Evoltra

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 



 

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This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Evoltra 1 mg/ml concentrate for solution for infusion 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

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. 

 

 

3. PHARMACEUTICAL FORM 

 

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. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

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). 

 

4.2 Posology and method of administration 

 

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 



 

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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 



 

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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). 

 

4.3 Contraindications 

 

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). 

 

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 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 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.  

 



 

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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 5 day 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 patients are 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 adjustments). 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. 



 

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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 leukaemia.  

 

There are currently limited data on the safety and efficacy of clofarabine when administered for more 

than 3 treatment cycles. 

 

Each vial of Evoltra 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. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

No interaction studies have been performed. 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. 

 



 

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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 (see sections 4.4, 4.8 and 5.2).   

 

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 (see sections 4.4 and 

4.8). 

 

Patients taking medicinal products known to affect blood pressure or cardiac function should be 

closely monitored during treatment with clofarabine (see sections 4.4 and 4.8). 

 

4.6 Fertility, pregnancy and lactation 
 

Contraception in males and females 

 

Females of childbearing potential and sexually active males must use effective methods of 

contraception during treatment.   

 

Pregnancy 

 

There are no data on the use of clofarabine in pregnant women. Studies in animals have shown 

reproductive toxicity including teratogenicity (see section 5.3). Clofarabine may cause serious birth 

defects when administered during pregnancy. Therefore, Evoltra 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. 

 

Breast-feeding 

 

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 Evoltra (see section 4.3). 

 

Fertility 

 

Dose related toxicities on male reproductive organs have been observed in mice, rats and dogs, and 

toxicities on female reproductive organs have been observed in mice (see section 5.3). As the effect of 

clofarabine treatment on human fertility is unknown, reproductive planning should be discussed with 

patients as appropriate. 

 

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. 

 

4.8 Undesirable effects 
 

Summary of the safety profile 

 

Nearly all patients (98%) experienced at least one adverse event considered by the study investigator 

to be related to clofarabine.  Those most frequently reported were nausea (61% of patients), vomiting 



 

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(59%), febrile neutropaenia (35%), headache (24%), rash (21%), diarrhoea (20%), pruritus (20%), 

pyrexia (19%), palmar-plantar erythrodysaesthesia syndrome (15%), fatigue (14%), anxiety (12%), 

mucosal inflammation (11%), and flushing (11%).  Sixty-eight patients (59%) experienced at least 

one serious clofarabine-related adverse event. One patient discontinued treatment due to grade 4 

hyperbilirubinaemia considered as related to clofarabine after receiving 52 mg/m2/day clofarabine. 

Three patients died of adverse events considered by the study investigator to be related to treatment 

with clofarabine: one patient died from respiratory distress, hepatocellular damage, and capillary leak 

syndrome; one patient from VRE sepsis and multi-organ failure; and one patient from septic shock 

and multi-organ failure. 

 

Tabulated list of adverse reactions 

 

The information provided is based on data generated from clinical trials in which 115 patients (> 1 

and ≤  21 years old) with either ALL or acute myeloid leukaemia (AML) received at least one dose of 

clofarabine at the recommended dose of 52 mg/m2 daily x 5.  

 

Adverse reactions are listed by system organ class and frequency (very common ( 1/10); common 

( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100; rare ( 1/10,000 to < 1/1,000) and very rare 

(< 1/10,000)) in the table below. Adverse reactions reported during the post-marketing period are also 

included in the table under the frequency category “not known” (cannot be estimated from the 

available data). Within each frequency grouping, adverse reactions are presented in order of 

decreasing seriousness. 

 

Patients with advanced stages of ALL or AML may have confounding medical conditions that make 

causality of adverse events difficult to assess due to the variety of symptoms related to the underlying 

disease, its progression and the co-administration of numerous medicinal products. 

 

 

Adverse reactions considered to be related to clofarabine  

reported at frequencies ≥ 1/1,000 (i.e. in > 1/115 patients) in clinical trials 

and post-marketing  

Infections and infestations Common: Septic shock*, sepsis, bacteraemia, 

pneumonia, herpes zoster, herpes simplex, oral 

candidiasis 

Frequency not known: C. difficile colitis 

Neoplasms benign and malignant 

(including cysts and polyps) 

Common: Tumour lysis syndrome* 

Blood and lymphatic system disorders Very common: Febrile neutropaenia  

Common: Neutropaenia 

Immune system disorders Common: Hypersensitivity 

Metabolism and nutrition disorders Common: Anorexia, decreased appetite, dehydration 

Frequency not known: hyponatremia 

Psychiatric disorders Very common: Anxiety 

Common: Agitation, restlessness, mental status change 

Nervous system disorders Very common: Headache 

Common: Somnolence, peripheral neuropathy, 

paraesthesia, dizziness, tremor  

Ear and labyrinth disorders Common: Hypoacusis 

Cardiac disorders Common: Pericardial effusion*, tachycardia*  

Vascular disorders Very common: Flushing* 

Common: Hypotension*, capillary leak syndrome, 

haematoma 



 

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Respiratory, thoracic and mediastinal 

disorders 

Common: Respiratory distress, epistaxis, dyspnoea, 

tachypnoea, cough  

Gastrointestinal disorders Very common: Vomiting, nausea, diarrhoea 

Common: Mouth haemorrhage, gingival bleeding, 

haematemesis, abdominal pain, stomatitis, upper 

abdominal pain, proctalgia, mouth ulceration  

Frequency not known: Pancreatitis elevations in serum 

amylase and lipase, enterocolitis, neutropaenic colitis, 

caecitis 

Hepato-biliary disorders 

 

Common: Hyperbilirubinaemia, jaundice, veno-

occlusive disease,  increases in alanine (ALT)* and 

aspartate (AST)* aminotransferases, hepatic failure 

Uncommon: Hepatitis  

General disorders and administration site 

conditions  

Very common: Fatigue, pyrexia, mucosal inflammation  

Common: Multi-organ failure, systemic inflammatory 

response syndrome*, pain, chills, irritability, oedema, 

peripheral oedema, feeling hot, feeling abnormal  

Skin and subcutaneous tissue disorders Very common: Palmar-plantar erythrodysaesthesia 

syndrome, pruritus 

Common: Maculo-papular rash, petechiae, erythema, 

pruritic rash, skin exfoliation, generalised rash, alopecia, 

skin hyperpigmentation, generalised erythema,  

erythematous rash, dry skin, hyperhidrosis  

Frequency not known: Stevens Johnson Syndrome 

(SJS), toxic epidermal necrolysis (TEN) 

