Clofarabine

CLOFARABINE- clofarabine injection
Winthrop U.S.

1 INDICATIONS AND USAGE

Clofarabine 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 clofarabine.

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.

  • 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 × 109 /L.
  • Provide supportive care, such as intravenous fluids, antihyperuricemic treatment, and alkalinize urine throughout the 5 days of clofarabine administration to reduce the effects of tumor lysis and other adverse reactions.
  • Discontinue clofarabine if hypotension develops during the 5 days of administration.
  • Monitor renal and hepatic function during the 5 days of clofarabine administration [see Warnings and Precautions (5.7, 5.8)].
  • Monitor patients taking medications known to affect blood pressure. Monitor cardiac function during administration of clofarabine.

2.2 Recommended Dosage Reduction for Renal Impairment

  • 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 (8.7)].

2.3 Potential Concomitant Medications and Medications to Avoid

  • Consider prophylactic antiemetic medications as clofarabine 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 clofarabine administration since the risk of renal toxicity may be increased.
  • Avoid concomitant use of medications known to induce hepatic toxicity.

2.4 Dose Modifications and Reinitiation of Therapy after Adverse Reactions

Hematologic Toxicity

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

Non-hematologic Toxicity

  • Withhold clofarabine if a patient develops a clinically significant infection, until the infection is controlled, then restart at the full dose.
  • Withhold clofarabine 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 clofarabine administration at a 25% dose reduction when resolution or return to baseline.
  • Discontinue clofarabine administration for a Grade 4 non-infectious non-hematologic toxicity.
  • Discontinue clofarabine administration if a patient shows early signs or symptoms of SIRS or capillary leak syndrome (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema) occur and provide appropriate supportive measures.
  • Discontinue clofarabine administration if Grade 3 or higher increases in creatinine or bilirubin are noted. Re-institute clofarabine 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.

2.5 Reconstitution/Preparation

Filter clofarabine 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 0.4 mg/mL. Use within 24 hours of preparation. Store diluted clofarabine at room temperature (15°C to 30°C).

Discard unused portion in vial.

3 DOSAGE FORMS AND STRENGTHS

Injection: 20 mg/20 mL (1 mg/mL) clear solution in single-dose vial

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

Clofarabine 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 clofarabine treatment and appears to be dose-dependent. Monitor complete blood counts [see Dosage and Administration (2.4)].

5.2 Hemorrhage

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 [see Adverse Reactions (6.2)].

5.3 Infections

Clofarabine 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 clofarabine treatment, including fungal, viral and bacterial infections. Monitor patients for signs and symptoms of infection, discontinue clofarabine, and treat promptly.

5.4 Tumor Lysis Syndrome

Administration of clofarabine 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.

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

Clofarabine 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 multiorgan failure. Close monitoring for this syndrome and early intervention may reduce the risk. Immediately discontinue clofarabine 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 syndrome. Consider use of diuretics and/or albumin. After the patient is stabilized and organ function has returned to baseline, retreatment with clofarabine can be considered with a 25% dose reduction.

5.6 Venous Occlusive Disease of the Liver

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 monotherapy studies were considered related to study drug. Monitor for and discontinue clofarabine if VOD is suspected.

5.7 Hepatotoxicity

Severe and fatal hepatotoxicity, including hepatitis and hepatic failure, has occurred with the use of clofarabine. In clinical studies, Grade 3–4 liver enzyme elevations were observed in pediatric patients during treatment with clofarabine 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 clofarabine 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 multiorgan 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 multiorgan failure. Monitor hepatic function, and for signs and symptoms of hepatitis and hepatic failure. Discontinue clofarabine immediately for Grade 3 or greater liver enzyme and/or bilirubin elevations [see Dosage and Administration (2.4)].

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