ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
EXJADE 125 mg dispersible tablets
2.
Each dispersible tablet contains 125 mg deferasirox.
Excipient: Each dispersible tablet contains 136 mg lactose.
For a full list of excipients, see section 6.1.
3.
Dispersible tablet
Off-white, round, flat tablets with bevelled edges and imprints (NVR on one face and J 125 on the
other).
4.
EXJADE is indicated for the treatment of chronic iron overload due to frequent blood transfusions
(7 ml/kg/month of packed red blood cells) in patients with beta thalassaemia major aged 6 years and
older.
EXJADE is also indicated for the treatment of chronic iron overload due to blood transfusions when
deferoxamine therapy is contraindicated or inadequate in the following patient groups:
-
in patients with other anaemias,
-
in patients aged 2 to 5 years,
-
in patients with beta thalassaemia major with iron overload due to infrequent blood transfusions
(<7 ml/kg/month of packed red blood cells).
Treatment with EXJADE should be initiated and maintained by physicians experienced in the
treatment of chronic iron overload due to blood transfusions. It is recommended that treatment be
started after the transfusion of approximately 20 units (about 100 ml/kg) of packed red blood cells or
when there is evidence from clinical monitoring that chronic iron overload is present (e.g. serum
ferritin >1,000 µg/l). Doses (in mg/kg) must be calculated and rounded to the nearest whole tablet size.
The goals of iron chelation therapy are to remove the amount of iron administered in transfusions and,
as required, to reduce the existing iron burden.
Posology
Starting dose
The recommended initial daily dose of EXJADE is 20 mg/kg body weight.
An initial daily dose of 30 mg/kg may be considered for patients who require reduction of elevated
body iron levels and who are also receiving more than 14 ml/kg/month of packed red blood cells
(approximately >4 units/month for an adult).
2
An initial daily dose of 10 mg/kg may be considered for patients who do not require reduction of body
iron levels and who are also receiving less than 7 ml/kg/month of packed red blood cells
(approximately <2 units/month for an adult). The patient’s response must be monitored and a dose
increase should be considered if sufficient efficacy is not obtained (see section 5.1).
For patients already well managed on treatment with deferoxamine, a starting dose of EXJADE that is
numerically half that of the deferoxamine dose could be considered (e.g. a patient receiving
40 mg/kg/day of deferoxamine for 5 days per week (or equivalent) could be transferred to a starting
daily dose of 20 mg/kg/day of EXJADE). When this results in a daily dose less than 20 mg/kg body
weight, the patient’s response must be monitored and a dose increase should be considered if sufficient
efficacy is not obtained (see section 5.1).
Maintenance dose
It is recommended that serum ferritin be monitored every month and that the dose of EXJADE be
adjusted, if necessary, every 3 to 6 months based on the trends in serum ferritin. Dose adjustments
may be made in steps of 5 to 10 mg/kg and are to be tailored to the individual patient’s response and
therapeutic goals (maintenance or reduction of iron burden). In patients not adequately controlled with
doses of 30 mg/kg (e.g. serum ferritin levels persistently above 2,500 µg/l and not showing a
decreasing trend over time), doses of up to 40 mg/kg may be considered. The availability of long-term
efficacy and safety data with EXJADE used at doses above 30 mg/kg is currently limited (264 patients
followed for an average of 1 year after dose escalation). If only very poor haemosiderosis control is
achieved at doses up to 30 mg/kg, a further increase (to a maximum of 40 mg/kg) may not achieve
satisfactory control, and alternative treatment options may be considered. If no satisfactory control is
achieved at doses above 30 mg/kg, treatment at such doses should not be maintained and alternative
treatment options should be considered whenever possible. Doses above 40 mg/kg are not
recommended because there is only limited experience with doses above this level.
In patients treated with doses greater than 30 mg/kg, dose reductions in steps of 5 to 10 mg/kg should
be considered when control has been achieved (e.g. serum ferritin levels persistently below 2,500 µg/l
and showing a decreasing trend over time). In patients whose serum ferritin level has reached the
target (usually between 500 and 1,000 µg/l), dose reductions in steps of 5 to 10 mg/kg should be
considered to maintain serum ferritin levels within the target range. If serum ferritin falls consistently
below 500 µg/l, an interruption of treatment should be considered (see section 4.4).
Elderly patients (≥65 years of age)
The dosing recommendations for elderly patients are the same as described above. In clinical trials,
elderly patients experienced a higher frequency of adverse reactions than younger patients (in
particular, diarrhoea) and should be monitored closely for adverse events that may require a dose
adjustment.
Paediatric population
The dosing recommendations for paediatric patients aged 2 to 17 years are the same as for adult
patients. Changes in weight of paediatric patients over time must be taken into account when
calculating the dose. In children aged between 2 and 5 years, exposure is lower than in adults (see
section 5.2). This age group may therefore require higher doses than are necessary in adults. However,
the initial dose should be the same as in adults, followed by individual titration.
The safety and efficacy of EXJADE in children from birth to 23 months of age have not yet been
established.
Patients with renal impairment
EXJADE has not been studied in patients with renal impairment and is contraindicated in patients with
estimated creatinine clearance <60 ml/min (see sections 4.3 and 4.4).
3
Patients with hepatic impairment
EXJADE has not been studied in patients with hepatic impairment and must be used with caution in
such patients. The initial dosing recommendations for patients with hepatic impairment are the same as
described above. Hepatic function in all patients should be monitored before treatment, every 2 weeks
during the first month and then every month (see section 4.4).
Method of administration
For oral use.
EXJADE must be taken once daily on an empty stomach at least 30 minutes before food, preferably at
the same time each day (see sections 4.5 and 5.2). The tablets are dispersed by stirring in a glass of
water or orange or apple juice (100 to 200 ml) until a fine suspension is obtained. After the suspension
has been swallowed, any residue must be resuspended in a small volume of water or juice and
swallowed. The tablets must not be chewed or swallowed whole (see also section 6.2).
Hypersensitivity to the active substance or to any of the excipients.
Combination with other iron chelator therapies as the safety of such combinations has not been
established (see section 4.5).
Patients with estimated creatinine clearance <60 ml/min.
Renal function:
EXJADE has been studied only in patients with baseline serum creatinine within the age-appropriate
normal range.
During clinical trials, increases in serum creatinine of >33% on ≥2 consecutive occasions, sometimes
above the upper limit of the normal range, occurred in about 36% of patients. These were dose-
dependent. About two-thirds of the patients showing serum creatinine increase returned below the
33% level without dose adjustment. In the remaining third the serum creatinine increase did not
always respond to a dose reduction or a dose interruption. Cases of acute renal failure have been
reported following post-marketing use of EXJADE (see section 4.8). In some post-marketing cases,
renal function deterioration has led to renal failure requiring temporary or permanent dialysis.
The causes of the rises in serum creatinine have not been elucidated. Particular attention should
therefore be paid to monitoring of serum creatinine in patients who are concomitantly receiving
medicinal products that depress renal function, and in patients who are receiving high doses of
EXJADE and/or low rates of transfusion (<7 ml/kg/month of packed red blood cells or <2 units/month
for an adult). While no increase in renal adverse events was observed after dose escalation to doses
above 30 mg/kg in clinical trials, an increased risk of renal adverse events with EXJADE doses above
30 mg/kg cannot be excluded.
It is recommended that serum creatinine be assessed in duplicate before initiating therapy.
Serum
creatinine, creatinine clearance
(estimated with the Cockcroft-Gault or MDRD formula in adults and
with the Schwartz formula in children) and/or plasma cystatin C levels
should be monitored weekly
in the first month after initiation or modification of therapy with EXJADE, and monthly
thereafter
. Patients with pre-existing renal conditions and patients who are receiving medicinal
products that depress renal function may be more at risk of complications. Care should be taken to
maintain adequate hydration in patients who develop diarrhoea or vomiting.
4
For adult patients, the daily dose may be reduced by 10 mg/kg if a rise in serum creatinine by >33%
above the average of the pre-treatment measurements and estimated creatinine clearance decreases
below the lower limit of the normal range (<90 ml/min) are seen at two consecutive visits, and cannot
be attributed to other causes (see section 4.2). For paediatric patients, the dose may be reduced by
10 mg/kg if estimated creatinine clearance decreases below the lower limit of the normal range
(<90 ml/min) and/or serum creatinine levels rise above the age-appropriate upper limit of normal at
two consecutive visits.
After a dose reduction, for adult and paediatric patients, treatment should be interrupted if a rise in
serum creatinine >33% above the average of the pre-treatment measurements is observed and/or the
calculated creatinine clearance falls below the lower limit of the normal range. Treatment may be
reinitiated depending on the individual clinical circumstances.
Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated
with EXJADE. Tests for proteinuria should be performed monthly. As needed, additional markers of
renal tubular function (e.g. glycosuria in non-diabetics and low levels of serum potassium, phosphate,
magnesium or urate, phosphaturia, aminoaciduria) may also be monitored. Dose reduction or
interruption may be considered if there are abnormalities in levels of tubular markers and/or if
clinically indicated.
If, despite dose reduction and interruption, the serum creatinine remains significantly elevated and
there is also persistent abnormality in another marker of renal function (e.g. proteinuria, Fanconi’s
Syndrome), the patient should be referred to a renal specialist, and further specialised investigations
(such as renal biopsy) may be considered.
Hepatic function:
Liver function test elevations have been observed in patients treated with EXJADE. Postmarketing
cases of hepatic failure, sometimes fatal, have been reported in patients treated with EXJADE. Most
reports of hepatic failure involved patients with significant morbidities including pre-existing liver
cirrhosis. However, the role of EXJADE as a contributing or aggravating factor cannot be excluded
(see section 4.8).
It is recommended that
serum transaminases, bilirubin and alkaline phosphatase be checked before the
initiation of treatment, every 2 weeks during the first month and monthly thereafter. If there is a
persistent and progressive increase in serum transaminase levels that cannot be attributed to other
causes, EXJADE should be interrupted. Once the cause of the liver function test abnormalities has
been clarified or after return to normal levels, cautious re-initiation of treatment at a lower dose
followed by gradual dose escalation may be considered.
EXJADE is not recommended in patients with severe hepatic impairment as it has not been studied in
such patients. Treatment has been initiated only in patients with baseline liver transaminase levels up
to 5 times the upper limit of the normal range (see section 5.2).
In patients with a short life expectancy (e.g. high-risk myelodysplastic syndromes), especially when
co-morbidities could increase the risk of adverse events, the benefit of EXJADE might be limited and
may be inferior to risks. As a consequence, treatment with EXJADE is not recommended in these
patients.
Caution should be used in elderly patients due to a higher frequency of adverse reactions (in particular,
diarrhoea).
