Ivozall

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
  



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1. NAME OF THE MEDICINAL PRODUCT 
 
Ivozall 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 70.77 mg of sodium . 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion (sterile concentrate).  
 
Clear, practically colourless solution with a pH of 4.5 to 7.5 and an osmolarity of 270 to 310 mOsm/l, 
free from visible particles. 
 
 
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 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). 



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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). 



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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  
 
Ivozall is for intravenous use. The recommended dosage should be administered by intravenous 
infusion although it has been administered via a central venous catheter in ongoing clinical trials.  
 
Ivozall 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 
 
Ivozall 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 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 insufficiency 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 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.  
 
Excipient with known effect 
Each vial of Ivozall contains 70.77 mg of sodium. This is equivalent to 3.08 mmol (or 70.77 mg) of 
sodium which is equivalent to 3.53% of the WHO recommended maximum daily intake of 2 g sodium 
for an adult 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, Ivozall 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, she 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 Ivozall (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 
 



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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 
(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 neutropenia   
Common: Neutropenia  

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*   



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Vascular disorders  Very common: Flushing*  
Common: Hypotension*, capillary leak syndrome, 
haematoma  

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, neutropenic 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*, 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).  
 



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Vascular disorders  
Sixty-four patients of 115 (55.7%) experienced at least one vascular disorders adverse reaction. 
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.  
 
Cardiac disorders  
Fifty percent of patients experienced at least one cardiac disorders adverse reaction. 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 reactions were 
reported in the first 2 cycles.  
 
Pericardial effusion and pericarditis were reported as an adverse reaction 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 
reaction. 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 reactions 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 reaction (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.  



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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 reaction in 5% (6/115) of paediatric 
patients (5 ALL, 1 AML) (see section 4.4). Thirteen events of tumour lysis syndrome, capillary leak 
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, purine analogues, ATC code: 
L01BB06. 
 
Mechanism of action 
 
Clofarabine is a purine nucleoside anti-metabolite. Its antitumour activity is believed to be due to 
3 mechanisms: 
 

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• DNA polymerase α inhibition resulting in termination of DNA chain elongation and/or DNA 
synthesis / repair.  

• Ribonucleotide reductase inhibition with reduction of cellular deoxynucleotide triphosphate 
(dNTP) pools.  

• 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 α 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 



13 

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). 
 
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)  



14 

*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.  

 
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  

 
The reference medicinal product containing clofarabine 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 the reference 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 accordingly to the reference medicinal product SmPC. 
 
 
 
5.2 Pharmacokinetic properties 
 
Absorption 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). 
 

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  



15 

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:  
β 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. 
 
 
 
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.  
 



16 

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) 

 
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. 
 
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 



17 

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 
 
Unopened vial 
3 years 
 
After dilution 
Chemical and physical in-use stability has been demonstrated for seven days at room temperature and 
under refrigeration (2°C - 8°C) at a concentration range of 0.15 mg/ml to 0.83 mg/ml after dilution 
with sodium chloride 9 mg/ml (0.9%). 
From a microbiological point of view, the product 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 
 



18 

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 grey chlorobutyl fluoropolymer coated 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 vial.  
 
6.6 Special precautions for disposal and other handling 
 
Special precautions for administration  
 
Ivozall 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 (the use of hydrophilic PVDF syringe filter is 
recommended) and then diluted in sodium chloride 9 mg/ml (0.9%) intravenous transparent PVC or 
polyolefine (polypropylene) infusion bags 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.  
 

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.  
 
Storage at low temperatures, i.e. below 15°C, might lead to formation of particles, which can be re-
dissolved by letting the vial warm to room temperature and gentle swirling until all visible particles 
have dissolved. 
 
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 Ivozall. If the 
product comes into contact with eyes, skin or mucous membranes, rinse immediately with copious 
amounts of water. 
 
Ivozall should not be handled by pregnant women. 
 
Disposal  
Ivozall is for single use only. Any unused medicinal product or waste material should be disposed of 
in accordance with local requirements. 



19 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
ORPHELIA Pharma  
85 boulevard Saint-Michel  
75005 PARIS  
France 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/19/1396/001 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
:  
 
 
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  



21 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Haupt Pharma Wolfratshausen GmbH 
Pfaffenrieder Straße 5 
82515 Wolfratshausen 
Germany  
 
 
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 update reports (PSURs) 
 
The requirements for submission of PSURs 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 marketing authorisation holder (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 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



24 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ivozall 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  
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use after dilution  
 
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 
 
8. EXPIRY DATE 
 
EXP:  
 
 



25 

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 

 
. 
Discard unused contents appropriately. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
ORPHELIA Pharma  
85 boulevard Saint-Michel  
75005 PARIS  
France 
 
