ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Evoltra 1 mg/ml concentrate for solution for infusion
2.
Each ml of concentrate contains 1 mg of clofarabine. Each 20 ml vial contains 20 mg of clofarabine.
Excipient:
Each 20 ml vial contains 180 mg of sodium chloride.
For a full list of excipients, see section 6.1.
3.
Concentrate for solution for infusion .
Clear, practically colourless solution with a pH of 4.5 to 7.5 and an osmolarity of 270 to 310 mOsm/l.
4.
Treatment of acute lymphoblastic leukaemia (ALL) in paediatric patients who have relapsed or are
refractory after receiving at least two prior regimens and where there is no other treatment option
anticipated to result in a durable response. Safety and efficacy have been assessed in studies of
patients ≤ 21 years old at initial diagnosis (see section 5.1).
Therapy must be initiated and supervised by a physician experienced in the management of patients
with acute leukaemias.
Posology
Adult population (including the elderly)
There are currently insufficient data to establish the safety and efficacy of clofarabine in adult patients
(see section 5.2).
Paediatric population
The recommended dose is 52 mg/m
2
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 × 10
9
/l) and return to baseline organ function. A 25% dose reduction may be warranted
in patients experiencing significant toxicities (see below). There is currently limited experience of
patients receiving more than 3 treatment cycles (see section 4.4).
The majority of patients who respond to clofarabine achieve a response after 1 or 2 treatment cycles
(see section 5.1). Therefore, the potential benefit and risks associated with continued therapy in
patients who do not show haematological and/or clinical improvement after 2 treatment cycles should
be assessed by the treating physician (see section 4.4).
2
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.
Patients with renal insufficiency:
There is no experience in patients with renal insufficiency (serum
creatinine ≥ 2 x ULN for age) and clofarabine is predominately excreted via the kidneys. Therefore,
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). To date,
there are insufficient data on the pharmacokinetics of clofarabine in patients with decreased creatinine
clearance to advise a dose reduction in such patients. However, these limited data indicate that
clofarabine may accumulate in patients with decreased creatinine clearance (see sections 4.4 and 5.2).
Patients with 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).
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 × 10
9
/l. Should patients experience an ANC < 0.5 × 10
9
/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).
Method of administration
3
For instructions on dilution of the medicinal product before administration, see section 6.6. The
recommended dosage should be administered by intravenous infusion although it has been
administered via a central venous catheter in ongoing clinical trials. Evoltra must not be mixed with
or concomitantly administered using the same intravenous line as other medicinal products (see
section 6.2).
Hypersensitivity to clofarabine or to any of the excipients (see section 6.1).
Use in patients with severe renal insufficiency or severe hepatic impairment.
Breast-feeding should be discontinued prior to, during and following treatment with Evoltra (see
section 4.6).
Evoltra is a potent antineoplastic agent with potentially significant haematological and
non-haematological adverse reactions (see section 4.8).
The following parameters should be closely monitored in patients undergoing treatment with
clofarabine:
Complete blood and platelet counts should be obtained at regular intervals, more frequently in
patients who develop cytopenias.
Renal and hepatic function prior to, during active treatment and following therapy. Clofarabine
should be discontinued immediately if substantial increases in creatinine or bilirubin are observed.
Respiratory status, blood pressure, fluid balance and weight throughout and immediately after the
5 day clofarabine administration period.
Suppression of bone marrow should be anticipated. This is usually reversible and appears to be dose-
dependent. Severe bone marrow suppression, including neutropaenia, anaemia and thrombocytopenia
have been observed in patients treated with clofarabine. In addition, at initiation of treatment, most
patients in the clinical studies had haematological impairment as a manifestation of leukaemia.
Because of the pre-existing immuno-compromised condition of these patients and prolonged
neutropaenia that can result from treatment with clofarabine, patients are at increased risk for severe
opportunistic infections, including severe sepsis, with potentially fatal outcomes. Patients should be
monitored for signs and symptoms of infection and treated promptly.
Occurrences of enterocolitis, including neutropaenic colitis 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.
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/m
2
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
4
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.
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).
There is no experience in patients with renal insufficiency (serum creatinine ≥ 2 x ULN for age) and
clofarabine is predominately excreted via the kidneys. Therefore, clofarabine should be used with
caution in patients with mild to moderate renal insufficiency (see sections 4.2 and 4.3). To date, there
are insufficient data on the pharmacokinetics of clofarabine in patients with decreased creatinine
clearance to advise a dose reduction in such patients. However, these limited data indicate that
clofarabine may accumulate in patients with decreased creatinine clearance (see sections 4.2 and 5.2).
