with prior, concomitant or subsequent treatment with alkylating agents, topoisomerase inhibitors, or irradiation have been reported.
6.2Infections Serious
and sometimes fatal infections, including opportunistic infections and reactivations of latent viral infections such as VZV (herpes zoster), Epstein-Barr virus and JC virus (progressive multifocal leukoencephalopathy) have been reported in patients treated with fludarabine phosphate. Rare cases of Epstein-Barr (EBV) associated lymphoproliferative disorders have been reported in patients treated with fludarabine phosphate.
In post-marketing experience, cases of progressive multifocal leukoencephalopathy have been reported. Most cases had a fatal outcome. Many of these cases were confounded by prior and/or concurrent chemotherapy. The time to onset ranged from a few weeks to approximately one year after initiating treatment. Of the 133 adult CLL patients in the two trials, there were 29 fatalities during study, approximately 50% of which were due to infection.
6.3Metabolic
Tumor lysis syndrome has been reported in CLL patients treated with fludarabine phosphate. This complication may include hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria, and renal failure. The onset of this syndrome may be heralded by flank pain and hematuria.
6.4Nervous System
Objective weakness, agitation, confusion, seizures, visual disturbances, optic neuritis, optic neuropathy, blindness and coma have occurred in CLL patients treated with fludarabine phosphate at the recommended dose. Peripheral neuropathy has been observed in patients treated with fludarabine phosphate and one case of wrist-drop was reported. There have been additional reports of cerebral hemorrhage though the frequency is not known [see Warnings and Precautions ( 5 )].
6.5Pulmonary System Pneumonia,
a frequent manifestation of infection in CLL patients, occurred in 16%, and 22% of those treated with fludarabine phosphate in the MDAH and SWOG studies, respectively. Pulmonary hypersensitivity reactions to fludarabine phosphate characterized by dyspnea, cough and interstitial pulmonary infiltrate have been observed. In post-marketing experience, cases of severe pulmonary toxicity have been observed with fludarabine phosphate use which resulted in ARDS, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, pneumonitis and respiratory failure.
After an infectious origin has been excluded, some patients experienced symptom improvement with corticosteroids.
6.6Gastrointestinal System
Gastrointestinal disturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis, and hemorrhage have been reported in patients treated with fludarabine phosphate. Elevations of pancreatic enzyme levels have also been reported.
6.7Cardiovascular
Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with fludarabine phosphate. There have been reports of heart failure and arrhythmia. No other severe cardiovascular events were considered to be drug related.
6.8Genitourinary System
Hemorrhagic cystitis has been reported in patients treated with fludarabine phosphate.
6.9Skin
Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with fludarabine phosphate. Erythema multiforme, Steven-Johnson syndrome, toxic epidermal necrolysis and pemphigus have been reported, with fatal outcomes in some cases.
6.10Neoplasms Worsening
or flare-up of preexisting skin cancer lesions, as well as new onset of skin cancer, has been reported in patients during or after treatment with fludarabine phosphate.
6.11Hepatobiliary Disorders Elevations
of hepatic enzyme levels have been reported.
6.12Adverse Reactions from Clinical Trials Data in Table
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
