For Intravenous Use Only

Rx only
WARNING: FludarabinePhosphate for Injection, USP should be administered under the supervisionof a qualified physician experienced in the use of antineoplastictherapy. Fludarabine Phosphate for Injection, USP can severely suppressbone marrow function. When used at high doses in dose-ranging studiesin patients with acute leukemia, Fludarabine Phosphate for Injection,USP was associated with severe neurologic effects, including blindness,coma, and death. This severe central nervous system toxicity occurredin 36% of patients treated with doses approximately four times greater(96 mg/m2/day for 5 to 7 days) than the recommended dose.Similar severe central nervous system toxicity, including coma, seizures,agitation and confusion, has been reported in patients treated atdoses in the range of the dose recommended for chronic lymphocyticleukemia.

DESCRIPTION

Fludarabine Phosphate for Injection, USP containsfludarabine phosphate, USP, a fluorinated nucleotide analog of theantiviral agent vidarabine, 9-β-D-arabinofuranosyladenine (ara-A)that is relatively resistant to deamination by adenosine deaminase.Each vial of sterile lyophilized solid cake contains 50 mg of theactive ingredient fludarabine phosphate, USP, 50 mg of mannitol, andsodium hydroxide to adjust pH to 7.7. The pH range for the final productis 7.2 to 8.2. Reconstitution with 2 mL of Sterile Water for Injection,USP results in a solution containing 25 mg/mL of fludarabine phosphate,USP intended for intravenous administration.

The chemical name for fludarabine phosphate, USP is 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono- β - D-arabinofuranosyl)(2-fluoro-ara-AMP).The molecular formula of fludarabine phosphate, USP is C10H13FN5O7P (MW 365.2) and the structureis:

CLINICAL PHARMACOLOGY

Fludarabine phosphate, USP is rapidly dephosphorylatedto 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidinekinase to the active triphosphate, 2-fluoro-ara-ATP. This metaboliteappears to act by inhibiting DNA polymerase alpha, ribonucleotidereductase and DNA primase, thus inhibiting DNA synthesis. The mechanismof action of this antimetabolite is not completely characterized andmay be multi-faceted.

Phase I studies in humanshave demonstrated that fludarabine phosphate, USP is rapidly convertedto the active metabolite, 2-fluoro-ara-A, within minutes after intravenousinfusion. Consequently, clinical pharmacology studies have focusedon 2-fluoro-ara-A pharmacokinetics. After the five daily doses of25 mg 2-fluoro-ara-AMP/m2 to cancer patients infused over30 minutes, 2-fluoro-ara-A concentrations show a moderate accumulation.During a 5-day treatment schedule, 2-fluoro-ara-A plasma trough levelsincreased by a factor of about 2. The terminal half-life of 2-fluoro-ara-Awas estimated as approximately 20 hours. In vitro, plasma protein binding of fludarabine rangedbetween 19% and 29%.

A correlation was notedbetween the degree of absolute granulocyte count nadir and increasedarea under the concentration x time curve (AUC).

Special Populations

Pediatric Patients

Limited pharmacokinetic data for fludarabinephosphate, USP are available from a published study of children (ages1 to 21 years) with refractory acute leukemias or solid tumors (Children’sCancer Group Study 0971). When fludarabine phosphate, USPwas administered as a loading dose over 10 minutes immediately followedby a 5-day continuous infusion, steady-state conditions were reachedearly.

Patients withRenal Impairment

The total body clearanceof the principal metabolite 2-fluoro-ara-A correlated with the creatinineclearance, indicating the importance of the renal excretion pathwayfor the elimination of the drug. Renal clearance represents approximately40% of the total body clearance. Patients with moderate renal impairment(17 to 41 mL/min/m2) receiving 20% reduced fludarabinephosphate, USP dose had a similar exposure (AUC; 21 versus 20 nM•h/mL)compared to patients with normal renal function receiving the recommendeddose. The mean total body clearance was 172 mL/min for normal and124 mL/min for patients with moderately impaired renal function.