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).
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.
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 10
9
/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/m
2
) when used in combination with etoposide (100 mg/m
2
) and cyclophosphamide
(440 mg/m
2
). Severe hepatotoxic events have been reported in an ongoing Phase 1/2 combination
study of clofarabine in paediatric patients with relapsed or refractory acute leukemia.
There are currently limited data on the safety and efficacy of clofarabine when administered for more
than 3 treatment cycles.
Each vial of Evoltra contains 180 mg of sodium chloride. This is equivalent to 3.08 mmol (or
70.77 mg) of sodium and should be taken into consideration for patients on a controlled sodium diet.
5
No formal interaction studies have been performed to date with clofarabine. 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/m
2
/day. As a result, it is not expected to affect the
metabolism of active substances which are known substrates for these enzymes.
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).
Contraception in males and females
Females of childbearing potential and sexually active males must use effective methods of
contraception during treatment.
Pregnancy
There are no data on the use of clofarabine in pregnant women. Studies in animals have shown
reproductive toxicity including teratogenicity (see section 5.3). Clofarabine may cause serious birth
defects when administered during pregnancy. Therefore, Evoltra should not be used during
pregnancy, especially not during the first trimester, unless clearly necessary (i.e. only if the potential
benefit to the mother outweighs the risk to the foetus). If a patient becomes pregnant during treatment
with clofarabine, they should be informed of the possible hazard to the foetus.
Breast-feeding
It is unknown whether clofarabine or its metabolites are excreted in human breast milk. The excretion
of clofarabine in milk has not been studied in animals. However, because of the potential for serious
adverse reactions in nursing infants, breastfeeding should be discontinued prior to, during and
following treatment with Evoltra (see section 4.3).
Fertility
Dose related toxicities on male reproductive organs have been observed in mice, rats and dogs, and
toxicities on female reproductive organs have been observed in mice (see section 5.3). As the effect of
clofarabine treatment on human fertility is unknown, reproductive planning should be discussed with
patients as appropriate.
6
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.
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/m
2
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.
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/m
2
/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.
Adverse reactions considered to be related to clofarabine
reported at frequencies ≥ 1/100 (i.e. in > 1/115 patients) in clinical trials
and post-marketing
Infections and infestations
Common:
Septic shock*, sepsis, bacteraemia,
pneumonia, herpes zoster, herpes simplex, oral
candidiasis
Frequency not known:
C. difficile
colitis
Neoplasms benign and malignant
(including cysts and polyps)
Common:
Tumour lysis syndrome*
Blood and lymphatic system disorders
Very common:
Febrile neutropaenia
Common:
Neutropaenia
Immune system disorders
Common:
Hypersensitivity
Metabolism and nutrition disorders
Common:
Anorexia, decreased appetite, dehydration
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,
7
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, neutropaenic colitis
Hepato-biliary disorders
Common:
Hyperbilirubinaemia, jaundice, veno-
occlusive disease, increases in alanine (ALT)* and
aspartate (AST)* aminotransferases
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*
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 events (1.7%)) are included in this
table
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.
Vascular disorders:
Sixty-four patients of 115 (55.7%) experienced at least one vascular disorders
adverse event. Twenty-three patients out of 115 experienced a vascular disorder considered to be
related to clofarabine, the most frequently reported being flushing (13 events; not serious) and
hypotension (5 events; all of which were considered to be serious; see section 4.4). However, the
majority of these hypotensive events were reported in patients who had confounding severe infections.
Cardiac disorders:
Fifty percent of patients experienced at least one cardiac disorders adverse event.
Eleven events in 115 patients were considered to be related to clofarabine, none of which were serious
and the most frequently reported cardiac disorder was tachycardia (35%) (see section 4.4); 6.1%
(7/115) patient's tachycardia were considered to be related to clofarabine. Most of the cardiac adverse
events were reported in the first 2 cycles.
Pericardial effusion and pericarditis were reported as an adverse event in 9% (10/115) of patients.
Three of these events were subsequently assessed as being related to clofarabine: pericardial effusion
(2 events; 1 of which was serious) and pericarditis (1 event; not serious). In the majority of patients
(8/10), the pericardial effusion and pericarditis were deemed to be asymptomatic and of little or no
8
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.
