d 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. 5.2 bone 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. 5.3 autoimmune 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. 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 pregnancy category d 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.

uch patients should be monitored closely for excessive toxicity and the dose modified accordingly. the optimal duration of treatment has not been clearly established. it is recommended that three additional cycles of fludarabine phosphate injection be administered following the achievement of a maximal response and then the drug should be discontinued. 2.2 renal impairment adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with creatinine clearance 30 to 79 ml/min, as estimated by the cockroft-gault equations. these adjustments are based on a pharmacokinetic study in patients with renal impairment. fludarabine phosphate injection should not be administered to patients with creatinine clearance less than 30 ml/min. starting dose adjustment for renal impairment creatinine clearance starting dose ≥ 80 ml/min 25 mg/m 2 (full dose) 50 to 79 ml/min 20 mg/m 2 30 to 49 ml/min 15 mg/m 2 < 30 ml/min do not administer renally impaired patients should be monitored closely for excessive toxicity and the dose modified accordingly. 2.3 use of infusion solutions fludarabine phosphate injection contains no antimicrobial preservative and should be used within 8 hours of opening. care must be taken to assure sterility of infusion solutions. parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. fludarabine phosphate injection should not be mixed with other drugs.

( 6 ). to report suspected adverse reactions, contact sagent pharmaceuticals, inc. at 1-866-625-1618 or fda at 1-800-fda-1088 or www.fda.gov/medwatch . 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. 6.8 genitourinary system hemorrhagic cystitis has been reported in patients treated with fludarabine phosphate. 6.9 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 swog (n=101) (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 supra ventricular 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.

ody weight decreases at 7.2 times the human iv dose. in rabbits, repeated intravenous doses of fludarabine phosphate at 3.8 times the human iv 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 iv 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. 8.3 nursing mothers it is not known whether fludarabine phosphate is excreted in human milk. because many drugs are excreted in human milk and because of the potential for serious adverse reactions including tumorigenicity in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother. 8.4 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. 8.6 patients with renal impairment the total body clearance of the principal metabolite 2-fluoro-ara-a correlated with the creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the drug. renal clearance represents approximately 40% of the total body clearance. patients with creatinine clearance 30 to 79 ml/min should have their fludarabine phosphate dose reduced and be monitored closely for excessive toxicity. due to insufficient data, fludarabine phosphate should not be administered to patients with creatinine clearance less than 30 ml/min [see dosage and administration ( 2.2 ), warnings and precautions ( 5.9 )].

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 iv 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.

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.

eased by a factor of about 2. the terminal half-life of 2-fluoro-ara-a was estimated as approximately 20 hours. in vitro , plasma protein binding of fludarabine ranged between 19% and 29%. a correlation was noted between the degree of absolute granulocyte count nadir and increased area under the concentration x time curve (auc).

crosis of spermatogenic epithelium of the testes in mice, rats and dogs. the possible adverse effects on fertility in humans have not been adequately evaluated [see warnings and precautions ( 5.7 )].

ithelium of the testes in mice, rats and dogs. the possible adverse effects on fertility in humans have not been adequately evaluated [see warnings and precautions ( 5.7 )].

response in refractory patients suggests minimal cross-resistance with commonly used anti-cll agents. the median time to response in the mdah and swog studies was 7 weeks (range of 1 to 68 weeks) and 21 weeks (range of 1 to 53 weeks), respectively. the median duration of disease control was 91 weeks (mdah) and 65 weeks (swog). the median survival of all refractory cll patients treated with fludarabine phosphate was 43 weeks and 52 weeks in the mdah and swog studies, respectively. rai stage improved to stage ii or better in 7 of 12 mdah responders (58%) and in 5 of 7 swog responders (71%) who were stage iii or iv at baseline. in the combined studies, mean hemoglobin concentration improved from 9.0 g/dl at baseline to 11.8 g/dl at the time of response in a subgroup of anemic patients. similarly, average platelet count improved from 63,500/mm 3 to 103,300/mm 3 at the time of response in a subgroup of patients who were thrombocytopenic at baseline.

n of fludarabine phosphate injection solution. the use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. if the solution contacts the skin or mucous membranes, wash thoroughly with soap and water; rinse eyes thoroughly with plain water. avoid exposure by inhalation or by direct contact of the skin or mucous membranes. discard unused portion. sterile, nonpyrogenic, preservative-free. the container closure is not made with natural rubber latex.