Musculoskeletal, connective tissue and 

bone disorders 

Common: Pain in extremity, myalgia, bone pain, chest 

wall pain, arthralgia, neck and back pain 

Renal and urinary disorders Common: Haematuria* 

Common: Renal failure, acute renal failure 

Investigations Common: Weight decreased  

Injury, poisoning and procedural 

complications 

Common: Contusion 

* = see below 

**All adverse reactions occurring at least twice (i.e., 2 or more reactions (1.7%)) are included in this 

table 

 

Description of selected adverse reactions 

 

Blood and lymphatic system disorders 

The most frequent haematological laboratory abnormalities observed in patients treated with 

clofarabine were anaemia (83.3%; 95/114); leucopaenia (87.7%; 100/114); lymphopaenia (82.3%; 

93/113), neutropaenia (63.7%; 72/113), and thrombocytopaenia (80.7%; 92/114).The majority of 

these events were of grade  3. 

 

During the post-marketing period prolonged cytopaenias (thrombocytopaenia, anaemia, neutropaenia 

and leukopaenia) and bone marrow failure have been reported. Bleeding events have been observed in 

the setting of thrombocytopaenia. Haemorrhage, including cerebral, gastrointestinal and pulmonary 

haemorrhage, has been reported and may be associated with a fatal outcome (see section 4.4). 

 

Vascular disorders  

Sixty-four patients of 115 (55.7%) experienced at least one vascular disorders adverse event.  Twenty-

three patients out of 115 experienced a vascular disorder  considered to be related to clofarabine, the 

most frequently reported being flushing (13 events; not serious) and hypotension (5 events; all of 

which were considered to be serious; see section 4.4).  However, the majority of these hypotensive 

events were reported in patients who had confounding severe infections. 



 

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Cardiac disorders  

Fifty percent of patients experienced at least one cardiac disorders adverse event. Eleven events in 

115 patients were considered to be related to clofarabine, none of which were serious and the most 

frequently reported cardiac disorder was tachycardia (35%) (see section 4.4); 6.1% (7/115) patient's 

tachycardia were considered to be related to clofarabine. Most of the cardiac adverse events were 

reported in the first 2 cycles. 

 

Pericardial effusion and pericarditis were reported as an adverse event in 9% (10/115) of patients. 

Three of these events were subsequently assessed as being related to clofarabine: pericardial effusion 

(2 events; 1 of which was serious) and pericarditis (1 event; not serious). In the majority of patients 

(8/10), the pericardial effusion and pericarditis were deemed to be asymptomatic and of little or no 

clinical significance on echocardiographic assessment. However, the pericardial effusion was 

clinically significant in 2 patients with some associated haemodynamic compromise. 

 

Infections and infestations  

Forty-eight percent of patients had one or more ongoing infections prior to receiving treatment with 

clofarabine. A total of 83% of patients experienced at least 1 infection after clofarabine treatment, 

including fungal, viral and bacterial infections (see section 4.4). Twenty-one (18.3%) events were 

considered to be related to clofarabine of which catheter related infection (1 event), sepsis (2 events) 

and septic shock (2 events; 1 patient died (see above)) were considered to be serious. 

 

During the post-marketing period, bacterial, fungal and viral infections have been reported and may 

be fatal. These infections may lead to septic shock, respiratory failure, renal failure, and/or multi-

organ failure. 

 

Renal and urinary disorders  

Forty-one patients of 115 (35.7%) experienced at least one renal and urinary disorders adverse event.  

The most prevalent renal toxicity in paediatric patients was elevated creatinine. Grade 3 or 4 elevated 

creatinine occurred in 8% of patients. Nephrotoxic medicinal products, tumour lysis, and tumour lysis 

with hyperuricemia may contribute to renal toxicity (see sections 4.3 and 4.4). Haematuria was 

observed in 13% of patients overall. Four renal adverse events in 115 patients were considered to be 

related to clofarabine, none of which were serious; haematuria (3 events) and acute renal failure 

(1 event) (see sections 4.3 and 4.4).   

 

Hepato-biliary disorders  

The liver is a potential target organ for clofarabine toxicity and 25.2% of patients experienced at least 

one hepato-biliary disorders adverse event (see sections 4.3 and 4.4). Six events were considered to be 

related to clofarabine of which acute cholecystitis (1 event), cholelithiasis (1 event), hepatocellular 

damage (1 event; patient died (see above)) and hyperbilirubinaemia (1 event; the patient discontinued 

therapy (see above)) were considered to be serious. Two paediatric reports (1.7%) of veno-occlusive 

disease (VOD) were considered related to study drug.  

 

VOD cases reported during the post-marketing period in paediatric and adult patients have been 

associated with a fatal outcome (see section 4.4).  

 

In addition, 50/113 patients receiving clofarabine had at least severely (at least US NCI CTC Grade 3) 

elevated ALT, 36/100 elevated AST and 15/114 elevated bilirubin levels.  The majority of elevations 

in ALT and AST occurred within 10 days of clofarabine administration and returned to  grade 2 

within 15 days. Where follow-up data are available, the majority of bilirubin elevations returned 

to  grade 2 within 10 days. 

 

Systemic inflammatory response syndrome (SIRS) or capillary leak syndrome  

SIRS, capillary leak syndrome (signs and symptoms of cytokine release, e.g., tachypnea, tachycardia, 

hypotension, pulmonary oedema) were reported as an adverse event in 5% (6/115) of paediatric 

patients (5 ALL, 1 AML) (see section 4.4). Thirteen events of tumour lysis syndrome, capillary leak 



 

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syndrome or SIRS have been reported; SIRS (2 events; both were considered to be serious), capillary 

leak syndrome (4 events; 3 of which were considered serious and related) and tumour lysis syndrome 

(7 events; 6 of which were considered related and 3 of which were serious). 