Renal and urinary disorders:
Forty-one patients of 115 (35.7%) experienced at least one renal and
urinary disorders adverse event. The most prevalent renal toxicity in paediatric patients was elevated
creatinine. Grade 3 or 4 elevated creatinine occurred in 8% of patients. Nephrotoxic medicinal
products, tumour lysis, and tumour lysis with hyperuricemia may contribute to renal toxicity (see
sections 4.3 and 4.4). Haematuria was observed in 13% of patients overall. Four renal adverse events
in 115 patients were considered to be related to clofarabine, none of which were serious; haematuria
(3 events) and acute renal failure (1 event) (see sections 4.3 and 4.4).
Hepato-biliary disorders:
The liver is a potential target organ for clofarabine toxicity and 25.2% of
patients experienced at least one hepato-biliary disorders adverse event (see sections 4.3 and 4.4). Six
events were considered to be related to clofarabine of which acute cholecystitis (1 event),
cholelithiasis (1 event), hepatocellular damage (1 event; patient died (see above)) and
hyperbilirubinaemia (1 event; the patient discontinued therapy (see above)) were considered to be
serious. Two paediatric reports (1.7%) of veno-occlusive disease (VOD) were considered related to
study drug.
In addition, 50/113 patients receiving clofarabine had at least severely (at least US NCI CTC Grade 3)
elevated ALT, 36/100 elevated AST and 15/114 elevated bilirubin levels. The majority of elevations
in ALT and AST occurred within 10 days of clofarabine administration and returned to grade 2
within 15 days. Where follow-up data are available, the majority of bilirubin elevations returned
to grade 2 within 10 days.
Systemic Inflammatory Response Syndrome (SIRS) or capillary leak syndrome:
SIRS, capillary leak
syndrome (signs and symptoms of cytokine release, e.g., tachypnea, tachycardia, hypotension,
pulmonary oedema) were reported as an adverse event in 5% (6/115) of paediatric patients (5 ALL, 1
AML) (see section 4.4). Thirteen events of tumour lysis syndrome, capillary leak 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).
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/m
2
for 5 consecutive days (2 paediatric ALL patients).
The toxicities observed in these patients included vomiting, hyperbilirubinaemia, elevated
transaminase levels and maculo-papular rash.
No specific antidotal therapy exists. Immediate discontinuation of therapy, careful observation and
initiation of appropriate supportive measures are recommended.
5.
5.1 Pharmacodynamic properties
9
Pharmacotherapeutic group: Antineoplastic agents, antimetabolites, ATC code: L01BB06.
Mechanism of action:
Clofarabine is a purine nucleoside anti-metabolite. Its antitumour activity is
believed to be due to 3 mechanisms:
DNA polymerase inhibition resulting in termination of DNA chain elongation and/or DNA
synthesis / repair.
Ribonucleotide reductase inhibition with reduction of cellular deoxynucleotide triphosphate
(dNTP) pools.
Disruption of mitochondrial membrane integrity with the release of cytochrome C and other
proapoptotic factors leading to programmed cell death even in non-dividing lymphocytes.
Clofarabine must first diffuse or be transported into target cells where it is sequentially phosphorylated
to the mono- and bi-phosphate by intracellular kinases, and then finally to the active conjugate,
clofarabine 5’-triphosphate. Clofarabine has high affinity for one of the activating phosphorylating
enzymes, deoxycytidine kinase, which exceeds that of the natural substrate, deoxycytidine.
In addition, clofarabine possesses greater resistance to cellular degradation by adenosine deaminase
and decreased susceptibility to phosphorolytic cleavage than other active substances in its class whilst
the affinity of clofarabine triphosphate for DNA polymerase and ribonucleotide reductase is similar
to or greater than that of deoxyadenosine triphosphate.
Pharmacodynamic effects:
In vitro
studies have demonstrated that clofarabine inhibits cell growth in
and is cytotoxic to a variety of rapidly proliferating haematological and solid tumour cell lines. It was
also active against quiescent lymphocytes and macrophages. In addition, clofarabine delayed tumour
growth and, in some cases, caused tumour regression in an assortment of human and murine tumour
xenografts implanted in mice.
