EVOLTRA 1mg / ml concentrate for injection / infusion solution medication leaflet

Evoltra 1 mg/ml concentrate for solution for infusion

Each ml of concentrate contains 1 mg of clofarabine.

Each 20 ml vial contains 20 mg of clofarabine.

Each 20 ml vial contains 180 mg of sodium chloride, which is equivalent to 3.6 mg of sodium per ml(0.2 mmol).

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

Clear, practically colourless solution with a pH of 4.5 to 7.5 and an osmolarity of 270 to 310 mOsm/l.

Treatment of acute lymphoblastic leukaemia (ALL) in paediatric patients who have relapsed or arerefractory after receiving at least two prior regimens and where there is no other treatment optionanticipated to result in a durable response. Safety and efficacy have been assessed in studies ofpatients ≤ 21 years old at initial diagnosis (see section 5.1).

Therapy must be initiated and supervised by a physician experienced in the management of patientswith acute leukaemias.

Adult population (including elderly)

There are currently insufficient data to establish the safety and efficacy of clofarabine in adult patients(see section 5.2).

Children and adolescents (≥ 1 year old)

The recommended dose in monotherapy is 52 mg/m2 of body surface area administered by intravenousinfusion over 2 hours daily for 5 consecutive days. Body surface area must be calculated using theactual height and weight of the patient before the start of each cycle. Treatment cycles should berepeated every 2 to 6 weeks (from the starting day of the previous cycle) following recovery of normalhaematopoiesis (i.e. ANC ≥ 0.75 × 109/l) and return to baseline organ function. A 25% dose reductionmay be warranted in patients experiencing significant toxicities (see below). There is currently limitedexperience 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 inpatients who do not show haematological and/or clinical improvement after 2 treatment cycles shouldbe 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 andirritability, 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, asafe 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 notevident, it is recommended that the dose for the next cycle be reduced by 25% of the previous dosefollowing recovery of ANC to ≥ 0.75 × 109/l. Should patients experience an ANC < 0.5 × 109/l formore than 4 weeks from the start of the last cycle, it is recommended that the dose for the next cyclebe 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 theinfection is clinically controlled. At this time, treatment may be reinitiated at the full dose. In the eventof a second clinically significant infection, clofarabine treatment should be withheld until the infectionis 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 bedelayed until the toxicities resolve to baseline parameters or to the point where they are no longersevere and the potential benefit of continued treatment with clofarabine outweighs the risk of suchcontinuation. 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 bedelayed until the toxicity resolves to baseline parameters or to the point where it is no longer severeand the potential benefit of continued treatment with clofarabine outweighs the risk of suchcontinuation. 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 notrecover 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).

The limited data available indicate that clofarabine may accumulate in patients with decreasedcreatinine clearance (see sections 4.4 and 5.2). Clofarabine is contraindicated in patients with severerenal insufficiency (see section 4.3) and should be used with caution in patients with mild to moderaterenal insufficiency (see section 4.4).

Patients with moderate renal impairment (creatinine clearance 30 - < 60 ml/min) require a 50% dosereduction (see section 5.2).

There is no experience in patients with hepatic impairment (serum bilirubin > 1.5 x ULN plus ASTand ALT > 5 x ULN) and the liver is a potential target organ for toxicity. Therefore, clofarabine iscontraindicated in patients with severe hepatic impairment (see section 4.3) and should be used withcaution in patients with mild to moderate hepatic impairment (see section 4.4).

The recommended dosage should be administered by intravenous infusion although it has beenadministered via a central venous catheter in clinical trials. Evoltra must not be mixed with orconcomitantly administered using the same intravenous line as other medicinal products (seesection 6.2). For instructions on filtration and dilution of the medicinal product before administration(see section 6.6).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Use in patients with severe renal insufficiency or severe hepatic impairment.

Breast-feeding (see section 4.6).

Evoltra is a potent antineoplastic agent with potentially significant haematological andnon-haematological adverse reactions (see section 4.8).

The following parameters should be closely monitored in patients undergoing treatment withclofarabine:

* Complete blood and platelet counts should be obtained at regular intervals, more frequently inpatients who develop cytopaenias.