Gastrointestinal
Upper gastrointestinal ulceration and haemorrhage have been reported in patients, including children
and adolescents, receiving EXJADE. Multiple ulcers have been observed in some patients (see section
4.8). There have been reports of fatal gastrointestinal haemorrhages, especially in elderly patients who
5
had haematological malignancies and/or low platelet counts. Physicians and patients should remain
alert for signs and symptoms of gastrointestinal ulceration and haemorrhage during EXJADE therapy
and promptly initiate additional evaluation and treatment if a serious gastrointestinal adverse event is
suspected. Caution should be exercised in patients who are taking EXJADE in combination with
substances that have known ulcerogenic potential, such as NSAIDs, corticosteroids, or oral
bisphosphonates, in patients receiving anticoagulants and in patients with platelet counts below
50,000/mm
3
(50 x 10
9
/l) (see section 4.5).
Skin disorders
Skin rashes may appear during EXJADE treatment. The rashes resolve spontaneously in most cases.
When interruption of treatment may be necessary, treatment may be reintroduced after resolution of
the rash, at a lower dose followed by gradual dose escalation. In severe cases this reintroduction could
be conducted in combination with a short period of oral steroid administration.
Hypersensitivity reactions
Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported
in patients receiving EXJADE, with the onset of the reaction occurring in the majority of cases within
the first month of treatment (see section 4.8). If such reactions occur, EXJADE should be discontinued
and appropriate medical intervention instituted.
Vision and hearing
Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported (see section
4.8). Auditory and ophthalmic testing (including fundoscopy) is recommended before the start of
treatment and at regular intervals thereafter (every 12 months). If disturbances are noted during the
treatment, dose reduction or interruption may be considered.
Blood disorders
There have been post-marketing reports of leukopenia, thrombocytopenia or pancytopenia, or
aggravation of these cytopenias in patients treated with EXJADE. Most of these patients had pre-
existing haematological disorders that are frequently associated with bone marrow failure. However, a
contributory or aggravating
role cannot be excluded. Interruption of treatment should be considered in
patients who develop unexplained cytopenia.
Other considerations
Monthly monitoring of serum ferritin is recommended in order to assess the patient’s response to
therapy (see section 4.2). If serum ferritin falls consistently below 500 µg/l, an interruption of
treatment should be considered.
The results of the tests for serum creatinine, serum ferritin and serum transaminases should be
recorded and regularly assessed for trends. The results should also be noted in the provided patient’s
booklet.
In one clinical study, growth and sexual development of paediatric patients treated with EXJADE for
up to 5 years were not affected. However, as a general precautionary measure in the management of
paediatric patients with transfusional iron overload, body weight, height and sexual development
should be monitored at regular intervals (every 12 months).
Cardiac dysfunction is a known complication of severe iron overload. Cardiac function should be
monitored in patients with severe iron overload during long-term treatment with EXJADE.
Each tablet contains 136 mg lactose. Patients with rare hereditary problems of galactose intolerance,
the Lapp lactase deficiency, glucose-galactose malabsorption or severe lactase deficiency should not
take this medicine.
6
The concomitant use of deferasirox with aluminium-containing antacid preparations is not
recommended. The concomitant use of deferasirox with repaglinide (a CYP2C8 substrate) or with
CYP1A2 substrates that have a narrow therapeutic index, such as theophylline, clozapine or tizanidine,
is not recommended (see section 4.5).
The concomitant administration of EXJADE and aluminium-containing antacid preparations has not
been formally studied. Although deferasirox has a lower affinity for aluminium than for iron, it is not
recommended to take EXJADE tablets with aluminium-containing antacid preparations (see section
4.4).
The bioavailability of deferasirox was increased to a variable extent when taken along with food.
EXJADE must therefore be taken on an empty stomach at least 30 minutes before food, preferably at
the same time each day (see sections 4.2 and 5.2).
Deferasirox metabolism depends on UGT enzymes. In a healthy volunteer study, the concomitant
administration of EXJADE (single dose of 30 mg/kg) and the potent UGT inducer, rifampicin,
(repeated dose of 600 mg/day) resulted in a decrease of deferasirox exposure by 44% (90% CI: 37% -
51%). Therefore, the concomitant use of EXJADE with potent UGT inducers (e.g. rifampicin,
carbamazepine, phenytoin, phenobarbital, ritonavir) may result in a decrease in EXJADE efficacy (see
section 4.4). The patient’s serum ferritin should be monitored during and after the combination, and
the dose of EXJADE adjusted if necessary.
In a healthy volunteer study, the concomitant administration of EXJADE and midazolam (a CYP3A4
probe substrate) resulted in a decrease of midazolam exposure by 17% (90% CI: 8% - 26%). In the
clinical setting, this effect may be more pronounced. Therefore, due to a possible decrease in efficacy,
caution should be exercised when deferasirox is combined with substances metabolised through
CYP3A4 (e.g. ciclosporin, simvastatin, hormonal contraceptive agents, bepridil, ergotamine).
The safety of EXJADE in combination with other iron chelators has not been established. Therefore, it
must not be combined with other iron chelator therapies (see section 4.3).
No interaction was observed between EXJADE and digoxin in healthy adult volunteers.
In a healthy volunteer study, the concomitant administration of deferasirox as a moderate CYP2C8
inhibitor (30 mg/kg daily), with repaglinide, a CYP2C8 substrate, given as a single dose of 0.5 mg,
increased repaglinide AUC and C
max
about 2.3-fold (90% CI [2.03-2.63]) and 1.6-fold (90% CI
[1.42-1.84]), respectively. Since the interaction has not been established with dosages higher than
0.5 mg for repaglinide, the concomitant use of deferasirox with repaglinide should be avoided. If the
combination appears necessary, careful clinical and blood glucose monitoring should be performed
(see section 4.4). An interaction between deferasirox and other CYP2C8 substrates like paclitaxel
cannot be excluded (see section 4.4).
In a healthy volunteer study, the concomitant administration of EXJADE as a CYP1A2 inhibitor
(repeated dose of 30 mg/kg/day) and the CYP1A2 substrate theophylline (single dose of 120 mg)
resulted in an increase of theophylline AUC by 84% (90% CI: 73% to 95%). The single dose C
max
was
not affected, but an increase of theophylline C
max
is expected to occur with chronic dosing. Therefore,
the concomitant use of EXJADE with theophylline is not recommended. If EXJADE and theophylline
are used concomitantly, monitoring of theophylline concentration and theophylline dose reduction
should be considered. An interaction between EXJADE and other CYP1A2 substrates cannot be
excluded. For substances that are predominantly metabolised by CYP1A2 and that have a narrow
therapeutic index (e.g. clozapine, tizanidine), the same recommendations apply as for theophylline
(see section 4.4).
The concomitant administration of EXJADE and vitamin C has not been formally studied. Doses of
vitamin C up to 200 mg per day have not been associated with adverse consequences.
7
The concomitant administration of EXJADE with substances that have known ulcerogenic potential,
such as NSAIDs (including acetylsalicylic acid at high dosage), corticosteroids or oral
bisphosphonates may increase the risk of gastrointestinal toxicity (see section 4.4). The concomitant
administration of EXJADE with anticoagulants may also increase the risk of gastrointestinal
haemorrhage. Close clinical monitoring is required when deferasirox is combined with these
substances.
Pregnancy
No clinical data on exposed pregnancies are available for deferasirox. Studies in animals have shown
some reproductive toxicity at maternally toxic doses (see section 5.3). The potential risk for humans is
unknown.
As a precaution, it is recommended that EXJADE not be used during pregnancy unless clearly
necessary.
Breast-feeding
In animal studies, deferasirox was found to be rapidly and extensively secreted into maternal milk. No
effect on the offspring was noted. It is not known if deferasirox is secreted into human milk. Breast-
feeding while taking EXJADE is not recommended.
Fertility
No fertility data is available for humans. In animals, no adverse effects on male or female fertility
were found (see section 5.3).
No studies on the effects of EXJADE on the ability to drive and use machines have been performed.
Patients experiencing the uncommon adverse reaction of dizziness should exercise caution when
driving or operating machinery (see section 4.8).
Summary of the safety profile
The most frequent reactions reported during chronic treatment with EXJADE in adult and paediatric
patients include gastrointestinal disturbances in about 26% of patients (mainly nausea, vomiting,
diarrhoea or abdominal pain) and skin rash in about 7% of patients. Diarrhoea is reported more
commonly in paediatric patients aged 2 to 5 years than in older patients. These reactions are dose-
dependent, mostly mild to moderate, generally transient and mostly resolve even if treatment is
continued.
During clinical trials, increases in serum creatinine of >33% on ≥2 consecutive occasions, sometimes
above the upper limit of the normal range, occurred in about 36% of patients. These were dose-
dependent. About two-thirds of the patients showing serum creatinine increase returned below the
33% level without dose adjustment. In the remaining third the serum creatinine increase did not
always respond to a dose reduction or a dose interruption. Indeed, in some cases, only a stabilisation
of the serum creatinine values has been observed after dose reduction (see section 4.4).
Gallstones and related biliary disorders were reported in about 2% of patients. Elevations of liver
transaminases were reported as an adverse drug reaction in 2% of patients. Elevations of transaminases
greater than 10 times the upper limit of the normal range, suggestive of hepatitis, were uncommon
(0.3%). During postmarketing experience, hepatic failure, sometimes fatal, has been reported with
EXJADE, especially in patients with pre-existing liver cirrhosis (see section 4.4). As with other iron
chelator treatment, high-frequency hearing loss and lenticular opacities (early cataracts) have been
uncommonly observed in patients treated with EXJADE (see section 4.4).
8
Tabulated list of adverse reactions
Adverse reactions are ranked below using the following convention: 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); very rare
(<1/10,000); not known (cannot be estimated from the available data). Within each frequency
grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1
Blood and lymphatic system disorders
Not known: Pancytopenia
1
, thrombocytopenia
1
Immune system disorders
Not known:
Hypersensitivity reactions (including anaphylaxis and angioedema)
1
Psychiatric disorders
Uncommon: Anxiety, sleep disorder
Nervous system disorders
Uncommon:
Headache
Eye disorders
Uncommon: Early cataract, maculopathy
Ear and labyrinth disorders
Uncommon: Hearing loss
Respiratory, thoracic and mediastinal disorders
Uncommon: Pharyngolaryngeal pain
Gastrointestinal disorders
Common:
Diarrhoea, constipation, vomiting, nausea, abdominal pain,
abdominal distension, dyspepsia
Uncommon:
Gastrointestinal haemorrhage, gastric ulcer (including multiple
ulcers), duodenal ulcer, gastritis
Rare:
Oesophagitis
Hepatobiliary disorders
Common: Transaminases increased
Uncommon: Hepatitis, cholelithiasis
Not known: Hepatic failure
1
Skin and subcutaneous tissue disorders
Common: Rash, pruritus
Uncommon: Pigmentation disorder
Not known: Leukocytoclastic vasculitis
1
, urticaria
1
, erythema multiforme
1
,
alopecia
1
Renal and urinary disorders
Very common: Blood creatinine increased
Common: Proteinuria
Uncommon: Renal tubulopathy (acquired Fanconi’s syndrome), glycosuria
Not known: Acute renal failure
1
General disorders and administration site conditions
Uncommon:
Pyrexia, oedema, fatigue
1
Adverse reactions reported during postmarketing experience. These are derived from
spontaneous reports for which it is not always possible to reliably establish frequency or a
causal relationship to exposure to the medicinal product.