Clinical efficacy and safety:
Clinical efficacy:
To enable systematic evaluation of the responses seen in patients, an unblinded
Independent Response Review Panel (IRRP) determined the following response rates based on
definitions produced by the Children’s Oncology Group:
CR = Complete Remission
Patients who met each of the following criteria:
No evidence of circulating blasts or extramedullary
disease
An M1 bone marrow (≤ 5% blasts)
Recovery of peripheral counts (platelets 100 x 10
9
/l
and ANC 1.0 x 10
9
/l)
Patients who met all of the criteria for a CR except
for recovery of platelet counts to > 100 x 10
9
/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/m
2
/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
10
CRp = Complete Remission in the
Absence of Total Platelet Recovery
clofarabine 52 mg/m
2
/day. Of the 17 ALL patients, 2 achieved a complete remission (12%; CR) and 2
a partial remission (12%; PR) at varying doses. Dose-limiting toxicities in this study were
hyperbilirubinaemia, elevated transaminase levels and maculo-papular rash experienced at
70 mg/m
2
/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/m
2
/day clofarabine was
administered by intravenous infusion for 5 consecutive days every 2 to 6 weeks. The table below
summarises the key efficacy results for this study.
Patients with ALL must not have been eligible for therapy of higher curative potential and must have
been in second or subsequent relapse and/or refractory i.e. failed to achieve remission after at least two
prior regimens. Before enrolling in the trial, 58 of the 61 patients (95%) had received 2 to 4 different
induction regimens and 18/61 (30%) of these patients had undergone at least 1 prior haematological
stem cell transplant (HSCT). The median age of treated patients (37 males, 24 females) was 12 years
old.
Administration of clofarabine resulted in a dramatic and rapid reduction in peripheral leukaemia cells
in 31 of the 33 patients (94%) who had a measurable absolute blast count at baseline. The 12 patients
who achieved an overall remission (CR + CRp) had a median survival time of 66.6 weeks as of the
data collection cut-off date. Responses were seen in different immunophenotypes of ALL, including
pre-B cell and T-cell. Although transplantation rate was not a study endpoint, 10/61 patients (16%)
went on to receive a HSCT after treatment with clofarabine (3 after achieving a CR, 2 after a CRp,
3 after a PR, 1 patient that was considered a treatment failure by the IRRP and 1 that was considered
not evaluable by the IRRP). Response durations are confounded in patients who received a HSCT.
Efficacy results from the pivotal study in patients (≤ 21 years old at initial diagnosis) with
relapsed or refractory ALL after at least two prior regimens
Response
category
ITT*
patients
(n = 61)
Median duration
of remission
(weeks)
(95% CI)
Median time to
progression
(weeks)**
(95% CI)
Median overall
survival (weeks)
(95% CI)
Overall
remission
(CR + CRp)
12
(20%)
32.0
(9.7 to
47.9)
38.2
(15.4 to
56.1)
69.5
(58.
6 to
-)
CR
7
(12%)
47.9
(6.1 to -)
56.1
(13.7 to -)
72.4
(66.6 to
-)
CRp
5
(8%)
28.6
(4.6 to
38.3)
37.0
(9.1 to
42)
53.7
(9.1 to -)
PR
6
(10%)
11.0
(
5.
0
to -)
14.4
(7.0
to -)
33.0
(18.1 to -)
CR + CRp + PR
18
(30%)
21.5
(
7
.6
to 47.9)
28.7
(13.7 to 56.1)
66.6
(42.0 to
-)
Treatment
failure
33
(54%)
N/A
4.0
(3.4 to 5.1)
7.6
(6.7 to 12.6)
Not evaluable
10
(16%)
N/A
All patients
61
(100%)
N/A
5.4
(4.0 to 6.1)
12.9
(7.9 to 18.1)
*ITT = intention to treat.
**Patients alive and in remission at the time of last follow up were censored at that time point for
the analysis.
11
Individual duration remission and survival data for patients who achieved CR or CRp
Best Response
Time to OR
(weeks)
Duration of
Remission
(weeks)
Overall
Survival
(weeks)
Patients who did not undergo transplant
CR 5.7 4.3 66.6
CR 14.3 6.1 58.6
CR 8.3 47.9 66.6
CRp 4.6 4.6 9.1
CR 3.3 58.6 72.4
CRp 3.7 11.7 53.7
Patients who underwent transplant while in continued
remission*
CRp 8.4 11.6+ 145.1+
CR 4.1 9.0+ 111.9+
CRp 3.7 5.6+ 42.0
CR 7.6 3.7+ 96.3+
Patients who underwent transplant after alternative therapy or
relapse*
CRp
4.0
35.4
113.3+**
CR
4.0
9.7
89.4***
* Duration of remission censored at the time of transplant
** Patient received a transplant following alternate therapy
*** Patient received a transplant following relapse
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to
the rarity of the disease it has not been possible to obtain complete information on this medicinal
product. The European Medicines Agency will review any new information which may become
available every year and this SmPC will be updated as necessary.