 

Capillary leak syndrome cases reported during the post-marketing period have been associated with a 

fatal outcome (See section 4.4). 

 

Gastrointestinal disorders  

Occurrences of enterocolitis, including neutropaenic colitis, caecitis, and C. difficile colitis have been 

reported during treatment with clofarabine. Enterocolitis may lead to necrosis, perforation or sepsis 

complications and may be associated with fatal outcome (see section 4.4). 

 

Skin and subcutaneous disorders  

Stevens - Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal cases, have 

been reported in patients who were receiving or had recently been treated with clofarabine. Other 

exfoliative conditions have also been reported. 

 

Reporting of suspected adverse reactions 

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

4.9 Overdose 

 

Symptoms 

 

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. 

 

Management  

 

No specific antidotal therapy exists. Immediate discontinuation of therapy, careful observation and 

initiation of appropriate supportive measures are recommended. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1  Pharmacodynamic properties 

 

Pharmacotherapeutic group: Antineoplastic agents, antimetabolites, ATC code: L01BB06.  

 

Mechanism of action  

 

Clofarabine is a purine nucleoside anti-metabolite. Its antitumour activity is believed to be due to 

3 mechanisms:  

 

• DNA polymerase  inhibition resulting in termination of DNA chain elongation and/or DNA 

synthesis / repair. 

• Ribonucleotide reductase inhibition with reduction of cellular deoxynucleotide triphosphate 

(dNTP) pools. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

12 

• Disruption of mitochondrial membrane integrity with the release of cytochrome C and other 

proapoptotic factors leading to programmed cell death even in non-dividing lymphocytes. 

 

Clofarabine must first diffuse or be transported into target cells where it is sequentially 

phosphorylated to the mono- and bi-phosphate by intracellular kinases, and then finally to the active 

conjugate, clofarabine 5’-triphosphate. Clofarabine has high affinity for one of the activating 

phosphorylating enzymes, deoxycytidine kinase, which exceeds that of the natural substrate, 

deoxycytidine. 

 

In addition, clofarabine possesses greater resistance to cellular degradation by adenosine deaminase 

and decreased susceptibility to phosphorolytic cleavage than other active substances in its class whilst 

the affinity of clofarabine triphosphate for DNA polymerase  and ribonucleotide reductase is similar 

to or greater than that of deoxyadenosine triphosphate. 

 

Pharmacodynamic effects  

 

In vitro studies have demonstrated that clofarabine inhibits cell growth in and is cytotoxic to a variety 

of rapidly proliferating haematological and solid tumour cell lines.  It was also active against 

quiescent lymphocytes and macrophages.  In addition, clofarabine delayed tumour growth and, in 

some cases, caused tumour regression in an assortment of human and murine tumour xenografts 

implanted in mice. 

 

Clinical efficacy and safety 

 

Clinical efficacy: To enable systematic evaluation of the responses seen in patients, an unblinded 

Independent Response Review Panel (IRRP) determined the following response rates based on 

definitions produced by the Children’s Oncology Group: 

 

CR = Complete Remission Patients who met each of the following criteria: 

• No evidence of circulating blasts or extramedullary 

disease 

• An M1 bone marrow (≤ 5% blasts) 

• Recovery of peripheral counts (platelets  100 x 109/l 

and ANC  1.0 x 109/l) 

CRp = Complete Remission in the 

Absence of Total Platelet Recovery 

• Patients who met all of the criteria for a CR except 

for recovery of platelet counts to > 100 x 109/l 

PR = Partial Remission Patients who met each of the following criteria: 

• Complete disappearance of circulating blasts 

• An M2 bone marrow ( 5% and ≤ 25% blasts) and 

appearance of normal progenitor cells 

• An M1 marrow that did not qualify for CR or CRp 

Overall Remission (OR) Rate - (Number of patients with a CR + Number of patients 

with a CRp) ÷ Number of eligible patients who 

received clofarabine 

 

The safety and efficacy of clofarabine were evaluated in a phase I, open-label, non-comparative, 

dose-escalation study in 25 paediatric patients with relapsed or refractory leukaemia (17 ALL; 

8 AML) who had failed standard therapy or for whom no other therapy existed.  Dosing commenced 

at 11.25 with escalation to 15, 30, 40, 52 and 70 mg/m2/day by intravenous infusion for 5 days every 

2 to 6 weeks depending on toxicity and response. Nine of 17 ALL patients were treated with 

clofarabine 52 mg/m2/day.  Of the 17 ALL patients, 2 achieved a complete remission (12%; CR) and 2 

a partial remission (12%; PR) at varying doses. Dose-limiting toxicities in this study were 

hyperbilirubinaemia, elevated transaminase levels and maculo-papular rash experienced at 

70 mg/m2/day (2 ALL patients; see section 4.9). 

 



 

13 

A multi-centre, phase II, open-label, non-comparative study of clofarabine was conducted to 

determine the overall remission (OR) rate in heavily pretreated patients (≤ 21 years old at initial 

diagnosis) with relapsed or refractory ALL defined using the French-American-British classification. 

The maximum tolerated dose identified in the phase I study described above of 52 mg/m2/day 

clofarabine was administered by intravenous infusion for 5 consecutive days every 2 to 6 weeks. The 

table below summarises the key efficacy results for this study. 

 

Patients with ALL must not have been eligible for therapy of higher curative potential and must have 

been in second or subsequent relapse and/or refractory i.e. failed to achieve remission after at least 

two prior regimens. Before enrolling in the trial, 58 of the 61 patients (95%) had received 

2 to 4 different induction regimens and 18/61 (30%) of these patients had undergone at least 1 prior 

haematological stem cell transplant (HSCT). The median age of treated patients (37 males, 

24 females) was 12 years old. 

 

Administration of clofarabine resulted in a dramatic and rapid reduction in peripheral leukaemia cells 

in 31 of the 33 patients (94%) who had a measurable absolute blast count at baseline. The 12 patients 

who achieved an overall remission (CR + CRp) had a median survival time of 66.6 weeks as of the 

data collection cut-off date. Responses were seen in different immunophenotypes of ALL, including 

pre-B cell and T-cell. Although transplantation rate was not a study endpoint, 10/61 patients (16%) 

went on to receive a HSCT after treatment with clofarabine (3 after achieving a CR, 2 after a CRp, 

3 after a PR, 1 patient that was considered a treatment failure by the IRRP and 1 that was considered 

not evaluable by the IRRP). Response durations are confounded in patients who received a HSCT. 

