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Clolar®

The following is an announcement issued by the U.S. Food and Drug Administration on December 28, 2004 regarding the marketing approval of Genzyme Oncology's product, Clolar, for the treatment of children with refractory or relapsed acute lymphoblastic leukemia (ALL):

On December 28 , 2004, the U. S. Food and Drug Administration granted accelerated approval for clofarabine (Clolar®) For Intravenous Infusion, ILEX Products Inc.), a purine nucleoside antimetabolite, for treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. The approval of this indication is based on the induction of complete responses. Clinical studies demonstrating increased survival or other clinical benefit have not been conducted. Approval was granted under accelerated approval regulations that require the sponsor to conduct and complete additional clinical studies to confirm clinical benefit.

Efficacy and safety were demonstrated in a single multi-center trial that enrolled 49 patients. Most patients had received 2 to 4 prior regimens and 15/49 (31%) had undergone at least one transplant. The median age was 12 years. Clofarabine was given at a dose of 52 mg/m2, intravenously, over 2 hours daily x 5 repeated every 2 to 6 weeks following recovery or return to baseline organ function. The study endpoints were the rate of complete response (CR) and the rate of complete response without platelet recovery (CRp). The former was defined as no evidence of circulating blasts or extramedullary disease, an M1 bone marrow, and recovery of peripheral platelet and absolute neutrophil counts; the latter was defined as meeting all criteria for CR except for platelet count recovery. Response rates were determined by an Independent Response Review Panel (IRRP).

Six patients (12%) achieved a CR and 4 patients (8%) achieved a CRp, and 5 patients (10%) achieved a PR. Of the 15 responding patients, 6 had post-clofarabine bone marrow transplantation. Hence, response durations could not be determined. In the patients who were not transplanted, the response durations for CR were 43, 50, 82, 93+, and 160+ days; for CRp the response duration was 32 days.

The principal clofarabine toxicities were nausea, vomiting, hematologic toxicity, febrile neutropenia, hepatobiliary toxicity, infections and renal toxicity. Clofarabine can produce systemic inflammatory response syndrome/capillary leak syndrome (SIRS), manifested by the rapid development of tachypnea, tachycardia, hypotension, shock, and multi-organ failure. Cardiac toxicity was characterized as left ventricular systolic dysfunction; tachycardia may also occur.

Review the full prescribing information; including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

For more information about Clolar, please call 1-800-RX CLOLAR or visit www.clolar.com.

6662 (10/05)
DESCRIPTION
CLOLAR" For Intravenous Infusion (CLOLAR"; clofarabine) contains clofarabine, a purine nucleoside anti-metabolite. CLOLAR" (1 mg/mL) is supplied in a 20 mL, single-use vial. The 20 mL vial contains 20 mg clofarabine formulated in 20 mL unbuffered normal saline (comprised of Water for Injection, USP, and Sodium Chloride, USP). The pH range of the solution is 4.5 to 7.5. The solution is sterile, clear and practically colorless, and free from foreign matter. The chemical structure of clofarabine is 2-chloro-9-(2-deoxy-2-fluoro-ß-D-arabinofuranosyl)- 9H-purin-6-amine. The molecular formula of clofarabine is C10H11ClFN5O3 with a molecular weight of 303.68.

CLINICAL PHARMACOLOGY
Mechanism of Action
Clofarabine is sequentially metabolized intracellularly to the 5-monophosphate metabolite by deoxycytidine kinase and mono- and di-phospho-kinases to the active 5-triphosphate metabolite. Clofarabine has high affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine.

Clofarabine inhibits DNA synthesis by decreasing cellular deoxynucleotide triphosphate pools through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through incorporation into the DNA chain by competitive inhibition of DNA polymerases. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading to programmed cell death. Clofarabine is cytotoxic to rapidly proliferating and quiescent cancer cell types in vitro.

Human Pharmacokinetics
The population pharmacokinetics of CLOLAR" were studied in 40 pediatric patients aged 2 to 19 years (21 males/19 females) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). At the given 52 mg/m2 dose, similar concentrations were obtained over a wide range of body surface areas (BSAs).

Clofarabine was 47% bound to plasma proteins, predominantly to albumin. Based on noncompartmental analysis, systemic clearance and volume of distribution at steady-state were estimated to be 28.8 L/h/m2 and 172 L/m2, respectively. The terminal half-life was estimated to be 5.2 hours. No apparent difference in pharmacokinetics was observed between patients with ALL and AML or between males and females.
No relationship between clofarabine or clofarabine triphosphate exposure and toxicity or response was found in this population.