5.2 Pharmacokinetic properties
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).
12
Pharmacokinetics in patients aged between 2 to 19 years old with relapsed or refractory
ALL or AML following administration of multiple doses of clofarabine by intravenous
infusion
Parameter
Estimates based on
non-compartmental
analysis
(n = 14 / n = 14)
Estimates based on other
analysis
Distribution:
Volume of distribution (steady
state)
172 l/m
2
Plasma protein binding
47.1%
Serum albumin
27.0%
Elimination:
half-life of clofarabine
5.2 hours
Half-life of clofarabine triphosphate
> 24 hours
Systemic clearance
28.8 l/h/m
2
Renal clearance
10.8 l/h/m
2
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/m
2
clofarabine produced equivalent exposure across
a wide range of weights. However, C
max
is inversely proportional to patient weight and, therefore,
small children may have a higher C
max
at the end of infusion than a typical 40 kg child given the same
dose of clofarabine per m
2
. Accordingly, longer infusion times should be considered in children
weighing 20 kg (see section 4.2).
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/m
2
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/m
2
clofarabine by intravenous infusion over 2 hours for 5 consecutive days.
Elderly patients (≥ 65 years old):
There are currently insufficient data to establish the safety and
efficacy of clofarabine in elderly patients.
Patients with renal insufficiency:
There is no experience in patients with renal insufficiency (serum
creatinine ≥ 2 x ULN for age) and clofarabine is predominately excreted via the kidneys (see
sections 4.3 and 4.4). To date, there are limited data on the pharmacokinetics of clofarabine in
13
patients with decreased creatinine clearance. However, these data indicate that clofarabine may
accumulate in such patients (see figure below and sections 4.2 and 4.4).
Clofarabine AUC
0-24 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)
3000
Clofarabine
AUC 0-24 hours
(ng*h/ml)
2500
2000
1500
1000
500
0
0
50
100
150
200
250
Estimated creatinine clearance (ml/min)
Patients with 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 (C
max
) 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 seen in dogs following acute administration of high doses, but was also not accompanied by
changes in serum chemistry.
14
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/m
2
/day), and cell
degeneration of the epididymis and degeneration of the seminiferous epithelium in dogs at clinically
relevant exposure levels (> 7.5 mg/m
2
/day clofarabine).
Delayed ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice
at the only dose used of 225 mg/m
2
/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/m
2
/day) and in
rabbits receiving 12 mg/m
2
/day clofarabine. (There are no exposure data in rabbits.) The threshold
for developmental toxicity was considered to be 6 mg/m
2
/day in rats and 1.2 mg/m
2
/day in rabbits.
The no-observable effect level for maternal toxicity in rats was 18 mg/m
2
/day and in rabbits was more
than 12 mg/m
2
/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.
6.1 List of excipients
Sodium chloride
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
3 years
The diluted concentrate is chemically and physically stable for 3 days at 2
°
C to 8
°
C and at room
temperature. From a microbiological point of view, it should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 24 hours at 2
°
C to 8
°
C unless dilution has taken place under
controlled and validated aseptic conditions.
6.4
Special precautions for storage
Do not freeze.
For storage conditions of the diluted medicinal product, see section 6.3.
6.5
Nature and contents of container
15
Type I glass vial with bromobutyl rubber stopper, polypropylene flip-off cap and aluminium overseal.
The vials contain 20 ml concentrate for solution for infusion and are packaged in a box. Each box
contains 1, 3, 4, 10 or 20 vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Evoltra 1 mg/ml concentrate for solution for infusion must be diluted prior to administration. It should
be filtered through a sterile 0.2 micrometre syringe filter and then diluted with sodium chloride
9 mg/ml (0.9%) intravenous infusion to produce a total volume according to the examples given in the
table below. However, the final dilution volume may vary depending on the patient’s clinical status
and physician discretion. (If the use of a 0.2 micrometre syringe filter is not feasible, the concentrate
should be pre-filtered with a 5 micrometre filter, diluted and then administered through a
0.22 micrometre in-line filter.)
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 m
2
, 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 m
2
, the contents of between 1 to 7 vials will be required to
produce the recommended daily dosage of clofarabine.
Suggested dilution schedule based on the recommended dosage of 52 mg/m
2
/day clofarabine
Body surface area (m
2
)
Concentrate (ml)*
The diluted concentrate should be a clear, colourless solution. It should be visually inspected for
particulate matter and discolouration prior to administration.