* Renal and hepatic function prior to, during active treatment and following therapy. Clofarabineshould be discontinued immediately if substantial increases in creatinine, liver enzymes and/orbilirubin are observed.

* Respiratory status, blood pressure, fluid balance and weight throughout and immediately after the5 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 thrombocytopaeniahave been observed in patients treated with clofarabine. Haemorrhage, including cerebral,gastrointestinal and pulmonary haemorrhage, has been reported and may be fatal. The majority of thecases were associated with thrombocytopaenia (see section 4.8).

In addition, at initiation of treatment, most patients in the clinical studies had haematologicalimpairment as a manifestation of leukaemia. Because of the pre-existing immuno-compromisedcondition 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, withpotentially fatal outcomes. Patients should be monitored for signs and symptoms of infection andtreated promptly.

Occurrences of enterocolitis, including neutropaenic colitis, caecitis, and C. difficile colitis, have beenreported during treatment with clofarabine. This has occurred more frequently within 30 days oftreatment, 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.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal cases, havebeen 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. Patientsundergoing treatment with clofarabine should be evaluated and monitored for signs and symptoms oftumour lysis syndrome and cytokine release (e.g. tachypnoea, tachycardia, hypotension, pulmonaryoedema) that could develop into Systemic Inflammatory Response Syndrome (SIRS), capillary leaksyndrome and/or organ dysfunction (see section 4.8).

* Prophylactic administration of allopurinol should be considered if hyperuricemia (tumour lysis) isexpected.

* Patients should receive intravenous fluids throughout the 5 day clofarabine administration periodto 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 ofbenefit 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 measuresinstituted. In addition, clofarabine treatment should be discontinued if the patient developshypotension 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 hasreturned 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 inpatients who do not show haematological and/or clinical improvement after 2 treatment cycles shouldbe assessed by the treating physician.

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

There is no clinical study experience in paediatric patients with renal insufficiency (defined in clinicalstudies as serum creatinine ≥ 2 x ULN for age) and clofarabine is predominately excreted via thekidneys. Pharmacokinetic data indicate that clofarabine may accumulate in patients with decreasedcreatinine clearance (see section 5.2). Therefore, clofarabine should be used with caution in patientswith mild to moderate renal insufficiency (see section 4.2 for dose adjustments). The safety profile ofclofarabine has not been established in patients with severe renal impairment or patients receivingrenal replacement therapy (see section 4.3). The concomitant use of medicinal products that have beenassociated 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 clofarabineadministration period; preference should be given to those medicinal products that are not known to benephrotoxic (see sections 4.5 and 4.8). Renal failure or acute renal failure have been observed as aconsequence of infections, sepsis and tumour lysis syndrome (see section 4.8). Patients should bemonitored for renal toxicity and clofarabine should be discontinued as necessary.

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

Patients receiving clofarabine may experience vomiting and diarrhoea; they should, therefore, beadvised regarding appropriate measures to avoid dehydration. Patients should be instructed to seekmedical 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 ASTand ALT > 5 x ULN) and the liver is a potential target organ for toxicity. Therefore, clofarabineshould be used with caution in patients with mild to moderate hepatic impairment (seesections 4.2 and 4.3). The concomitant use of medicinal products that have been associated withhepatic 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 athird occasion, a severe toxicity that does not recover within 14 days (excluding nausea/vomiting) or alife-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 higherrisk for hepatotoxicity suggestive of veno-occlusive disease (VOD) following treatment withclofarabine (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 hepatotoxicadverse 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 clofarabinetreatment (see section 4.8).

Most patients received conditioning regimens that included busulfan, melphalan, and/or thecombination of cyclophosphamide and total body irradiation. Severe hepatotoxic events have beenreported in a Phase 1/2 combination study of clofarabine in paediatric patients with relapsed orrefractory acute leukaemia.

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

Evoltra contains sodium

This medicinal product contains 72 mg sodium per vial, equivalent to 3.6% of the WHOrecommended maximum daily intake for sodium. The maximum daily dose of this product isequivalent to 23.4% of the WHO recommended maximum daily intake for sodium.