Based on 24-hour urine collections in the pediatric studies, 49-60% of the dose is excretedin the urine unchanged. In vitro studies using isolated human hepatocytes indicate very limited metabolism (0.2%); therefore, the pathways of non-renal elimination remain unknown.

Although no clinical drug-drug interaction studies have been conducted to date, on the basis of the in vitro studies, cytochrome p450 inhibitors and inducers are unlikely to affect the metabolism of clofarabine. The effect of clofarabine on the metabolism of cytochrome p450 substrates has not been studied. The pharmacokinetics of clofarabine have not been evaluated in patients with renal or hepatic dysfunction.

CLINICAL STUDIES
Sixty-six (66) pediatric ALL patients were exposed to CLOLAR". Fifty-eight (58) of the patients received the recommended pediatric dose of CLOLAR" 52 mg/m2 daily x 5 as an intravenous infusion (IVI).

The safety and efficacy of CLOLAR" were evaluated in pediatric patients with refractory or relapsed hematologic malignancies in an open-label, dose-escalation, noncomparative study. The starting dose of CLOLAR" was 11.25 mg/m2/day IVI daily x 5 and escalated to 70 mg/m2/day IVI daily x 5. This dosing schedule was repeated every 2 to 6 weeks depending on toxicity and response. Nine of 17 ALL patients were treated with CLOLAR" 52 mg/m2 daily x 5. In the 17 ALL patients there were 2 complete remissions (12.5%) and 2 partial remissions (12.5%) at varying doses. Dose-limiting toxicities (DLTs) in this study were reversible hyperbilirubinemia and elevated transaminase levels and skin rash, experienced at 70 mg/m2. As a result of this study, the recommended dose for subsequent study in pediatric patients was determined to be 52 mg/m2/day for 5 days.

Single Arm Study in Pediatric ALL A single arm study was conducted in relapsed/ refractory pediatric patients with ALL at a single dose. All patients had disease that had relapsed after and/or was refractory to two or more prior therapies. Most patients, 46/49 (93.8%), had received 2 to 4 prior regimens and 15/49 (30.6%) of the patients had undergone at least 1 prior transplant. The median age of the treated patients was 12 years. There were more males, 29/49 (59.2%), than females, 20/49 (40.8%). Most of the patients were either Caucasian (n=20, 40.8%) or Hispanic (n=20, 40.8%), with 12.2% African-American (n=6), and 6.1% Other race (n=3). All patients received a dose of 52 mg/m2 daily x 5 IVI. There was no dose modification during the remission induction phase of treatment (maximum of 2 cycles). Doses could be modified (reduced/delayed) during the post-induction phase. There was no dose escalation. The planned study endpoint was the rate of Complete Remission (CR), defined as no evidence of circulating blasts or extramedullary disease, an M1 bone marrow (<5% blasts), and recovery of peripheral counts [platelets >100 x 109/L and absolute neutrophil count (ANC) >1.0 x 109/L] and Complete Remission in the Absence of Total Platelet Recovery (CRp), defined as meeting all criteria for CR except for recovery of platelet counts to >100 x 109/L.

Partial Response (PR) was also determined, defined as complete disappearance of circulating blasts, an M2 bone marrow (>5% and <25% blasts), and appearance of normal progenitor cells or an M1 bone marrow that did not qualify for CR or CRp. Transplantation rate was not a study endpoint.
Response rates for these studies were determined by an unblinded Independent Response Review Panel (IRRP).

Table 1 summarizes results for the pediatric ALL study. Responses were seen in both pre-B and T-cell immunophenotypes of ALL. The median cumulative dose was 540 mg (range 29-1905 mg) in 1 (42.9%), 2 (38.8%) or 3 or more (18.4%) cycles.

Table 1: Results in Pediatric ALL Study Of the 15 responding pediatric ALL patients, 6 had post-clofarabine bone marrow transplantation, so that duration of response could not be determined. In the 9 responding patients who were not transplanted, the response durations for CR were 43, 50, 82, 93+, and 160+ days; for CRp the response duration was 32 days; and for PR the response durations were 7, 16, and 21 days.

INDICATIONS AND USAGE
CLOLAR" is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted.

