CLOLAR- clofarabine_injection

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/m 2 2 2 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% to 60% of the dose is excreted in the urine unchanged. In vitro Clofarabine has not been studied in patients with hepatic impairment. Drug-Drug Interactions In vitro in vivo An in vitro.

Clolar registered Clolar is a 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.

Administer the recommended pediatric dose of 52 mg/m 2 2. 1 Provide supportive care, such as intravenous infusion fluids, antihyperuricemic treatment, and alkalinization of urine throughout the 5 days of Clolar administration to reduce the risk of tumor lysis and other adverse reactions. 1 Discontinue Clolar if hypotension develops during the 5 days of administration. 1 Reduce the dose in patients with renal impairment. 2 Use dose modification for toxicity. 4 Administer the recommended pediatric dose of 52 mg/m 2 Repeat treatment cycles following recovery or return to baseline organ function, approximately every 2 to 6 weeks. Base dosage 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, do not administer other medications through the same intravenous line. Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle and provided the patient's ANC is >=0. 75 × 10 9 Provide supportive care, such as intravenous fluids, antihyperuricemic treatment, and alkalinize urine throughout the 5 days of Clolar administration to reduce the effects of tumor lysis and other adverse reactions. Discontinue Clolar if hypotension develops during the 5 days of administration. Monitor renal and hepatic function during the 5 days of Clolar administration [see Warnings and Precautions (5. 8) Monitor patients taking medications known to affect blood pressure. Monitor cardiac function during administration of Clolar. Reduce the dose by 50% in patients with creatinine clearance (CrCL) between 30 and 60 mL/min. There is insufficient information to make a dosage recommendation in patients with CrCL less than 30 mL/min [see Use in Specific Populations (8. 6) Consider prophylactic antiemetic medications as Clolar is moderately emetogenic. Consider the use of prophylactic steroids to mitigate Systemic Inflammatory Response Syndrome (SIRS) or capillary leak syndrome (e. , hypotension, tachycardia, tachypnea, and pulmonary edema). Minimize exposure to drugs with known renal toxicity during the 5 days of Clolar administration since the risk of renal toxicity may be increased. Avoid concomitant use of medications known to induce hepatic toxicity. Hematologic Toxicity If a patient experiences a Grade 4 neutropenia (ANC <0. 5 × 10 9 Non-hematologic Toxicity Withhold Clolar if a patient develops a clinically significant infection, until the infection is controlled, then restart at the full dose. Withhold Clolar for a Grade 3 non-infectious non-hematologic toxicity (excluding transient elevations in serum transaminases and/or serum bilirubin and/or nausea/vomiting controlled by antiemetic therapy). Re-institute Clolar administration at a 25% dose reduction when resolution or return to baseline. Discontinue Clolar administration for a Grade 4 non-infectious non-hematologic toxicity. Discontinue Clolar administration if a patient shows early signs or symptoms of SIRS or capillary leak syndrome (e. , hypotension, tachycardia, tachypnea, and pulmonary edema) occur and provide appropriate supportive measures. Discontinue Clolar administration if Grade 3 or higher increases in creatinine or bilirubin are noted. Re-institute Clolar with a 25% dose reduction, when the patient is stable and organ function has returned to baseline. If hyperuricemia is anticipated (tumor lysis), initiate measures to control uric acid. Filter Clolar through a sterile 0. 2 micron syringe filter and then dilute 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. Use within 24 hours of preparation. Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit. Store diluted Clolar at room temperature (15°C to 30°C). Discard unused portion in vial.

