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CLOLAR- clofarabine injection
Genzyme Corporation

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 use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted.

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.

• 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, allopurinol, 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 [see WARNINGS AND PRECAUTIONS (5.6)].
• Monitor patients taking medications known to affect blood pressure. Monitor cardiac function during administration of Clolar.

2.2 Recommended Concomitant Medications and Medications to Avoid

• Consider prophylactic anti-emetic medications as Clolar is moderately emetogenic.

• Consider the use of prophylactic steroids to prevent signs or symptoms of Systemic Inflammatory Response Syndrome (SIRS) or capillary leak (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema).

• Consider avoiding drugs with known renal toxicity during the 5 days of Clolar administration.

• Consider avoiding concomitant use of medications known to induce hepatic toxicity.

2.3 Dose Modifications and Reinitiation of Therapy

• Hematologic Toxicity
  • Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle 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 clinically controlled and then restart at the full dose.
  • Withhold Clolar if a Grade 3 non-infectious non-hematologic toxicity (excluding transient elevations in serum transaminases and/or serum bilirubin and/or nausea/vomiting that was controlled by antiemetic therapy) occurs. Re-institute Clolar administration at a 25% dose reduction when resolution or return to baseline.
  • Discontinue Clolar administration if a Grade 4 non-infectious non-hematologic toxicity occurs.
  • 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 when the patient is stable and organ function has returned to baseline, generally with a 25% dose reduction. If hyperuricemia is anticipated (tumor lysis), prophylactically administer allopurinol.

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 (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).

2.5 Incompatibilities

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

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

Clolar should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.

5.1 Hematologic Toxicity

Monitor complete blood counts and platelet counts during Clolar therapy.

Suppression of bone marrow function should be anticipated. This is usually reversible and appears to be dose dependent. Severe bone marrow suppression, including neutropenia, anemia, and thrombocytopenia, has been observed in patients treated with Clolar. At initiation of treatment, most patients in the clinical studies had hematological impairment as a manifestation of leukemia. Because of the pre-existing immunocompromised condition of these patients and prolonged neutropenia that can result from treatment with Clolar, patients are at increased risk for severe opportunistic infections.

5.2 Infections

The use of Clolar is likely to increase the risk of infection, including severe sepsis, as a result of bone marrow suppression. Monitor patients for signs and symptoms of infection and treat promptly.

5.3 Hyperuricemia (Tumor Lysis)

Administration of Clolar may result in a rapid reduction in peripheral leukemia cells. Evaluate and monitor patients undergoing treatment for signs and symptoms of tumor lysis syndrome. Provide intravenous infusion fluids throughout the five days of Clolar administration to reduce the effects of tumor lysis and other adverse events. Administer Allopurinol if hyperuricemia (tumor lysis) is expected.

5.4 Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome

Evaluate and monitor patients undergoing treatment with Clolar for signs and symptoms of cytokine release (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that could develop into systemic inflammatory response syndrome (SIRS), capillary leak syndrome and organ dysfunction. Discontinue Clolar immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome, either of which can be fatal, and consider use of steroids, diuretics, and albumin. Re-institute Clolar when the patient is stable, generally with a 25% dose reduction. The use of prophylactic steroids may be of benefit in preventing signs and symptoms of cytokine release.

5.5 Hepatic Enzymes

Hepato-biliary enzyme elevations were frequently observed in pediatric patients during treatment with Clolar. Some patients discontinued treatment due to hepatic enzyme abnormalities [see ADVERSE REACTIONS (6.1)].

5.6 Hepatic and Renal Impairment

Clolar has not been studied in patients with hepatic or renal dysfunction. Its use in such patients should be undertaken only with the greatest caution [see DOSAGE AND ADMINISTRATION (2.2)].

Patients who have previously received a hematopoietic stem cell transplant (HSCT) may be at higher risk for hepatotoxicity suggestive of veno-occlusive disease (VOD) 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 an ongoing Phase 1/2 combination study of clofarabine in pediatric patients with relapsed or refractory acute leukemia.

5.7 Use in Pregnancy

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)].

6 ADVERSE REACTIONS

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

• Severe Bone Marrow Suppression [see WARNINGS AND PRECAUTIONS (5.1)]
• Serious Infections [see WARNINGS AND PRECAUTIONS (5.2)]
• Hyperuricemia (Tumor Lysis) [see WARNINGS AND PRECAUTIONS (5.3)]
• Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome [see WARNINGS AND PRECAUTIONS (5.4)]
• Hepatic and Renal Impairment [see WARNINGS AND PRECAUTIONS (5.6)]
• Use in Pregnancy [see WARNINGS AND PRECAUTIONS (5.7)]

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).

One hundred and fifteen (115) of the 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.

The most common adverse reactions 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 events regardless of causality 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.

¹Patients 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.

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, Parainfluenzae 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).

Hematologic Toxicity

The most frequently reported hematologic adverse reactions in pediatric patients included febrile neutropenia (55%) and non-febrile neutropenia (10%).

Infection

At baseline, 48% of the pediatric patients had 1 or more concurrent infections. A total of 83% of patients experienced at least 1 infection after Clolar treatment, including fungal, viral and bacterial infections.

Hepatic

Hepato-biliary toxicities were frequently observed in pediatric patients during treatment with Clolar. Grade 3 or 4 elevated aspartate aminotransferase (AST) occurred in 36% of patients and grade 3 or 4 elevated alanine aminotransferase (ALT) occurred in 44% of patients. 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, one patient had multi-organ failure and died. Two reports (2%) of veno-occlusive disease (VOD) were considered related to study drug.

For patients with follow-up data, elevations in AST and ALT were transient and typically ≤ 15 days duration. The majority of AST and ALT elevations occurred within 10 days of Clolar administration and returned to ≤ grade 2 within 15 days. Where follow-up data are available, the majority of bilirubin elevations returned to ≤ grade 2 within 10 days. Eight patients 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.

Renal

The most prevalent renal toxicity in pediatric patients was elevated creatinine. Grade 3 or 4 elevated creatinine occurred in 8% of patients. Acute renal failure was reported in 3 patients (3%) at grade 3 and 2 patients (2%) with grade 4. Nephrotoxic medications, tumor lysis, and tumor lysis with hyperuricemia may contribute to renal toxicity. Hematuria was observed in 13% of patients overall.

Systemic Inflammatory Response Syndrome (SIRS)

Adverse reactions of SIRS were reported in 2 patients (2%) [see WARNINGS AND PRECAUTIONS (5.4)].

Capillary Leak Syndrome

Adverse reactions of capillary leak syndrome were reported in 4 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 are recommended. 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. Physicians should be alert to early indications of this syndrome and should immediately discontinue Clolar administration if they occur and provide appropriate supportive measures. After the patient is stabilized and organ function has returned to baseline, re-treatment with Clolar can be considered with a 25% dose reduction.