Evoltra is considered high in sodium. This should be particularly taken into account for those on a lowsalt diet.

No interaction studies have been performed. However, there are no known clinically significantinteractions 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. Inaddition, 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 achievedfollowing intravenous infusion of 52 mg/m2/day. As a result, it is not expected to affect themetabolism of active substances which are known substrates for these enzymes.

Clofarabine is predominately excreted via the kidneys. Thus, the concomitant use of medicinalproducts that have been associated with renal toxicity and those eliminated by tubular secretion suchas NSAIDs, amphotericin B, methotrexate, aminosides, organoplatines, foscarnet, pentamidine,cyclosporin, tacrolimus, acyclovir and valganciclovir, should be avoided particularly during the 5 dayclofarabine administration period (see sections 4.4, pct. 4.8 and 5.2).

The liver is a potential target organ for toxicity. Thus, the concomitant use of medicinal products thathave been associated with hepatic toxicity should be avoided wherever possible (see sections 4.4 and4.8).

Patients taking medicinal products known to affect blood pressure or cardiac function should beclosely monitored during treatment with clofarabine (see sections 4.4 and 4.8).

Contraception in men and women

Due to the genotoxic risk of clofarabine (see section 5.3), women of childbearing potential must useeffective methods of contraception during treatment with clofarabine and for 6 months followingcompletion of treatment.

Men should use effective methods of contraception and be advised to not father a child while receivingclofarabine, and for 3 months following completion of treatment.

There are no data on the use of clofarabine in pregnant women. Studies in animals have shownreproductive toxicity including teratogenicity (see section 5.3). Clofarabine may cause serious birthdefects 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 themother outweighs the risk to the foetus). If a patient becomes pregnant during treatment withclofarabine, they should be informed of the possible hazard to the foetus.

It is unknown whether clofarabine or its metabolites are excreted in human breast milk. The excretionof clofarabine in milk has not been studied in animals. However, because of the potential for seriousadverse reactions in nursing infants, breastfeeding should be discontinued prior to, during and within2 weeks after completion of treatment with Evoltra (see section 4.3).

Dose related toxicities on male reproductive organs have been observed in mice, rats and dogs, andtoxicities on female reproductive organs have been observed in mice (see section 5.3). As the effect ofclofarabine treatment on human fertility is unknown, reproductive planning should be discussed withpatients as appropriate.

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 suchcircumstances.

Nearly all patients (98%) experienced at least one adverse event considered by the study investigatorto 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 oneserious clofarabine-related adverse event. One patient discontinued treatment due to grade 4hyperbilirubinaemia 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 treatmentwith clofarabine: one patient died from respiratory distress, hepatocellular damage, and capillary leaksyndrome; one patient from VRE sepsis and multi-organ failure; and one patient from septic shock andmulti-organ failure.

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 ofclofarabine 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 alsoincluded in the table under the frequency category “not known” (cannot be estimated from theavailable data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

Patients with advanced stages of ALL or AML may have confounding medical conditions that makecausality of adverse events difficult to assess due to the variety of symptoms related to the underlyingdisease, its progression and the co-administration of numerous medicinal products.

Adverse reactions considered to be related to clofarabinereported at frequencies ≥ 1/1,000 (i.e. in > 1/115 patients) in clinical trialsand post-marketing

Infections and infestations Common: Septic shock*, sepsis, bacteraemia,pneumonia, herpes zoster, herpes simplex, oralcandidiasis

Frequency not known: C. difficile colitis

Neoplasms benign and malignant Common: Tumour lysis syndrome*(including cysts and polyps)

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

Respiratory, thoracic and mediastinal Common: Respiratory distress, epistaxis, dyspnoea,disorders tachypnoea, cough

Gastrointestinal disorders Very common: Vomiting, nausea, diarrhoea

Common: Mouth haemorrhage, gingival bleeding,haematemesis, abdominal pain, stomatitis, upperabdominal pain, proctalgia, mouth ulceration

Frequency not known: Pancreatitis elevations in serumamylase and lipase, enterocolitis, neutropaenic colitis,caecitis

