Clolar for Intravenous Infusion (Genzyme)

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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 clear and practically colorless, and free from foreign matter.

The chemical structure of clofarabine is 2-chloro-9-(2-deoxy-2-fluoro-(beta)-D-arabinofuranosyl)-9H-purin-6-amine. The molecular formula of clofarabine is C ₁₀ H ₁₁ ClFN ₅ O ₃ 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-phosphokinases 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/m ² 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 non-compartmental analysis, systemic clearance and volume of distribution at steady-state were estimated to be 28.8 L/h/m ² and 172 L/m ² , 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 excreted in 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/m ² daily × 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/m ² /day IVI daily × 5 and escalated to 70 mg/m ² /day IVI daily × 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/m ² daily × 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/m ² . As a result of this study, the recommended dose for subsequent study in pediatric patients was determined to be 52 mg/m ² /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/m ² daily × 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 × 10 ⁹ /L and absolute neutrophil count (ANC) > 1.0 × 10 ⁹ /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 × 10 ⁹ /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.

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/m ² /day (approximately equivalent to the recommended clinical dose on a mg/m ² basis), and in rabbits receiving 12 mg/m ² /day (approximately 23% of the recommended clinical dose on a mg/m ² 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, 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.

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/m ² /day, approximately 17% of the recommended clinical dose on a mg/m ² basis). The testes of rats receiving 25 mg/kg/day (150 mg/m ² /day, approximately 3 times the recommended clinical dose on a mg/m ² 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 mg/m ² /day, approximately 14% of the recommended clinical dose on a mg/m ² basis). Ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice at 75 mg/kg/day (225 mg/m ² /day, approximately 4-fold of the recommended human dose on a mg/m ² 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/m ² /day administered as a 1- to 2-hour IVI daily × 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/m ² daily × 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/m ² /day dose group. More detailed information and follow-up of certain events is given below.

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 follow-up 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 for this syndrome and early intervention are recommended. The use of prophylactic steroids (e.g., 100 mg/m ² 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/m ² basis) has been 70 mg/m ² /day × 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/m ² 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 patient's 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/m ² 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 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

CLOLAR™ should be filtered through a sterile 0.2 µm 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 1mL. 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 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:

AAI Development Services

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

www.clolar.com

800-RX-CLOLAR

Genzyme

Oncology

©2005 Genzyme Corporation. All rights reserved.

Clolar is a trademark of Genzyme Corporation.

CLO/US/P001/0405

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