 

Efficacy results from the pivotal study in patients (≤ 21 years old at initial diagnosis) with 

relapsed or refractory ALL after at least two prior regimens 

Response 

category 

ITT* 

patients 

(n = 61) 

Median duration 

of remission 

(weeks) 

(95% CI) 

Median time to 

progression 

(weeks)** 

(95% CI) 

Median overall 

survival (weeks) 

(95% CI) 

Overall 

remission 

(CR + CRp) 

12 

(20%) 

32.0 

(9.7 to 47.9) 

38.2 

(15.4 to 56.1) 

69.5 

(58.6 to -) 

CR 7 

(12%) 

47.9 

(6.1 to -) 

56.1 

(13.7 to -) 

72.4 

(66.6 to -) 

CRp 5 

(8%) 

28.6 

(4.6 to 38.3) 

37.0 

(9.1 to 42) 

53.7 

(9.1 to -) 

PR 6 

(10%) 

11.0 

(5.0 to -) 

14.4 

(7.0 to -) 

33.0 

(18.1 to -) 

CR + CRp + PR 18 

(30%) 

21.5 

(7.6 to 47.9) 

28.7 

(13.7 to 56.1) 

66.6 

(42.0 to -) 

Treatment 

failure 

33 

(54%) 

N/A  

4.0 

(3.4 to 5.1) 

 

7.6 

(6.7 to 12.6) Not evaluable 10 

(16%) 

N/A 

All patients 61 

(100%) 

N/A 5.4 

(4.0 to 6.1) 

12.9 

(7.9 to 18.1) 

*ITT = intention to treat. 

**Patients alive and in remission at the time of last follow up were censored at that time point for 

the analysis. 

 



 

14 

Individual duration remission and survival data for patients who achieved CR or CRp  

Best Response 

Time to OR 

(weeks) 

Duration of 

Remission 

(weeks) 

Overall 

Survival 

(weeks) 

Patients who did not undergo transplant 

CR 5.7 4.3 66.6 

CR 14.3 6.1 58.6 

CR 8.3 47.9 66.6 

CRp 4.6 4.6 9.1 

CR 3.3 58.6 72.4 

CRp 3.7 11.7 53.7 

Patients who underwent transplant while in continued 

remission* 

CRp 8.4 11.6+ 145.1+ 

CR 4.1 9.0+ 111.9+  

CRp 3.7 5.6+ 42.0 

CR 7.6 3.7+ 96.3+  

Patients who underwent transplant after alternative therapy or 

relapse* 

CRp 4.0 35.4 113.3+** 

CR 4.0 9.7 89.4*** 

* Duration of remission censored at the time of transplant 

** Patient received a transplant following alternate therapy 

*** Patient received a transplant following relapse 

 

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to 

the rarity of the disease it has not been possible to obtain complete information on this medicinal 

product. 

The European Medicines Agency will review any new information which may become available every 

year and this SmPC will be updated as necessary. 

 

5.2 Pharmacokinetic properties 

 

Adsorption and distribution 

 

The pharmacokinetics of clofarabine were studied in 40 patients aged between 2 to 19 years old with 

relapsed or refractory ALL or AML. The patients were enrolled into a single phase I (n = 12) or two 

phase II (n = 14 / n = 14) safety and efficacy studies, and received multiple doses of clofarabine by 

intravenous infusion (see section 5.1). 

 



 

15 

Pharmacokinetics in patients aged between 2 to 19 years old with relapsed or refractory 

ALL or AML following administration of multiple doses of clofarabine by intravenous 

infusion 

Parameter Estimates based on 

non-compartmental 

analysis 

(n = 14 / n = 14) 

Estimates based on other 

analysis 

Distribution: 

Volume of distribution (steady 

state) 

172 l/m2  

Plasma protein binding  47.1% 

Serum albumin  27.0% 

Elimination: 

 half-life of clofarabine 5.2 hours  

Half-life of clofarabine 

triphosphate 

 > 24 hours 

Systemic clearance 28.8 l/h/m2  

Renal clearance 10.8 l/h/m2  

Dose excreted in urine 57%  

 

Multivariate analysis showed that the pharmacokinetics of clofarabine are weight dependent and 

although white blood cell (WBC) count was identified as having an impact on clofarabine 

pharmacokinetics, this did not appear sufficient to individualise a patient’s dosage regimen based on 

their WBC count.  Intravenous infusion of 52 mg/m2 clofarabine produced equivalent exposure across 

a wide range of weights.  However, Cmax is inversely proportional to patient weight and, therefore, 

small children may have a higher Cmax at the end of infusion than a typical 40 kg child given the same 

dose of clofarabine per m2.  Accordingly, longer infusion times should be considered in children 

weighing  20 kg (see section 4.2). 

 

Biotransformation and elimination 

 

Clofarabine is eliminated by a combination of renal and non-renal excretion.  After 24 hours, about 

60% of the dose is excreted unchanged in the urine.  Clofarabine clearance rates appear to be much 

higher than glomerular filtration rates suggesting filtration and tubular secretion as kidney elimination 

mechanisms.  However, as clofarabine is not detectably metabolised by the cytochrome P450 (CYP) 

enzyme system, pathways of non-renal elimination currently remain unknown. 

 

No apparent difference in pharmacokinetics was observed between patients with ALL or AML, or 

between males and females. 

 

No relationship between clofarabine or clofarabine triphosphate exposure and either efficacy or 

toxicity has been established in this population. 

 

Special populations 

 

Adults (> 21 and < 65 years old)  

There are currently insufficient data to establish the safety and efficacy of clofarabine in adult 

patients.  However, the pharmacokinetics of clofarabine in adults with relapsed or refractory AML 

following administration of a single dose of 40 mg/m2 clofarabine by intravenous infusion over 1 hour 

were comparable to those described above in patients aged between 2 to 19 years old with relapsed or 

refractory ALL or AML following administration of 52 mg/m2 clofarabine by intravenous infusion 

over 2 hours for 5 consecutive days. 

