Fludarabine Phosphate (Page 2 of 5)

5.4 Transfusion Associated Graft-Versus-Host Disease

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.

5.6 Pregnancy

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)].

5.7 Male 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)].

5.8 Tumor 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.

5.9 Renal 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.

6 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.

6.1 Hematopoietic 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.

6.2 Infections

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.

6.3 Metabolic

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.

6.4 Nervous 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)].

6.5 Pulmonary 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.

6.6 Gastrointestinal 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.

6.7 Cardiovascular

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.

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