CLOLAR- clofarabine injection
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CLOLAR safely and effectively. See full prescribing information for CLOLAR.
Clolar® (clofarabine) Injection for intravenous use
Initial U.S. Approval: 2004
INDICATIONS AND USAGE
Clolar (clofarabine) injection is a purine nucleoside metabolic inhibitor 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 indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Clolar. (1)
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
WARNINGS AND PRECAUTIONS
Most common adverse reactions (≥ 10%): nausea, vomiting, diarrhea, febrile neutropenia, headache, rash, pruritus, pyrexia, fatigue, palmar-plantar erythrodysesthesia syndrome, anxiety, flushing, and mucosal inflammation. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-800-RX-CLOLAR or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION.
FULL PRESCRIBING INFORMATION: CONTENTS*
Clolar® (clofarabine) Injection 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 indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Clolar.
Administer the recommended pediatric dose of 52 mg/m2 as an intravenous infusion over 2 hours daily for 5 consecutive days.
Clolar should be filtered through a sterile 0.2 micron syringe filter and then diluted with 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, prior to intravenous (IV) infusion to a final concentration between 0.15 mg/mL and 0.4 mg/mL. Use within 24 hours of preparation. Store diluted Clolar at room temperature (15–30ºC).
Clolar can cause fetal harm when administered to a pregnant woman. Intravenous doses of clofarabine in rats and rabbits administered during organogenesis caused an increase in resorptions, malformations, and variations [see Use in Specific Populations (8.1)].
The following adverse reactions are discussed in greater detail in other sections of the label:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to Clolar in 115 pediatric patients with relapsed or refractory Acute Lymphoblastic Leukemia (ALL) (70 patients) or Acute Myelogenous Leukemia (AML) (45 patients).
In total, 115 pediatric patients treated in clinical trials received the recommended dose of Clolar 52 mg/m2 daily × 5. The median number of cycles was 2. The median cumulative amount of Clolar received by pediatric patients during all cycles was 540 mg.
The most common adverse reactions occurring in 10% or more of patients treated with Clolar are: nausea, vomiting, diarrhea, febrile neutropenia, headache, rash, pruritus, pyrexia, fatigue, palmar-plantar erythrodysesthesia syndrome, anxiety, flushing, and mucosal inflammation.
Table 1 lists adverse reactions by System Organ Class, including severe or life-threatening (NCI CTC Grade 3 or Grade 4), reported in ≥ 5% of the 115 patients in the 52 mg/m2/day dose group (pooled analysis of pediatric patients with ALL and AML). More detailed information and follow-up of certain events is given below.
|Worst NCI Common Terminology Criteria Grade*|
|System Organ Class*||Preferred Term*||N||%||N||%||N||%||N||%|
|Blood and Lymphatic System Disorders||Febrile neutropenia||63||54.8||59||51.3||3||2.6||.||.|
|Cardiac Disorders||Pericardial effusion||9||7.8||.||.||1||0.9||.||.|
|Gastrointestinal Disorders||Abdominal pain||40||34.8||8||7.0||.||.||.||.|
|Abdominal pain upper||9||7.8||1||0.9||.||.||.||.|
|Gingival or mouth bleeding||20||17.4||8||7.0||1||0.9||.||.|
|Oral mucosal petechiae||6||5.2||4||3.5||.||.||.||.|
|General Disorders and Administration Site Conditions||Asthenia||12||10.4||1||0.9||1||0.9||.||.|
|Infections and Infestations||Bacteremia||10||8.7||10||8.7||.||.||.||.|
|Catheter related infection||14||12.2||13||11.3||.||.||.||.|
|Sepsis, including septic shock||19||16.5||6||5.2||4||3.5||9||7.8|
|Upper respiratory tract infection||6||5.2||1||0.9||.||.||.||.|
|Metabolism and Nutrition Disorders||Anorexia||34||29.6||6||5.2||8||7.0||.||.|
|Musculoskeletal and Connective Tissue Disorders||Arthralgia||10||8.7||3||2.6||.||.||.||.|
|Pain in extremity||34||29.6||6||5.2||.||.||.||.|
|Neoplasms Benign, Malignant and Unspecified (incl. cysts and polyps)||Tumor lysis syndrome||7||6.1||7||6.1||.||.||.||.|
|Nervous System Disorders||Headache||49||42.6||6||5.2||.||.||.||.|
|Renal and Urinary Disorders||Hematuria||15||13.0||2||1.7||.||.||.||.|
|Respiratory, Thoracic and Mediastinal Disorders||Dyspnea||15||13.0||6||5.2||2||1.7||.||.|
|Skin and Subcutaneous Tissue Disorders||Erythema||13||11.3||.||.||.||.||.||.|
|Palmar-plantar erythrodysesthesia syndrome||18||15.7||8||7.0||.||.||.||.|
The following less common adverse reactions have been reported in 1–4% of the 115 pediatric patients with ALL or AML:
Gastrointestinal Disorders: cecitis, pancreatitis
Hepatobiliary Disorders: hyperbilirubinemia
Immune System Disorders: hypersensitivity
Infections and Infestations: bacterial infection, Enterococcal bacteremia, Escherichia bacteremia, Escherichia sepsis, fungal infection, fungal sepsis, gastroenteritis adenovirus, infection, influenza, parainfluenza virus infection, pneumonia fungal, pneumonia primary atypical, Respiratory syncytial virus infection, sinusitis, staphylococcal infection
Investigations: blood creatinine increased
Psychiatric Disorders: mental status change
Respiratory, Thoracic and Mediastinal Disorder: pulmonary edema
Table 2 lists the incidence of treatment-emergent laboratory abnormalities after Clolar administration at 52 mg/m2 among pediatric patients with ALL and AML (N=115).