Paediatric population
Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years than in older patients.
Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated
with EXJADE.
9
Common:
Dizziness
Cases of overdose (2-3 times the prescribed dose for several weeks) have been reported. In one case,
this resulted in subclinical hepatitis which resolved after a dose interruption. Single doses of 80 mg/kg
in iron-overloaded thalassaemic patients caused mild nausea and diarrhoea.
treated by induction of emesis or by gastric lavage, and by symptomatic treatment.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Iron chelating agent, ATC code: V03AC03
Mechanism of action
Deferasirox is an orally active chelator that is highly selective for iron (III). It is a tridentate ligand that
binds iron with high affinity in a 2:1 ratio. Deferasirox promotes excretion of iron, primarily in the
faeces. Deferasirox has low affinity for zinc and copper, and does not cause constant low serum levels
of these metals.
Pharmacodynamic effects
In an iron-balance metabolic study in iron-overloaded adult thalassaemic patients, EXJADE at daily
doses of 10, 20 and 40 mg/kg induced the mean net excretion of 0.119, 0.329 and 0.445 mg Fe/kg
body weight/day, respectively.
Clinical efficacy and safety
EXJADE has been investigated in 411 adult (age 16 years) and 292 paediatric patients (aged 2 to
<16 years) with chronic iron overload due to blood transfusions. Of the paediatric patients 52 were
aged 2 to 5 years. The underlying conditions requiring transfusion included beta-thalassaemia, sickle
cell disease and other congenital and acquired anaemias (myelodysplastic syndromes, Diamond-
Blackfan syndrome, aplastic anaemia and other very rare anaemias).
Daily treatment at doses of 20 and 30 mg/kg for one year in frequently transfused adult and paediatric
patients with beta-thalassaemia led to reductions in indicators of total body iron; liver iron
concentration was reduced by about -0.4 and -8.9 mg Fe/g liver (biopsy dry weight (dw)) on average,
respectively, and serum ferritin was reduced by about -36 and -926 µg/l on average, respectively. At
these same doses the ratios of iron excretion : iron intake were 1.02 (indicating net iron balance) and
1.67 (indicating net iron removal), respectively. EXJADE induced similar responses in iron-
overloaded patients with other anaemias. Daily doses of 10 mg/kg for one year could maintain liver
iron and serum ferritin levels and induce net iron balance in patients receiving infrequent transfusions
or exchange transfusions. Serum ferritin assessed by monthly monitoring reflected changes in liver
iron concentration indicating that trends in serum ferritin can be used to monitor response to therapy.
Limited clinical data (29 patients with normal cardiac function at baseline) using MRI indicate that
treatment with EXJADE 10-30 mg/kg/day for 1 year may also reduce levels of iron in the heart (on
average, MRI T2* increased from 18.3 to 23.0 milliseconds).
The principal analysis of the pivotal comparative study in 586 patients suffering from beta-
thalassaemia and transfusional iron overload did not demonstrate non-inferiority of EXJADE to
deferoxamine in the analysis of the total patient population. It appeared from a post-hoc analysis of
this study that, in the subgroup of patients with liver iron concentration ≥7 mg Fe/g dw treated with
EXJADE (20 and 30 mg/kg) or deferoxamine (35 to ≥50 mg/kg), the non-inferiority criteria were
achieved. However, in patients with liver iron concentration <7 mg Fe/g dw treated with EXJADE (5
and 10 mg/kg) or deferoxamine (20 to 35 mg/kg), non-inferiority was not established due to imbalance
in the dosing of the two chelators. This imbalance occurred because patients on deferoxamine were
10
allowed to remain on their pre-study dose even if it was higher than the protocol specified dose. Fifty-
six patients under the age of 6 years participated in this pivotal study, 28 of them receiving EXJADE.
It appeared from preclinical and clinical studies that EXJADE could be as active as deferoxamine
when used in a dose ratio of 2:1 (i.e. a dose of EXJADE that is numerically half of the deferoxamine
dose). However, this dosing recommendation was not prospectively assessed in the clinical trials.
In addition, in patients with liver iron concentration ≥7 mg Fe/g dw with various rare anaemias or
sickle cell disease, EXJADE up to 20 and 30 mg/kg produced a decrease in liver iron concentration
and serum ferritin comparable to that obtained in patients with beta-thalassaemia.
5.2 Pharmacokinetic properties
Absorption
Deferasirox is absorbed following oral administration with a median time to maximum plasma
concentration (t
max
) of about 1.5 to 4 hours. The absolute bioavailability (AUC) of deferasirox from
EXJADE tablets is about 70% compared to an intravenous dose. Total exposure (AUC) was
approximately doubled when taken along with a high-fat breakfast (fat content >50% of calories) and
by about 50% when taken along with a standard breakfast. The bioavailability (AUC) of deferasirox
was moderately (approx. 13–25%) elevated when taken 30 minutes before meals with normal or high
fat content.
Distribution
Deferasirox is highly (99%) protein bound to plasma proteins, almost exclusively serum albumin, and
has a small volume of distribution of approximately 14 litres in adults.
Biotransformation
Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion.
Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling)
is likely to occur: in a healthy volunteer study, the administration of cholestyramine after a single dose
of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC).
Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalysed
(oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). No inhibition of
deferasirox metabolism by hydroxyurea was observed
in vitro
.
Elimination
Deferasirox and its metabolites are primarily excreted in the faeces (84% of the dose). Renal excretion
of deferasirox and its metabolites is minimal (8% of the dose). The mean elimination half-life (t
1/2
)
ranged from 8 to 16 hours. The transporters MRP2 and MXR (BCRP) are involved in the biliary
excretion of deferasirox.
Linearity / non-linearity
The C
max
and AUC
0-24h
of deferasirox increase approximately linearly with dose under steady-state
conditions. Upon multiple dosing exposure increased by an accumulation factor of 1.3 to 2.3.
Characteristics in patients
Paediatric patients
The overall exposure of adolescents (12 to ≤17
years) and children (2 to <12 years) to deferasirox after
single and multiple doses was lower than that in adult patients. In children younger than 6 years old
exposure was about 50% lower than in adults. Since dosing is individually adjusted according to
response this is not expected to have clinical consequences.
Gender
Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males.
Since dosing is individually adjusted according to response this is not expected to have clinical
consequences.
11
Elderly patients
The pharmacokinetics of deferasirox have not been studied in elderly patients (aged 65 or older).
Renal or hepatic impairment
The pharmacokinetics of deferasirox have not been studied in patients with renal or hepatic
impairment. The pharmacokinetics of deferasirox were not influenced by liver transaminase levels up
to 5 times the upper limit of the normal range.
5.3 Preclinical safety data
Preclinical data reveal no special hazard for patients with iron overload, based on conventional studies
of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential. The main
findings were kidney toxicity and lens opacity (cataracts). Similar findings were observed in neonatal
and juvenile animals. The kidney toxicity is considered mainly due to iron deprivation in animals that
were not previously overloaded with iron.
Tests of genotoxicity
in vitro
were either negative (Ames test, chromosomal aberration test) or positive
(V79 screen). Deferasirox caused formation of micronuclei
in vivo
in the bone marrow, but not liver,
of non-iron-loaded rats at lethal doses. No such effects were observed in iron-preloaded rats.
Deferasirox was not carcinogenic when administered to rats in a 2-year study and transgenic p53+/-
heterozygous mice in a 6-month study.
The potential for toxicity to reproduction was assessed in rats and rabbits. Deferasirox was not
teratogenic, but caused increased frequency of skeletal variations and stillborn pups in rats at high
doses that were severely toxic to the non-iron-overloaded mother. Deferasirox did not cause other
effects on fertility or reproduction.
6.
6.1 List of excipients
Lactose monohydrate
Crospovidone type A
Cellulose, microcrystalline
Povidone
Sodium lauryl sulphate
Silica, colloidal anhydrous
Magnesium stearate
6.2 Incompatibilities
Dispersion in carbonated drinks or milk is not recommended due to foaming and slow dispersion,
respectively.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from moisture.
12
6.5 Nature and contents of container
PVC/PE/PVDC/Aluminium blisters.
Packs containing 28, 84 or 252 dispersible tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/06/356/001
EU/1/06/356/002
EU/1/06/356/007
9.
28.08.2006
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
13
1.
EXJADE 250 mg dispersible tablets
2.
Each dispersible tablet contains 250 mg deferasirox.
Excipient: Each dispersible tablet contains 272 mg lactose.
For a full list of excipients, see section 6.1.
3.
Dispersible tablet
Off-white, round, flat tablets with bevelled edges and imprints (NVR on one face and J 250 on the
other).
4.
EXJADE is indicated for the treatment of chronic iron overload due to frequent blood transfusions
(7 ml/kg/month of packed red blood cells) in patients with beta thalassaemia major aged 6 years and
older.
EXJADE is also indicated for the treatment of chronic iron overload due to blood transfusions when
deferoxamine therapy is contraindicated or inadequate in the following patient groups:
-
in patients with other anaemias,
-
in patients aged 2 to 5 years,
-
in patients with beta thalassaemia major with iron overload due to infrequent blood transfusions
(<7 ml/kg/month of packed red blood cells).
Treatment with EXJADE should be initiated and maintained by physicians experienced in the
treatment of chronic iron overload due to blood transfusions. It is recommended that treatment be
started after the transfusion of approximately 20 units (about 100 ml/kg) of packed red blood cells or
when there is evidence from clinical monitoring that chronic iron overload is present (e.g. serum
ferritin >1,000 µg/l). Doses (in mg/kg) must be calculated and rounded to the nearest whole tablet size.
The goals of iron chelation therapy are to remove the amount of iron administered in transfusions and,
as required, to reduce the existing iron burden.
Posology
Starting dose
The recommended initial daily dose of EXJADE is 20 mg/kg body weight.
