Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use
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.

Blood and lymphatic disorders
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 (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 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, caecitis and C. difficile colitis , 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 (see section 4.8).
Patients should be monitored for signs and symptoms of enterocolitis.

Skin and subcutaneous tissue disorders
Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), including fatal cases, have been reported (see section 4.8). Clofarabine must be discontinued for exfoliative or bullous rash, or if SJS or TEN is suspected.


Neoplasms benign and malignant (including cysts and polyps) and Immune systems disorders 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 (see section 4.8).
• Prophylactic administration of allopurinol should be considered if hyperuricemia (tumour lysis) is expected.
• Patients should receive intravenous fluids throughout the five days of clofarabine administration period to reduce the effects of tumour lysis and other events.
• 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.

Clofarabine should be discontinued immediately if patients show early signs or symptoms of SIRS, capillary leak syndrome or substantial organ dysfunction and appropriate supportive measures instituted. In addition, clofarabine treatment should be discontinued if the patient develops hypotension for any reason during the 5 days of administration. Further treatment with clofarabine, generally at a lower dose, can be considered when patient is stabilised and organ function has returned to baseline.

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.

Cardiac disorders
Patients with cardiac disease and those taking medicinal products known to affect blood pressure or cardiac function should be closely monitored during treatment with clofarabine (see sections 4.5 and 4.8).

Renal and urinary disorders
There is no clinical study experience in paediatric patients with renal insufficiency (defined in clinical studies as serum creatinine ≥ 2 x ULN for age) and clofarabine is predominately excreted via the kidneys. Pharmacokinetic data indicate that clofarabine may accumulate in patients with decreased creatinine clearance (see section 5.2). Therefore, clofarabine should be used with caution in patients with mild to moderate renal insufficiency (see section 4.2 for dose adjustment).
The safety profile of clofarabine has not been established in patients with severe renal impairment or patients receiving renal replacement therapy (see section 4.3). 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; preference should be given to those medicinal products that are not known to be nephrotoxic (see sections 4.5 and 4.8).
Renal failure or acute renal failure have been observed as a consequence of infections, sepsis and tumour lysis syndrome (see section 4.8). Patients should be monitored for renal toxicity and clofarabine should be discontinued as necessary.

It was observed that the frequency and severity of adverse reactions, in particular infection, myelosuppression (neutropenia) and hepatotoxicity, are increased when clofarabine is used in combination. In this regard, patients should be closely monitored when clofarabine is used in combined regimens.

Patients receiving clofarabine may experience vomiting and diarrhoea; 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, fainting spells, or decreased urine output.
Prophylactic anti-emetic medicinal products should be considered.

Hepato biliary disorders
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 should be used with caution in patients with mild to moderate hepatic impairment (see sections 4.2 and 4.3). The concomitant use of medicinal products that have been associated with hepatic toxicity should be avoided wherever possible (see sections 4.5 and 4.8).
If a patient experiences a hematologic toxicity of Grade 4 neutropaenia (ANC <0.5 x 109/l) lasting ≥4 weeks, then the dose should be reduced by 25% for the next cycle.

Any patient who experiences a severe non-hematologic toxicity (US NCI CTC Grade 3 toxicity) on a third occasion, a severe toxicity that does not recover within 14 days (excluding nausea/ vomiting) or a life-threatening or disabling non-infectious non-hematologic toxicity (US NCI CTC Grade 4 toxicity) should be withdrawn from treatment with clofarabine (see section 4.2).

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). In the post-marketing period, following treatment with clofarabine, serious hepatotoxic adverse reactions of VOD in paediatric and adult patients have been associated with a fatal outcome.
Cases of hepatitis and hepatic failure, including fatal outcomes, have been reported with clofarabine treatment (see section 4.8).
Most patients received conditioning regimens that included busulfan, melphalan, and/or the combination of cyclophosphamide and total body irradiation.
Severe hepatotoxic events have been reported in a Phase 1/2 combination study of clofarabine in paediatric patients with relapsed or refractory acute leukemia.


There are currently limited data on the safety and efficacy of clofarabine when administered for more than 3 treatment cycles.

Evoltra contains sodium
This medicinal product contains 72 mg sodium per vial, equivalent to 3.6% of the WHO recommended maximum daily intake for sodium.
The maximum daily dose of this product is equivalent to 23.4% of the WHO recommended maximum daily intake for sodium. Evoltra is considered high in sodium. This should be particularly taken into account for those on a low salt diet.

Effects on Driving

4.7   Effects on ability to drive and use machines

No studies on the effects of clofarabine on the ability to drive and use machines have been performed.
However, patients should be advised that they may experience undesirable effects such as dizziness, light-headedness or fainting spells during treatment and told not to drive or operate machines in such circumstances.