CONTRAINDICATIONS
None

WARNINGS
CLOLAR" should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Suppression of bone marrow function should be anticipated. This is usually reversible and appears to be dose dependent. The use of CLOLAR" is likely to increase the risk of infection, including severe sepsis, as a result of bone marrow suppression. Administration of CLOLAR" results in a rapid reduction in peripheral leukemia cells. For this reason, patients undergoing treatment with CLOLAR" should be evaluated and monitored for signs and symptoms of tumor lysis syndrome, as well as signs and symptoms of cytokine release (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that could develop into systemic inflammatory response syndrome (SIRS)/ capillary leak syndrome, and organ dysfunction. Physicians are encouraged to give continuous IV fluids throughout the five days of CLOLAR" administration to reduce the effects of tumor lysis and other adverse events. Allopurinol should be administered if hyperuricemia is expected. CLOLAR" should be discontinued immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome, either of which can be fatal, and use of steroids, diuretics, and albumin considered. CLOLAR" can be re-instituted when the patient is stable, generally at a lower dose.

Severe bone marrow suppression, including neutropenia, anemia, and thrombocytopenia, has been observed in patients treated with CLOLAR". At initiation of treatment, most patients in the clinical studies had hematological impairment as a manifestation of leukemia. Because of the pre-existing immunocompromised condition of these patients and prolonged neutropenia that can result from treatment with CLOLAR", patients are at increased risk for severe opportunistic infections. Careful hematological monitoring during therapy is important, and hepatic and renal function should be assessed prior to and during treatment with CLOLAR" because of CLOLAR"s predominantly renal excretion and because the liver is a target organ for CLOLAR" toxicity. The respiratory status and blood pressure should be closely monitored during infusion of CLOLAR".
Hepatic and Renal Impairment CLOLAR" has not been studied in patients with hepatic or renal dysfunction. Its use in such patients should be undertaken only with the greatest caution. Pregnancy Teratogenic Effects: Pregnancy Category D CLOLAR" (clofarabine) may cause fetal harm when administered to a pregnant woman.

Clofarabine was teratogenic in rats and rabbits. Developmental toxicity (reduced fetal body weight and increased post-implantation loss) and increased incidences of malformations and variations (gross external, soft tissue, skeletal and retarded ossification) were observed in rats receiving 54 mg/m2/day (approximately equivalent to the recommended clinical dose on a mg/m2 basis), and in rabbits receiving 12 mg/m2/day (approximately 23% of the recommended clinical dose on a mg/m2 basis).

There are no adequate and well-controlled studies in pregnant women using clofarabine. 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 while receiving treatment with clofarabine.

PRECAUTIONS
Information for Patients and Caregivers
Physicians are advised to discuss the following with patients to whom CLOLAR" will be administered and patient caregivers, as appropriate. Dehydration/Hypotension Patients receiving CLOLAR" may experience vomiting and diarrhea; they should therefore be advised regarding appropriate measures to avoid dehydration. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, lightheadedness, fainting spells, or decreased urine output. CLOLAR" administration should be stopped if the patient develops hypotension for any reason during the 5 days of administration. If hypotension is transient and resolves without pharmacological intervention, CLOLAR" treatment can be re-instituted, generally at a lower dose.

Concomitant Medications

Since CLOLAR" is excreted primarily by the kidneys, drugs with known renal toxicity should be avoided during the 5 days of CLOLAR" administration. In addition, since the liver is a known target organ for CLOLAR" toxicity, concomitant use of medications known to induce hepatic toxicity should also be avoided. Patients taking medications known to affect blood pressure or cardiac function should be closely monitored during administration of CLOLAR".

Pregnancy/Nursing
All patients should be advised to use effective contraceptive measures to prevent pregnancy. Female patients should be advised to avoid breast-feeding during treatment with CLOLAR".

Laboratory Tests
Complete blood counts and platelet counts should be obtained at regular intervals during CLOLAR" therapy, and more frequently in patients who develop cytopenias. In addition, liver and kidney function should be monitored frequently during the 5 days of CLOLAR" administration.

Drug Interactions
Although no clinical drug-drug interaction studies have been conducted to date, on the basis of the in vitro studies, ctochrome p450 inhibitors and inducers are unlikely to affect the metabolism of clofarabine. The effect of clofarabine on the metabolism of cytochrome p450 substrates has not been studied.

Drug/Laboratory Tests Interactions
There are no known clinically significant interactions of CLOLAR" with other medications or laboratory tests. No formal drug/laboratory test interaction studies have been conducted with CLOLAR".

Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis Clofarabine has not been tested for carcinogenic potential. Mutagenesis Clofarabine showed clastogenic activity in the in vitro mammalian cell chromosome aberration assay (CHO cells) and in the in vivo rat micronucleus assay. It did not show evidence of mutagenic activity in the bacterial mutation assay (Ames test).