Hepato-biliary disorders Common: Hyperbilirubinaemia, jaundice, veno-occlusive disease, increases in alanine (ALT)* andaspartate (AST)* aminotransferases, hepatic failure

Uncommon: Hepatitis

General disorders and administration site Very common: Fatigue, pyrexia, mucosal inflammationconditions Common: Multi-organ failure, systemic inflammatoryresponse syndrome*, pain, chills, irritability, oedema,peripheral oedema, feeling hot, feeling abnormal

Skin and subcutaneous tissue disorders Very common: Palmar-plantar erythrodysaesthesiasyndrome, 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 Common: Pain in extremity, myalgia, bone pain, chestbone disorders 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 Common: Contusioncomplications

* = see below

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

The most frequent haematological laboratory abnormalities observed in patients treated withclofarabine 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 theseevents were of grade ≥ 3.

During the post-marketing period prolonged cytopaenias (thrombocytopaenia, anaemia, neutropaeniaand leukopaenia) and bone marrow failure have been reported. Bleeding events have been observed inthe setting of thrombocytopaenia. Haemorrhage, including cerebral, gastrointestinal and pulmonaryhaemorrhage, has been reported and may be associated with a fatal outcome (see section 4.4).

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, themost frequently reported being flushing (13 events; not serious) and hypotension (5 events; all ofwhich were considered to be serious; see section 4.4). However, the majority of these hypotensiveevents were reported in patients who had confounding severe infections.

Fifty percent of patients experienced at least one cardiac disorders adverse event. Eleven events in115 patients were considered to be related to clofarabine, none of which were serious and the mostfrequently reported cardiac disorder was tachycardia (35%) (see section 4.4); 6.1% (7/115) patient'stachycardia were considered to be related to clofarabine. Most of the cardiac adverse events werereported 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 noclinical significance on echocardiographic assessment. However, the pericardial effusion wasclinically significant in 2 patients with some associated haemodynamic compromise.

Forty-eight percent of patients had one or more ongoing infections prior to receiving treatment withclofarabine. 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 wereconsidered 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 befatal. These infections may lead to septic shock, respiratory failure, renal failure, and/or multi-organfailure.

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 elevatedcreatinine occurred in 8% of patients. Nephrotoxic medicinal products, tumour lysis, and tumour lysiswith hyperuricemia may contribute to renal toxicity (see sections 4.3 and 4.4). Haematuria wasobserved in 13% of patients overall. Four renal adverse events in 115 patients were considered to berelated 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 leastone hepato-biliary disorders adverse event (see sections 4.3 and 4.4). Six events were considered to berelated to clofarabine of which acute cholecystitis (1 event), cholelithiasis (1 event), hepatocellulardamage (1 event; patient died (see above)) and hyperbilirubinaemia (1 event; the patient discontinuedtherapy (see above)) were considered to be serious. Two paediatric reports (1.7%) of veno-occlusivedisease (VOD) were considered related to study drug.

VOD cases reported during the post-marketing period in paediatric and adult patients have beenassociated 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 elevationsin ALT and AST occurred within 10 days of clofarabine administration and returned to ≤ grade 2within 15 days. Where follow-up data are available, the majority of bilirubin elevations returnedto ≤ 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 paediatricpatients (5 ALL, 1 AML) (see section 4.4). Thirteen events of tumour lysis syndrome, capillary leaksyndrome or SIRS have been reported; SIRS (2 events; both were considered to be serious), capillaryleak 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 afatal outcome (See section 4.4).

Occurrences of enterocolitis, including neutropaenic colitis, caecitis, and C. difficile colitis have beenreported during treatment with clofarabine. Enterocolitis may lead to necrosis, perforation or sepsiscomplications 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, havebeen reported in patients who were receiving or had recently been treated with clofarabine. Otherexfoliative conditions have also been reported.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No case of overdose has been reported. However, possible symptoms of overdose are expected toinclude nausea, vomiting, diarrhoea and severe bone marrow suppression. To date, the highest dailydose 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, elevatedtransaminase levels and maculo-papular rash.