An initial daily dose of 30 mg/kg may be considered for patients who require reduction of elevated
body iron levels and who are also receiving more than 14 ml/kg/month of packed red blood cells
(approximately >4 units/month for an adult).
14
An initial daily dose of 10 mg/kg may be considered for patients who do not require reduction of body
iron levels and who are also receiving less than 7 ml/kg/month of packed red blood cells
(approximately <2 units/month for an adult). The patient’s response must be monitored and a dose
increase should be considered if sufficient efficacy is not obtained (see section 5.1).
For patients already well managed on treatment with deferoxamine, a starting dose of EXJADE that is
numerically half that of the deferoxamine dose could be considered (e.g. a patient receiving
40 mg/kg/day of deferoxamine for 5 days per week (or equivalent) could be transferred to a starting
daily dose of 20 mg/kg/day of EXJADE). When this results in a daily dose less than 20 mg/kg body
weight, the patient’s response must be monitored and a dose increase should be considered if sufficient
efficacy is not obtained (see section 5.1).
Maintenance dose
It is recommended that serum ferritin be monitored every month and that the dose of EXJADE be
adjusted, if necessary, every 3 to 6 months based on the trends in serum ferritin. Dose adjustments
may be made in steps of 5 to 10 mg/kg and are to be tailored to the individual patient’s response and
therapeutic goals (maintenance or reduction of iron burden). In patients not adequately controlled with
doses of 30 mg/kg (e.g. serum ferritin levels persistently above 2,500 µg/l and not showing a
decreasing trend over time), doses of up to 40 mg/kg may be considered. The availability of long-term
efficacy and safety data with EXJADE used at doses above 30 mg/kg is currently limited (264 patients
followed for an average of 1 year after dose escalation). If only very poor haemosiderosis control is
achieved at doses up to 30 mg/kg, a further increase (to a maximum of 40 mg/kg) may not achieve
satisfactory control, and alternative treatment options may be considered. If no satisfactory control is
achieved at doses above 30 mg/kg, treatment at such doses should not be maintained and alternative
treatment options should be considered whenever possible. Doses above 40 mg/kg are not
recommended because there is only limited experience with doses above this level.
In patients treated with doses greater than 30 mg/kg, dose reductions in steps of 5 to 10 mg/kg should
be considered when control has been achieved (e.g. serum ferritin levels persistently below 2,500 µg/l
and showing a decreasing trend over time). In patients whose serum ferritin level has reached the
target (usually between 500 and 1,000 µg/l), dose reductions in steps of 5 to 10 mg/kg should be
considered to maintain serum ferritin levels within the target range. If serum ferritin falls consistently
below 500 µg/l, an interruption of treatment should be considered (see section 4.4).
Elderly patients (≥65 years of age)
The dosing recommendations for elderly patients are the same as described above. In clinical trials,
elderly patients experienced a higher frequency of adverse reactions than younger patients (in
particular, diarrhoea) and should be monitored closely for adverse events that may require a dose
adjustment.
Paediatric population
The dosing recommendations for paediatric patients aged 2 to 17 years are the same as for adult
patients. Changes in weight of paediatric patients over time must be taken into account when
calculating the dose. In children aged between 2 and 5 years, exposure is lower than in adults (see
section 5.2). This age group may therefore require higher doses than are necessary in adults. However,
the initial dose should be the same as in adults, followed by individual titration.
The safety and efficacy of EXJADE in children from birth to 23 months of age have not yet been
established.
Patients with renal impairment
EXJADE has not been studied in patients with renal impairment and is contraindicated in patients with
estimated creatinine clearance <60 ml/min (see sections 4.3 and 4.4).
15
Patients with hepatic impairment
EXJADE has not been studied in patients with hepatic impairment and must be used with caution in
such patients. The initial dosing recommendations for patients with hepatic impairment are the same as
described above. Hepatic function in all patients should be monitored before treatment, every 2 weeks
during the first month and then every month (see section 4.4).
Method of administration
For oral use.
EXJADE must be taken once daily on an empty stomach at least 30 minutes before food, preferably at
the same time each day (see sections 4.5 and 5.2). The tablets are dispersed by stirring in a glass of
water or orange or apple juice (100 to 200 ml) until a fine suspension is obtained. After the suspension
has been swallowed, any residue must be resuspended in a small volume of water or juice and
swallowed. The tablets must not be chewed or swallowed whole (see also section 6.2).
Hypersensitivity to the active substance or to any of the excipients.
Combination with other iron chelator therapies as the safety of such combinations has not been
established (see section 4.5).
Patients with estimated creatinine clearance <60 ml/min.
Renal function:
EXJADE has been studied only in patients with baseline serum creatinine within the age-appropriate
normal range.
During clinical trials, increases in serum creatinine of >33% on ≥2 consecutive occasions, sometimes
above the upper limit of the normal range, occurred in about 36% of patients. These were dose-
dependent. About two-thirds of the patients showing serum creatinine increase returned below the
33% level without dose adjustment. In the remaining third the serum creatinine increase did not
always respond to a dose reduction or a dose interruption. Cases of acute renal failure have been
reported following post-marketing use of EXJADE (see section 4.8). In some post-marketing cases,
renal function deterioration has led to renal failure requiring temporary or permanent dialysis.
The causes of the rises in serum creatinine have not been elucidated. Particular attention should
therefore be paid to monitoring of serum creatinine in patients who are concomitantly receiving
medicinal products that depress renal function, and in patients who are receiving high doses of
EXJADE and/or low rates of transfusion (<7 ml/kg/month of packed red blood cells or <2 units/month
for an adult). While no increase in renal adverse events was observed after dose escalation to doses
above 30 mg/kg in clinical trials, an increased risk of renal adverse events with EXJADE doses above
30 mg/kg cannot be excluded.
It is recommended that serum creatinine be assessed in duplicate before initiating therapy.
Serum
creatinine, creatinine clearance
(estimated with the Cockcroft-Gault or MDRD formula in adults and
with the Schwartz formula in children) and/or plasma cystatin C levels
should be monitored weekly
in the first month after initiation or modification of therapy with EXJADE, and monthly
thereafter
. Patients with pre-existing renal conditions and patients who are receiving medicinal
products that depress renal function may be more at risk of complications. Care should be taken to
maintain adequate hydration in patients who develop diarrhoea or vomiting.
16
For adult patients, the daily dose may be reduced by 10 mg/kg if a rise in serum creatinine by >33%
above the average of the pre-treatment measurements and estimated creatinine clearance decreases
below the lower limit of the normal range (<90 ml/min) are seen at two consecutive visits, and cannot
be attributed to other causes (see section 4.2). For paediatric patients, the dose may be reduced by
10 mg/kg if estimated creatinine clearance decreases below the lower limit of the normal range
(<90 ml/min) and/or serum creatinine levels rise above the age-appropriate upper limit of normal at
two consecutive visits.
After a dose reduction, for adult and paediatric patients, treatment should be interrupted if a rise in
serum creatinine >33% above the average of the pre-treatment measurements is observed and/or the
calculated creatinine clearance falls below the lower limit of the normal range. Treatment may be
reinitiated depending on the individual clinical circumstances.
Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated
with EXJADE. Tests for proteinuria should be performed monthly. As needed, additional markers of
renal tubular function (e.g. glycosuria in non-diabetics and low levels of serum potassium, phosphate,
magnesium or urate, phosphaturia, aminoaciduria) may also be monitored. Dose reduction or
interruption may be considered if there are abnormalities in levels of tubular markers and/or if
clinically indicated.
If, despite dose reduction and interruption, the serum creatinine remains significantly elevated and
there is also persistent abnormality in another marker of renal function (e.g. proteinuria, Fanconi’s
Syndrome), the patient should be referred to a renal specialist, and further specialised investigations
(such as renal biopsy) may be considered.
Hepatic function:
Liver function test elevations have been observed in patients treated with EXJADE. Postmarketing
cases of hepatic failure, sometimes fatal, have been reported in patients treated with EXJADE. Most
reports of hepatic failure involved patients with significant morbidities including pre-existing liver
cirrhosis. However, the role of EXJADE as a contributing or aggravating factor cannot be excluded
(see section 4.8).
It is recommended that
serum transaminases, bilirubin and alkaline phosphatase be checked before the
initiation of treatment, every 2 weeks during the first month and monthly thereafter. If there is a
persistent and progressive increase in serum transaminase levels that cannot be attributed to other
causes, EXJADE should be interrupted. Once the cause of the liver function test abnormalities has
been clarified or after return to normal levels, cautious re-initiation of treatment at a lower dose
followed by gradual dose escalation may be considered.
EXJADE is not recommended in patients with severe hepatic impairment as it has not been studied in
such patients. Treatment has been initiated only in patients with baseline liver transaminase levels up
to 5 times the upper limit of the normal range (see section 5.2).
In patients with a short life expectancy (e.g. high-risk myelodysplastic syndromes), especially when
co-morbidities could increase the risk of adverse events, the benefit of EXJADE might be limited and
may be inferior to risks. As a consequence, treatment with EXJADE is not recommended in these
patients.
Caution should be used in elderly patients due to a higher frequency of adverse reactions (in particular,
diarrhoea).
Gastrointestinal
Upper gastrointestinal ulceration and haemorrhage have been reported in patients, including children
and adolescents, receiving EXJADE. Multiple ulcers have been observed in some patients (see section
4.8). There have been reports of fatal gastrointestinal haemorrhages, especially in elderly patients who
17
had haematological malignancies and/or low platelet counts. Physicians and patients should remain
alert for signs and symptoms of gastrointestinal ulceration and haemorrhage during EXJADE therapy
and promptly initiate additional evaluation and treatment if a serious gastrointestinal adverse event is
suspected. Caution should be exercised in patients who are taking EXJADE in combination with
substances that have known ulcerogenic potential, such as NSAIDs, corticosteroids, or oral
bisphosphonates, in patients receiving anticoagulants and in patients with platelet counts below
50,000/mm
3
(50 x 10
9
/l) (see section 4.5).
Skin disorders
Skin rashes may appear during EXJADE treatment. The rashes resolve spontaneously in most cases.
When interruption of treatment may be necessary, treatment may be reintroduced after resolution of
the rash, at a lower dose followed by gradual dose escalation. In severe cases this reintroduction could
be conducted in combination with a short period of oral steroid administration.
Hypersensitivity reactions
Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported
in patients receiving EXJADE, with the onset of the reaction occurring in the majority of cases within
the first month of treatment (see section 4.8). If such reactions occur, EXJADE should be discontinued
and appropriate medical intervention instituted.
