Clolar

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Clolar uses


1. INDICATIONS AND USAGE

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.

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)

2. DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

Administer the recommended pediatric dose of 52 mg/m2 as an intravenous infusion over 2 hours daily for 5 consecutive days.

2.2 Supportive Medications and Medications to Avoid

2.3 Dose Modifications and Reinitiation of Therapy

2.4 Reconstitution/Preparation

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 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).

2.5 Incompatibilities

Do not administer any other medications through the same intravenous line.

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3. DOSAGE FORMS AND STRENGTHS

20 mg/20 mL (1 mg/mL) single-use vial

4. CONTRAINDICATIONS

None

5. WARNINGS AND PRECAUTIONS

5.1 Hematologic Toxicity

Clolar causes myelosuppression which may be severe and prolonged. Febrile neutropenia occurred in 55% and non-febrile neutropenia in an additional 10% of pediatric patients in clinical trials. At initiation of treatment, most patients in the clinical studies had hematological impairment as a manifestation of leukemia. Myelosuppression is usually reversible with interruption of Clolar treatment and appears to be dose-dependent. Monitor complete blood counts and platelet counts daily during the 5 days of Clolar administration, then 1–2 times weekly or as clinically indicated [see Dosage and Administration (2.3) ].

5.2 Infections

Clolar increases the risk of infection, including severe and fatal sepsis, and opportunistic infections. At baseline, 48% of the pediatric patients had one or more concurrent infections. A total of 83% of patients experienced at least one infection after Clolar treatment, including fungal, viral and bacterial infections. Monitor patients for signs and symptoms of infection, discontinue Clolar, and treat promptly.

5.3 Hyperuricemia

Administration of Clolar may result in tumor lysis syndrome associated with the break-down metabolic products from peripheral leukemia cell death. Monitor patients undergoing treatment for signs and symptoms of tumor lysis syndrome and initiate preventive measures including adequate intravenous fluids and measures to control uric acid.

5.4 Systemic Inflammatory Response Syndrome and Capillary Leak Syndrome

Clolar may cause a cytokine release syndrome (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that may progress to the systemic inflammatory response syndrome (SIRS) with capillary leak syndrome and organ impairment which may be fatal. Monitor patients frequently for these conditions. In clinical trials, SIRS was reported in two patients (2%); capillary leak syndrome was reported in four patients (4%). Symptoms included rapid onset of respiratory distress, hypotension, pleural and pericardial effusion, and multi-organ failure. Close monitoring for this syndrome and early intervention may reduce the risk. Immediately discontinue Clolar and provide appropriate supportive measures. 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. Consider use of diuretics and/or albumin. After the patient is stabilized and organ function has returned to baseline, re-treatment with Clolar can be considered with a 25% dose reduction.

5.5 Venous Occlusive Disease of the Liver

Patients who have previously received a hematopoietic stem cell transplant are at higher risk for veno-occlusive disease (VOD) of the liver following treatment with Clolar (40 mg/m2) when used in combination with etoposide (100 mg/m2) and cyclophosphamide (440 mg/m2). Severe hepatotoxic events have been reported in a combination study of Clolar in pediatric patients with relapsed or refractory acute leukemia. Two cases (2%) of VOD in the mono-therapy studies were considered related to study drug. Monitor for and discontinue Clolar if VOD is suspected.

5.6 Hepatotoxicity

Severe and fatal hepatotoxicity has occurred with the use of Clolar. In clinical studies, Grade 3–4 liver enzyme elevations were observed in pediatric patients during treatment with Clolar at the following rates: elevated aspartate aminotransferase (AST) occurred in 36% of patients; elevated alanine aminotransferase (ALT) occurred in 44% of patients. AST and ALT elevations typically occurred within 10 days of Clolar administration and returned to Grade 2 or less within 15 days. Grade 3 or 4 elevated bilirubin occurred in 13% of patients, with 2 events reported as Grade 4 hyperbilirubinemia (2%), one of which resulted in treatment discontinuation and one patient had multi-organ failure and died. Eight patients (7%) had Grade 3 or 4 elevations in serum bilirubin at the last time point measured; these patients died due to sepsis and/or multi-organ failure. Monitor hepatic function and discontinue Clolar for Grade 3 or greater liver enzyme elevations [see Adverse Reactions (6.1) ].

