Clolar

Overdose

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

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.

Contraindications

None

Undesirable effects

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

• Myelosuppression
• Hemorrhage
• Serious Infections
• Hyperuricemia (Tumor Lysis)
• Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome
• Venous Occlusive Disease of the Liver
• Hepatotoxicity
• Renal Toxicity
• Enterocolitis
• Skin Reactions

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 x 5. The median number of cycles was 2. The median cumulative amount of Clolar received by pediatric patients during all cycles was 540 mg.

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 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.

Table 1: Most Commonly Reported ( ≥ 5% Overall) Adverse Reactions by System Organ Class (N=115 pooled analysis)

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).

Table 2: Incidence of Treatment-Emergent Laboratory Abnormalities after Clolar Administration

The following adverse reactions have been identified during postapproval 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.

• Gastrointestinal disorders: Gastrointestinal hemorrhage including fatalities
• Metabolism and nutrition disorders: hyponatremia
• Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN)

Therapeutic indications

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.

Pharmacokinetic properties

The population pharmacokinetics of Clolar were studied in 40 pediatric patients aged 2 to 19 years (21 males/19 females) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). At the given 52 mg/m² dose, similar concentrations were obtained over a wide range of body surface areas (BSAs). Clofarabine was 47% bound to plasma proteins, predominantly to albumin. Based on noncompartmental analysis, systemic clearance and volume of distribution at steady-state were 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.

Clofarabine has not been studied in patients with hepatic impairment.

Date of revision of the text

Name of the medicinal product

Fertility, pregnancy and lactation

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 postimplantation 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.

Qualitative and quantitative composition

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

Clolar (clofarabine) Injection is supplied in single-dose flint vials containing 20 mg of clofarabine in 20 mL of solution. Each box contains one Clolar vial (NDC 0024-5860-01). 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.

Manufactured by: Teva Pharmachemie, Swensweg 5, Haarlem, The Netherlands. Manufactured for: Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142. Distributed by: sanofi-aventis U.S. LLC, Bridgewater, NJ 08807. Revised: Oct 2016

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

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 dosedependent. Monitor complete blood counts.

Serious and fatal hemorrhage, including cerebral, gastrointestinal and pulmonary hemorrhage, has occurred. The majority of the cases were associated with thrombocytopenia. Monitor platelets and coagulation parameters and treat accordingly.

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.

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.

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.

Patients who have previously received a hematopoietic stem cell transplant (HSCT) are at higher risk for veno-occlusive disease (VOD) of the liver following treatment with clofarabine (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 clofarabine 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.

Severe and fatal hepatotoxicity, including hepatitis and hepatic failure, 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 for signs and symptoms of hepatitis and hepatic failure. Discontinue Clolar immediately for Grade 3 or greater liver enzyme and/or bilirubin elevations.

Clolar may cause acute renal failure. In Clolar treated patients in clinical studies, Grade 3 or 4 elevated creatinine occurred in 8% of patients and acute renal failure was reported as Grade 3 in three patients (3%) and Grade 4 in two patients (2%). Patients with infection, sepsis, or tumor lysis syndrome may be at increased risk of renal toxicity when treated with Clolar.

Hematuria occurred in 13% of Clolar treated patients overall. Monitor patients for renal toxicity and interrupt or discontinue Clolar as necessary.

Fatal and serious cases of enterocolitis, including neutropenic colitis, cecitis, and C. difficile colitis, have occurred during treatment with clofarabine. This has occurred more frequently within 30 days of treatment, and in the setting of combination chemotherapy. Enterocolitis may lead to necrosis, perforation, hemorrhage or sepsis complications. Monitor patients for signs and symptoms of enterocolitis and treat promptly.

Serious and fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported. Discontinue Clofarabine for exfoliative or bullous rash, or if SJS or TEN is suspected.

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.

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.

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 postimplantation 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 breastfeeding 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).

Dosage (Posology) and method of administration

Administer the recommended pediatric dose of 52 mg/m² as an intravenous infusion 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.
• 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 events.
• Discontinue Clolar if hypotension develops during the 5 days of administration.
• Monitor renal and hepatic function during the 5 days of Clolar administration.
• 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.

• Consider prophylactic anti-emetic medications as Clolar is moderately emetogenic.
• Consider the use of prophylactic steroids to mitigate Systemic Inflammatory Response Syndrome (SIRS) or capillary leak syndrome (e.g., 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.
• Consider avoiding concomitant use of medications known to induce hepatic toxicity.

• Hematologic Toxicity
  • 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 x 109/L.
  • If a patient experiences a Grade 4 neutropenia (ANC < 0.5 x 109/L) lasting ≥ 4 weeks, reduce dose by 25% for the next cycle.
• 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 nonhematologic 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 (e.g., 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.

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 (15-30°C).

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

Interaction with other medicinal products and other forms of interaction

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

• Myelosuppression
• Hemorrhage
• Serious Infections
• Hyperuricemia (Tumor Lysis)
• Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome
• Venous Occlusive Disease of the Liver
• Hepatotoxicity
• Renal Toxicity
• Enterocolitis
• Skin Reactions

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 x 5. The median number of cycles was 2. The median cumulative amount of Clolar received by pediatric patients during all cycles was 540 mg.

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 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.

Table 1: Most Commonly Reported ( ≥ 5% Overall) Adverse Reactions by System Organ Class (N=115 pooled analysis)

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).

Table 2: Incidence of Treatment-Emergent Laboratory Abnormalities after Clolar Administration

The following adverse reactions have been identified during postapproval 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.

• Gastrointestinal disorders: Gastrointestinal hemorrhage including fatalities
• Metabolism and nutrition disorders: hyponatremia
• Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN)

No information provided.