|Parameter||Any Grade||Grade 3 or higher|
|Anemia (N=114)||95 (83.3%)||86 (75.4%)|
|Leukopenia (N=114)||100 (87.7%)||100 (87.7%)|
|Lymphopenia (N=113)||93 (82.3%)||93 (82.3%)|
|Neutropenia (N=113)||72 (63.7%)||72 (63.7%)|
|Thrombocytopenia (N=114)||92 (80.7%)||91 (79.8%)|
|Elevated Creatinine (N=115)||57 (49.5%)||9 (7.8%)|
|Elevated SGOT (N=100)||74 (74.0%)||36 (36.0%)|
|Elevated SGPT (N=113)||91 (80.5%)||49 (43.4%)|
|Elevated Total Bilirubin (N=114)||51 (44.7%)||15 (13.2%)|
The following adverse reactions have been identified during post-approval use of Clolar. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) reported frequency of the reaction, or (3) strength of causal connection to Clolar.
No in-vivo drug interaction studies have been conducted [see Clinical Pharmacology (12.3)].
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. All patients should be advised to use effective contraceptive measures to prevent pregnancy.
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. Female patients should be advised to avoid breast-feeding during treatment with Clolar.
Safety and effectiveness have been established in pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia.
Safety and effectiveness of Clolar has not been established in geriatric patients aged 65 and older.
Safety and effectiveness have not been established in adults.
Reduce the Clolar starting dose by 50% in patients with CrCL of 30 to 60 mL/min. There is insufficient information to make a dosage recommendation in patients with CrCL less than 30 mL/min or in patients on dialysis.
The pharmacokinetics of clofarabine in patients with renal impairment and normal renal function were obtained from a population pharmacokinetic analysis of three pediatric and two adult studies. In patients with CrCL 60 to less than 90 mL/min (N = 47) and CrCL 30 to less than 60 mL/min (N = 30), the average AUC of clofarabine increased by 60% and 140%, respectively, compared to patients with normal (N = 66) renal function (CrCL greater than 90 mL/min).
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 × 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.
In a Phase 1 study of adults with refractory and/or relapsed hematologic malignancies, the recommended pediatric dose of 52 mg/m2/day was not tolerated.
Clolar (clofarabine) Injection contains clofarabine, a purine nucleoside metabolic inhibitor. 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 is preservative-free.
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 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.
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 non-compartmental analysis, systemic clearance and volume of distribution at steady-state were 28.8 L/h/m2 and 172 L/m2, respectively. The terminal half-life was 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%). The pathways of non-hepatic elimination remain unknown.
In vitro studies suggested that clofarabine undergoes limited metabolism and does not inhibit or induce major CYP enzymes. CYP inhibitors and inducers are unlikely to affect the metabolism of clofarabine. Clofarabine is unlikely to affect the metabolism of CYP substrates. However, no in vivo drug interaction studies have been conducted.
An in vitro transporter study suggested that clofarabine is a substrate of human transporters OAT1, OAT3, and OCT1. A preclinical study using perfused rat kidney demonstrated that the renal excretion of clofarabine was decreased by cimetidine, an inhibitor of the hOCT2. Although the clinical implications of this finding have not been determined, signs of Clolar toxicity should be monitored when administered with other hOAT1, hOAT3, hOCT1 and hOCT2 substrates or inhibitors.
Clofarabine has not been tested for carcinogenic potential.
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).
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 clinical recommended 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 mg/m2/day, approximately 14% of the clinical recommended 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 recommended human dose on a mg/m2 basis), the only dose administered to female mice. The effect on human fertility is unknown.
Seventy-eight (78) pediatric patients with ALL were exposed to Clolar. Seventy (70) of the patients received the recommended pediatric dose of Clolar 52 mg/m2 daily for 5 days as an intravenous (IV) infusion.
Dose Escalation Study in Pediatric Patients with Hematologic Malignancies
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 IV infusion daily × 5 and escalated to 70 mg/m2/day IV infusion 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/m2 daily for 5 days. In the 17 ALL patients there were 2 complete remissions (12%) and 2 partial remissions (12%) 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
Clolar was evaluated in an open-label, single-arm study of 61 pediatric patients with relapsed/refractory ALL. Patients received a dose of 52 mg/m2 over 2 hours for 5 consecutive days repeated every 2 to 6 weeks for up to 12 cycles. There was no dose escalation in this study.