No specific antidotal therapy exists. Immediate discontinuation of therapy, careful observation andinitiation of appropriate supportive measures are recommended.

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

Clofarabine is a purine nucleoside anti-metabolite. Its antitumour activity is believed to be due to3 mechanisms:

* DNA polymerase α inhibition resulting in termination of DNA chain elongation and/or DNAsynthesis/repair.

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

* Disruption of mitochondrial membrane integrity with the release of cytochrome C and otherproapoptotic 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 phosphorylatedto 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 phosphorylatingenzymes, deoxycytidine kinase, which exceeds that of the natural substrate, deoxycytidine.

In addition, clofarabine possesses greater resistance to cellular degradation by adenosine deaminaseand decreased susceptibility to phosphorolytic cleavage than other active substances in its class whilstthe affinity of clofarabine triphosphate for DNA polymerase α and ribonucleotide reductase is similarto or greater than that of deoxyadenosine triphosphate.

In vitro studies have demonstrated that clofarabine inhibits cell growth in and is cytotoxic to a varietyof rapidly proliferating haematological and solid tumour cell lines. It was also active against quiescentlymphocytes 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: To enable systematic evaluation of the responses seen in patients, an unblinded

Independent Response Review Panel (IRRP) determined the following response rates based ondefinitions produced by the Children’s Oncology Group:

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

* No evidence of circulating blasts or extramedullarydisease

* An M1 bone marrow (≤ 5% blasts)

* Recovery of peripheral counts (platelets ≥ 100 x 109/land ANC ≥ 1.0 x 109/l)

CRp = Complete Remission in the * Patients who met all of the criteria for a CR except

Absence of Total Platelet Recovery 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) andappearance 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 patientswith a CRp) ÷ Number of eligible patients whoreceived 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 at11.25 with escalation to 15, 30, 40, 52 and 70 mg/m2/day by intravenous infusion for 5 days every2 to 6 weeks depending on toxicity and response. Nine of 17 ALL patients were treated withclofarabine 52 mg/m2/day. Of the 17 ALL patients, 2 achieved a complete remission (12%; CR) and 2a partial remission (12%; PR) at varying doses. Dose-limiting toxicities in this study werehyperbilirubinaemia, elevated transaminase levels and maculo-papular rash experienced at70 mg/m2/day (2 ALL patients; see section 4.9).

A multi-centre, phase II, open-label, non-comparative study of clofarabine was conducted todetermine the overall remission (OR) rate in heavily pretreated patients (≤ 21 years old at initialdiagnosis) 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/dayclofarabine was administered by intravenous infusion for 5 consecutive days every 2 to 6 weeks. Thetable 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 havebeen in second or subsequent relapse and/or refractory i.e. failed to achieve remission after at least twoprior regimens. Before enrolling in the trial, 58 of the 61 patients (95%) had received 2 to 4 differentinduction regimens and 18/61 (30%) of these patients had undergone at least 1 prior haematologicalstem cell transplant (HSCT). The median age of treated patients (37 males, 24 females) was 12 yearsold.

Administration of clofarabine resulted in a dramatic and rapid reduction in peripheral leukaemia cellsin 31 of the 33 patients (94%) who had a measurable absolute blast count at baseline. The 12 patientswho achieved an overall remission (CR + CRp) had a median survival time of 69.5 weeks as of thedata collection cut-off date. Responses were seen in different immunophenotypes of ALL, includingpre-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 considerednot 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) withrelapsed or refractory ALL after at least two prior regimens

Response ITT* Median duration Median time to Median overallcategory patients of remission progression survival (weeks)(n = 61) (weeks) (weeks)** (95% CI)(95% CI) (95% CI)

Overall 12 32.0 38.2 69.5remission (20%) (9.7 to 47.9) (15.4 to 56.1) (58.6 to -)(CR + CRp)

CR 7 47.9 56.1 72.4(12%) (6.1 to -) (13.7 to -) (66.6 to -)

CRp 5 28.6 37.0 53.7(8%) (4.6 to 38.3) (9.1 to 42) (9.1 to -)

PR 6 11.0 14.4 33.0(10%) (5.0 to -) (7.0 to -) (18.1 to -)

CR + CRp + PR 18 21.5 28.7 66.6(30%) (7.6 to 47.9) (13.7 to 56.1) (42.0 to -)

Treatment 33 N/Afailure (54%) 4.0 7.6

Not evaluable 10 N/A (3.4 to 5.1) (6.7 to 12.6)(16%)

All patients 61 N/A 5.4 12.9(100%) (4.0 to 6.1) (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 forthe analysis.