Impairment of Fertility
Studies in mice, rats, and dogs have demonstrated dose-related adverse effects on male reproductive organs. Seminiferous tubule and testicular degeneration and atrophy were reported in male mice receiving intraperitoneal (IP) doses of 3 mg/kg/day (9 mg/m2/day, approximately 17% of the recommended clinical dose on a mg/m2 basis). The testes of rats receiving 25 mg/kg/day (150 mg/m2/day, approximately 3 times the recommended clinical dose on a mg/m2 basis) in a 6-month IV study had bilateral degeneration of the seminiferous epithelium with retained spermatids and atrophy of interstitial cells. In a 6-month IV dog study, cell degeneration of the epididymis and degeneration of the seminiferous epithelium in the testes were observed in dogs receiving 0.375 mg/kg/day (7.5 Clofarabine
Responses n % 95% CI
CR 6 12.2 4.6 to 24.8
CRp 4 8.2 2.3 to 19.6
PR 5 10.2 3.4 to 22.2
n=49

Table 2: Most Commonly Reported (.10% Overall) Adverse Events by System Organ
Class (N=96) (continued) 1 Patients with more than one occurrence of the same preferred term are counted only once. Grade 4 includes deaths (Grade 5).

Cardiovascular
The most frequently reported cardiac disorder was tachycardia (34%), which was, however, already present in 27.4% of patients at study entry. Most of the cardiac adverse events were reported in the first 2 cycles. Pericardial effusion was a frequent finding in these patients on post-treatment studies, [19/55 (35%)]. The effusion was almost always minimal to small and in no cases had hemodynamic significance.

Left ventricular systolic dysfunction (LVSD) was also noted. Fifteen out of fifty-five patients [15/55 (27%)] had some evidence of LVSD after study entry. In most cases where subsequent follow-up data were available, the LVSD appeared to be transient. The exact etiology for the LVSD is unclear because of previous therapy or serious concurrent illness.

Hepatic
Hepato-biliary toxicities were frequently observed in pediatric patients during treatment with CLOLAR.. Grade 3 or 4 elevated aspartate aminotransferase (AST) occurred in 38% of patients and grade 3 or 4 elevated alanine aminotransferase (ALT) occurred in 44% of patients. Grade 3 or 4 elevated bilirubin occurred in 15% of patients, with 2 cases of grade 4 hyperbilirubinemia resulting in treatment discontinuation.
For patients with follow-up data, elevations in AST and ALT were transient and typically of <2 weeks duration. The majority of AST and ALT elevations occurred within 1 week of CLOLAR. administration and returned to baseline or .grade 2 within several days.

Although less common, elevations in bilirubin appeared to be more persistent. Where followup data are available, the median time to recovery from grade 3 and grade 4 elevations in bilirubin to .grade 2 was 6 days.

Infection
At baseline, 47% of the patients had 1 or more concurrent infections. A total of 85% of patients experienced at least 1 infection after CLOLAR. treatment, including fungal, viral and bacterial infections.

Renal
The most prevalent renal toxicity was elevated creatinine. Grade 3 or 4 elevated creatinine occurred in 6% of patients. Nephrotoxic medications, tumor lysis, and tumor lysis with hyperuricemia may contribute to renal toxicity.

Systemic Inflammatory Response Syndrome (SIRS)/Capillary Leak Syndrome Capillary leak syndrome or SIRS (signs and symptoms of cytokine release, e.g., tachypnea, tachycardia, hypotension, pulmonary edema) occurred in 4 pediatric patients overall (3 ALL, 1 AML). Several patients developed rapid onset of respiratory distress, hypotension, capillary leak (pleural and pericardial effusions), and multi-organ failure. Close monitoring
52mg/m2 (N=96)
Total Grade 3 Grade 4
N % n % n %
System Organ Class
Adverse Event1
Musculoskeletal, Connective Tissue and Bone Disorders
Arthralgia 11 11 3 3 . .
Back pain 12 13 3 3 . .
Myalgia 13 14 . . . .
Pain in limb 28 29 5 5 . .
Nervous System Disorders
Dizziness (except vertigo) 15 16 . . . .
Headache NOS 44 46 4 4 . .
Somnolence 10 10 1 1 . .
Tremor NEC 10 10 . . . .
Psychiatric Disorders
Anxiety NEC 21 22 2 2 . .
Depression NEC 11 11 1 1 . .
Irritability 11 11 1 1 . .
Renal and Urinary Disorders
Hematuria 16 17 2 2 . .
Respiratory, Thoracic and Mediastinal Disorders
Cough 18 19 . . . .
Dyspnea NOS 12 13 4 4 2 2
Epistaxis 30 31 14 15 . .
Pleural effusion 10 10 3 3 2 2
Respiratory distress 13 14 6 6 5 5
Skin and Subcutaneous Tissue Disorders
Contusion 11 11 1 1 . .
Dermatitis NOS 39 41 7 7 . .
Dry skin 10 10 1 1 . .
Erythema NEC 17 18 . . . .
Palmar-plantar erythrodysesthesia syndrome 12 13 4 4 . .
Petechiae 28 29 7 7 . .
Pruritus NOS 45 47 1 1 . .
Vascular Disorders
Flushing 17 18 . . . .
Hypertension NOS 11 11 4 4 . .
Hypotension NOS 28 29 12 13 7 7
mg/m2/day, approximately 14% of the recommended clinical dose on a mg/m2 basis).

Ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice at 75 mg/kg/day (225 mg/m2/day, approximately 4-fold of the recommended human dose on a mg/m2 basis), the only dose administered to female mice. The effect on human fertility is unknown.

Pregnancy
Teratogenic Effects: Pregnancy Category D
See WARNINGS.

Nursing Mothers
It is not known whether clofarabine or its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for clofarabine in animal studies and the potential for serious adverse reactions, women treated with clofarabine should not nurse.

Other Special Population: Adults Safety and efficacy have not been established in adults. One study was performed in highly refractory and/or relapsed adult patients with hematologic malignancies. The Phase 2 dose of CLOLAR. was determined to be 40 mg/m2/day administered as a 1- to 2-hour IVI daily x 5 every 28 days.

ADVERSE REACTIONS
One hundred thirteen (113) pediatric patients with ALL (67) or AML (46) were exposed to CLOLAR.. Ninety-six (96) of the pediatric patients treated in clinical trials received the recommended dose of CLOLAR. 52 mg/m2 daily x 5.

The most common adverse effects after CLOLAR. treatment, regardless of causality, were gastrointestinal tract symptoms, including vomiting, nausea, and diarrhea; hematologic effects, including anemia, leukopenia, thrombocytopenia, neutropenia, and febrile neutropenia; and infection.

Table 2 lists adverse events by System Organ Class regardless of causality, including severe or life-threatening events (NCI CTC grade 3 or grade 4), reported in .10% of the 96 patients in the 52 mg/m2/day dose group. More detailed information and follow-up of certain events is given below.

Table 2: Most Commonly Reported (.10% Overall) Adverse Events by System Organ Class (N=96) for this syndrome and early intervention are recommended. The use of prophylactic steroids (e.g., 100 mg/m2 hydrocortisone on Days 1 through 3) may be of benefit in preventing signs or symptoms of SIRS or capillary leak. Physicians should be alert to early indications of this syndrome and should immediately discontinue CLOLAR. administration if they occur and provide appropriate supportive measures. After the patient is stabilized and organ function has returned to baseline, re-treatment with CLOLAR. can be considered at a lower dose.

Overdosage
There were no known overdoses of CLOLAR.. The highest daily dose administered to a human to date (on a mg/m2 basis) has been 70 mg/m2/day x 5 days (2 pediatric ALL patients). The toxicities included in these 2 patients included grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash.

DOSAGE AND ADMINISTRATION
Recommended Dose
CLOLAR. should be diluted per instructions below with 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, prior to intravenous infusion (IVI).

The recommended pediatric dose and schedule is 52 mg/m2 administered by intravenous infusion (IVI) over 2 hours daily for 5 consecutive days. Treatment cycles are repeated following recovery or return to baseline organ function, approximately every 2 to 6 weeks. The dosage is based on the patientfs body surface area (BSA), calculated using the actual height and weight before the start of each cycle. To prevent drug incompatibilities, no other medications should be administered through the same intravenous line.

CLOLAR. has not been studied in patients with hepatic or renal dysfunction. Its use in such patients should be undertaken only with the greatest caution.
Physicians are encouraged to give continuous IV fluids throughout the 5 days of CLOLAR. administration to reduce the effects of tumor lysis and other adverse events. The use of prophylactic steroids (e.g., 100 mg/m2 hydrocortisone on Days 1 through 3) may be of benefit in preventing signs or symptoms of SIRS or capillary leak (e.g., hypotension). If patients show early signs or symptoms of SIRS or capillary leak (e.g., hypotension), the physician should immediately discontinue CLOLAR. administration and provide appropriate supportive measures. Close monitoring of renal and hepatic function during the 5 days of CLOLAR. administration is advised. If substantial increases in creatinine or bilirubin are noted, physicians should immediately discontinue administration of CLOLAR.. CLOLAR. should be re-instituted when the patient is stable and organ function has returned to baseline, possibly at a lower dose. If hyperuricemia is anticipated (tumor lysis), patients should prophylactically receive allopurinol.