 



 

16 

Elderly (≥ 65 years old)  

There are currently insufficient data to establish the safety and efficacy of clofarabine in patients 

65 years of age or older. 

 

Renal impairment  

To date, there are limited data on the pharmacokinetics of clofarabine in paediatric patients with 

decreased creatinine clearance.  However, these data indicate that clofarabine may accumulate in such 

patients (see figure below).   

 

Population pharmacokinetic data from adult and paediatric patients suggest that patients with stable 

moderate renal impairment (creatinine clearance 30 – < 60 ml/min) receiving a 50% dose reduction 

achieve similar clofarabine exposure to those with normal renal function receiving a standard dose.  

 

Clofarabine AUC0-24 hours by baseline estimated creatinine clearance in patients aged between 

2 to 19 years old with relapsed or refractory ALL or AML (n = 11 / n = 12) following 

administration of multiple doses of clofarabine by intravenous infusion 

(creatinine clearance estimated using Schwartz formula) 

Estimated creatinine clearance (ml/min)

Clofarabine

AUC 0-24 hours

(ng*h/ml)

0 50 100 150 200 250

0

500

1000

1500

2000

2500

3000

 
 

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 (see sections 4.3 and 4.4). 

 

5.3 Preclinical safety data 

 

Toxicology studies of clofarabine in mice, rats and dogs showed that rapidly proliferating tissues were 

the primary target organs of toxicity. 

 

Cardiac effects were observed in rats consistent with cardiomyopathy and contributed to signs of 

cardiac failure after repeated cycles of treatment. The incidence of these toxicities was dependent on 

both the dose of clofarabine administered and the duration of treatment. They were reported at 

exposure levels (Cmax) approximately 7 to 13 fold (after 3 or more dosing cycles) or 16 to 35 fold 

(after one or more dosing cycles) higher than clinical exposures. The minimal effects seen at lower 

doses suggest that there is a threshold for toxicities on the heart and nonlinear plasma 

pharmacokinetics in the rat may play a role in the observed effects. The potential risk for humans is 

unknown. 

 



 

17 

Glomerulonephropathy was reported in rats at exposure levels 3 to 5 fold higher than the clinical 

AUC after 6 dosing cycles of clofarabine. It was characterised by minor thickening of the glomerular 

basement membrane with only slight tubular damage and was not associated with changes in serum 

chemistry. 

 

Hepatic effects were observed in rats following chronic administration of clofarabine. These likely 

represent the superimposition of degenerative and regenerative changes as a result of treatment cycles, 

and were not associated with changes in serum chemistry. Histological evidence of hepatic effects 

was seen in dogs following acute administration of high doses, but was also not accompanied by 

changes in serum chemistry. 

 

Dose related toxicities on male reproductive organs were observed in mice, rats and dogs. These 

effects included bilateral degeneration of the seminiferous epithelium with retained spermatids and 

atrophy of interstitial cells in rats at exaggerated exposure levels (150 mg/m2/day), and cell 

degeneration of the epididymis and degeneration of the seminiferous epithelium in dogs at clinically 

relevant exposure levels (> 7.5 mg/m2/day clofarabine). 

 

Delayed ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice 

at the only dose used of 225 mg/m2/day clofarabine. 

 

Clofarabine was teratogenic in rats and rabbits. Increases in postimplantation loss, reduced foetal 

body weights and decreased litter sizes together with increases in the number of malformations (gross 

external, soft tissue) and skeletal alterations (including retarded ossification) were reported in rats 

receiving doses which produced approximately 2 to 3 fold the clinical exposure (54 mg/m2/day) and in 

rabbits receiving 12 mg/m2/day clofarabine. (There are no exposure data in rabbits.) The threshold for 

developmental toxicity was considered to be 6 mg/m2/day in rats and 1.2 mg/m2/day in rabbits. The 

no-observable effect level for maternal toxicity in rats was 18 mg/m2/day and in rabbits was more than 

12 mg/m2/day. No fertility studies have been conducted. 

 

Genotoxicity studies demonstrated that clofarabine was not mutagenic in the bacterial reverse 

mutation assay, but did induce clastogenic effects in the non-activated chromosomal aberration assay 

in Chinese Hamster Ovary (CHO) cells and in the in vivo rat micronucleus assay. 

 

No carcinogenicity studies have been performed. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Sodium chloride 

Water for injections 

 

6.2 Incompatibilities 

 

This medicinal product must not be mixed with other medicinal products except those mentioned in 

section 6.6. 

 

6.3 Shelf life 

 

3 years. 



 

18 

 

The diluted concentrate is chemically and physically stable for 3 days at 2°C to 8°C and at room 

temperature (up to 25°C). From a microbiological point of view, it should be used immediately.  If not 

used immediately, in-use storage times and conditions prior to use are the responsibility of the user 

and would normally not be longer than 24 hours at 2°C to 8°C unless dilution has taken place under 

controlled and validated aseptic conditions. 

 

6.4 Special precautions for storage 

 

Do not freeze. 

 

For storage conditions after dilution of the medicinal product, see section 6.3. 

 

6.5 Nature and contents of container 
 

Type I glass vial with bromobutyl rubber stopper, polypropylene flip-off cap and aluminium overseal. 

The vials contain 20 ml concentrate for solution for infusion and are packaged in a box.  

Each box contains 1, 3, 4, 10 or 20 vials. 

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal and other handling 

 

Special precautions for administration 

 

Evoltra 1 mg/ml concentrate for solution for infusion must be diluted prior to administration. It should 

be filtered through a sterile 0.2 micrometre syringe filter and then diluted with sodium chloride 

9 mg/ml (0.9%) intravenous infusion to produce a total volume according to the examples given in the 

table below. However, the final dilution volume may vary depending on the patient’s clinical status 

and physician discretion. (If the use of a 0.2 micrometre syringe filter is not feasible, the concentrate 

should be pre-filtered with a 5 micrometre filter, diluted and then administered through a 

0.22 micrometre in-line filter.) 

