Presentation and Status in Health Basket
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Adult population (including the elderly): There are currently insufficient data to establish the safety and efficacy of clofarabine in adult patients.
Paediatric population: The recommended dose in monotherapy is 52 mg/m2 of body surface area administered by intravenous infusion over 2 hours daily for 5 consecutive days. Body surface area must be calculated using the actual height and weight of the patient before the start of each cycle. Treatment cycles should be repeated every 2 to 6 weeks (from the starting day of the previous cycle) following recovery of normal haematopoiesis (i.e. ANC ≥ 0.75 × 109/l) and return to baseline organ function. A 25% dose reduction may be warranted in patients experiencing significant toxicities. There is currently limited experience of patients receiving more than 3 treatment cycles. The majority of patients who respond to clofarabine achieve a response after 1 or 2 treatment cycles. Therefore, the potential benefit and risks associated with continued therapy in patients who do not show haematological and/or clinical improvement after 2 treatment cycles should be assessed by the treating physician.
Children (weighing < 20 kg): An infusion time of > 2 hours should be considered to help reduce symptoms of anxiety and irritability, and to avoid unduly high maximum concentrations of clofarabine.
Children (< 1 year old): There are no data on the pharmacokinetics, safety or efficacy of clofarabine in infants. Therefore, a safe and effective dosage recommendation for patients (< 1 year old) has yet to be established.
Patients with renal insufficiency: The limited data available indicate that clofarabine may accumulate in patients with decreased creatinine clearance. Clofarabine is contraindicated in patients with severe renal insufficiency and should be used with caution in patients with mild to moderate renal insufficiency. Patients with moderate renal impairment (creatinine clearance 30 – <60 ml/min) require a 50% dose reduction.
Patients with hepatic impairment: There is no experience in patients with hepatic impairment (serum bilirubin > 1.5 x ULN plus AST and ALT > 5 x ULN) and the liver is a potential target organ for toxicity. Therefore, clofarabine is contraindicated in patients with severe hepatic impairment and should be used with caution in patients with mild to moderate hepatic impairment.
Dose reduction for patients experiencing haematological toxicities: If the ANC does not recover by 6 weeks from the start of a treatment cycle, a bone marrow aspirate / biopsy should be performed to determine possible refractory disease. If persistent leukaemia is not evident, it is recommended that the dose for the next cycle be reduced by 25% of the previous dose following recovery of ANC to ≥ 0.75 × 109/l. Should patients experience an ANC < 0.5 × 109/l for more than 4 weeks from the start of the last cycle, it is recommended that the dose for the next cycle be reduced by 25%.
Dose reduction for patients experiencing non-haematological toxicities Infectious events: If a patient develops a clinically significant infection, clofarabine treatment may be withheld until the infection is clinically controlled. At this time, treatment may be reinitiated at the full dose. In the event of a second clinically significant infection, clofarabine treatment should be withheld until the infection is clinically controlled and may be reinitiated at a 25% dose reduction.
Non-infectious events: If a patient experiences one or more severe toxicities (US National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Grade 3 toxicities excluding nausea and vomiting), treatment should be delayed until the toxicities resolve to baseline parameters or to the point where they are no longer severe and the potential benefit of continued treatment with clofarabine outweighs the risk of such continuation. It is then recommended that clofarabine be administered at a 25% dose reduction. Should a patient experience the same severe toxicity on a second occasion, treatment should be delayed until the toxicity resolves to baseline parameters or to the point where it is no longer severe and the potential benefit of continued treatment with clofarabine outweighs the risk of such continuation. It is then recommended that clofarabine be administered at a further 25% dose reduction. Any patient who experiences a severe toxicity on a third occasion, a severe toxicity that does not recover within 14 days (see for exclusions), or a life-threatening or disabling toxicity (US NCI CTC Grade 4 toxicity) should be withdrawn from treatment with clofarabine.
Treatment of acute lymphoblastic leukaemia (ALL) in paediatric patients who have relapsed or are refractory after receiving at least two prior regimens and who are about to undergo transplantation. Safety and efficacy have been assessed in studies of patients ≤ 21 years old at initial diagnosis.
Hypersensitivity to clofarabine or to any of the excipients. Use in patients with severe renal insufficiency or severe hepatic impairment. Breast-feeding should be discontinued prior to, during and following treatment with the drug.