STORAGE AND HANDLING
Vials containing undiluted CLOLAR. should be stored at 259C (779F); excursions permitted
to 15-309C (59-869F).

CLOLAR. should be filtered through a sterile 0.2 ’Êm syringe filter and then further diluted with 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, prior to intravenous infusion (IVI). The resulting admixture may be stored at room temperature, but must be used within 24 hours of preparation.

HOW SUPPLIED
CLOLAR. is formulated at a concentration of 1 mg/mL in sodium chloride (9 mg/mL), USP, and Water for Injection, USP, quantity sufficient (qs) to 1 mL. CLOLAR. is supplied in 20 mL flint vials in a box of 4 (NDC 58468-0100-2). The 20 mL flint vials contain 20 mL (20 mg) of solution. The pH range of the solution is 4.5 to 7.5. The solution is sterile, clear and practically colorless, is preservative-free, and is free from foreign matter.
Rx only

U.S. Patents:
4,751,221; 4, 918,179; 5,384,310; 5,661,136; 6,680,382 B2.
Other patents pending.

NAME AND ADDRESS OF MANUFACTURER
Manufactured by:
AAIPharma Inc.
Charleston, SC 29405

Manufactured for:
Genzyme Corporation
4545 Horizon Hill Blvd
San Antonio, TX 78229

Distributed by:
Genzyme Corporation
500 Kendall Street
Cambridge, MA 02142
52mg/m2 (N=96)
Total Grade 3 Grade 4
N % n % n %
System Organ Class
Adverse Event1

Blood and Lymphatic System Disorders
Febrile neutropenia 55 57 51 53 3 3
Neutropenia 10 10 3 3 7 7
Transfusion reaction 10 10 3 3 . .
Cardiac Disorders
Tachycardia NOS 33 34 6 6 . .
Gastrointestinal Disorders
Abdominal pain NOS 35 36 7 7 . .
Constipation 20 21 . . . .
Diarrhea NOS 51 53 10 10 . .
Gingival bleeding 14 15 7 7 1 1
Nausea 72 75 14 15 1 1
Sore throat NOS 13 14 . . . .
Vomiting NOS 80 83 8 8 1 1
General Disorders and Administration Site Conditions
Edema NOS 19 20 1 1 2 2
Fatigue 35 36 3 3 1 1
Injection site pain 13 14 1 1 . .
Lethargy 11 11 . . . .
Mucosal inflammation NOS 17 18 3 3 . .
Pain NOS 18 19 6 6 1 1
Pyrexia 39 41 15 16 . .
Rigors 36 38 3 3 . .
Hepato-Biliary Disorders
Hepatomegaly 14 15 8 8 . .
Jaundice NOS 14 15 2 2 . .
Infections and Infestations
Bacteremia 10 10 10 10 . .
Cellulitis 11 11 9 9 . .
Herpes simplex 11 11 6 6 . .
Oral candidiasis 12 13 2 2 . .
Pneumonia NOS 10 10 5 5 2 2
Sepsis NOS 14 15 7 7 7 7
Staphylococcal infection NOS 12 13 10 10 . .
Investigations
Weight decreased 10 10 1 1 . .
Metabolism and Nutrition Disorders
Anorexia 30 31 5 5 7 7
Appetite decreased NOS 11 11 . . . .
c2005 Genzyme Corporation. All rights reserved.
Clolar is a trademark of Genzyme Corporation.
6662 (10/05)
www.clolar.com
800-RX-CLOLAR

FDA Will Grant ILEX's Clofarabine Additional Six-Month Pediatric Exclusivity; Incentive Provides Extended Patent Protection Upon Marketing Approval

SAN ANTONIO, Jul 21, 2004 - ILEX(TM) Oncology Inc. (Nasdaq:ILXO) announced today that the U.S. Food and Drug Administration (FDA) will grant six months of extended market exclusivity to clofarabine under the Best Pharmaceuticals for Children Act. Clofarabine is currently under priority review by the FDA for the treatment of refractory or relapsed acute leukemia in children. If approved by the FDA, clofarabine would be the first drug to be labeled initially for pediatric leukemia in more than a decade.