 

Suggested dilution schedule based on the recommended dosage of 52 mg/m2/day clofarabine 

Body surface area (m2) Concentrate (ml)* Total diluted volume 

≤ 1.44 ≤ 74.9 100 ml 

1.45 to 2.40 75.4 to 124.8 150 ml 

2.41 to 2.50 125.3 to 130.0 200 ml 

*Each ml of concentrate contains 1 mg of clofarabine. Each 20 ml vial contains 20 mg of 

clofarabine. Therefore, for patients with a body surface area ≤ 0.38 m2, the partial contents of a 

single vial will be required to produce the recommended daily dosage of clofarabine. However, for 

patients with a body surface area > 0.38 m2, the contents of between 1 to 7 vials will be required to 

produce the recommended daily dosage of clofarabine. 

 

The diluted concentrate should be a clear, colourless solution. It should be visually inspected for 

particulate matter and discolouration prior to administration. 

 

Instructions for handling 

 

Procedures for proper handling of antineoplastic agents should be observed. Cytotoxic medicinal 

products should be handled with caution. 

 

The use of disposable gloves and protective garments is recommended when handling Evoltra. If the 

product comes into contact with eyes, skin or mucous membranes, rinse immediately with copious 

amounts of water. 



 

19 

 

Evoltra should not be handled by pregnant women. 

 

Disposal 

 

Evoltra is for single use only. Any unused medicinal product or waste material should be disposed of 

in accordance with local requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Genzyme Europe BV  

Paasheuvelweg 25 

1105 BP Amsterdam 

The Netherlands  

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/06/334/001 3 vials 

EU/1/06/334/002 4 vials 

EU/1/06/334/003 10 vials 

EU/1/06/334/004 20 vials 

EU/1/06/334/005 1 vial 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 29 May 2006. 

Date of latest renewal: 14 January 2016 

 

 

10. DATE OF REVISION OF THE TEXT 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu/. 

 

 

http://www.ema.europa.eu/


 

20 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND 

USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 

SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION 

MEASURES FOR THE MARKETING AUTHORISATION UNDER 

EXCEPTIONAL CIRCUMSTANCES 



 

21 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer responsible for batch release 

 

Genzyme Limited 

37 Hollands Road 

Haverhill 

Suffolk  

CB9 8PU 

United Kingdom 

 

SANOFI WINTHROP INDUSTRIE 

30-36, avenue Gustave Eiffel 

37100 Tours 

France 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

• Periodic Safety Updated Reports 

 

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 

USE OF THE MEDICINAL PRODUCT 

 

• Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in 

the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 

subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency 

• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 

 

 

 

 



 

22 

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 

FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES 

 

This being an approval under exceptional circumstances and pursuant to Article 14(8) of Regulation 

(EC) No 726/2004, the MAH shall conduct, within the stated timeframe, the following measures: 

 

Description Due date 

 

The MAH shall provide yearly updates on any new information concerning 

efficacy and safety of the product in paediatric patients with acute lymphoblastic 

leukaemia 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. 

 

Yearly, 

simultaneously 

with 

submission of 

Periodic Safety 

Update reports 



 

23 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



 

24 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 



 

25 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Evoltra 1 mg/ml concentrate for solution for infusion 

clofarabine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each 20 ml vial contains 20 mg of clofarabine 

 

 

3. LIST OF EXCIPIENTS 

 

Excipients: Sodium chloride and water for injections. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Concentrate for solution for infusion 

20 mg/20 ml 

 

1 vial 

3 vials 

4 vials 

10 vials 

20 vials 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Intravenous use. 

 

Dilute before use. 

For single use only. 

 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

Cytotoxic 

 



 

26 

 

8. EXPIRY DATE 

 

EXP: 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not freeze. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

Any unused product or waste material should be disposed of in accordance with local requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Genzyme Europe BV  

Paasheuvelweg 25 

1105 BP AmsterdamThe Netherlands  

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/06/334/001 3 vials 

EU/1/06/334/002 4 vials 

EU/1/06/334/003 10 vials 

EU/1/06/334/004 20 vials 

EU/1/06/334/005 1 vial 

 

 

13. BATCH NUMBER 

 

BN: 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted 

 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 



 

27 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN:  



 

28 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Evoltra 1 mg/ml concentrate for solution for infusion 

clofarabine 

Intravenous use 

 

 

2. METHOD OF ADMINISTRATION 

 

Read the package leaflet before use 

 

 

3. EXPIRY DATE 

 

EXP: 

 

 

4. BATCH NUMBER 

 

BN: 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

20 mg/20 ml 

 

 

6. OTHER 

 

Genzyme Europe B.V. 



 

29 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 

 



 

30 

Package leaflet: Information for the user 

 

Evoltra 1 mg/ml concentrate for solution for infusion 

clofarabine 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 

 

Read all of this leaflet carefully before you start using this medicine because it contains 

important information for you. 

• Keep this leaflet. You may need to read it again. 

• If you have any further questions, ask your doctor. 

• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

• If you get any side effects, talk to your doctor. This includes any possible side effects not listed in 

this leaflet. See section 4. 

 

What is in this leaflet 

1. What Evoltra is and what it is used for 

2. What you need to know before you use Evoltra 

3. How to use Evoltra 

4. Possible side effects 

5. How to store Evoltra 

6. Contents of the pack and other information 

 

 

1. What Evoltra is and what it is used for 
 

Evoltra contains the active substance clofarabine. Clofarabine is one of a family of medicines called 

anticancer medicines. It works by hindering the growth of abnormal white blood cells, and eventually 

kills them. It works best against cells which are multiplying quickly – such as cancer cells. 

 

Evoltra is used to treat children (≥ 1 year old), teenagers and young adults up to 21 years old with 

acute lymphoblastic leukaemia (ALL) when previous treatments have not worked or have stopped 

working. Acute lymphoblastic leukaemia is caused by abnormal growth of some types of white blood 

cells. 

 

 

2. What you need to know before you use Evoltra 
 

Do not use Evoltra: 

- if you are allergic to clofarabine or any of the other ingredients of this medicine (listed in 

section 6); 

- if you are breast-feeding (please read the section “Pregnancy and breast-feeding” below); 

- if you have severe kidney or liver problems. 

