Evoltra 1 mg/ml concentrate for solution for infusion
Each ml of concentrate contains 1 mg of clofarabine.
Each 20 ml vial contains 20 mg of clofarabine.
Excipient with known effect
Each 20 ml vial contains 180 mg of sodium chloride.
For the full list of excipients, see section 6.1.
Concentrate for solution for infusion.
Clear, practically colourless solution with a pH of 4.5 to 7.5 and an osmolarity of 270 to 310 mOsm/l.
Treatment of acute lymphoblastic leukaemia (ALL) in paediatric patients who have relapsed or are refractory after receiving at least two prior regimens and where there is no other treatment option anticipated to result in a durable response. Safety and efficacy have been assessed in studies of patients ≤ 21 years old at initial diagnosis (see section 5.1).
Therapy must be initiated and supervised by a physician experienced in the management of patients with acute leukaemias
Posology
Adult population (including elderly)
There are currently insufficient data to establish the safety and efficacy of clofarabine in adult patients (see section 5.2).
Paediatric population
Children and adolescents (≥ 1 year old)
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 (see below). There is currently limited experience of patients receiving more than 3 treatment cycles (see section 4.4).
The majority of patients who respond to clofarabine achieve a response after 1 or 2 treatment cycles (see section 5.1). 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 (see section 4.4).
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 (see section 5.2).
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.
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 above for exclusions), or a life-threatening or disabling toxicity (US NCI CTC Grade 4 toxicity) should be withdrawn from treatment with clofarabine (see section 4.4).
Special populations
Renal impairment
The limited data available indicate that clofarabine may accumulate in patients with decreased creatinine clearance (see sections 4.4 and 5.2). Clofarabine is contraindicated in patients with severe renal insufficiency (see section 4.3) and should be used with caution in patients with mild to moderate renal insufficiency (see section 4.4).
Patients with moderate renal impairment (creatinine clearance 30 – < 60 ml/min) require a 50% dose reduction (see section 5.2).
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 (see section 4.3) and should be used with caution in patients with mild to moderate hepatic impairment (see section 4.4).
Method of administration
The recommended dosage should be administered by intravenous infusion although it has been administered via a central venous catheter in ongoing clinical trials. Evoltra must not be mixed with or concomitantly administered using the same intravenous line as other medicinal products (see section 6.2). For instructions on dilution of the medicinal product before administration (see section 6.6).
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Use in patients with severe renal insufficiency or severe hepatic impairment.
Breast-feeding (see section 4.6).
Evoltra is a potent antineoplastic agent with potentially significant haematological and non-haematological adverse reactions (see section 4.8).
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, liver enzymes and/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 thrombocytopaenia 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 (see section 4.8).
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 neutrop