"This is an important milestone for children with cancer and for the FDA because children are usually an afterthought in oncology drug development," said Children's Cause for Advocacy President, Susan L. Weiner, Ph.D. "Hopefully this good news will set a precedent for other companies to make children with cancer a priority in their drug development plans."

The Best Pharmaceuticals for Children Act offers extended market exclusivity to drug developers as an incentive to increase therapeutic research in children.

Clofarabine was previously granted orphan drug designation for the treatment of adult and pediatric acute lymphoblastic leukemia and acute myeloid leukemia. In the United States, orphan drug status provides for seven years of market exclusivity for the orphan drug indication following the FDA's marketing approval.

About Clofarabine
Clofarabine is a next generation of the drug class purine nucleoside analogs which all inhibit DNA production necessary for cancer cell growth. Bioenvision Inc. (AMEX:BIV) sub-licensed ILEX the right to develop and market clofarabine for human cancer indications in the United States and Canada. Bioenvision is entitled to milestone payments tied to the development of the compound and is entitled to royalties on North American sales. As is its exclusive right, Bioenvision is developing clofarabine in the rest of the world. Bioenvision originally obtained clofarabine development and commercialization rights under patents held by Southern Research Institute.

About ILEX
ILEX Oncology Inc. is an oncology drug development company with a marketed product, CAMPATH(R) in the United States and MABCAMPATH(R) in the European Union, as well as a pipeline of investigational compounds focused on the treatment of cancer. ILEX maintains a core competency in oncology drug development in San Antonio, Texas. ILEX also conducts research in angiogenesis inhibition, cell signaling, medical chemistry and nuclear receptor biology at its laboratories in Boston, Mass., and Geneva, Switzerland. In February 2004, ILEX entered into an agreement and plan of merger with Genzyme(R) Corporation, a leading global biotechnology company. The merger is expected to close this summer, but remains subject to clearance by the Federal Trade Commission and other customary closing conditions. Further information about ILEX can be found on the company's Web site at www.ilexonc.com.

About Bioenvision Inc.
Bioenvision's (AMEX:BIV) primary focus is the development and distribution of compounds and technologies for the treatment of cancer. Bioenvision has a broad pipeline of products for the treatment of cancer, including: clofarabine (in co-development with ILEX Oncology Inc.); Modrenal(R) (for which Bioenvision has obtained regulatory approval for marketing in the United Kingdom for the treatment of post-menopausal breast cancer); and other products in clinical trials. Bioenvision also is developing anti-infective technologies, including the OLIGON technology, an advanced biomaterial that has been approved for certain indications by the FDA in the United States, and is being sold by a co-development partner of Bioenvision. Further information about Bioenvision can be found on the company's Web site at www.bioenvision.com.

Bioenvision's Clofarabine Receives a Positive Opinion from the European Medicines Agency; Bioenvision Prepares for Marketing Launch

23.02.2006 - Bioenvision (Nasdaq: BIVN) today announced that theEuropean Medicines Agency has adopted a positive opinion on themarketing authorization application for Evoltra(TM) (clofarabine).Evoltra(TM) is indicated for the treatment of acute lymphoblasticleukemia (ALL) in pediatric patients who have relapsed or arerefractory to at least two prior regimens.
Originally the Agency's scientific committee, the Committee forMedicinal Products for Human Use (CHMP), was expected to formallyadopt an opinion at their meeting of March 20-23, 2006. However,Bioenvision is pleased to receive this positive opinion a monthearlier than anticipated. The CHMP positive opinion must now beconverted into a Marketing Authorization by the European Commission, aprocess that is expected to take 3 months, at which time Bioenvisionwill launch Evoltra(TM) throughout Europe. Evoltra(TM) has alreadybeen granted orphan drug designation, providing marketing exclusivityfor 10 years in Europe following this Marketing Authorization.

"Evoltra(TM) is the first new drug for children with multiplerelapsed or refractory leukemia to receive a positive opinion inEurope in more than a decade. It offers a genuine hope of response anddisease free survival for this patient group," said Hugh Griffith,Bioenvision's Chief Operating Officer. Mr. Griffith continued: "Theachievement of this significant milestone enables Bioenvision tofurther build out its commercial infrastructure to ensure thesuccessful launch of Evoltra(TM) throughout Europe."

"Pediatric hematologists will be very interested by the CHMPpositive opinion on the favorable benefit to risk profile ofEvoltra(TM) in this vulnerable patient group," said Professor AndreBaruchel, Head of Pediatric Haematology Department, HopitalSaint-Louis, Paris, France. Professor Baruchel added: "achieving a 20%to 30% overall response rate, which can be durable, in children andadolescents with ALL who have relapsed or are refractory, is verypromising."