 

Tell your doctor if any of these conditions apply to you.  If you are the parent of a child who is 

being treated with Evoltra, tell the doctor if any of them apply to your child. 

 

Warnings and precautions 

Tell your doctor if any of these apply to you.  Evoltra may not be suitable for you: 

- if you have suffered a severe reaction after previously using this medicine; 

- if you have kidney disease, or used to have it; 

- if you have liver disease, or used to have it; 



 

31 

- if you have heart disease, or used to have it. 

 

Tell your doctor or carer immediately if you experience any of the following as you may need to 

stop treatment: 

- if you get a fever or high temperature – because clofarabine reduces the number of blood cells 

made in the bone marrow, you may be more likely to catch infections; 

- if you have breathing difficulties, rapid breathing, or breathlessness; 

- if you feel a change in your heart rate; 

- if you suffer from dizziness (light-headedness) or fainting – it may be a symptom of low blood 

pressure; 

- if you feel sick or have diarrhoea (loose bowels); 

- if your urine is darker than usual – it is important to drink plenty of water to avoid dehydration; 

- if you get a rash with blisters or mouth ulcers;  

- if you lose your appetite, have nausea (feeling sick), vomiting, diarrhea, dark-colored urine and 

light-coloured stools, stomach pain, jaundice (yellowing of the skin and eyes), or if you feel 

generally unwell, these could be symptoms of an inflammation of the liver (hepatitis), or liver 

damage (hepatic failure); 

- if you pass little or no urine, or experience drowsiness, nausea, vomiting, breathlessness, loss of 

appetite and / or weakness (these may be signs of acute kidney failure / kidney failure).  

 

 If you are the parent of a child who is being treated with Evoltra, tell the doctor if any of the 

above conditions apply to your child. 

 

During treatment with Evoltra, your doctor will carry out regular blood tests and other tests to 

monitor your health.  Because of the way this medicine works, it will affect your blood and other 

organs. 

 

Talk to your doctor about contraception.  Young men and women must use effective contraception 

during and after treatment.  See the section ‘Pregnancy and breast-feeding’ below.  Evoltra may harm 

both male and female reproductive organs.  Ask your doctor to explain what can be done to protect 

you or allow you to have a family. 

 

Other medicines and Evoltra 

Tell your doctor if you are using or have recently used: 

- medicines for heart disease; 

- any medicine that changes your blood pressure; 

- medicines that affect your liver or kidneys; 

- any other medicines including those obtained without a prescription. 

 

Pregnancy and breast-feeding 

Clofarabine should not be used during pregnancy unless clearly necessary. 

Women who are able to get pregnant: you must use effective contraception during treatment with 

clofarabine.  Clofarabine may cause harm to unborn babies when used by pregnant women.  If you are 

pregnant or you become pregnant during treatment with clofarabine, get medical advice 

immediately. 

 

Men must also use effective contraception while they or their partner are treated with clofarabine. 

 

If you are breast-feeding, you must stop breast-feeding before starting the treatment, and must not 

breast-feed during your treatment and within 3 months after completion of your treatment. 

 

Driving and using machines 

Do not drive or use any tools or machines if you feel dizzy, light-headed or faint. 

 

 

 



 

32 

Evoltra contains salt 

Each vial contains 180 mg of salt (sodium chloride). This is equivalent to 3.08 mmol (or 70.77 mg) of 

sodium. You need to allow for this if you are on a controlled sodium diet. 

 

3. How to use Evoltra 
 

Your treatment with Evoltra has been prescribed by a qualified doctor experienced in treating 

leukaemia. 

 

Your doctor will work out the dose that is right for you depending on your height, weight and how 

well you are. Before Evoltra is given to you, it will be diluted in a sodium chloride solution (salt and 

water). Tell your doctor if you are on a controlled sodium diet as it could affect how you will be given 

your medicine. 

 

Your doctor will give you Evoltra once every day for 5 days. It will be given to you as an infusion 

through a long thin tube which goes into a vein (a drip), or into a small medical appliance that is 

inserted under the skin (port-a-cath) if you (or your child) have one implanted. The infusion will be 

given over 2 hours. If you (or your child) weigh less than 20 kg, the infusion time may be longer. 

 

Your doctor will monitor your health and may change your dose depending on your response to the 

treatment. It is important to drink plenty of water to avoid dehydration. 

 

If you use more Evoltra than you should 

If you think you may have been given too much medicine, tell your doctor straight away. 

 

If you forget to use Evoltra 

Your doctor will tell you when you need to be given this medicine. If you think that you have missed 

a dose, tell your doctor straight away. 

 

If you have any further questions on the use of this medicine, ask your doctor. 

 

 

4. Possible side effects 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Very common (may affect more than 1 in 10 people): 

 - anxiety, headache, fever, tiredness; 

- feeling and being sick, diarrhoea (loose bowels); 

- flushing, itching and inflamed skin, inflammation of mucus (moist) linings such as the mouth 

and other areas; 

- you may have more infections than normal because Evoltra can lower the number of certain 

types of blood cells in your body; 

- skin rashes which may be itchy, red, painful or peeling skin including palms of the hands and 

soles of the feet, or small reddish or purple spots underneath the skin. 

 

Common (may affect up to 1 in 10 people): 

- infections of the blood, pneumonia, shingles, implant infections, infections of the mouth such 

as thrush and cold sores; 

- changes in blood chemistry, changes in white blood cells; 

- allergic reactions; 

- feeling thirsty and producing darker or less urine than normal, decreased or loss of appetite, 

weight loss; 

- agitation, irritability, or restlessness; 

- feeling numb or weak in the arms and legs, numbness of the skin, sleepiness, dizziness, tremor; 

- hearing problems; 



 

33 

- water collecting around the heart, fast heartbeat; 

- low blood pressure, lump due to bad bruising; 

- leaking from tiny blood vessels, rapid breathing, nosebleeds, breathing difficulties, 

breathlessness, cough; 

- vomiting blood, stomach ache, pain in the bottom; 

- bleeding inside the head, stomach, intestine or lungs, mouth or gums, mouth ulcers, inflamed 

mouth lining; 

- yellowing of the skin and eyes (also called jaundice), or other liver disorders; 

- bruising, hair loss, changes to skin colour, increased sweating, dry skin, or other skin problems; 

- pain in the chest wall or bones, neck or back pain, pain in limbs, muscles, or joints; 

- blood in urine; 

- failure of organs, pain, increased muscle tension, water retention and swelling in parts of the 

body, including the arms and legs, changes in mental state, feeling hot, cold or abnormal; 

- clofarabine may affect the levels of certain substances in the blood.  Your doctor will carry out 

regular blood tests to check whether your body is working properly;  

- liver damage (liver failure). 