This drug is a potent antineoplastic agent with potentially significant haematological and non-haematological adverse reactions. The following parameters should be closely monitored in patients undergoing treatment with clofarabine: Complete blood and platelet counts should be obtained at regular intervals, more frequently in patients who develop cytopaenias. Renal and hepatic function prior to, during active treatment and following therapy. Clofarabine should be discontinued immediately if substantial increases in creatinine or bilirubin are observed. Respiratory status, blood pressure, fluid balance and weight throughout and immediately after the 5 day clofarabine administration period. Suppression of bone marrow should be anticipated. This is usually reversible and appears to be dose-dependent. Severe bone marrow suppression, including neutropaenia, anaemia and thrombocytopenia have been observed in patients treated with clofarabine. Haemorrhage, including cerebral, gastrointestinal and pulmonary haemorrhage, has been reported and may be fatal. The majority of the cases were associated with thrombocytopaenia. In addition, at initiation of treatment, most patients in the clinical studies had haematological impairment as a manifestation of leukaemia. Because of the pre-existing immuno-compromised condition of these patients and prolonged neutropaenia that can result from treatment with clofarabine, patients are at increased risk for severe opportunistic infections, including severe sepsis, with potentially fatal outcomes. Patients should be monitored for signs and symptoms of infection and treated promptly.
Occurrences of enterocolitis, including neutropaenic colitis, C. difficile colitisand caecitis, have been reported 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 or sepsis complications and may be associated with fatal outcome. Patients should be monitored for signs and symptoms of enterocolitis. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal cases, have been reported. Clofarabine must be discontinued for exfoliative or bullous rash, or if SJS or TEN is suspected. Administration of clofarabine results in a rapid reduction in peripheral leukaemia cells. Patients undergoing treatment with clofarabine should be evaluated and monitored for signs and symptoms of tumour lysis syndrome and cytokine release (e.g. tachypnoea, tachycardia, hypotension, pulmonary oedema) that could develop into Systemic Inflammatory Response Syndrome (SIRS), capillary leak syndrome and/or organ dysfunction. Prophylactic administration of allopurinol should be considered if hyperuricemia (tumour lysis) is expected.
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Those most frequently reported adverse events were nausea, vomiting, febrile neutropenia, headache, rash, diarrhoea, pruritus, pyrexia, palmar-plantar erythrodysaesthesia syndrome, fatigue, anxiety, mucosal inflammation, and flushing.
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No formal interaction studies have been performed to date with clofarabine. However, there are no known clinically significant interactions with other medicinal products or laboratory tests. Clofarabine is not detectably metabolised by the cytochrome P450 (CYP) enzyme system. Therefore, it is unlikely to interact with active substances which inhibit or induce cytochrome P450 enzymes. In addition, clofarabine is unlikely to inhibit any of the major 5 human CYP isoforms (1A2, 2C9, 2C19, 2D6 and 3A4) or to induce 2 of these isoforms (1A2 and 3A4) at the plasma concentrations achieved following intravenous infusion of 52 mg/m2/day. As a result, it is not expected to affect the metabolism of active substances which are known substrates for these enzymes. Clofarabine is predominately excreted via the kidneys. Thus, the concomitant use of medicinal products that have been associated with renal toxicity and those eliminated by tubular secretion such as NSAIDs, amphotericin B, methotrexate, aminosides, organoplatines, foscarnet, pentamidine, cyclosporin, tacrolimus, acyclovir and valganciclovir, should be avoided particularly during the 5 day clofarabine administration period. The liver is a potential target organ for toxicity. Thus, the concomitant use of medicinal products that have been associated with hepatic toxicity should be avoided wherever possible. Patients taking medicinal products known to affect blood pressure or cardiac function should be closely monitored during treatment with clofarabine.
Pregnancy and Lactation
Pregnancy: There are no data on the use of clofarabine in pregnant women. Studies in animals have shown reproductive toxicity including teratogenicity. Clofarabine may cause serious birth defects when administered during pregnancy. Therefore, the drug should not be used during pregnancy, especially not during the first trimester, unless clearly necessary (i.e. only if the potential benefit to the mother outweighs the risk to the foetus). If a patient becomes pregnant during treatment with clofarabine, they should be informed of the possible hazard to the foetus.
Lactation: It is unknown whether clofarabine or its metabolites are excreted in human breast milk. The excretion of clofarabine in milk has not been studied in animals. However, because of the potential for serious adverse reactions in nursing infants, breastfeeding should be discontinued prior to, during and following treatment with this drug.
No case of overdose has been reported. However, possible symptoms of overdose are expected to include nausea, vomiting, diarrhoea and severe bone marrow suppression. To date, the highest daily dose administered to human beings is 70 mg/m2 for 5 consecutive days (2 paediatric ALL patients). The toxicities observed in these patients included vomiting, hyperbilirubinaemia, elevated transaminase levels and maculo-papular rash. No specific antidotal therapy exists. Immediate discontinuation of therapy, careful observation and initiation of appropriate supportive measures are recommended.
Each vial of the drug contains 180 mg of sodium chloride. This is equivalent to 3.08 mmol (or 70.77 mg) of sodium and should be taken into consideration for patients on a controlled sodium diet. The drug must be diluted prior to administration. Once prepared and diluted, the drug should be used straight away or within 24 hours if stored in a refrigerator (at 2 to 8°C).
The drug should be stored at room temperature (25°C). The drug should not be frozen.
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