5.7 Renal Toxicity

In clinical studies, Grade 3 or 4 elevated creatinine occurred in 8% of patients; acute renal failure was reported as Grade 3 in three patients and Grade 4 in two patients (2%). Hematuria was observed in 13% of patients overall. Monitor patients for renal toxicity and interrupt or discontinue Clolar as necessary.

5.8 Embryo-fetal Toxicity

Clolar can cause fetal harm when administered to a pregnant woman. Intravenous doses of Clolar in rats and rabbits administered during organogenesis caused an increase in resorptions, malformations, and variations [see Use in Specific Populations (8.1) ].

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6. ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:


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.

6.1 Clinical Trials Experience

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 GradePatients with more than one preferred term within a SOC are counted only once in the SOC totals. Patients with more than one occurrence of the same preferred term are counted only once within that term and at the highest severity grade.
ALL/AML (N=115) 3 4 5
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 . .
Neutropenia 11 9.6 3 2.6 8 7.0 . .
Cardiac Disorders Pericardial effusion 9 7.8 . . 1 0.9 . .
Tachycardia 40 34.8 6 5.2 . . . .
Gastrointestinal Disorders Abdominal pain 40 34.8 8 7.0 . . . .
Abdominal pain upper 9 7.8 1 0.9 . . . .
Diarrhea 64 55.7 14 12.2 . . . .
Gingival or mouth bleeding 20 17.4 8 7.0 1 0.9 . .
Nausea 84 73.0 16 13.9 1 0.9 . .
Oral mucosal petechiae 6 5.2 4 3.5 . . . .
Proctalgia 9 7.8 2 1.7 . . . .
Stomatitis 8 7.0 1 0.9 . . . .
Vomiting 90 78.3 9 7.8 1 0.9 . .
General Disorders and Administration Site Conditions Asthenia 12 10.4 1 0.9 1 0.9 . .
Chills 39 33.9 3 2.6 . . . .
Fatigue 39 33.9 3 2.6 2 1.7 . .
Irritability 11 9.6 1 0.9 . . . .
Mucosal inflammation 18 15.7 2 1.7 . . . .
Edema 14 12.2 2 1.7 . . . .
Pain 17 14.8 7 6.1 1 0.9 . .
Pyrexia 45 39.1 16 13.9 . . . .
Hepatobiliary Disorder Jaundice 9 7.8 2 1.7 . . . .
Infections and Infestations Bacteremia 10 8.7 10 8.7 . . . .
Candidiasis 8 7.0 1 0.9 . . . .
Catheter related infection 14 12.2 13 11.3 . . . .
Cellulitis 9 7.8 7 6.1 . . . .
Clostridium colitis 8 7.0 6 5.2 . . . .
Herpes simplex 11 9.6 6 5.2 . . . .
Herpes zoster 8 7.0 6 5.2 . . . .
Oral candidiasis 13 11.3 2 1.7 . . . .
Pneumonia 11 9.6 6 5.2 1 0.9 1 0.9
Sepsis, including septic shock 19 16.5 6 5.2 4 3.5 9 7.8
Staphylococcal bacteremia 7 6.1 5 4.4 1 0.9 . .
Staphylococcal sepsis 6 5.2 5 4.4 1 0.9 . .
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 . . . .
Back pain 12 10.4 3 2.6 . . . .
Bone pain 11 9.6 3 2.6 . . . .
Myalgia 16 13.9 . . . . . .
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 . . . .
Lethargy 12 10.4 1 0.9 . . . .
Somnolence 11 9.6 1 0.9 . . . .
Psychiatric Disorders Agitation 6 5.2 1 0.9 . . . .
Anxiety 24 20.9 2 1.7 . . . .
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 . .
Epistaxis 31 27.0 15 13.0 . . . .
Pleural effusion 14 12.2 4 3.5 2 1.7 . .
Respiratory distress 12 10.4 5 4.4 4 3.5 1 0.9
Tachypnea 10 8.7 4 3.5 1 0.9 . .
Skin and Subcutaneous Tissue Disorders Erythema 13 11.3 . . . . . .
Palmar-plantar erythrodysesthesia syndrome 18 15.7 8 7.0 . . . .
Petechiae 30 26.1 7 6.1 . . . .
Pruritus 49 42.6 1 0.9 . . . .
Rash 44 38.3 8 7.0 . . . .
Rash pruritic 9 7.8 . . . . . .
Vascular Disorders Flushing 22 19.1 . . . . . .
Hypertension 15 13.0 6 5.2 . . . .
Hypotension 33 28.7 13 11.3 9 7.8 . .