Vision and hearing
Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported (see section
4.8). Auditory and ophthalmic testing (including fundoscopy) is recommended before the start of
treatment and at regular intervals thereafter (every 12 months). If disturbances are noted during the
treatment, dose reduction or interruption may be considered.
Blood disorders
There have been post-marketing reports of leukopenia, thrombocytopenia or pancytopenia, or
aggravation of these cytopenias in patients treated with EXJADE. Most of these patients had pre-
existing haematological disorders that are frequently associated with bone marrow failure. However, a
contributory or aggravating role cannot be excluded. Interruption of treatment should be considered in
patients who develop unexplained cytopenia.
Other considerations
Monthly monitoring of serum ferritin is recommended in order to assess the patient’s response to
therapy (see section 4.2). If serum ferritin falls consistently below 500 µg/l, an interruption of
treatment should be considered.
The results of the tests for serum creatinine, serum ferritin and serum transaminases should be
recorded and regularly assessed for trends. The results should also be noted in the provided patient’s
booklet.
In one clinical study, growth and sexual development of paediatric patients treated with EXJADE for
up to 5 years were not affected. However, as a general precautionary measure in the management of
paediatric patients with transfusional iron overload, body weight, height and sexual development
should be monitored at regular intervals (every 12 months).
Cardiac dysfunction is a known complication of severe iron overload. Cardiac function should be
monitored in patients with severe iron overload during long-term treatment with EXJADE.
Each tablet contains 272 mg lactose. Patients with rare hereditary problems of galactose intolerance,
the Lapp lactase deficiency, glucose-galactose malabsorption or severe lactase deficiency should not
take this medicine.
18
The concomitant use of deferasirox with aluminium-containing antacid preparations is not
recommended. The concomitant use of deferasirox with repaglinide (a CYP2C8 substrate) or with
CYP1A2 substrates that have a narrow therapeutic index, such as theophylline, clozapine or tizanidine,
is not recommended (see section 4.5).
The concomitant administration of EXJADE and aluminium-containing antacid preparations has not
been formally studied. Although deferasirox has a lower affinity for aluminium than for iron, it is not
recommended to take EXJADE tablets with aluminium-containing antacid preparations (see section
4.4).
The bioavailability of deferasirox was increased to a variable extent when taken along with food.
EXJADE must therefore be taken on an empty stomach at least 30 minutes before food, preferably at
the same time each day (see sections 4.2 and 5.2).
Deferasirox metabolism depends on UGT enzymes. In a healthy volunteer study, the concomitant
administration of EXJADE (single dose of 30 mg/kg) and the potent UGT inducer, rifampicin,
(repeated dose of 600 mg/day) resulted in a decrease of deferasirox exposure by 44% (90% CI: 37% -
51%). Therefore, the concomitant use of EXJADE with potent UGT inducers (e.g. rifampicin,
carbamazepine, phenytoin, phenobarbital, ritonavir) may result in a decrease in EXJADE efficacy (see
section 4.4). The patient’s serum ferritin should be monitored during and after the combination, and
the dose of EXJADE adjusted if necessary.
In a healthy volunteer study, the concomitant administration of EXJADE and midazolam (a CYP3A4
probe substrate) resulted in a decrease of midazolam exposure by 17% (90% CI: 8% - 26%). In the
clinical setting, this effect may be more pronounced. Therefore, due to a possible decrease in efficacy,
caution should be exercised when deferasirox is combined with substances metabolised through
CYP3A4 (e.g. ciclosporin, simvastatin, hormonal contraceptive agents, bepridil, ergotamine).
The safety of EXJADE in combination with other iron chelators has not been established. Therefore, it
must not be combined with other iron chelator therapies (see section 4.3).
No interaction was observed between EXJADE and digoxin in healthy adult volunteers.
In a healthy volunteer study, the concomitant administration of deferasirox as a moderate CYP2C8
inhibitor (30 mg/kg daily), with repaglinide, a CYP2C8 substrate, given as a single dose of 0.5 mg,
increased repaglinide AUC and C
max
about 2.3-fold (90% CI [2.03-2.63]) and 1.6-fold (90% CI
[1.42-1.84]), respectively. Since the interaction has not been established with dosages higher than
0.5 mg for repaglinide, the concomitant use of deferasirox with repaglinide should be avoided. If the
combination appears necessary, careful clinical and blood glucose monitoring should be performed
(see section 4.4). An interaction between deferasirox and other CYP2C8 substrates like paclitaxel
cannot be excluded (see section 4.4).
In a healthy volunteer study, the concomitant administration of EXJADE as a CYP1A2 inhibitor
(repeated dose of 30 mg/kg/day) and the CYP1A2 substrate theophylline (single dose of 120 mg)
resulted in an increase of theophylline AUC by 84% (90% CI: 73% to 95%). The single dose C
max
was
not affected, but an increase of theophylline C
max
is expected to occur with chronic dosing. Therefore,
the concomitant use of EXJADE with theophylline is not recommended. If EXJADE and theophylline
are used concomitantly, monitoring of theophylline concentration and theophylline dose reduction
should be considered. An interaction between EXJADE and other CYP1A2 substrates cannot be
excluded. For substances that are predominantly metabolised by CYP1A2 and that have a narrow
therapeutic index (e.g. clozapine, tizanidine), the same recommendations apply as for theophylline
(see section 4.4).
The concomitant administration of EXJADE and vitamin C has not been formally studied. Doses of
vitamin C up to 200 mg per day have not been associated with adverse consequences.
19
The concomitant administration of EXJADE with substances that have known ulcerogenic potential,
such as NSAIDs (including acetylsalicylic acid at high dosage), corticosteroids or oral
bisphosphonates may increase the risk of gastrointestinal toxicity (see section 4.4). The concomitant
administration of EXJADE with anticoagulants may also increase the risk of gastrointestinal
haemorrhage. Close clinical monitoring is required when deferasirox is combined with these
substances.
Pregnancy
No clinical data on exposed pregnancies are available for deferasirox. Studies in animals have shown
some reproductive toxicity at maternally toxic doses (see section 5.3). The potential risk for humans is
unknown.
As a precaution, it is recommended that EXJADE not be used during pregnancy unless clearly
necessary.
Breast-feeding
In animal studies, deferasirox was found to be rapidly and extensively secreted into maternal milk. No
effect on the offspring was noted. It is not known if deferasirox is secreted into human milk. Breast-
feeding while taking EXJADE is not recommended.
Fertility
No fertility data is available for humans. In animals, no adverse effects on male or female fertility
were found (see section 5.3).
No studies on the effects of EXJADE on the ability to drive and use machines have been performed.
Patients experiencing the uncommon adverse reaction of dizziness should exercise caution when
driving or operating machinery (see section 4.8).
Summary of the safety profile
The most frequent reactions reported during chronic treatment with EXJADE in adult and paediatric
patients include gastrointestinal disturbances in about 26% of patients (mainly nausea, vomiting,
diarrhoea or abdominal pain) and skin rash in about 7% of patients. Diarrhoea is reported more
commonly in paediatric patients aged 2 to 5 years than in older patients. These reactions are dose-
dependent, mostly mild to moderate, generally transient and mostly resolve even if treatment is
continued.
During clinical trials, increases in serum creatinine of >33% on ≥2 consecutive occasions, sometimes
above the upper limit of the normal range, occurred in about 36% of patients. These were dose-
dependent. About two-thirds of the patients showing serum creatinine increase returned below the
33% level without dose adjustment. In the remaining third the serum creatinine increase did not
always respond to a dose reduction or a dose interruption. Indeed, in some cases, only a stabilisation
of the serum creatinine values has been observed after dose reduction (see section 4.4).
Gallstones and related biliary disorders were reported in about 2% of patients. Elevations of liver
transaminases were reported as an adverse drug reaction in 2% of patients. Elevations of transaminases
greater than 10 times the upper limit of the normal range, suggestive of hepatitis, were uncommon
(0.3%). During postmarketing experience, hepatic failure, sometimes fatal, has been reported with
EXJADE, especially in patients with pre-existing liver cirrhosis (see section 4.4). As with other iron
chelator treatment, high-frequency hearing loss and lenticular opacities (early cataracts) have been
uncommonly observed in patients treated with EXJADE (see section 4.4).
20
Tabulated list of adverse reactions
Adverse reactions are ranked below using the following convention: 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); very rare
(<1/10,000); not known (cannot be estimated from the available data). Within each frequency
grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1
Blood and lymphatic system disorders
Not known: Pancytopenia
1
, thrombocytopenia
1
Immune system disorders
Not known:
Hypersensitivity reactions (including anaphylaxis and angioedema)
1
Psychiatric disorders
Uncommon: Anxiety, sleep disorder
Nervous system disorders
Common:
Headache
Uncommon:
Dizziness
Eye disorders
Uncommon: Early cataract, maculopathy
Ear and labyrinth disorders
Uncommon: Hearing loss
Respiratory, thoracic and mediastinal disorders
Uncommon: Pharyngolaryngeal pain
Gastrointestinal disorders
Common:
Diarrhoea, constipation, vomiting, nausea, abdominal pain,
abdominal distension, dyspepsia
Uncommon:
Gastrointestinal haemorrhage, gastric ulcer (including multiple
ulcers), duodenal ulcer, gastritis
Rare:
Oesophagitis
Hepatobiliary disorders
Common: Transaminases increased
Uncommon: Hepatitis, cholelithiasis
Not known: Hepatic failure
1
Skin and subcutaneous tissue disorders
Common: Rash, pruritus
Uncommon: Pigmentation disorder
Not known: Leukocytoclastic vasculitis
1
, urticaria
1
, erythema multiforme
1
,
alopecia
1
Renal and urinary disorders
Very common: Blood creatinine increased
Common: Proteinuria
Uncommon: Renal tubulopathy (acquired Fanconi’s syndrome), glycosuria
Not known: Acute renal failure
1
General disorders and administration site conditions
Uncommon:
Pyrexia, oedema, fatigue
1
Adverse reactions reported during postmarketing experience. These are derived from
spontaneous reports for which it is not always possible to reliably establish frequency or a
causal relationship to exposure to the medicinal product.
Paediatric population
Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years than in older patients.
Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated
with EXJADE.
21
Cases of overdose (2-3 times the prescribed dose for several weeks) have been reported. In one case,
this resulted in subclinical hepatitis which resolved after a dose interruption. Single doses of 80 mg/kg
in iron-overloaded thalassaemic patients caused mild nausea and diarrhoea.
treated by induction of emesis or by gastric lavage, and by symptomatic treatment.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Iron chelating agent, ATC code: V03AC03
Mechanism of action
Deferasirox is an orally active chelator that is highly selective for iron (III). It is a tridentate ligand that
binds iron with high affinity in a 2:1 ratio. Deferasirox promotes excretion of iron, primarily in the
faeces. Deferasirox has low affinity for zinc and copper, and does not cause constant low serum levels
of these metals.