 
12. MARKETING AUTHORISATION NUMBER  
 
EU/1/19/1396/001 
1 vial 
 
 
13. BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
  



26 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Ivozall 1 mg/ml sterile concentrate  
clofarabine  
Intravenous use after dilution.  
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use  
 
 
3. EXPIRY DATE 
 
EXP:  
 
4. BATCH NUMBER 
 
Lot 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
20 mg/20 ml  
 
6. OTHER 
 
 
ORPHELIA Pharma 
 
  



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



28 

Package leaflet: Information for the user 
 

Ivozall 1 mg/ml concentrate for solution for infusion 
clofarabine 

 
 
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 Ivozall is and what it is used for  
2. What you need to know before you use Ivozall  
3. How to use Ivozall  
4. Possible side effects  
5. How to store Ivozall  
6. Contents of the pack and other information 
 
 
1. What Ivozall is and what it is used for 
 
Ivozall 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.  
 
Ivozall 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 Ivozall 
 
Do not use Ivozall 
- - 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 Ivozall, tell the doctor if any of them apply to your child.  
 
 
Warnings and precautions  
Tell your doctor if any of these apply to you. Ivozall 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;  
-  if you have heart disease, or used to have it.  
 



29 

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 Ivozall, tell the doctor if any of the above 
conditions apply to your child.  
 
During treatment with Ivozall, 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. Ivozall 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 Ivozall 
Tell your doctor if you are using or have recently used:  
- medicines for heart disease (e.g. amiodarone, valsartan);  
- any medicine that changes your blood pressure (e.g. captopril, propranolol);  
- medicines that affect your liver (e.g. paracetamol, diclofenac) or kidneys (e.g. ibuprofen, 

amphotericin B);  
- 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.  
 
Ivozall contains sodium  
Each vial contains 70.77mg sodium (main component of cooking/table salt). This is equivalent to 
3.53% of the recommended maximum daily intake of sodium for an adult. You need to allow for this 
if you are on a controlled sodium diet.  



30 

 
 
3. How to use Ivozall 
 
Your treatment with Ivozall 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 Ivozall 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 Ivozall 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 Ivozall than you should  
If you think you may have been given too much medicine, tell your doctor straight away.  
 
If you forget to use Ivozall  
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 Ivozall 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;  
- water collecting around the heart, fast heartbeat;  
- low blood pressure, lump due to bad bruising;  



31 

- 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 Ivozall 
 
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.  
 
Chemical and physical in-use stability has been demonstrated for seven days at room temperature and 
under refrigeration (2°C - 8°C) at a concentration range of 0.15 mg/ml to 0.83 mg/ml after dilution 
with sodium chloride 9 mg/ml (0.9%). 
 
From a microbiological point of view, the product 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. 
 
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 Ivozall 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. See section 2 “Ivozall contains 
sodium”. 
  
 

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


32 

What Ivozall looks like and contents of the pack 
Ivozall is a concentrate for solution for infusion. It is a clear 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 clofarabine and 
are packaged in a box. Each box contains 1vial.  
 
Marketing Authorisation Holder  
ORPHELIA Pharma  
85 boulevard Saint-Michel  
75005 PARIS  
France 
 
Manufacturer  
Haupt Pharma Wolfratshausen GmbH 
Pfaffenrieder Straße 5 
82515 Wolfratshausen 
Germany  
 
 
  

This leaflet was last revised in  
 
  
Ivozall contains the same active substance and works in the same way as a ‘reference medicine’ 
already authorised in the EU. The reference medicine for Ivozall 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 the reference medicine. 
The European Medicines Agency will review any new information on the reference medicine every 
year and any updates for the reference medicine will also be included as appropriate in the information 
for Ivozall, such as this leaflet. 
 
 
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.  
 
------------------------------------------------------------------------------------------------------------------------ 
 
The following information is intended for healthcare professionals only: 
 
Ivozall 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 (the use of hydrophilic PVDF 
syringe filter is recommended) ) 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.  
 
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.  



33 

 
The diluted concentrate should be a clear, colourless solution. It should be visually inspected for 
particulate matter and discolouration prior to administration.  
 
Storage at low temperatures, i.e. below 15°C, might lead to formation of particles, which can be 
redissolved by letting the vial warm to room temperature and gentle swirling until all visible 
particles have dissolved.  
 
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 clofarabine. 
If the product comes into contact with eyes, skin or mucous membranes, rinse immediately with 
copious amounts of water.  
Ivozall should not be handled by pregnant women.   
 
Disposal  
Ivozall is for single use only. Any unused medicinal product or waste material should be disposed 
of in accordance with local requirements.  
 
 


	ANNEX ISUMMARY OF PRODUCT CHARACTERISTICS
	ANNEX II
	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 ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	ANNEX IIILABELLING AND PACKAGE LEAFLET
	A. LABELLING
	B. PACKAGE LEAFLET