"The introduction of Evoltra(TM) into the European market is thecornerstone of Bioenvision's commercial strategic plan," commented Dr.Christopher Wood, Chairman and CEO of Bioenvision. Dr. Wood added,"this positive opinion provides a solid foundation for building theEvoltra(TM) franchise throughout Europe and the rest of the world."

Bioenvision has already begun preparation for the marketing ofEvoltra(TM) in Europe with the appointment of general managers incertain of the major European markets. Bioenvision will expand itsexisting sales and marketing team across Europe in preparation for thelaunch of Evoltra(TM). Once formally approved via the CentralizedProcedure, Evoltra(TM) can be marketed throughout all 25 member statesof the European Union which has a population of approximately 450million.

About Evoltra(TM) (clofarabine)

The CHMP have adopted a positive opinion for the use ofEvoltra(TM) (clofarabine) in "the treatment of acute lymphoblasticleukemia (ALL) in pediatric patients who have relapsed or arerefractory to at least two prior regimens and where there is no othertreatment option anticipated to result in a durable response. Safetyand efficacy have been assessed in studies of patients less than orequal to 21 years old at initial diagnosis."

Bioenvision is also developing Evoltra(TM) for the treatment ofadult acute myeloid leukemia (AML) as first-line therapy. The Companyhas completed enrollment of its Phase II clinical trial for thetreatment of adult AML in elderly patients unfit for intensivechemotherapy and expects to file a Marketing Authorization Applicationin mid-2006 for the Company's first label-extension for Evoltra(TM).

In addition, clofarabine is in clinical development for thetreatment of myelodysplastic syndrome (MDS), chronic lymphocyticleukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin's lymphoma(NHL), multiple myeloma (MM), solid tumors and as a preconditioningregimen for transplantation. Bioenvision is also conducting late-stagepreclinical development of Evoltra(TM) for the treatment of psoriasisand is planning further worldwide development of Evoltra(TM) inautoimmune diseases.

Evoltra(TM) (clofarabine) is a next generation purine nucleosideanalog. Bioenvision holds an exclusive worldwide license forclofarabine. Bioenvision granted an exclusive sublicense to Genzyme toco-develop clofarabine for cancer indications in the US and Canada.Genzyme is commercializing clofarabine for cancer indications in theUS and Canada under the brand name Clolar(R). Bioenvision holds anexclusive license in the US and Canada for all non-cancer indications.Bioenvision originally obtained clofarabine development andcommercialization rights under patents held by Southern ResearchInstitute.

Clofarabine has been granted orphan drug designation for thetreatment of both ALL and AML in the U.S. and Europe. In Europe, thedesignation provides marketing exclusivity for 10 years followingMarketing Authorization.

About Bioenvision

Bioenvision's primary focus is the development, distribution andmarketing of compounds and technologies for the treatment of cancer.Bioenvision has a broad pipeline of products for the treatment ofcancer, including: Evoltra(TM) (in co-development with GenzymeCorporation), Modrenal(R) (for which Bioenvision has obtainedregulatory approval for marketing in the United Kingdom for thetreatment of post-menopausal breast cancer following relapse toinitial hormone therapy), and other products. Bioenvision is alsodeveloping anti-infective technologies, including the OLIGON(R)technology, an advanced biomaterial that has been incorporated intovarious FDA approved medical devices. For more information onBioenvision please visit our Web site at www.bioenvision.com.

Certain statements contained herein are "forward-looking"statements (as such term is defined in the Private SecuritiesLitigation Reform Act of 1995). Because these statements include risksand uncertainties, actual results may differ materially from thoseexpressed or implied by such forward-looking statements. Specifically,factors that could cause actual results to differ materially fromthose expressed or implied by such forward-looking statements include,but are not limited to: risks associated with preclinical and clinicaldevelopments in the biopharmaceutical industry in general and inBioenvision's compounds under development in particular; the potentialfailure of Bioenvision's compounds under development to prove safe andeffective for treatment of disease; uncertainties inherent in theearly stage of Bioenvision's compounds under development; failure tosuccessfully implement or complete clinical trials; failure to receivemarketing clearance from regulatory agencies for our compounds underdevelopment; acquisitions, divestitures, mergers, licenses orstrategic initiatives that change Bioenvision's business, structure orprojections; the development of competing products; uncertaintiesrelated to Bioenvision's dependence on third parties and partners; andthose risks described in Bioenvision's filings with the SEC.Bioenvision disclaims any obligation to update these forward-lookingstatements.

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