Clinical Studies

Two single-arm open-label studies of fludarabine phosphate,USP have been conducted in adult patients with CLL refractory to atleast one prior standard alkylating-agent containing regimen. In astudy conducted by M.D. Anderson Cancer Center (MDAH), 48 patientswere treated with a dose of 22 to 40 mg/m2 daily for 5days every 28 days. Another study conducted by the Southwest OncologyGroup (SWOG) involved 31 patients treated with a dose of 15 to 25mg/m2 daily for 5 days every 28 days. The overall objectiveresponse rates were 48% and 32% in the MDAH and SWOG studies, respectively.The complete response rate in both studies was 13%; the partial responserate was 35% in the MDAH study and 19% in the SWOG study. These responserates were obtained using standardized response criteria developedby the National Cancer Institute CLL Working Group3 andwere achieved in heavily pre-treated patients. The ability of fludarabinephosphate, USP to induce a significant rate of response in refractorypatients suggests minimal cross-resistance with commonly used anti-CLLagents.

The median time to response in the MDAHand 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 diseasecontrol was 91 weeks (MDAH) and 65 weeks (SWOG). The median survivalof all refractory CLL patients treated with fludarabine phosphate,USP 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 MDAHresponders (58%) and in 5 of 7 SWOG responders (71%) who were StageIII or IV at baseline. In the combined studies, mean hemoglobin concentrationimproved from 9.0 g/dL at baseline to 11.8 g/dL at the time of responsein a subgroup of anemic patients. Similarly, average platelet countimproved from 63,500/mm3 to 103,300/mm3 at thetime of response in a subgroup of patients who were thrombocytopenicat baseline.

INDICATIONS AND USAGE

Fludarabine Phosphate for Injection, USP is indicatedfor the treatment of adult patients with B-cell chronic lymphocyticleukemia (CLL) who have not responded to or whose disease has progressedduring treatment with at least one standard alkylating-agent containingregimen. The safety and effectiveness of fludarabine phosphate, USPin previously untreated or non-refractory patients with CLL have notbeen established.

CONTRAINDICATIONS

Fludarabine phosphate, USP is contraindicated inthose patients who are hypersensitive to this drug or its components.

WARNINGS

(See BOXED WARNINGS)

There are clear dose-dependent toxic effectsseen with fludarabine phosphate, USP. Dose levels approximately 4times greater (96 mg/m2/day for 5 to 7 days) than thatrecommended for CLL (25 mg/m2/day for 5 days) were associatedwith a syndrome characterized by delayed blindness, coma and death.Symptoms appeared from 21 to 60days following the last dose.Thirteen of 36 patients (36%) who received fludarabine phosphate,USP at high doses (96 mg/m2/day for 5 to 7 days) developedthis severe neurotoxicity. Similar severe central nervous system toxicity,including coma, seizures, agitation and confusion, has been reportedin patients treated at doses in the range of the dose recommendedfor chronic lymphocytic leukemia.

The effectof chronic administration of fludarabine phosphate, USP on the centralnervous system is unknown; however, patients have received the recommendeddose for up to 15 courses of therapy.

Severebone marrow suppression, notably anemia, thrombocytopenia and neutropenia,has been reported in patients treated with fludarabine phosphate,USP. In a Phase I study in adult solid tumor patients, the mediantime to nadir counts was 13 days (range, 3 to 25 days) for granulocytesand 16 days (range, 2 to 32) for platelets. Most patients had hematologicimpairment at baseline either as a result of disease or as a resultof prior myelosuppressive therapy. Cumulative myelosuppression maybe seen. While chemotherapy-induced myelosuppression is often reversible,administration of fludarabine phosphate, USP requires careful hematologicmonitoring.

Several instances of trilineagebone marrow hypoplasia or aplasia resulting in pancytopenia, sometimesresulting in death, have been reported in adult patients. The durationof clinically significant cytopenia in the reported cases has rangedfrom approximately 2 months to approximately 1 year. These episodeshave occurred both in previously treated or untreated patients.

Instances of life-threatening and sometimes fatal autoimmunephenomena such as hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenicpurpura (ITP), Evan’s syndrome, and acquired hemophilia havebeen reported to occur after one or more cycles of treatment withfludarabine phosphate, USP in patients with or without a previoushistory of autoimmune hemolytic anemia or a positive Coombs’test and who may or may not be in remission from their disease. Steroidsmay or may not be effective in controlling these hemolytic episodes.The majority of patients rechallenged with fludarabine phosphate,USP developed a recurrence in the hemolytic process. The mechanism(s)which predispose patients to the development of this complicationhas not been identified. Patients undergoing treatment with fludarabinephosphate, USP should be eva luated and closely monitored for hemolysis.Discontinuation of therapy with fludarabine phosphate, USP is recommendedin case of hemolysis.