Evoltra is for single use only. Any unused product must be discarded.
Procedures for proper handling of antineoplastic agents should be observed. Cytotoxic medicinal
products should be handled with caution.
The use of disposable gloves and protective garments is recommended when handling Evoltra. If the
product comes into contact with eyes, skin or mucous membranes, rinse immediately with copious
amounts of water.
Evoltra should not be handled by pregnant women.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Genzyme Europe BV
Gooimeer 10
1411DD Naarden
The Netherlands
Tel: +31 (0)35 699 12 00
Fax: +31 (0) 35 694 32 14
16
8.
EU/1/06/334/001 3 vials
EU/1/06/334/002 4 vials
EU/1/06/334/003 10 vials
EU/1/06/334/004 20 vials
EU/1/06/334/005 1 vial
9.
Date of first authorisation: 29 May 2006.
Date of latest renewal:
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
.
17
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE
FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
C.
SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
18
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Pharmachemie B.V. (PCH)
Swensweg 5
Haarlem
The Netherlands
Genzyme Limited
37 Hollands Road
Haverhill
Suffolk
CB9 8PU
United Kingdom
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in the Detailed
Description of Pharmacovigilance System, presented in Module 1.8.1. of the Marketing
Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities
detailed in the Pharmacovigilance Plan, as agreed in version 3 of the Risk Management Plan
(RMP) presented in Module 1.8.2. of the Marketing Authorisation and any subsequent updates
of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
19
At the request of the European Medicines Agency
PSURs
The MAH will continue to submit yearly PSURs, unless otherwise specified by the CHMP.
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
The Marketing Authorisation Holder (MAH) shall complete the following programme of studies
within the specified time frame, the results of which shall form the basis of the annual reassessment of
the benefit/risk profile.
Clinical aspects
1.
The MAH has committed to provide data from a population PK analysis of paediatric and adult
clofarabine concentrations, as well as additional data, which will support a recommendation of
dose adjustments in patients with moderate renal impairment, by 09 February 2011. The MAH
will also consider the need for an additional clinical study, by this date.
2.
The MAH has committed to monitor and report toxicity in all ongoing and planned clinical trials.
The marketing authorisation holder will provide updates in accordance with standard PSUR
timings. Due date: Standard PSUR timings.
3.
The MAH has committed to set up a voluntary adverse event reporting system as detailed in the
risk management plan. The objective of the registry is to collect from prescribers that participate
on a voluntary basis, relevant information about patient and disease characteristics, and treatment
(including concomitant medicinal products) for all registered patients together with information on
any serious (especially unexpected) treatment-emergent possibly drug-related events, any
emergent CTC grade 3 or higher renal, hepatic, or cardiac events, all possibly drug-related deaths,
all cases of suspected tumour lysis syndrome, Systemic Inflammatory Response Syndrome (SIRS)
and capillary-leak syndrome, all cases with a suspected drug interaction, all grade 3 or higher
possibly drug-related events occurring after 3 or more cycles of use, any suspected cases of veno-
occlusive disease (VOD) in patients receiving clofarabine treatment. Due date: Recruitment status
update to be submitted every 6 months. Analyses from the registry to be submitted annually.
4.
The MAH has committed to monitor veno-occlusive disease (VOD) after haematological stem cell
transplant (HSCT). Due date: Standard PSUR timings.
20
ANNEX III
LABELLING AND PACKAGE LEAFLET
21
A. LABELLING
22
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Evoltra 1 mg/ml concentrate for solution for infusion
clofarabine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each 20 ml vial contains 20 mg of clofarabine
3.
LIST OF EXCIPIENTS
Excipients: Sodium chloride and water for injections.
4.
Concentrate for solution for infusion
20 mg/20 ml
1 vial
3 vials
4 vials
10 vials
20 vials
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Dilute before use.
For single use only.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Cytotoxic
23
8.
EXPIRY DATE
EXP:
9.
SPECIAL STORAGE CONDITIONS
Do not freeze.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused product or waste material should be disposed of in accordance with local requirements.
Genzyme Europe BV
Gooimeer 10
1411DD Naarden
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
13. BATCH NUMBER
BN:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
24
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1.
Evoltra 1 mg/ml concentrate for solution for infusion
clofarabine
Intravenous use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use
3.
EXPIRY DATE
EXP:
4.
BATCH NUMBER
BN:
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
20 mg/20 ml
6.
OTHER
Genzyme Europe B.V.