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

Duration of Overall

Time to OR Remission Survival

Best Response (weeks) (weeks) (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 continuedremission*

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 orrelapse*

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 tothe rarity of the disease it has not been possible to obtain complete information on this medicinalproduct.

The European Medicines Agency will review any new information which may become available everyyear and this SmPC will be updated as necessary.

Adsorption and distribution

The pharmacokinetics of clofarabine were studied in 40 patients aged between 2 to 19 years old withrelapsed or refractory ALL or AML. The patients were enrolled into a single phase I (n = 12) or twophase II (n = 14/n = 14) safety and efficacy studies, and received multiple doses of clofarabine byintravenous 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 intravenousinfusion

Parameter Estimates based on Estimates based on othernon-compartmental analysisanalysis(n = 14/n = 14)

Volume of distribution (steady 172 l/m2state)

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 andalthough white blood cell (WBC) count was identified as having an impact on clofarabinepharmacokinetics, this did not appear sufficient to individualise a patient’s dosage regimen based ontheir WBC count. Intravenous infusion of 52 mg/m2 clofarabine produced equivalent exposure acrossa 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 samedose of clofarabine per m2. Accordingly, longer infusion times should be considered in childrenweighing < 20 kg (see section 4.2).

Clofarabine is eliminated by a combination of renal and non-renal excretion. After 24 hours, about60% of the dose is excreted unchanged in the urine. Clofarabine clearance rates appear to be muchhigher than glomerular filtration rates suggesting filtration and tubular secretion as kidney eliminationmechanisms. 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, orbetween males and females.

No relationship between clofarabine or clofarabine triphosphate exposure and either efficacy ortoxicity has been established in this population.

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 followingadministration of a single dose of 40 mg/m2 clofarabine by intravenous infusion over 1 hour werecomparable to those described above in patients aged between 2 to 19 years old with relapsed orrefractory ALL or AML following administration of 52 mg/m2 clofarabine by intravenous infusionover 2 hours for 5 consecutive days.

Elderly (≥ 65 years old)

There are currently insufficient data to establish the safety and efficacy of clofarabine in patients65 years of age or older.

To date, there are limited data on the pharmacokinetics of clofarabine in paediatric patients withdecreased creatinine clearance. However, these data indicate that clofarabine may accumulate in suchpatients (see figure below).

Population pharmacokinetic data from adult and paediatric patients suggest that patients with stablemoderate renal impairment (creatinine clearance 30 - < 60 ml/min) receiving a 50% dose reductionachieve 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 between2 to 19 years old with relapsed or refractory ALL or AML (n = 11/n = 12) followingadministration of multiple doses of clofarabine by intravenous infusion(creatinine clearance estimated using Schwartz formula)

Clofarabine 2500

AUC 0-24 hours(ng*h/ml) 20000 50 100 150 200 250

Estimated creatinine clearance (ml/min)

There is no experience in patients with hepatic impairment (serum bilirubin > 1.5 x ULN plus ASTand ALT > 5 x ULN) and the liver is a potential target organ for toxicity (see sections 4.3 and 4.4).

Toxicology studies of clofarabine in mice, rats and dogs showed that rapidly proliferating tissues werethe primary target organs of toxicity.

Cardiac effects were observed in rats consistent with cardiomyopathy and contributed to signs ofcardiac failure after repeated cycles of treatment. The incidence of these toxicities was dependent onboth the dose of clofarabine administered and the duration of treatment. They were reported atexposure levels (Cmax) approximately 7 to 13 fold (after 3 or more dosing cycles) or 16 to 35 fold (afterone or more dosing cycles) higher than clinical exposures. The minimal effects seen at lower dosessuggest that there is a threshold for toxicities on the heart and nonlinear plasma pharmacokinetics inthe 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 AUCafter 6 dosing cycles of clofarabine. It was characterised by minor thickening of the glomerularbasement membrane with only slight tubular damage and was not associated with changes in serumchemistry.