Transfusion-associatedgraft-versus-host disease has been observed after transfusion of non-irradiatedblood in fludarabine phosphate, USP treated patients. Fatal outcomeas a consequence of this disease has been reported. Therefore, tominimize the risk of transfusion-associated graft-versus-host disease,patients who require blood transfusion and who are undergoing, orwho have received, treatment with fludarabine phosphate, USP shouldreceive irradiated blood only.

In a clinicalinvestigation using fludarabine phosphate, USP in combination withpentostatin (deoxycoformycin) for the treatment of refractory chroniclymphocytic leukemia (CLL) in adults, there was an unacceptably highincidence of fatal pulmonary toxicity. Therefore, the use of fludarabinephosphate, USP in combination with pentostatin is not recommended.

Of the 133 adult CLL patients in the two trials, therewere 29 fatalities during study. Approximately 50% of the fatalitieswere due to infection and 25% due to progressive disease.

Pregnancy Category D: Based on its mechanism of action, fludarabine phosphate, USP cancause fetal harm when administered to a pregnant woman. There areno adequate and well-controlled studies of fludarabine phosphate,USP in pregnant women. Fludarabine phosphate was embryolethal andteratogenic in both rats and rabbits. If fludarabine phosphate, USPis used during pregnancy, or if the patient becomes pregnant whiletaking this drug, the patient should be apprised of the potentialhazard to the fetus. Women of childbearing potential should be advisedto avoid becoming pregnant. Women of childbearing potential and fertilemales must take contraceptive measures during and at least for sixmonths after cessation of treatment with fludarabine phosphate, USP.

Fludarabine phosphate, USP was embryolethal and teratogenicin rats and rabbits.

Fludarabine phosphate,USP was administered at doses of 0, 1, 10 or 30 mg/kg/day (0.24, 2.4times and 7.2 times the recommended human dose on a mg/m2 basis, respectively) to pregnant rats on days 6 to 15 of gestation.At 10 and 30 mg/kg/day administered during organogenesis, there wasa dose-related increase in various skeletal variations and a decreasein mean fetal body weights. Maternal toxicity was not apparent at10 mg/kg/day, and was limited to slight body weight decreases at 30mg/kg/day. In a dose finding study malformations, such as limb andtail defects, were induced at 40 mg/kg/day (9.6 times the recommendedhuman dose on a mg/m2 basis). In a reproduction toxicitystudy on rabbits Fludarabine phosphate was administered intravenouslyat doses of 0, 1, 5 or 8 mg/kg/day (approximately 0.5, 2.4, and 3.8times the recommended human dose on a mg/m2 basis) on days6 to 18 of gestation. A dose of 8 mg/kg/day administered during organogenesisincreased embryo and fetal lethality as indicated by a higher numberof resorptions and a decrease in live fetuses. Compound-related teratogeniceffects manifested by external deformities and skeletal malformationswere observed at 8 mg/kg/day. The most frequent external malformationsobserved in rabbits were cleft palate, adactyly, brachydactyly andsyndactyly along with skeletal malformations such as fused metatarsals,phalanges, sternebrae and limb bones and some soft tissue malformations(diaphragmatic herniae). Fetal body weights were decreased in rabbitsgiven 8 mg/kg/day.

PRECAUTIONS

General

Fludarabine phosphate, USP is a potent antineoplasticagent with potentially significant toxic side effects. Patients undergoingtherapy should be closely observed for signs of hematologic and nonhematologictoxicity. Periodic assessment of peripheral blood counts is recommendedto detect the development of anemia, neutropenia and thrombocytopenia.

Tumor lysis syndrome associated with fludarabine phosphate,USP treatment has been reported in CLL patients with large tumor burdens.Since fludarabine phosphate, USP can induce a response as early asthe first week of treatment, precautions should be taken in thosepatients at risk of developing this complication.

In patients with impaired state of health, fludarabine phosphate,USP should be given with caution and after careful risk/benefit consideration.This applies especially for patients with severe impairment of bonemarrow function (thrombocytopenia, anemia, and/or granulocytopenia),immunodeficiency or with a history of opportunistic infection. Prophylactictreatment should be considered in patients at increased risk of developingopportunistic infections.