The following clinically significant adverse reactions are discussed in greater detail in other sections of the label: Myelosuppression [see Warnings and Precautions (5. 1) Hemorrhage [see Warnings and Precautions (5. 2) Serious Infections [see Warnings and Precautions (5. 3) Hyperuricemia (tumor lysis syndrome) [see Warnings and Precautions (5. 4) Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome [see Warnings and Precautions (5. 5) Venous Occlusive Disease of the Liver [see Warnings and Precautions (5. 6) Hepatotoxicity [see Warnings and Precautions (5. 7) Renal Toxicity [see Warnings and Precautions (5. 8) Enterocolitis [see Warnings and Precautions (5. 9) Skin Reactions [see Warnings and Precautions (5. 10) Most common adverse reactions (>=25%): vomiting, nausea, diarrhea, febrile neutropenia, pruritus, headache, bacteremia, pyrexia, rash, tachycardia, abdominal pain, chills, fatigue, anorexia, pain in extremity, hypotension, epistaxis, and petechiae. ( 6 To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-800-RX-CLOLAR or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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/m 2 Most common adverse reactions (>=25%): vomiting, nausea, diarrhea, febrile neutropenia, pruritus, headache, bacteremia, pyrexia, rash, tachycardia, abdominal pain, chills, fatigue, anorexia, pain in extremity, hypotension, epistaxis, and petechiae. Table 1 lists adverse reactions by System Organ Class, including severe or life-threatening (NCI CTCAE Grade 3 or Grade 4), reported in >=5% of the 115 patients in the 52 mg/m 2 Table 1: Most Commonly Reported (>=5% Overall) Adverse Reactions by System Organ Class (N=115 pooled analysis) System Organ Class Patients with more than one adverse reaction (MedDRA preferred term ) Adverse Reaction ALL/AML Worst Grade 3 4 5 N % N % N % N % Blood and Lymphatic System Disorders Febrile neutropenia 63 55 59 51 3 3. Neutropenia 11 10 3 3 8 7. Cardiac Disorders Pericardial effusion 9 8. Tachycardia 40 35 6 5. Gastrointestinal Disorders Abdominal pain 40 35 8 7. Abdominal pain upper 9 8 1 1. Diarrhea 64 56 14 12. Gingival or mouth bleeding 20 17 8 7 1 1. Nausea 84 73 16 14 1 1. Oral mucosal petechiae 6 5 4 4. Proctalgia 9 8 2 2. Stomatitis 8 7 1 1. Vomiting 90 78 9 8 1 1. General Disorders and Administration Site Conditions Asthenia 12 10 1 1 1 1. Chills 39 34 3 3. Fatigue 39 34 3 3 2 2. Irritability 11 10 1 1. Mucosal inflammation 18 16 2 2. Edema 14 12 2 2. Pain 17 15 7 6 1 1. Pyrexia 45 39 16 14. Hepatobiliary Disorder Jaundice 9 8 2 2. Infections and Infestations Bacteremia 10 9 10 9. Candidiasis 8 7 1 1. Catheter related infection 14 12 13 11. Cellulitis 9 8 7 6. Clostridium colitis 8 7 6 5. Herpes simplex 11 10 6 5. Herpes zoster 8 7 6 5. Oral candidiasis 13 11 2 2. Pneumonia 11 10 6 5 1 1 1 1 Sepsis, including septic shock 19 17 6 5 4 4 9 8 Staphylococcal bacteremia 7 6 5 4 1 1. Staphylococcal sepsis 6 5 5 4 1 1. Upper respiratory tract infection 6 5 1 1. Metabolism and Nutrition Disorders Anorexia 34 30 6 5 8 7. Musculoskeletal and Connective Tissue Disorders Arthralgia 10 9 3 3. Back pain 12 10 3 3. Bone pain 11 10 3 3. Myalgia 16 14. Pain in extremity 34 30 6 5. Neoplasms Benign, Malignant and Unspecified (incl. cysts and polyps) Tumor lysis syndrome 7 6 7 6. Nervous System Disorders Headache 49 43 6 5. Lethargy 12 10 1 1. Somnolence 11 10 1 1. Psychiatric Disorders Agitation 6 5 1 1. Anxiety 24 21 2 2. Renal and Urinary Disorders Hematuria 15 13 2 2. Respiratory, Thoracic and Mediastinal Disorders Dyspnea 15 13 6 5 2 2. Epistaxis 31 27 15 13. Pleural effusion 14 12 4 4 2 2. Respiratory distress 12 10 5 4 4 4 1 1 Tachypnea 10 9 4 4 1 1. Skin and Subcutaneous Tissue Disorders Erythema 13 11. Palmar-plantar erythrodysesthesia syndrome 18 16 8 7. Petechiae 30 26 7 6. Pruritus 49 43 1 1. Rash 44 38 8 7. Rash pruritic 9 8. Vascular Disorders Flushing 22 19. Hypertension 15 13 6 5. Hypotension 33 29 13 11 9 8. The following adverse reactions were reported in <5% of the 115 pediatric patients with ALL or AML: Gastrointestinal Disorders: Hepatobiliary Disorders: Immune System Disorders: Infections and Infestations: Investigations: Psychiatric Disorders: Respiratory, Thoracic and Mediastinal Disorder: Table 2 lists the incidence of treatment-emergent laboratory abnormalities after Clolar administration at 52 mg/m 2 Table 2: Incidence of Treatment-Emergent Laboratory Abnormalities after Clolar Administration Parameter Any Grade Grade 3 or higher Anemia (N=114) 83% 75% Leukopenia (N=114) 88% 88% Lymphopenia (N=113) 82% 82% Neutropenia (N=113) 64% 64% Thrombocytopenia (N=114) 81% 80% Elevated Creatinine (N=115) 50% 8% Elevated SGOT (N=100) 74% 36% Elevated SGPT (N=113) 81% 43% Elevated Total Bilirubin (N=114) 45% 13% 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. Gastrointestinal disorders: gastrointestinal hemorrhage including fatalities. Metabolism and nutrition disorders: hyponatremia Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (including fatal cases).