Pharmacodynamic effects
In an iron-balance metabolic study in iron-overloaded adult thalassaemic patients, EXJADE at daily
doses of 10, 20 and 40 mg/kg induced the mean net excretion of 0.119, 0.329 and 0.445 mg Fe/kg
body weight/day, respectively.
Clinical efficacy and safety
EXJADE has been investigated in 411 adult (age 16 years) and 292 paediatric patients (aged 2 to
<16 years) with chronic iron overload due to blood transfusions. Of the paediatric patients 52 were
aged 2 to 5 years. The underlying conditions requiring transfusion included beta-thalassaemia, sickle
cell disease and other congenital and acquired anaemias (myelodysplastic syndromes, Diamond-
Blackfan syndrome, aplastic anaemia and other very rare anaemias).
Daily treatment at doses of 20 and 30 mg/kg for one year in frequently transfused adult and paediatric
patients with beta-thalassaemia led to reductions in indicators of total body iron; liver iron
concentration was reduced by about -0.4 and -8.9 mg Fe/g liver (biopsy dry weight (dw)) on average,
respectively, and serum ferritin was reduced by about -36 and -926 µg/l on average, respectively. At
these same doses the ratios of iron excretion : iron intake were 1.02 (indicating net iron balance) and
1.67 (indicating net iron removal), respectively. EXJADE induced similar responses in iron-
overloaded patients with other anaemias. Daily doses of 10 mg/kg for one year could maintain liver
iron and serum ferritin levels and induce net iron balance in patients receiving infrequent transfusions
or exchange transfusions. Serum ferritin assessed by monthly monitoring reflected changes in liver
iron concentration indicating that trends in serum ferritin can be used to monitor response to therapy.
Limited clinical data (29 patients with normal cardiac function at baseline) using MRI indicate that
treatment with EXJADE 10-30 mg/kg/day for 1 year may also reduce levels of iron in the heart (on
average, MRI T2* increased from 18.3 to 23.0 milliseconds).
The principal analysis of the pivotal comparative study in 586 patients suffering from beta-
thalassaemia and transfusional iron overload did not demonstrate non-inferiority of EXJADE to
deferoxamine in the analysis of the total patient population. It appeared from a post-hoc analysis of
this study that, in the subgroup of patients with liver iron concentration ≥7 mg Fe/g dw treated with
EXJADE (20 and 30 mg/kg) or deferoxamine (35 to ≥50 mg/kg), the non-inferiority criteria were
achieved. However, in patients with liver iron concentration <7 mg Fe/g dw treated with EXJADE (5
and 10 mg/kg) or deferoxamine (20 to 35 mg/kg), non-inferiority was not established due to imbalance
in the dosing of the two chelators. This imbalance occurred because patients on deferoxamine were
22
allowed to remain on their pre-study dose even if it was higher than the protocol specified dose. Fifty-
six patients under the age of 6 years participated in this pivotal study, 28 of them receiving EXJADE.
It appeared from preclinical and clinical studies that EXJADE could be as active as deferoxamine
when used in a dose ratio of 2:1 (i.e. a dose of EXJADE that is numerically half of the deferoxamine
dose). However, this dosing recommendation was not prospectively assessed in the clinical trials.
In addition, in patients with liver iron concentration ≥7 mg Fe/g dw with various rare anaemias or
sickle cell disease, EXJADE up to 20 and 30 mg/kg produced a decrease in liver iron concentration
and serum ferritin comparable to that obtained in patients with beta-thalassaemia.
5.2 Pharmacokinetic properties
Absorption
Deferasirox is absorbed following oral administration with a median time to maximum plasma
concentration (t
max
) of about 1.5 to 4 hours. The absolute bioavailability (AUC) of deferasirox from
EXJADE tablets is about 70% compared to an intravenous dose. Total exposure (AUC) was
approximately doubled when taken along with a high-fat breakfast (fat content >50% of calories) and
by about 50% when taken along with a standard breakfast. The bioavailability (AUC) of deferasirox
was moderately (approx. 13–25%) elevated when taken 30 minutes before meals with normal or high
fat content.
Distribution
Deferasirox is highly (99%) protein bound to plasma proteins, almost exclusively serum albumin, and
has a small volume of distribution of approximately 14 litres in adults.
Biotransformation
Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion.
Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling)
is likely to occur: in a healthy volunteer study, the administration of cholestyramine after a single dose
of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC).
Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalysed
(oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). No inhibition of
deferasirox metabolism by hydroxyurea was observed
in vitro
.
Elimination
Deferasirox and its metabolites are primarily excreted in the faeces (84% of the dose). Renal excretion
of deferasirox and its metabolites is minimal (8% of the dose). The mean elimination half-life (t
1/2
)
ranged from 8 to 16 hours. The transporters MRP2 and MXR (BCRP) are involved in the biliary
excretion of deferasirox.
Linearity / non-linearity
The C
max
and AUC
0-24h
of deferasirox increase approximately linearly with dose under steady-state
conditions. Upon multiple dosing exposure increased by an accumulation factor of 1.3 to 2.3.
Characteristics in patients
Paediatric patients
The overall exposure of adolescents (12 to ≤17
years) and children (2 to <12 years) to deferasirox after
single and multiple doses was lower than that in adult patients. In children younger than 6 years old
exposure was about 50% lower than in adults. Since dosing is individually adjusted according to
response this is not expected to have clinical consequences.
Gender
Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males.
Since dosing is individually adjusted according to response this is not expected to have clinical
consequences.
23
Elderly patients
The pharmacokinetics of deferasirox have not been studied in elderly patients (aged 65 or older).
Renal or hepatic impairment
The pharmacokinetics of deferasirox have not been studied in patients with renal or hepatic
impairment. The pharmacokinetics of deferasirox were not influenced by liver transaminase levels up
to 5 times the upper limit of the normal range.
5.3 Preclinical safety data
Preclinical data reveal no special hazard for patients with iron overload, based on conventional studies
of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential. The main
findings were kidney toxicity and lens opacity (cataracts). Similar findings were observed in neonatal
and juvenile animals. The kidney toxicity is considered mainly due to iron deprivation in animals that
were not previously overloaded with iron.
Tests of genotoxicity
in vitro
were either negative (Ames test, chromosomal aberration test) or positive
(V79 screen). Deferasirox caused formation of micronuclei
in vivo
in the bone marrow, but not liver,
of non-iron-loaded rats at lethal doses. No such effects were observed in iron-preloaded rats.
Deferasirox was not carcinogenic when administered to rats in a 2-year study and transgenic p53+/-
heterozygous mice in a 6-month study.
The potential for toxicity to reproduction was assessed in rats and rabbits. Deferasirox was not
teratogenic, but caused increased frequency of skeletal variations and stillborn pups in rats at high
doses that were severely toxic to the non-iron-overloaded mother. Deferasirox did not cause other
effects on fertility or reproduction.
6.
6.1 List of excipients
Lactose monohydrate
Crospovidone type A
Cellulose, microcrystalline
Povidone
Sodium lauryl sulphate
Silica, colloidal anhydrous
Magnesium stearate
6.2 Incompatibilities
Dispersion in carbonated drinks or milk is not recommended due to foaming and slow dispersion,
respectively.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from moisture.
24
6.5 Nature and contents of container
PVC/PE/PVDC/Aluminium blisters.
Packs containing 28, 84 or 252 dispersible tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/06/356/003
EU/1/06/356/004
EU/1/06/356/008
9.
28.08.2006
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
25
1.
EXJADE 500 mg dispersible tablets
2.
Each dispersible tablet contains 500 mg deferasirox.
Excipient: Each dispersible tablet contains 544 mg lactose.
For a full list of excipients, see section 6.1.
3.
Dispersible tablet
Off-white, round, flat tablets with bevelled edges and imprints (NVR on one face and J 500 on the
other).
4.
EXJADE is indicated for the treatment of chronic iron overload due to frequent blood transfusions
(7 ml/kg/month of packed red blood cells) in patients with beta thalassaemia major aged 6 years and
older.
EXJADE is also indicated for the treatment of chronic iron overload due to blood transfusions when
deferoxamine therapy is contraindicated or inadequate in the following patient groups:
-
in patients with other anaemias,
-
in patients aged 2 to 5 years,
-
in patients with beta thalassaemia major with iron overload due to infrequent blood transfusions
(<7 ml/kg/month of packed red blood cells).
Treatment with EXJADE should be initiated and maintained by physicians experienced in the
treatment of chronic iron overload due to blood transfusions. It is recommended that treatment be
started after the transfusion of approximately 20 units (about 100 ml/kg) of packed red blood cells or
when there is evidence from clinical monitoring that chronic iron overload is present (e.g. serum
ferritin >1,000 µg/l). Doses (in mg/kg) must be calculated and rounded to the nearest whole tablet size.
The goals of iron chelation therapy are to remove the amount of iron administered in transfusions and,
as required, to reduce the existing iron burden.
Posology
Starting dose
The recommended initial daily dose of EXJADE is 20 mg/kg body weight.
An initial daily dose of 30 mg/kg may be considered for patients who require reduction of elevated
body iron levels and who are also receiving more than 14 ml/kg/month of packed red blood cells
(approximately >4 units/month for an adult).
26
An initial daily dose of 10 mg/kg may be considered for patients who do not require reduction of body
iron levels and who are also receiving less than 7 ml/kg/month of packed red blood cells
(approximately <2 units/month for an adult). The patient’s response must be monitored and a dose
increase should be considered if sufficient efficacy is not obtained (see section 5.1).
For patients already well managed on treatment with deferoxamine, a starting dose of EXJADE that is
numerically half that of the deferoxamine dose could be considered (e.g. a patient receiving
40 mg/kg/day of deferoxamine for 5 days per week (or equivalent) could be transferred to a starting
daily dose of 20 mg/kg/day of EXJADE). When this results in a daily dose less than 20 mg/kg body
weight, the patient’s response must be monitored and a dose increase should be considered if sufficient
efficacy is not obtained (see section 5.1).