There are inadequatedata on dosing of patients with renal insufficiency. Fludarabine phosphate,USP must be administered cautiously in patients with renal insufficiency.The total body clearance of 2-fluoro-ara-A has been shown to be directlycorrelated with creatinine clearance. Patients with moderate impairmentof renal function (creatinine clearance 30 to 70 mL/min/1.73 m2) should have their fludarabine dose reduced by 20% and bemonitored closely. Fludarabine is not recommended for patients withseverely impaired renal function (creatinine clearance less than 30mL/min/1.73m2).

Fludarabine phosphate, USP mayreduce the ability to drive or use machines, since fatigue, weakness,visual disturbances, confusion, agitation and seizures have been observed.

Laboratory Tests

During treatment, the patient’s hematologicprofile (particularly neutrophils and platelets) should be monitoredregularly to determine the degree of hematopoietic suppression.

Drug Interactions

The use of fludarabine phosphate, USP in combinationwith pentostatin is not recommended due to the risk of severe pulmonarytoxicity (see WARNINGS section).

Carcinogenesis

No animal carcinogenicity studies with fludarabinephosphate, USP have been conducted.

Mutagenesis

Fludarabinephosphate, USP was not mutagenic to bacteria (Ames test) or mammaliancells (HGRPT assay in Chinese hamster ovary cells) either in the presenceor absence of metabolic activation. Fludarabine phosphate, USP wasclastogenic in vitro to Chinesehamster ovary cells (chromosome aberrations in the presence of metabolicactivation) and induced sister chromatid exchanges both with and withoutmetabolic activation. In addition, fludarabine phosphate, USP wasclastogenic in vivo (mousemicronucleus assay) but was not mutagenic to germ cells (dominantlethal test in male mice).

Impairment of Fertility

Studies in mice, rats and dogs have demonstrated dose-related adverseeffects on the male reproductive system. Observations consisted ofa decrease in mean testicular weights in mice and rats with a trendtoward decreased testicular weights in dogs and degeneration and necrosisof spermatogenic epithelium of the testes in mice, rats and dogs.The possible adverse effects on fertility in humans have not beenadequately eva luated.

Pregnancy

Pregnancy Category D: (See WARNINGS section).

Nursing Mothers

It is not known whether fludarabine phosphate, USPis excreted in human milk. Because many drugs are excreted in humanmilk and because of the potential for serious adverse reactions includingtumorgenicity in nursing infants, a decision should be made to discontinuenursing or discontinue the drug, taking into account the importanceof the drug to the mother.

Pediatric Use

Data submitted to the FDA was insufficient to establishefficacy in any childhood malignancy. Fludarabine was eva luated in62 pediatric patients (median age 10, range 1 to 21) with refractoryacute leukemia (45patients) or solid tumors (17 patients). Thefludarabine regimen tested for pediatric acute lymphocytic leukemia(ALL) patients was a loading bolus of 10.5 mg/m2/day followedby a continuous infusion of 30.5 mg/m2/day for 5 days.In 12 pediatric patients with solid tumors, dose-limiting myelosuppressionwas observed with a loading dose of 8mg/m2/day followedby a continuous infusion of 23.5 mg/m2/day for 5 days.The maximum tolerated dose was a loading dose of 7 mg/m2/day followed by a continuous infusion of 20 mg/m2/dayfor 5 days. Treatment toxicity included bone marrow suppression. Plateletcounts appeared to be more sensitive to the effects of fludarabinethan hemoglobin and white blood cell counts. Other adverse eventsincluded fever, chills, asthenia, rash, nausea, vomiting, diarrhea,and infection. There were no reported occurrences of peripheral neuropathyor pulmonary hypersensitivity reaction.

Vaccination

Duringand after treatment with fludarabine phosphate, USP, vaccination withlive vaccines should be avoided.

Disease Progression

Disease progression and transformation (e.g. Richter’s syndrome)have been reported in CLL patients.