25
B. PACKAGE LEAFLET
26
PACKAGE LEAFLET: INFORMATION FOR THE USER
Evoltra 1 mg/ml concentrate for solution for infusion
clofarabine
Read all of this leaflet carefully before you start using this medicine.
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. Do not pass it on to others. It may harm them, even if
their symptoms are the same as yours.
If any of the side effects gets severe, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet
:
1.
What Evoltra is and what it is used for
2.
Before you use Evoltra
4.
Possible side effects
5.
How to store Evoltra
6.
Further information
1.
WHAT EVOLTRA IS AND WHAT IT IS USED FOR
Evoltra is used to treat children, 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.
Clofarabine is one of a family of medicines called cytotoxic medicines. It works by hindering the
growth of these abnormal white blood cells, and eventually kills them. It works best against cells
which are multiplying quickly – such as cancer cells.
2.
BEFORE YOU USE EVOLTRA
Do not use Evoltra:
-
if you are allergic
(hypersensitive) to clofarabine or any of the other ingredients of Evoltra;
-
if you are breast-feeding
(please read the section “Pregnancy and breast-feeding” below);
-
if you have severe kidney or liver problems.
Tell your doctor if any of these conditions apply to you.
If you are the parent of a child who is
being treated with Evoltra,
tell the doctor if any of them apply to your child.
Take special care with Evoltra:
-
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.
Tell your doctor if any of these apply to you.
Evoltra may not be suitable for you.
27
3.
How to use Evoltra
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 are the parent
of a child who is being treated with Evoltra,
tell the doctor if any of the above
conditions apply to your child.
During treatment with Evoltra,
your doctor will carry out regular blood tests and other tests to
monitor your health. Because of the way this medicine works, it will affect your blood and other
organs.
Talk to your doctor about contraception.
Young men and women must use effective contraception
during and after treatment. See the section ‘Pregnancy and breast-feeding’ below. Evoltra may harm
both male and female reproductive organs. Ask your doctor to explain what can be done to protect
you or allow you to have a family.
Taking other medicines
Please tell your doctor if you are taking or have recently taken:
-
medicines for heart disease;
-
any medicine that changes your blood pressure;
-
medicines that affect your liver or kidneys;
-
any other medicines including those obtained without a prescription.
Pregnancy and breast-feeding
Clofarabine should not be used during pregnancy unless clearly necessary.
Women who are able to get pregnant:
you must use effective contraception during treatment with
clofarabine. Clofarabine may cause harm to unborn babies when used by pregnant women. If you are
pregnant or you become pregnant during treatment with clofarabine,
get medical advice immediately.
Men must also use effective contraception while they or their partner are treated with clofarabine.
If you are breast-feeding, you must stop breast-feeding before starting the treatment, and must not
breast-feed either during or after your treatment.
Driving and using machines
Do not drive or use any tools or machines if you feel dizzy, light-headed or faint.
Evoltra contains salt
Each vial contains 180 mg of salt (sodium chloride). This is equivalent to 3.08 mmol (or 70.77 mg) of
sodium. You need to allow for this if you are on a controlled sodium diet.
3.
HOW TO USE EVOLTRA
Your treatment with Evoltra has been prescribed by a qualified doctor experienced in treating
leukaemia.
Your doctor will work out the dose that is right for you
depending on your height, weight and how
well you are. Before Evoltra is given to you, it will be diluted in a sodium chloride solution (salt and
28
water). Tell your doctor if you are on a controlled sodium diet as it could affect how you will be given
your medicine.
Your doctor will give you Evoltra once every day for 5 days.
It will be given to you as an infusion
through a long thin tube which goes into a vein (a drip), or into a small medical appliance that is
inserted under the skin (port-a-cath) if you (or your child) have one implanted. The infusion will be
given over 2 hours. If you (or your child) weigh less than 20 kg, the infusion time may be longer.
Your doctor will monitor your health and may change your dose depending on your response to the
treatment. It is important to drink plenty of water to avoid dehydration.
If you use more Evoltra than you should
If you think you may have been given too much medicine, tell your doctor straight away.
If you forget to use Evoltra
Your doctor will tell you when you need to be given this medicine. If you think that you have missed
a dose, tell your doctor straight away.
If you have any further questions on the use of this medicine, ask your doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Evoltra can cause side effects.