Lactation: Advise not to breastfeed. 2 Risk Summary In animal reproduction studies, intravenous administration of clofarabine to pregnant rats and rabbits during organogenesis at doses approximately 0. 2 to 1-times the maximum recommended human dose of 52 mg/m 2 (see Data The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal data Intravenous administration of clofarabine to pregnant rats during organogenesis (gestation days [GD] 7en dash17) at doses of 1, 3 or 9 mg/kg/day (equivalent to 6, 18, 54 mg/m 2 2 When clofarabine was administered intravenously to pregnant rabbits during organogenesis (GD 6en dash18) at doses of 0. 3, or 1 mg/kg/day (equivalent to 1. 6, 12 mg/m 2 2 2 Risk Summary There are no data on the presence of clofarabine in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child including genotoxicity, advise patients not to breastfeed during treatment with Clolar, and for 2 weeks after the last dose. Clolar can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8. 1) Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating Clolar. Contraception Females Advise female patients to use effective contraception during treatment with Clolar and for 6 months after the last dose. Males Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with Clolar and for 3 months after the last dose [see Nonclinical Toxicology (13. 1) Infertility Females Based on findings from animal studies, Clolar may impair female fertility [see Nonclinical Toxicology (13. 1) Males Based on findings from animal studies, Clolar may impair male fertility [see Nonclinical Toxicology (13. 1) 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. 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).

OVERDOSAGE
There were no known overdoses of Clolar. The highest daily dose administered to a human to date (on a mg/m 2 2 In a Phase 1 study of adults with refractory and/or relapsed hematologic malignancies, the recommended pediatric dose of 52 mg/m 2
NONCLINICAL TOXICOLOGY
Clofarabine has not been tested for carcinogenic potential. Clofarabine was clastogenic in the in vitro in vivo 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 doses of 3 mg/kg/day (approximately 0.2-times the recommended human dose based on body surface area [BSA]). Rats receiving 25 mg/kg/day (approximately 3-times the recommended human dose based on BSA) in a 6-month intravenous study had testicular findings of bilateral degeneration of the seminiferous epithelium with retained spermatids and atrophy of interstitial cells. In a 6-month intravenous dog study, cell degeneration of the epididymis and degeneration of the seminiferous epithelium in the testes were observed at 0.375 mg/kg/day (approximately 0.1-times the recommended human dose on a BSA basis). Ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice at 75 mg/kg/day (approximately 4-times the recommended human dose on a mg/m 2
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/m 2 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 (NCT00042341, A Phase II, Open Label Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Lymphoblastic Leukemia). The starting dose of Clolar was 11. 25 mg/m 2 2 2 2 2 Single-Arm Study in Pediatric ALL Clolar was evaluated in an open-label, single-arm study (NCT00042341) of 61 pediatric patients with relapsed/refractory ALL. Patients received a dose of 52 mg/m 2 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 White, 38% were Hispanic or Latino, 12% were Black or 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 × 10 9 9 9 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 29en dash2815 mg) in 1 (41%), 2 (44%) or 3 or more (15%) cycles. The median number of cycles was 2 (range 1en dash12). The median time between cycles was 28 days with a range of 12 to 55 days. Table 3: Results in Single-Arm Pediatric ALL N=61 CR = Complete response CRp = Complete response without platelet recovery CR % [95% CI] 11. 2) CRp % [95% CI] 8. 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) The median duration of CR, including patients who received transplantation, was 47. 9 weeks (range 4. 7+), where + indicates the patient was still in CR by the study end. 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.
REFERENCES
OSHA Hazardous Drugs. OSHA.

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