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%)

6.2 Post-marketing Experience

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.

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7. DRUG INTERACTIONS

No in-vivo drug interaction studies have been conducted [see Clinical Pharmacology (12.3) ].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D

Clolar (clofarabine) may cause fetal harm when administered to a pregnant woman.

Clolar 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 Clolar. 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 Clolar. All patients should be advised to use effective contraceptive measures to prevent pregnancy.

8.3 Nursing Mothers

It is not known whether Clolar or its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for Clolar in animal studies and the potential for serious adverse reactions, women treated with Clolar should not nurse. Female patients should be advised to avoid breast-feeding during treatment with Clolar.

8.4 Pediatric Use

Safety and effectiveness have been established in pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia.

8.5 Geriatric Use

Safety and effectiveness of Clolar has not been established in geriatric patients aged 65 and older.

8.6 Adults with Hematologic Malignancies

Safety and effectiveness have not been established in adults.

8.7 Renal Impairment

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 Clolar 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 and CrCL 30 to less than 60 mL/min (N = 30), the average AUC of Clolar increased by 60% and 140%, respectively, compared to patients with normal (N = 66) renal function (CrCL greater than 90 mL/min).

8.8 Hepatic Impairment

Clolar has not been studied in patients with hepatic impairment.

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10. 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 × 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.

11. DESCRIPTION

Clolar (clofarabine) Injection contains Clolar, 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 Clolar 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.

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Clolar is sequentially metabolized intracellularly to the 5'-monophosphate metabolite by deoxycytidine kinase and mono- and di-phospho-kinases to the active 5'-triphosphate metabolite. Clolar has affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine. Clolar 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 Clolar triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, Clolar has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clolar 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.

Clolar is cytotoxic to rapidly proliferating and quiescent cancer cell types in vitro.

12.3 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). Clolar 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 Clolar or Clolar 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.

Drug-Drug Interactions

In vitro studies suggested that Clolar undergoes limited metabolism and does not inhibit or induce major CYP enzymes. CYP inhibitors and inducers are unlikely to affect the metabolism of Clolar. Clolar 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 Clolar is a substrate of human transporters OAT1, OAT3, and OCT1. A preclinical study using perfused rat kidney demonstrated that the renal excretion of Clolar 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.

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Clolar has not been tested for carcinogenic potential.

Clolar 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.

14. CLINICAL STUDIES

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)Does not include 4 patients who were transplanted (duration of response, including response after transplant, in these 4 patients was 28.6 to 107.7 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 Clolar, 5 patients required 2 courses and 1 patient achieved a CR after 3 cycles of therapy.

15. REFERENCES

16. HOW SUPPLIED/STORAGE AND HANDLING

Clolar (clofarabine) Injection is supplied in single-use flint vials containing 20 mg of Clolar 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

17. PATIENT COUNSELING INFORMATION

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) ].

Infection: Advise patients of the signs or symptoms of infection (e.g., fever) and report to the physician immediately if any occur [see Warnings and Precautions (5.2) 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.

Rash: Advise patients that they may experience skin rash with Clolar. If this symptom is significant, they should seek medical attention.

Manufactured by:

Teva Pharmachemie

Swensweg 5

Haarlem, The Netherlands

Manufactured for:

Genzyme Corporation

500 Kendall Street

Cambridge, MA 02142

Distributed by:

Genzyme Corporation

500 Kendall Street

Cambridge, MA 02142

www.clolar.com

©2013 Genzyme Corporation. All rights reserved.

Clolar is a registered trademark of Genzyme Corporation.

8036 (mm/yy)

Package Label - Principal Display Panel – 1 (20 mL) Single-Use Vial


NDC 58468-0100-1

Clolar® Clolar injection

MUST BE DILUTED PRIOR TO IV USE

Contains 1 (20 mL) Single-Use Vial

Each single-use 20 mL vial contains 20 mg Clolar dissolved in 20 mL of sodium chloride injection, USP 0.9%, pH 4.5-7.5. Contains no preservatives. Sterile.

Rx only

Genzyme Oncology

Clolar pharmaceutical active ingredients containing related brand and generic drugs:

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Clolar available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
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Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Clolar destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Clolar Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Clolar pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."CLOLAR (CLOFARABINE) INJECTION [GENZYME CORPORATION]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."CLOFARABINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "Clofarabine". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Clolar?

Depending on the reaction of the Clolar after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Clolar not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Clolar addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Clolar, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Clolar consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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