Fludarabine Phosphate Drug Information

Indication 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.

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. 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.

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.

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.

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.

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.

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.

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.

Genitourinary System Hemorrhagic cystitis has been reported in patients treated with fludarabine

phosphate.

Skin 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. 6.10 Neoplasms 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. 6.11 Hepatobiliary Disorders Elevations of hepatic enzyme levels have been reported. 6.12 Adverse Reactions from Clinical Trials Data in Table 1 are derived from the 133 patients with CLL who received fludarabine phosphate in the MDAH and SWOG studies. TABLE 1: PERCENT OF CLL PATIENTS REPORTING NON-HEMATOLOGIC ADVERSE REACTIONS ADVERSE REACTIONS MDAH (N=101) SWOG (N=32) ANY ADVERSE REACTION 88% 91% BODY AS A WHOLE 72 84 FEVER 60 69 CHILLS 11 19 FATIGUE 10 38 INFECTION 33 44 PAIN 20 22 MALAISE 8 6 DIAPHORESIS 1 13 ALOPECIA 0 3 ANAPHYLAXIS 1 0 HEMORRHAGE 1 0 HYPERGLYCEMIA 1 6 DEHYDRATION 1 0 NEUROLOGICAL 21 69 WEAKNESS 9 65 PARESTHESIA 4 12 HEADACHE 3 0 VISUAL DISTURBANCE 3 15 HEARING LOSS 2 6 SLEEP DISORDER 1 3 DEPRESSION 1 0 CEREBELLAR SYNDROME 1 0 IMPAIRED MENTATION 1 0 PULMONARY 35 69 COUGH 10 44 PNEUMONIA 16 22 DYSPNEA 9 22 SINUSITIS 5 0 PHARYNGITIS 0 9 UPPER RESPIRATORY INFECTION 2 16 ALLERGIC PNEUMONITIS 0 6 EPISTAXIS 1 0 HEMOPTYSIS 1 6 BRONCHITIS 1 0 HYPOXIA 1 0 GASTROINTESTINAL 46 63 NAUSEA/VOMITING 36 31 DIARRHEA 15 13 ANOREXIA 7 34 STOMATITIS 9 0 GI BLEEDING 3 13 ESOPHAGITIS 3 0 MUCOSITIS 2 0 LIVER FAILURE 1 0 ABNORMAL LIVER FUNCTION TEST 1 3 CHOLELITHIASIS 0 3 CONSTIPATION 1 3 DYSPHAGIA 1 0 CUTANEOUS 17 18 RASH 15 15 PRURITUS 1 3 SEBORRHEA 1 0 GENITOURINARY 12 22 DYSURIA 4 3 URINARY INFECTION 2 15 HEMATURIA 2 3 RENAL FAILURE 1 0 ABNORMAL RENAL FUNCTION TEST 1 0 PROTEINURIA 1 0 HESITANCY 0 3 CARDIOVASCULAR 12 38 EDEMA 8 19 ANGINA 0 6 CONGESTIVE HEART FAILURE 0 3 ARRHYTHMIA 0 3 SUPRAVENTRICULAR TACHYCARDIA 0 3 MYOCARDIAL INFARCTION 0 3 DEEP VENOUS THROMBOSIS 1 3 PHLEBITIS 1 3 TRANSIENT ISCHEMIC ATTACK 1 0 ANEURYSM 1 0 CEREBROVASCULAR ACCIDENT 0 3 MUSCULOSKELETAL 7 16 MYALGIA 4 16 OSTEOPOROSIS 2 0 ARTHRALGIA 1 0 TUMOR LYSIS SYNDROME 1 0 More than 3000 adult patients received fludarabine phosphate 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.

Pentostatin

The use of Fludarabine Phosphate Injection in combination with pentostatin is not recommended due to the risk of fatal pulmonary toxicity.

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.

Pediatric Use Data submitted to the FDA was insufficient to establish efficacy in any childhood malignancy. Fludarabine phosphate was evaluated in 62 pediatric patients (median age 10, range 1 to 21) with refractory acute leukemia (45 patients) or solid tumors (17 patients). Limited pharmacokinetic data for fludarabine phosphate are available in children (ages 1 to 21 years). When fludarabine phosphate was administered as a loading dose over 10 minutes immediately followed by a 5-day continuous infusion, steady-state conditions were reached early. The fludarabine phosphate regimen tested for pediatric lymphocytic leukemia (ALL) patients was a loading bolus of 10.5 mg/m 2 /day followed by a continuous infusion of 30.5 mg/m 2 /day for 5 days.

In 12 pediatric patients with solid tumors, dose-limiting myelosuppression was observed with a loading dose of 8 mg/m 2 /day followed by a continuous infusion of 23.5 mg/m 2 /day for 5 days. The maximum tolerated dose was a loading dose of 7 mg/m 2 /day followed by a continuous infusion of 20 mg/m 2 /day for 5 days. Treatment toxicity included bone marrow suppression.

Platelet counts appeared to be more sensitive to the effects of fludarabine phosphate than hemoglobin and white blood cell counts. Other adverse events included fever, chills, asthenia, rash, nausea, vomiting, diarrhea, and infection. There were no reported occurrences of peripheral neuropathy or pulmonary hypersensitivity reaction.

High doses of fludarabine phosphate have been associated with an irreversible central nervous system toxicity characterized by delayed blindness, coma and death. High doses are also associated with severe thrombocytopenia and neutropenia due to bone marrow suppression. There is no known specific antidote for fludarabine phosphate overdosage.

Treatment consists of drug discontinuation and supportive therapy.