Maintenance dose
It is recommended that serum ferritin be monitored every month and that the dose of EXJADE be
adjusted, if necessary, every 3 to 6 months based on the trends in serum ferritin. Dose adjustments
may be made in steps of 5 to 10 mg/kg and are to be tailored to the individual patient’s response and
therapeutic goals (maintenance or reduction of iron burden). In patients not adequately controlled with
doses of 30 mg/kg (e.g. serum ferritin levels persistently above 2,500 µg/l and not showing a
decreasing trend over time), doses of up to 40 mg/kg may be considered. The availability of long-term
efficacy and safety data with EXJADE used at doses above 30 mg/kg is currently limited (264 patients
followed for an average of 1 year after dose escalation). If only very poor haemosiderosis control is
achieved at doses up to 30 mg/kg, a further increase (to a maximum of 40 mg/kg) may not achieve
satisfactory control, and alternative treatment options may be considered. If no satisfactory control is
achieved at doses above 30 mg/kg, treatment at such doses should not be maintained and alternative
treatment options should be considered whenever possible. Doses above 40 mg/kg are not
recommended because there is only limited experience with doses above this level.
In patients treated with doses greater than 30 mg/kg, dose reductions in steps of 5 to 10 mg/kg should
be considered when control has been achieved (e.g. serum ferritin levels persistently below 2,500 µg/l
and showing a decreasing trend over time). In patients whose serum ferritin level has reached the
target (usually between 500 and 1,000 µg/l), dose reductions in steps of 5 to 10 mg/kg should be
considered to maintain serum ferritin levels within the target range. If serum ferritin falls consistently
below 500 µg/l, an interruption of treatment should be considered (see section 4.4).
Elderly patients (≥65 years of age)
The dosing recommendations for elderly patients are the same as described above. In clinical trials,
elderly patients experienced a higher frequency of adverse reactions than younger patients (in
particular, diarrhoea) and should be monitored closely for adverse events that may require a dose
adjustment.
Paediatric population
The dosing recommendations for paediatric patients aged 2 to 17 years are the same as for adult
patients. Changes in weight of paediatric patients over time must be taken into account when
calculating the dose. In children aged between 2 and 5 years, exposure is lower than in adults (see
section 5.2). This age group may therefore require higher doses than are necessary in adults. However,
the initial dose should be the same as in adults, followed by individual titration.
The safety and efficacy of EXJADE in children from birth to 23 months of age have not yet been
established.
Patients with renal impairment
EXJADE has not been studied in patients with renal impairment and is contraindicated in patients with
estimated creatinine clearance <60 ml/min (see sections 4.3 and 4.4).
27
Patients with hepatic impairment
EXJADE has not been studied in patients with hepatic impairment and must be used with caution in
such patients. The initial dosing recommendations for patients with hepatic impairment are the same as
described above. Hepatic function in all patients should be monitored before treatment, every 2 weeks
during the first month and then every month (see section 4.4).
Method of administration
For oral use.
EXJADE must be taken once daily on an empty stomach at least 30 minutes before food, preferably at
the same time each day (see sections 4.5 and 5.2). The tablets are dispersed by stirring in a glass of
water or orange or apple juice (100 to 200 ml) until a fine suspension is obtained. After the suspension
has been swallowed, any residue must be resuspended in a small volume of water or juice and
swallowed. The tablets must not be chewed or swallowed whole (see also section 6.2).
Hypersensitivity to the active substance or to any of the excipients.
Combination with other iron chelator therapies as the safety of such combinations has not been
established (see section 4.5).
Patients with estimated creatinine clearance <60 ml/min.
Renal function:
EXJADE has been studied only in patients with baseline serum creatinine within the age-appropriate
normal range.
During clinical trials, increases in serum creatinine of >33% on ≥2 consecutive occasions, sometimes
above the upper limit of the normal range, occurred in about 36% of patients. These were dose-
dependent. About two-thirds of the patients showing serum creatinine increase returned below the
33% level without dose adjustment. In the remaining third the serum creatinine increase did not
always respond to a dose reduction or a dose interruption. Cases of acute renal failure have been
reported following post-marketing use of EXJADE (see section 4.8). In some post-marketing cases,
renal function deterioration has led to renal failure requiring temporary or permanent dialysis.
The causes of the rises in serum creatinine have not been elucidated. Particular attention should
therefore be paid to monitoring of serum creatinine in patients who are concomitantly receiving
medicinal products that depress renal function, and in patients who are receiving high doses of
EXJADE and/or low rates of transfusion (<7 ml/kg/month of packed red blood cells or <2 units/month
for an adult). While no increase in renal adverse events was observed after dose escalation to doses
above 30 mg/kg in clinical trials, an increased risk of renal adverse events with EXJADE doses above
30 mg/kg cannot be excluded.
It is recommended that serum creatinine be assessed in duplicate before initiating therapy.
Serum
creatinine, creatinine clearance
(estimated with the Cockcroft-Gault or MDRD formula in adults and
with the Schwartz formula in children) and/or plasma cystatin C levels
should be monitored weekly
in the first month after initiation or modification of therapy with EXJADE, and monthly
thereafter
. Patients with pre-existing renal conditions and patients who are receiving medicinal
products that depress renal function may be more at risk of complications. Care should be taken to
maintain adequate hydration in patients who develop diarrhoea or vomiting.
28
For adult patients, the daily dose may be reduced by 10 mg/kg if a rise in serum creatinine by >33%
above the average of the pre-treatment measurements and estimated creatinine clearance decreases
below the lower limit of the normal range (<90 ml/min) are seen at two consecutive visits, and cannot
be attributed to other causes (see section 4.2). For paediatric patients, the dose may be reduced by
10 mg/kg if estimated creatinine clearance decreases below the lower limit of the normal range
(<90 ml/min) and/or serum creatinine levels rise above the age-appropriate upper limit of normal at
two consecutive visits.
After a dose reduction, for adult and paediatric patients, treatment should be interrupted if a rise in
serum creatinine >33% above the average of the pre-treatment measurements is observed and/or the
calculated creatinine clearance falls below the lower limit of the normal range. Treatment may be
reinitiated depending on the individual clinical circumstances.
Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated
with EXJADE. Tests for proteinuria should be performed monthly. As needed, additional markers of
renal tubular function (e.g. glycosuria in non-diabetics and low levels of serum potassium, phosphate,
magnesium or urate, phosphaturia, aminoaciduria) may also be monitored. Dose reduction or
interruption may be considered if there are abnormalities in levels of tubular markers and/or if
clinically indicated.
If, despite dose reduction and interruption, the serum creatinine remains significantly elevated and
there is also persistent abnormality in another marker of renal function (e.g. proteinuria, Fanconi’s
Syndrome), the patient should be referred to a renal specialist, and further specialised investigations
(such as renal biopsy) may be considered.
Hepatic function:
Liver function test elevations have been observed in patients treated with EXJADE. Postmarketing
cases of hepatic failure, sometimes fatal, have been reported in patients treated with EXJADE. Most
reports of hepatic failure involved patients with significant morbidities including pre-existing liver
cirrhosis. However, the role of EXJADE as a contributing or aggravating factor cannot be excluded
(see section 4.8).
It is recommended that
serum transaminases, bilirubin and alkaline phosphatase be checked before the
initiation of treatment, every 2 weeks during the first month and monthly thereafter. If there is a
persistent and progressive increase in serum transaminase levels that cannot be attributed to other
causes, EXJADE should be interrupted. Once the cause of the liver function test abnormalities has
been clarified or after return to normal levels, cautious re-initiation of treatment at a lower dose
followed by gradual dose escalation may be considered.
EXJADE is not recommended in patients with severe hepatic impairment as it has not been studied in
such patients. Treatment has been initiated only in patients with baseline liver transaminase levels up
to 5 times the upper limit of the normal range (see section 5.2).
In patients with a short life expectancy (e.g. high-risk myelodysplastic syndromes), especially when
co-morbidities could increase the risk of adverse events, the benefit of EXJADE might be limited and
may be inferior to risks. As a consequence, treatment with EXJADE is not recommended in these
patients.
Caution should be used in elderly patients due to a higher frequency of adverse reactions (in particular,
diarrhoea).
Gastrointestinal
Upper gastrointestinal ulceration and haemorrhage have been reported in patients, including children
and adolescents, receiving EXJADE. Multiple ulcers have been observed in some patients (see section
4.8). There have been reports of fatal gastrointestinal haemorrhages, especially in elderly patients who
29
had haematological malignancies and/or low platelet counts. Physicians and patients should remain
alert for signs and symptoms of gastrointestinal ulceration and haemorrhage during EXJADE therapy
and promptly initiate additional evaluation and treatment if a serious gastrointestinal adverse event is
suspected. Caution should be exercised in patients who are taking EXJADE in combination with
substances that have known ulcerogenic potential, such as NSAIDs, corticosteroids, or oral
bisphosphonates, in patients receiving anticoagulants and in patients with platelet counts below
50,000/mm
3
(50 x 10
9
/l) (see section 4.5).
Skin disorders
Skin rashes may appear during EXJADE treatment. The rashes resolve spontaneously in most cases.
When interruption of treatment may be necessary, treatment may be reintroduced after resolution of
the rash, at a lower dose followed by gradual dose escalation. In severe cases this reintroduction could
be conducted in combination with a short period of oral steroid administration.
Hypersensitivity reactions
Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported
in patients receiving EXJADE, with the onset of the reaction occurring in the majority of cases within
the first month of treatment (see section 4.8). If such reactions occur, EXJADE should be discontinued
and appropriate medical intervention instituted.
Vision and hearing
Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported (see section
4.8). Auditory and ophthalmic testing (including fundoscopy) is recommended before the start of
treatment and at regular intervals thereafter (every 12 months). If disturbances are noted during the
treatment, dose reduction or interruption may be considered.
Blood disorders
There have been post-marketing reports of leukopenia, thrombocytopenia or pancytopenia, or
aggravation of these cytopenias in patients treated with EXJADE. Most of these patients had pre-
existing haematological disorders that are frequently associated with bone marrow failure. However, a
contributory or aggravating
role cannot be excluded. Interruption of treatment should be considered in
patients who develop unexplained cytopenia.
Other considerations
Monthly monitoring of serum ferritin is recommended in order to assess the patient’s response to
therapy (see section 4.2). If serum ferritin falls consistently below 500 µg/l, an interruption of
treatment should be considered.
The results of the tests for serum creatinine, serum ferritin and serum transaminases should be
recorded and regularly assessed for trends. The results should also be noted in the provided patient’s
booklet.
In one clinical study, growth and sexual development of paediatric patients treated with EXJADE for
up to 5 years were not affected. However, as a general precautionary measure in the management of
paediatric patients with transfusional iron overload, body weight, height and sexual development
should be monitored at regular intervals (every 12 months).
Cardiac dysfunction is a known complication of severe iron overload. Cardiac function should be
monitored in patients with severe iron overload during long-term treatment with EXJADE.
Each tablet contains 544 mg lactose. Patients with rare hereditary problems of galactose intolerance,
the Lapp lactase deficiency, glucose-galactose malabsorption or severe lactase deficiency should not
take this medicine.
