WARNINGS
Clolar® should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Suppression of bone marrow function should be anticipated. This is usually reversible and appears to be dose dependent. The use of Clolar® is likely to increase the risk of infection, including severe sepsis, as a result of bone marrow suppression. Administration of Clolar® results in a rapid reduction in peripheral leukemia cells. For this reason, patients undergoing treatment with Clolar® should be evaluated and monitored for signs and symptoms of tumor lysis syndrome, as well as 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. Physicians are encouraged to give continuous IV fluids throughout the five days of Clolar® administration to reduce the effects of tumor lysis and other adverse events. Allopurinol should be administered if hyperuricemia is expected. 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. Clolar® can be re-instituted when the patient is stable, generally with a 25% dose reduction.
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. Careful hematological monitoring during therapy is important, and hepatic and renal function should be assessed prior to and during treatment with Clolar® because of Clolar®’s predominantly renal excretion and because the liver is a target organ for Clolar® toxicity. The respiratory status and blood pressure should be closely monitored during infusion of Clolar®.
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. 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.
Pregnancy – Teratogenic Effects: Pregnancy Category D
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 post-implantation 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.
PRECAUTIONS
Information for Patients and Caregivers
Physicians are advised to discuss the following with patients to whom Clolar® will be administered and patient caregivers, as appropriate.
Dehydration/Hypotension
Patients receiving Clolar® may experience vomiting and diarrhea; they should therefore be advised regarding appropriate measures to avoid dehydration. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, lightheadedness, fainting spells, or decreased urine output. Clolar® administration should be stopped if the patient develops hypotension for any reason during the 5 days of administration. If hypotension is transient and resolves without pharmacological intervention, Clolar® treatment can be re-instituted, generally with a 25% dose reduction.
Concomitant Medications
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. Patients taking medications known to affect blood pressure or cardiac function should be closely monitored during administration of Clolar®.
Pregnancy/Nursing
All patients should be advised to use effective contraceptive measures to prevent pregnancy. Female patients should be advised to avoid breast feeding during treatment with Clolar®.
Laboratory Tests
Complete blood counts and platelet counts should be obtained at regular intervals during Clolar® therapy, and more frequently in patients who develop cytopenias. In addition, liver and kidney function should be monitored frequently during the 5 days of Clolar® administration.
Drug Interactions
Although no clinical drug-drug interaction studies have been conducted to date, on the basis of the in vitro studies, cytochrome p450 inhibitors and inducers are unlikely to affect the metabolism of clofarabine. The effect of clofarabine on the metabolism of cytochrome p450 substrates has not been studied.
Drug/Laboratory Tests Interactions
There are no known clinically significant interactions of Clolar® with other medications or laboratory tests. No formal drug/laboratory test interaction studies have been conducted with Clolar®.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Clofarabine has not been tested for carcinogenic potential.
Mutagenesis
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).
Impairment of Fertility
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.
Pregnancy
Teratogenic Effects: Pregnancy Category D
See WARNINGS .
Nursing Mothers
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.
Other Special Population: Adults
Safety and efficacy have not been established in adults. One study was performed in highly refractory and/or relapsed adult patients with hematologic malignancies. The Phase 2 dose of Clolar® was determined to be 40 mg/m2/day administered as a 1- to 2-hour IV infusion daily x 5 every 28 days.
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