All patients had disease that had relapsed after and/or was refractory to two or more prior therapies. Most patients, 38/61 (62%), had received > 2 prior regimens and 18/61 (30%) of the patients had undergone at least 1 prior transplant. The median age of the treated patients was 12 years, 61% were male, 39% were female, 44% were Caucasian, 38% were Hispanic, 12% were African-American, 2% were Asian and 5% were Other race.
The overall remission (OR) rate (Complete Remission [CR] + CR in the absence of total platelet recovery [CRp]) was evaluated. CR was defined as no evidence of circulating blasts or extramedullary disease, an M1 bone marrow (≤ 5% blasts), and recovery of peripheral counts [platelets ≥ 100 × 109/L and absolute neutrophil count (ANC) ≥ 1.0 × 109/L]. CRp was defined as meeting all criteria for CR except for recovery of platelet counts to ≥ 100 × 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 marrow that did not qualify for CR or CRp. Duration of remission was also evaluated. Transplantation rate was not a study endpoint.
Response rates for these studies were determined by an unblinded Independent Response Review Panel (IRRP).
Table 3 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 530 mg (range 29–2815 mg) in 1 (41%), 2 (44%) or 3 or more (15%) cycles. The median number of cycles was 2 (range 1–12). The median time between cycles was 28 days with a range of 12 to 55 days.
|N = 61|
|CR = Complete response|
|CRp = Complete response without platelet recovery|
|CR % [95% CI]||11.5 (4.7, 22.2)|
|CRp % [95% CI]||8.2 (2.7, 18.1)|
|Median Duration of CR plus CRp (range in weeks)*||10.7 (4.3 to 58.6)|
Six (9.8%) patients achieved a PR; the clinical relevance of a PR in this setting is unknown.
Of 35 patients who were refractory to their immediately preceding induction regimen, 6 (17%) achieved a CR or CRp. Of 18 patients who had at least 1 prior hematopoietic stem cell transplant (HSCT), 5 (28%) achieved a CR or CRp.
Among the 12 patients who achieved at least a CRp, 6 patients achieved the best response after 1 cycle of clofarabine, 5 patients required 2 courses and 1 patient achieved a CR after 3 cycles of therapy.
Clolar (clofarabine) Injection is supplied in single-use flint vials containing 20 mg of clofarabine in 20 mL of solution. Each box contains one Clolar vial (NDC 58468-0100-1) or four Clolar vials (NDC 58468-0100-2). The 20mL flint vials contain 20 mL (20 mg) of solution. The pH range of the solution is 4.5 to 7.5.
Vials containing undiluted Clolar should be stored at 25°C (77°F); excursions permitted to 15 – 30°C (59 – 86°F).
Diluted admixtures may be stored at room temperature, but must be used within 24 hours of preparation.
Procedures for proper handling and disposal should be utilized. Handling and disposal of Clolar should conform to guidelines issued for cytotoxic drugs. Several guidelines on this subject have been published. 1
Hematologic Toxicity: Advise patients to return for regular blood counts and to report any symptoms associated with hematologic toxicity (such as weakness, fatigue, pallor, shortness of breath, easy bruising, petechiae, purpura, fever) to their physician [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
Hepatic and Renal Toxicity: Advise patients to avoid medications including over the counter and herbal medications, which may be hepatotoxic or nephrotoxic, during the 5 days of Clolar administration. Also, advise patients of the possibility of developing liver function abnormalities and to immediately report signs or symptoms of jaundice [see Warnings and Precautions (5.6) (5.7)].
Systemic Inflammatory Response Syndrome (SIRS)/Capillary Leak Syndrome: Advise patients of the signs or symptoms of SIRS, such as fever, tachycardia, tachypnea, dyspnea and symptoms suggestive of hypotension [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].
Pregnancy and Breast-feeding: Advise male and female patients with reproductive potential to use effective contraceptive measures to prevent pregnancy [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)]. Advise female patients to avoid breast- feeding during Clolar treatment [see Use in Specific Populations (8.3)].
Gastrointestinal Disorders: Advise patients that they may experience nausea,vomiting, and/or diarrhea with Clolar. If these symptoms are significant, they should seek medical attention.
Haarlem, The Netherlands
500 Kendall Street
Cambridge, MA 02142
500 Kendall Street
Cambridge, MA 02142
©2013 Genzyme Corporation. All rights reserved.
Clolar is a registered trademark of Genzyme Corporation.
Package Label - Principal Display Panel – 1 (20 mL) Single-Use Vial
Clolar® clofarabine injection
MUST BE DILUTED PRIOR TO IV USE
Contains 1 (20 mL) Single-Use Vial
Each single-use 20 mL vial contains 20 mg clofarabine dissolved in 20 mL of sodium chloride injection, USP 0.9%, pH 4.5-7.5. Contains no preservatives. Sterile.
|Labeler - Genzyme Corporation (025322157)|
|Ash Stevens Inc.||051630135||API MANUFACTURE(58468-0100)|
|AAIPharma Services||832395235||LABEL(58468-0100), PACK(58468-0100)|
|Ferro Pfanstiehl Laboratories, Inc.||005203476||API MANUFACTURE(58468-0100)|
|Pharmichem Testing Services, Inc.||048531727||ANALYSIS(58468-0100)|