Hepatic effects were observed in rats following chronic administration of clofarabine. These likelyrepresent 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 wasseen in dogs following acute administration of high doses, but was also not accompanied by changesin serum chemistry.

Dose related toxicities on male reproductive organs were observed in mice, rats and dogs. Theseeffects included bilateral degeneration of the seminiferous epithelium with retained spermatids andatrophy of interstitial cells in rats at exaggerated exposure levels (150 mg/m2/day), and celldegeneration of the epididymis and degeneration of the seminiferous epithelium in dogs at clinicallyrelevant exposure levels (> 7.5 mg/m2/day clofarabine).

Delayed ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female miceat the only dose used of 225 mg/m2/day clofarabine.

Clofarabine was teratogenic in rats and rabbits. Increases in postimplantation loss, reduced foetal bodyweights and decreased litter sizes together with increases in the number of malformations (grossexternal, soft tissue) and skeletal alterations (including retarded ossification) were reported in ratsreceiving doses which produced approximately 2 to 3 fold the clinical exposure (54 mg/m2/day) and inrabbits receiving 12 mg/m2/day clofarabine. (There are no exposure data in rabbits.) The threshold fordevelopmental toxicity was considered to be 6 mg/m2/day in rats and 1.2 mg/m2/day in rabbits. Theno-observable effect level for maternal toxicity in rats was 18 mg/m2/day and in rabbits was more than12 mg/m2/day. No fertility studies have been conducted.

Genotoxicity studies demonstrated that clofarabine was not mutagenic in the bacterial reversemutation assay, but did induce clastogenic effects in the non-activated chromosomal aberration assayin Chinese Hamster Ovary (CHO) cells and in the in vivo rat micronucleus assay.

No carcinogenicity studies have been performed.

Sodium chloride

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

3 years.

The diluted concentrate is chemically and physically stable for 3 days at 2°C to 8°C and at roomtemperature (up to 25°C). From a microbiological point of view, it should be used immediately. If notused immediately, in-use storage times and conditions prior to use are the responsibility of the userand would normally not be longer than 24 hours at 2°C to 8°C unless dilution has taken place undercontrolled and validated aseptic conditions.

Do not freeze.

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

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.

Special precautions for administration

Evoltra 1 mg/ml concentrate for solution for infusion must be diluted prior to administration. It shouldbe filtered through a sterile 0.2 micrometre syringe filter and then diluted with sodium chloride9 mg/ml (0.9%) intravenous infusion to produce a total volume according to the examples given in thetable below. However, the final dilution volume may vary depending on the patient’s clinical statusand physician discretion. (If the use of a 0.2 micrometre syringe filter is not feasible, the concentrateshould be pre-filtered with a 5 micrometre filter, diluted and then administered through a0.22 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 ml1.45 to 2.40 75.4 to 124.8 150 ml2.41 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 berequired to produce the recommended daily dosage of clofarabine. However, for patients with a bodysurface area > 0.38 m2, the contents of between 1 to 7 vials will be required to produce therecommended daily dosage of clofarabine.

The diluted concentrate should be a clear, colourless solution. It should be visually inspected forparticulate matter and discolouration prior to administration.

Instructions for handling

Procedures for proper handling of antineoplastic agents should be observed. Cytotoxic medicinalproducts should be handled with caution.

The use of disposable gloves and protective garments is recommended when handling Evoltra. If theproduct comes into contact with eyes, skin or mucous membranes, rinse immediately with copiousamounts of water.

Evoltra should not be handled by pregnant women.

Evoltra is for single use only. Any unused medicinal product or waste material should be disposed ofin accordance with local requirements.

Sanofi B.V.

Paasheuvelweg 251105 BP Amsterdam

The Netherlands

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

Date of first authorisation: 29 May 2006.

Date of latest renewal: 14 January 2016

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

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