ADVERSE REACTIONS

The most common adverse events include myelosuppression(neutropenia, thrombocytopenia and anemia), fever and chills, infection,and nausea and vomiting. Other commonly reported events include malaise,fatigue, anorexia, and weakness. Serious opportunistic infectionshave occurred in CLL patients treated with fludarabine phosphate,USP. Adverse events, and those reactions which are more clearly relatedto 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 fludarabinephosphate, USP. During fludarabine phosphate, USP treatment of 133patients with CLL, the absolute neutrophil count decreased to lessthan 500/mm3 in 59% of patients, hemoglobin decreased frompretreatment values by at least 2 grams percent in 60%, and plateletcount decreased from pretreatment values by at least 50% in 55%. Myelosuppressionmay be severe, cumulative, and may affect multiple cell lines. Bonemarrow fibrosis occurred in one CLL patient treated with fludarabinephosphate, USP.

Several instances of trilineagebone marrow hypoplasia or aplasia resulting in pancytopenia, sometimesresulting in death, have been reported in postmarketing surveillance.The duration of clinically significant cytopenia in the reported caseshas ranged from approximately 2 months to approximately 1 year. Theseepisodes have occurred both in previously treated or untreated patients.

Life-threatening and sometimes fatal autoimmune phenomenasuch as hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenicpurpura (ITP), Evan’s syndrome, and acquired hemophilia havebeen reported to occur in patients receiving fludarabine phosphate,USP (see WARNINGS section). Themajority of patients rechallenged with fludarabine phosphate, USPdeveloped a recurrence in the hemolytic process.

In post-marketing experience, cases of myelodysplastic syndrome andacute myeloid leukemia mainly associated with prior, concomitant orsubsequent treatment with alkylating agents, topoisomerase inhibitors,or irradiation have been reported.

Infections: Serious, and sometimes fatalinfections, including opportunistic infections and reactivations oflatent viral infections such as VZV (Herpes zoster), Epstein-Barrvirus and JC virus (progressive multifocal leukoencephalopathy) havebeen reported in patients treated with fludarabine phosphate, USP.

Rare cases of Epstein Barr Virus (EBV) associated lymphoproliferativedisorders have been reported in patients treated with fludarabinephosphate, USP.

Metabolic: Tumor lysis syndrome has been reported in CLL patients treated withfludarabine phosphate, USP. This complication may include hyperuricemia,hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia,hematuria, urate crystalluria, and renal failure. The onset of thissyndrome 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 patientstreated with fludarabine phosphate, USP at the recommended dose. Peripheralneuropathy has been observed in patients treated with fludarabinephosphate, USP and one case of wrist-drop was reported.

In post-marketing experience, cases of progressive multifocalleukoencephalopathy 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 oneyear after initiating treatment.

Pulmonary System: Pneumonia, a frequentmanifestation of infection in CLL patients, occurred in 16%, and 22%of those treated with fludarabine phosphate, USP in the MDAH and SWOGstudies, respectively. Pulmonary hypersensitivity reactions to fludarabinephosphate, USP characterized by dyspnea, cough and interstitial pulmonaryinfiltrate have been observed.

In post-marketingexperience, cases of severe pulmonary toxicity have been observedwith fludarabine use which resulted in ARDS, respiratory distress,pulmonary hemorrhage, pulmonary fibrosis, and respiratory failure.After an infectious origin has been excluded, some patients experiencedsymptom improvement with corticosteroids.

Gastrointestinal System: Gastrointestinaldisturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis,and gastrointestinal bleeding have been reported in patients treatedwith fludarabine phosphate, USP.

Cardiovascular: Edema has been frequentlyreported. One patient developed a pericardial effusion possibly relatedto treatment with fludarabine phosphate, USP. No other severe cardiovascularevents were considered to be drug related.

Genitourinary System: Rare cases of hemorrhagiccystitis have been reported in patients treated with fludarabine phosphate,USP.

Skin: Skin toxicity, consisting primarily of skin rashes, has been reportedin patients treated with fludarabine phosphate, USP.

Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis,and pemphigus have been reported, with fatal outcomes in some cases.

Worsening or flare up of pre-existing skin cancer lesions,as well as new onset of skin cancer, has been reported in patientsduring or after treatment with fludarabine phosphate, USP.

Data in the following table are derived from the 133 patientswith CLL who received fludarabine phosphate, USP in the MDAH and SWOGstudies.

More than 3000 adult patients received fludarabinephosphate, USP in studies of other leukemias, lymphomas, and othersolid tumors. The spectrum of adverse effects reported in these studieswas consistent with the data presented above.

