SIDE EFFECTS

Very common adverse events 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 (such as latent viral reactivation, herpes zoster virus, Epstein-Barr virus, and progressive multifocal leukoencephalopathy) have occurred in CLL patients treated with FLUDARA (fludarabine) FOR INJECTION. Adverse events and those reactions which are more clearly related to the drug are arranged below according to body system.

Hematopoietic Systems

Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of CLL patients treated with FLUDARA (fludarabine) FOR INJECTION. During FLUDARA (fludarabine) FOR INJECTION treatment of 133 patients with CLL, the absolute neutrophil count decreased to less than 500/mm³ 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 FLUDARA (fludarabine) FOR INJECTION.

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 anemia, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia have been reported to occur in patients receiving FLUDARA FOR INJECTION (see WARNINGS section). The majority of patients rechallenged with FLUDARA (fludarabine) FOR INJECTION 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.

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 FLUDARA (fludarabine) FOR INJECTION.

Rare cases of Epstein-Barr virus (EBV) associated lymphoproliferative disorders have been reported in patients treated with FLUDARA (fludarabine) FOR INJECTION.

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 has 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.

Metabolic

Tumor lysis syndrome has been reported in CLL patients treated with FLUDARA (fludarabine) FOR INJECTION. 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.

Nervous System (see WARNINGS section)

Objective weakness, agitation, confusion, seizures, visual disturbances, optic neuritis, optic neuropathy, blindness and coma have occurred in CLL patients treated with FLUDARA (fludarabine) FOR INJECTION at the recommended dose. Peripheral neuropathy has been observed in patients treated with FLUDARA (fludarabine) FOR INJECTION and one case of wrist-drop was reported. There have been additional reports of cerebral hemorrhage though the frequency is not known.

Pulmonary System

Pneumonia, a frequent manifestation of infection in CLL patients, occurred in 16% and 22% of those treated with FLUDARA (fludarabine) FOR INJECTION in the MDAH and SWOG studies, respectively. Pulmonary hypersensitivity reactions to FLUDARA (fludarabine) FOR INJECTION characterized by dyspnea, cough and interstitial pulmonary infiltrate have been observed.

In post-marketing experience, cases of severe pulmonary toxicity have been observed with FLUDARA (fludarabine) FOR INJECTION 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.

Gastrointestinal System

Gastrointestinal disturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis and gastrointestinal bleeding and hemorrhage have been reported in patients treated with FLUDARA (fludarabine) FOR INJECTION. Elevations of pancreatic enzyme levels have also been reported.

Cardiovascular

Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with FLUDARA (fludarabine) FOR INJECTION. There have been additional reports of heart failure and arrhythmia though the frequency is rare. No other severe cardiovascular events were considered to be drug related.

Genitourinary System

Rare cases of hemorrhagic cystitis have been reported in patients treated with FLUDARA (fludarabine) FOR INJECTION.

Skin

Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with FLUDARA (fludarabine) FOR INJECTION. Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis and pemphigus have been reported, with fatal outcomes in some cases.

Neoplasms

Worsening or flare-up of pre-existing skin cancer lesions, as well as new onset of skin cancer, has been reported in patients during or after treatment with FLUDARA (fludarabine) FOR INJECTION.

Hepatobiliary Disorders

Elevations of hepatic enzyme levels have been reported.

Data in the following table are derived from the 133 patients with CLL who received FLUDARA (fludarabine) FOR INJECTION in the MDAH and SWOG studies.

PERCENT OF CLL PATIENTS REPORTING NONHEMATOLOGIC ADVERSE EVENTS

More than 3000 adult patients received FLUDARA (fludarabine) FOR INJECTION in studies of other leukemias, lymphomas, and other solid tumors. The spectrum of adverse effects reported in these studies was consistent with the data presented above.

Read the entire FDA prescribing information for Fludara (Fludarabine) »