- little or no urine, drowsiness, nausea, vomiting, breathlessness, loss of appetite and /or 

weakness (possible signs of acute kidney failure  or kidney failure). 

 

Uncommon side effects (may affect up to 1 in 100 people): 

- inflammation of the liver (hepatitis). 

 

Reporting of side effects 

If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 

leaflet. You can also report side effects directly via the national reporting system listed in 

Appendix V. By reporting side effects you can help provide more information on the safety of this 

medicine. 

 

 

5. How to store Evoltra 
 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the vial label and box after EXP. The 

expiry date refers to the last day of that month. 

 

Do not freeze. 

 

Once prepared and diluted, Evoltra should be used straight away or within 24 hours if stored in a 

refrigerator (at 2 oC to 8oC). 

 

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines 

you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Evoltra contains 

The active substance is clofarabine. Each ml contains 1 mg of clofarabine. Each 20 ml vial contains 

20 mg of clofarabine. 

The other ingredients are sodium chloride and water for injections. 

 

What Evoltra looks like and contents of the pack 

Evoltra is a concentrate for solution for infusion. It is a clear, almost colourless solution that is 

prepared and diluted before it is used. It is supplied in 20 ml glass vials. The vials contain 20 mg of 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

34 

clofarabine and are packaged in a box. Each box contains 1, 3, 4, 10 or 20 vials, but not all pack sizes 

may be marketed. 

 

Marketing Authorisation Holder 

Genzyme Europe B.V.  

 Paasheuvelweg 251105 BP Amsterdam The Netherlands  

Manufacturer 

Genzyme Limited 

37 Hollands Road 

Haverhill 

Suffolk  

CB9 8PU 

United Kingdom 

 

SANOFI WINTHROP INDUSTRIE 

30-36, avenue Gustave Eiffel 

37100 Tours 

France 

 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien/ 

Sanofi Belgium 

Tél/Tel: + 32 2 710 54 00 

 

Lietuva 

UAB”SANOFI-AVENTIS LIETUVA” 

Tel. +370 5 275 5224 

 

България 

SANOFI BULGARIA EOOD 

Tел: +359 (0) 2 9705300 

 

 

Česká republika 

sanofi-aventis, s.r.o. 

Tel: +420 233 086 111 

 

Luxembourg/Luxemburg 

Sanofi Belgium 

Tél/Tel: + 32 2 710 54 00 

(Belgique/Belgien) 

 

Magyarország 

sanofi-aventis Zrt. 

Tel: +36 1 505 0050 

 

 Malta 

Sanofi S.p.A 

Tel: +39 02 39394275 

 

Danmark 

Sanofi A/S  

Tlf: +45 45 16 70 00 

 

Nederland 

sanofi-aventis Netherlands B.V. 

Tel: +31 20 245 4000 

 

Deutschland 

Sanofi-Aventis Deutschland GmbH 

Tel.: 0800 04 36 996 

Tel. aus dem Ausland: +49 69 305 70 13 

 

 

Norge 

sanofi-aventis Norge AS 

Tlf: + 47 67 10 71 00 

Eesti 

sanofi-aventis Estonia OÜ 

Tel. +372 6 273 488 

 

Österreich 

sanofi-aventis GmbH 

Tel: + 43 1 80 185 - 0 

Ελλάδα 

sanofi-aventis AEBE  

Polska 

sanofi-aventis Sp. z o.o. 



 

35 

Τηλ: +30 210 900 1600 Tel.: +48 22 280 00 00 

 

España 

sanofi-aventis, S.A. 

Tel: +34 93 485 94 00 

  

Portugal 

Sanofi – Produtos Farmacêuticos, Lda. 

Tel: +351 21 35 89 400 

 

France 

sanofi-aventis France 

Tél : 0 800 222 555 

Appel depuis l’étranger : +33 1 57 63 23 23 
 

România 

Sanofi Romania SRL 

Tel: +40 (0) 21 317 31 36 

Hrvatska 

sanofi-aventis Croatia d.o.o. 

Tel: +385 1 600 34 00 

Slovenija 

sanofi-aventis d.o.o. 

Tel: +386 1 560 4800 

 

Ireland 

sanofi-aventis Ireland Ltd T/A SANOFI 

Tel:  +353 (0) 1 4035 600  

 

Slovenská republika 

sanofi-aventis Pharma Slovakia s.r.o. 

Tel.:  +421 2 33 100 100 

 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Suomi/Finland 

Sanofi Oy 

Puh/Tel: + 358 201 200 300 

 

Italia 

Sanofi S.p.A. 

Tel: +39 059 349 811 

 

Κύπρος 

sanofi-aventis Cyprus Ltd. 

Τηλ: +357 22 871600 

 

Sverige 

Sanofi AB 

Tel: +46 (0)8 634 50 00 

 

Latvija 

sanofi-aventis Latvia SIA 

Tel: +371 67 33 24 51 

 

United Kingdom 

Sanofi 

Tel: +44 (0) 845 372 7101 

 

This leaflet was last revised in  

 

This medicine has been authorised under “Exceptional Circumstances”.  This means that because of 

the rarity of this disease it has been impossible to get complete information on this medicine. The 

European Medicines Agency will review any new information on the medicine every year and this 

leaflet will be updated as necessary. 

 

Detailed information on this medicine is available on the European Medicines Agency  web site: 

http://www.ema.europa.eu/.  There are also links to other websites about rare diseases and treatments. 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVEUSE OF THE MEDICINAL PRODUCT
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURESFOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES
	A. LABELLING
	B. PACKAGE LEAFLET