OVERDOSAGE

High doses of fludarabine phosphate, USP (see WARNINGS section) have been associatedwith an irreversible central nervous system toxicity characterizedby delayed blindness, coma, and death. High doses are also associatedwith severe thrombocytopenia and neutropenia due to bone marrow suppression.There is no known specific antidote for fludarabine phosphate, USPoverdosage. Treatment consists of drug discontinuation and supportivetherapy.

DOSAGE AND ADMINISTRATION

Usual Dose:

The recommended adult dose of Fludarabine Phosphate forInjection, USP is 25 mg/m2 administered intravenously overa period of approximately 30 minutes daily for five consecutive days.Each 5 day course of treatment should commence every 28 days. Dosagemay be decreased or delayed based on evidence of hematologic or nonhematologictoxicity. Physicians should consider delaying or discontinuing thedrug if neurotoxicity occurs.

A number of clinicalsettings may predispose to increased toxicity from fludarabine phosphate,USP. These include advanced age, renal insufficiency, and bone marrowimpairment. Such patients should be monitored closely for excessivetoxicity 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,USP be administered following the achievement of a maximal responseand then the drug should be discontinued.

Renal Insufficiency

Adult patients with moderate impairment of renal function (creatinineclearance 30 to 70 mL/min/1.73 m2) should have a 20% dosereduction of fludarabine phosphate, USP. Fludarabine phosphate, USPshould not be administered to patients with severely impaired renalfunction (creatinine clearance less than 30 mL/min/1.73 m2).

Preparation ofSolutions:

Fludarabine Phosphate forInjection, USP should be prepared for parenteral use by asepticallyadding Sterile Water for Injection, USP. When reconstituted with 2mL of Sterile Water for Injection, USP, the solid cake should fullydissolve in 15 seconds or less; each mL of the resulting solutionwill contain 25 mg of fludarabine phosphate, USP, 25 mg of mannitol,and sodium hydroxide to adjust the pH to 7.7. The pH range for thefinal product is 7.2 to 8.2. In clinical studies, the product hasbeen diluted in 100 cc or 125 cc of 5% Dextrose Injection, USP or0.9% Sodium Chloride, USP.

Reconstituted FludarabinePhosphate for Injection, USP contains no antimicrobial preservativeand thus should be used within 8 hours of reconstitution. Care mustbe taken to assure the sterility of prepared solutions. Parenteraldrug products should be inspected visually for particulate matterand discoloration prior to administration.

FludarabinePhosphate for Injection, USP should not be mixed with other drugs.

Handling and Disposal:

Procedures for proper handling and disposalshould be considered. Consideration should be given to handling anddisposal according to guidelines issued for cytotoxic drugs. Severalguidelines on this subject have been published.1-4

Caution should be exercised in the handling and preparationof Fludarabine Phosphate for Injection, USP solution. The use of latexgloves and safety glasses is recommended to avoid exposure in caseof breakage of the vial or other accidental spillage. If the solutioncontacts the skin or mucous membranes, wash thoroughly with soap andwater; rinse eyes thoroughly with plain water. Avoid exposure by inhalationor by direct contact of the skin or mucous membranes.

HOW SUPPLIED

Fludarabine Phosphate for Injection, USP is suppliedas a white, lyophilized solid cake. Each vial contains 50 mg of fludarabinephosphate, USP, 50 mg of mannitol, and sodium hydroxide to adjustpH to 7.7. The pH range for the final product is 7.2 to 8.2. Storeat 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]Store upright.

Fludarabine Phosphate for Injection,USP is supplied in a clear glass single dose vial and cartoned individually.

NDC 61703-344-18

REFERENCES

1. Preventing Occupational Exposures to Antineoplasticand Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165.

2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999.http://www.osha.gov/dts/osta/otm/otm_vi_2.html

3. American Society of Health-System Pharmacists. ASHPguidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006:63: 1172-1193.

4. Polvich, M., White, J.M., & Kelleher, L.O. (eds.)2005. Chemotherapy and biotherapy guidelines and recommendations forpractice (2nd ed.).Pittsburgh,PA: Oncology Nursing Society.

Hospira, Inc.

Lake Forest, IL 60045

Product of Australia

Rev. April 2009

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