Very common side effects
These are likely to affect more than 1 in 10 patients:
-
anxiety, headache, fever, tiredness;
-
feeling and being sick, diarrhoea (loose bowels);
-
flushing, itching and inflamed skin, inflammation of mucus (moist) linings such as the mouth
and other areas;
-
you may have more infections than normal because Evoltra can lower the number of certain
types of blood cells in your body;
-
skin rashes which may be itchy, red, painful or peeling skin including palms of the hands and
soles of the feet, or small reddish or purple spots underneath the skin.
Common side effects
These are likely to affect more than 1 in every 100 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;
-
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;
-
water collecting around the heart, fast heartbeat;
-
low blood pressure, lump due to bad bruising;
-
leaking from tiny blood vessels, rapid breathing, nosebleeds, breathing difficulties,
breathlessness, cough;
-
vomiting blood, stomach ache, pain in the bottom;
-
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;
29
-
allergic reactions;
-
hearing problems;
-
bleeding mouth or gums, mouth ulcers, inflamed mouth lining;
-
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.
Talk to your doctor if you are concerned about any of these side effects or if there is anything you do
not understand.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor.
5.
HOW TO STORE EVOLTRA
Keep out of the reach and sight of children.
Do not use Evoltra after the expiry date which is stated on the vial label and box after EXP. The
expiry date refers to the last day of that month.
Do not freeze. Once prepared and diluted, Evoltra should be used straight away or within 24 hours if
stored in a refrigerator (at 2
o
C to 8
o
C).
Any unused medicine should be destroyed by your doctor.
6.
FURTHER INFORMATION
What Evoltra contains
The active substance is clofarabine. Each ml contains 1 mg of clofarabine. Each 20 ml vial contains
20 mg of clofarabine.
The other ingredients are sodium chloride and water for injections.
What Evoltra looks like and contents of the pack
Evoltra is a concentrate for solution for infusion . It is a clear, almost colourless solution that is
prepared and diluted before it is used. It is supplied in 20 ml glass vials. The vials contain 20 mg of
clofarabine and are packaged in a box. Each box contains 1, 3, 4, 10 or 20 vials, but not all pack sizes
may be marketed.
Marketing Authorisation Holder
Genzyme Europe B.V.
Gooimeer 10
1411DD Naarden
The Netherlands
Tel: +31 (0)35 699 12 00
Fax: +31 (0) 35 694 32 14
Manufacturer
Pharmachemie B.V. (PCH)
Swensweg 5
Haarlem
The Netherlands
30
Genzyme Limited
37 Hollands Road
Haverhill
Suffolk
CB9 8PU
United Kingdom
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien/
Luxemburg/Luxembourg
Genzyme Belgium N.V.
Tel/Tél: + 32 2 714 17 11
Italia/Malta
Genzyme Srl (Italia/Italja)
Tel: +39 059 349811
България
Търговско представителство на Genzyme CEE
GmbH
Тел: +359 2 971 1001
Magyarország
Genzyme Europe B.V. Képviselet
Tel: +36 1 310 7440
Česká Republika/Slovenská
Republika/Slovenija
Genzyme Czech, s.r.o.
Tel: +420 221 772 511
Nederland
Genzyme Europe B.V.
Tel: +31 35 6991200
Danmark/Norge/Sverige/Suomi/Finland/
Ísland
Genzyme A/S (Danmark/Tanska/Danmörk)
Tlf/Puh./Sími: + 45 32712600
Österreich
Genzyme Austria GmbH
Tel: + 43 1 774 65 38
Deutschland
Genzyme GmbH
Tel: +49 610236740
Polska/Eesti/Latvija/Lietuva
Genzyme Polska Sp. z o.o. (Poola/Polija/Lenkija)
Tel: +48 22 24 60 900
Ελλάδα/Κύπρος
Genzyme Hellas Ltd. (Ελλάδα)
Τηλ: +30 210 99 49 270
Portugal
Genzyme Portugal S.A.
Tel: +351 21 422 0100
España
Genzyme S.L.U.
Tel: +34 91 6591670
România
Genzyme Biopharma SRL
Tel: +40 21 24 34 228
France
Genzyme S.A.S.
Tél: + 33 (0) 825 825 863
United Kingdom/Ireland
Genzyme Therapeutics Ltd.(United Kingdom)
Tel: +44 1865 405200
This leaflet was last approved in
This medicine has been authorised under “Exceptional Circumstances”. This means that because of
the rarity of this disease it has been impossible to get complete information on this medicine. The
European Medicines Agency will review any new information on the medicine every year and this
leaflet will be updated as necessary.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/
.
There are also links to other websites about rare diseases and treatments.
31
Source: European Medicines Agency
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