Adverse Events

In clinical trials, one hundred thirteen (113) pediatric patients with ALL (67) or AML (46) were exposed to Clolar. Ninety six (96) of the pediatric patients treated in clinical trials received the recommended dose of Clolar 52 mg/m² daily × 5. In these patients, the most common adverse effects after Clolar treatment, regardless of causality, were gastrointestinal tract symptoms, including vomiting, nausea, and diarrhea; hematologic effects, including anemia, leukopenia, thrombocytopenia, neutropenia, and febrile neutropenia; and infection.

The table below lists adverse events by System Organ Class regardless of causality, including severe or life-threatening events (NCI CTC grade 3 or grade 4), reported in ≥10% of the 96 ALL or AML pediatric patients in the 52 mg/m²/day dose group.

Hepatic, renal, and cardiac abnormalities

Hepato-biliary toxicities were frequently observed in patients treated with Clolar. Grade 3 or 4 elevated aspartate aminotransferase (AST) occurred in 38% of patients and grade 3 or 4 elevated alanine aminotransferase (ALT) occurred in 44% of patients. For patients with follow-up data, elevations in AST and ALT were transient and typically of <2 weeks duration. The majority of AST and ALT elevations occurred within 1 week of Clolar administration and returned to baseline or ≤ grade 2 within several days.

Grade 3 or 4 elevated bilirubin was observed in 15% of patients, with two cases of grade 4 hyperbilirubinemia resulting in treatment discontinuation. Bilirubin elevations were more persistent; for patients with follow-up data, the median time to recovery from grade 3 and grade 4 to ≤ grade 2 was 6 days.

Grade 3 or 4 elevated creatinine was observed in 6% of patients. Nephrotoxic medications, tumor lysis, and tumor lysis with hyperuricemia may contribute to renal toxicity.

The most frequently reported cardiac disorder was tachycardia (34%), which was, however, already present in 27.4% of patients at study entry. Most of the cardiac adverse events were reported in the first two cycles. Pericardial effusion was a frequent finding in patients on post-treatment studies, and left ventricular systolic dysfunction was also noted.

Severe hepatotoxic events have been reported in an ongoing, phase 1/2 clinical trial investigating Clolar in combination with etoposide and cyclophosphamide in pediatric patients with relapsed or refractory acute leukemia. This study found that patients who had previously received a hematopoietic stem cell transplant may be at higher risk for hepatotoxicity.

Opportunistic infections

Patients receiving Clolar are at increased risk of severe opportunistic infections due to the prolonged neutropenia that can result from treatment with Clolar, as well as the pre-existing immunocompromised condition of patients with relapsed or refractory ALL. At baseline, 47% of the patients in the phase 2 trial had one or more concurrent infections. A total of 85% of patients experienced at least one infection (including fungal, viral, and bacterial infections). Antimicrobial prophylaxis may be considered.

Additional side effects and management

Palmar-plantar erythrodysesthesia (hand-foot syndrome) has been associated with use of Clolar. It is generally experienced initially as a tingling feeling a few days after treatment and progresses to redness, dryness, and possible flaking of skin on hands and/or feet. Elevation and application of moisturizers (applied lightly) may provide symptomatic relief. Steroids or antihistamines may also be considered. Excess heat, as well as activities that involve friction or pressure on hands and feet should be avoided.

During administration of Clolar, pediatric patients may experience anxiety and/or agitation and restlessness. If this occurs, immediately slow the infusion. Anxiolytics and/or antihistamines may provide relief. Premedication with an anxiolytic may be considered prior to the next Clolar cycle.

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Indication

Clolar 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.

Important Safety Considerations

Clolar should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Suppression of bone marrow function, which is usually reversible and dose dependent, should be anticipated and is likely to increase the risk of infection, including severe sepsis. Administration of Clolar results in a rapid reduction in peripheral leukemia cells. Patients should be evaluated and monitored for signs and symptoms of tumor lysis syndrome and cytokine release (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that could develop into systemic inflammatory response syndrome (SIRS)/capillary leak syndrome, and organ dysfunction. Clolar should be discontinued immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome, either of which can be fatal, and use of steroids, diuretics, and albumin considered.

The most common adverse effects after Clolar treatment, regardless of causality, were gastrointestinal tract symptoms, including vomiting (grade 3: 8%; grade 4: 1%), nausea (grade 3: 15%; grade 4: 1%), and diarrhea (grade 3: 10%); hematologic effects, including anemia (grade 3: 70%; grade 4: 18%), leukopenia (grade 4: 99%), thrombocytopenia (grade 3: 36%; grade 4: 64%), neutropenia (grade 3: 3%; grade 4: 7%), and febrile neutropenia (grade 3: 53%; grade 4: 3%); and infection (grade 3: 56%; grade 4: 18%).

Hepato-biliary toxicities were frequently observed in pediatric patients during treatment with Clolar. The most frequently reported cardiac disorder was tachycardia (34%), which was, however, already present in 27.4% of patients at study entry. Left ventricular systolic dysfunction was also noted. Since Clolar is excreted primarily by the kidneys, drugs with known renal toxicity should be avoided during the 5 days of Clolar administration. In addition, since the liver is a known target organ for Clolar toxicity, concomitant use of medications known to induce hepatic toxicity should also be avoided.

Severe bone marrow suppression, including neutropenia, anemia, and thrombocytopenia, have been observed in patients treated with Clolar. 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.

Pericardial effusion was a frequent finding in these patients on post-treatment studies. Careful hematologic monitoring during therapy is important. Hepatic and renal function should be assessed prior to and during treatment with Clolar, as the liver is a target organ for Clolar toxicity and the kidneys are the predominant mode of Clolar excretion. Severe hepatotoxic events have been reported in an ongoing, phase 1/2 clinical trial investigating Clolar in combination with etoposide and cyclophosphamide in pediatric patients with relapsed or refractory acute leukemia. This study found that patients who had previously received a hematopoietic stem cell transplant may be at higher risk for hepatotoxicity.

Patients receiving Clolar may experience vomiting and diarrhea; they should therefore be advised regarding appropriate measures to avoid dehydration. Clolar may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant and avoid breastfeeding while receiving treatment with Clolar.

For more information, please consult the Full Prescribing Information (PDF).