30
The concomitant use of deferasirox with aluminium-containing antacid preparations is not
recommended. The concomitant use of deferasirox with repaglinide (a CYP2C8 substrate) or with
CYP1A2 substrates that have a narrow therapeutic index, such as theophylline, clozapine or tizanidine,
is not recommended (see section 4.5).
The concomitant administration of EXJADE and aluminium-containing antacid preparations has not
been formally studied. Although deferasirox has a lower affinity for aluminium than for iron, it is not
recommended to take EXJADE tablets with aluminium-containing antacid preparations (see section
4.4).
The bioavailability of deferasirox was increased to a variable extent when taken along with food.
EXJADE must therefore be taken on an empty stomach at least 30 minutes before food, preferably at
the same time each day (see sections 4.2 and 5.2).
Deferasirox metabolism depends on UGT enzymes. In a healthy volunteer study, the concomitant
administration of EXJADE (single dose of 30 mg/kg) and the potent UGT inducer, rifampicin,
(repeated dose of 600 mg/day) resulted in a decrease of deferasirox exposure by 44% (90% CI: 37% -
51%). Therefore, the concomitant use of EXJADE with potent UGT inducers (e.g. rifampicin,
carbamazepine, phenytoin, phenobarbital, ritonavir) may result in a decrease in EXJADE efficacy (see
section 4.4). The patient’s serum ferritin should be monitored during and after the combination, and
the dose of EXJADE adjusted if necessary.
In a healthy volunteer study, the concomitant administration of EXJADE and midazolam (a CYP3A4
probe substrate) resulted in a decrease of midazolam exposure by 17% (90% CI: 8% - 26%). In the
clinical setting, this effect may be more pronounced. Therefore, due to a possible decrease in efficacy,
caution should be exercised when deferasirox is combined with substances metabolised through
CYP3A4 (e.g. ciclosporin, simvastatin, hormonal contraceptive agents, bepridil, ergotamine).
The safety of EXJADE in combination with other iron chelators has not been established. Therefore, it
must not be combined with other iron chelator therapies (see section 4.3).
No interaction was observed between EXJADE and digoxin in healthy adult volunteers.
In a healthy volunteer study, the concomitant administration of deferasirox as a moderate CYP2C8
inhibitor (30 mg/kg daily), with repaglinide, a CYP2C8 substrate, given as a single dose of 0.5 mg,
increased repaglinide AUC and C
max
about 2.3-fold (90% CI [2.03-2.63]) and 1.6-fold (90% CI
[1.42-1.84]), respectively. Since the interaction has not been established with dosages higher than
0.5 mg for repaglinide, the concomitant use of deferasirox with repaglinide should be avoided. If the
combination appears necessary, careful clinical and blood glucose monitoring should be performed
(see section 4.4). An interaction between deferasirox and other CYP2C8 substrates like paclitaxel
cannot be excluded (see section 4.4).
In a healthy volunteer study, the concomitant administration of EXJADE as a CYP1A2 inhibitor
(repeated dose of 30 mg/kg/day) and the CYP1A2 substrate theophylline (single dose of 120 mg)
resulted in an increase of theophylline AUC by 84% (90% CI: 73% to 95%). The single dose C
max
was
not affected, but an increase of theophylline C
max
is expected to occur with chronic dosing. Therefore,
the concomitant use of EXJADE with theophylline is not recommended. If EXJADE and theophylline
are used concomitantly, monitoring of theophylline concentration and theophylline dose reduction
should be considered. An interaction between EXJADE and other CYP1A2 substrates cannot be
excluded. For substances that are predominantly metabolised by CYP1A2 and that have a narrow
therapeutic index (e.g. clozapine, tizanidine), the same recommendations apply as for theophylline
(see section 4.4).
The concomitant administration of EXJADE and vitamin C has not been formally studied. Doses of
vitamin C up to 200 mg per day have not been associated with adverse consequences.
31
The concomitant administration of EXJADE with substances that have known ulcerogenic potential,
such as NSAIDs (including acetylsalicylic acid at high dosage), corticosteroids or oral
bisphosphonates may increase the risk of gastrointestinal toxicity (see section 4.4). The concomitant
administration of EXJADE with anticoagulants may also increase the risk of gastrointestinal
haemorrhage. Close clinical monitoring is required when deferasirox is combined with these
substances.
Pregnancy
No clinical data on exposed pregnancies are available for deferasirox. Studies in animals have shown
some reproductive toxicity at maternally toxic doses (see section 5.3). The potential risk for humans is
unknown.
As a precaution, it is recommended that EXJADE not be used during pregnancy unless clearly
necessary.
Breast-feeding
In animal studies, deferasirox was found to be rapidly and extensively secreted into maternal milk. No
effect on the offspring was noted. It is not known if deferasirox is secreted into human milk. Breast-
feeding while taking EXJADE is not recommended.
Fertility
No fertility data is available for humans. In animals, no adverse effects on male or female fertility
were found (see section 5.3).
No studies on the effects of EXJADE on the ability to drive and use machines have been performed.
Patients experiencing the uncommon adverse reaction of dizziness should exercise caution when
driving or operating machinery (see section 4.8).
Summary of the safety profile
The most frequent reactions reported during chronic treatment with EXJADE in adult and paediatric
patients include gastrointestinal disturbances in about 26% of patients (mainly nausea, vomiting,
diarrhoea or abdominal pain) and skin rash in about 7% of patients. Diarrhoea is reported more
commonly in paediatric patients aged 2 to 5 years than in older patients. These reactions are dose-
dependent, mostly mild to moderate, generally transient and mostly resolve even if treatment is
continued.
During clinical trials, increases in serum creatinine of >33% on ≥2 consecutive occasions, sometimes
above the upper limit of the normal range, occurred in about 36% of patients. These were dose-
dependent. About two-thirds of the patients showing serum creatinine increase returned below the
33% level without dose adjustment. In the remaining third the serum creatinine increase did not
always respond to a dose reduction or a dose interruption. Indeed, in some cases, only a stabilisation
of the serum creatinine values has been observed after dose reduction (see section 4.4).
Gallstones and related biliary disorders were reported in about 2% of patients. Elevations of liver
transaminases were reported as an adverse drug reaction in 2% of patients. Elevations of transaminases
greater than 10 times the upper limit of the normal range, suggestive of hepatitis, were uncommon
(0.3%). During postmarketing experience, hepatic failure, sometimes fatal, has been reported with
EXJADE, especially in patients with pre-existing liver cirrhosis (see section 4.4). As with other iron
chelator treatment, high-frequency hearing loss and lenticular opacities (early cataracts) have been
uncommonly observed in patients treated with EXJADE (see section 4.4).
32
Tabulated list of adverse reactions
Adverse reactions are ranked below using the following convention: 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); very rare
(<1/10,000); not known (cannot be estimated from the available data). Within each frequency
grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1
Blood and lymphatic system disorders
Not known: Pancytopenia
1
, thrombocytopenia
1
Immune system disorders
Not known:
Hypersensitivity reactions (including anaphylaxis and angioedema)
1
Psychiatric disorders
Uncommon: Anxiety, sleep disorder
Nervous system disorders
Uncommon:
Headache
Eye disorders
Uncommon: Early cataract, maculopathy
Ear and labyrinth disorders
Uncommon: Hearing loss
Respiratory, thoracic and mediastinal disorders
Uncommon: Pharyngolaryngeal pain
Gastrointestinal disorders
Common:
Diarrhoea, constipation, vomiting, nausea, abdominal pain,
abdominal distension, dyspepsia
Uncommon:
Gastrointestinal haemorrhage, gastric ulcer (including multiple
ulcers), duodenal ulcer, gastritis
Rare:
Oesophagitis
Hepatobiliary disorders
Common: Transaminases increased
Uncommon: Hepatitis, cholelithiasis
Not known: Hepatic failure
1
Skin and subcutaneous tissue disorders
Common: Rash, pruritus
Uncommon: Pigmentation disorder
Not known: Leukocytoclastic vasculitis
1
, urticaria
1
, erythema multiforme
1
,
alopecia
1
Renal and urinary disorders
Very common: Blood creatinine increased
Common: Proteinuria
Uncommon: Renal tubulopathy (acquired Fanconi’s syndrome), glycosuria
Not known: Acute renal failure
1
General disorders and administration site conditions
Uncommon:
Pyrexia, oedema, fatigue
1
Adverse reactions reported during postmarketing experience. These are derived from
spontaneous reports for which it is not always possible to reliably establish frequency or a
causal relationship to exposure to the medicinal product.
Paediatric population
Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years than in older patients.
Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated
with EXJADE.
33
Common:
Dizziness
Cases of overdose (2-3 times the prescribed dose for several weeks) have been reported. In one case,
this resulted in subclinical hepatitis which resolved after a dose interruption. Single doses of 80 mg/kg
in iron-overloaded thalassaemic patients caused mild nausea and diarrhoea.
treated by induction of emesis or by gastric lavage, and by symptomatic treatment.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Iron chelating agent, ATC code: V03AC03
Mechanism of action
Deferasirox is an orally active chelator that is highly selective for iron (III). It is a tridentate ligand that
binds iron with high affinity in a 2:1 ratio. Deferasirox promotes excretion of iron, primarily in the
faeces. Deferasirox has low affinity for zinc and copper, and does not cause constant low serum levels
of these metals.
Pharmacodynamic effects
In an iron-balance metabolic study in iron-overloaded adult thalassaemic patients, EXJADE at daily
doses of 10, 20 and 40 mg/kg induced the mean net excretion of 0.119, 0.329 and 0.445 mg Fe/kg
body weight/day, respectively.
Clinical efficacy and safety
EXJADE has been investigated in 411 adult (age 16 years) and 292 paediatric patients (aged 2 to
<16 years) with chronic iron overload due to blood transfusions. Of the paediatric patients 52 were
aged 2 to 5 years. The underlying conditions requiring transfusion included beta-thalassaemia, sickle
cell disease and other congenital and acquired anaemias (myelodysplastic syndromes, Diamond-
Blackfan syndrome, aplastic anaemia and other very rare anaemias).
Daily treatment at doses of 20 and 30 mg/kg for one year in frequently transfused adult and paediatric
patients with beta-thalassaemia led to reductions in indicators of total body iron; liver iron
concentration was reduced by about -0.4 and -8.9 mg Fe/g liver (biopsy dry weight (dw)) on average,
respectively, and serum ferritin was reduced by about -36 and -926 µg/l on average, respectively. At
these same doses the ratios of iron excretion : iron intake were 1.02 (indicating net iron balance) and
1.67 (indicating net iron removal), respectively. EXJADE induced similar responses in iron-
overloaded patients with other anaemias. Daily doses of 10 mg/kg for one year could maintain liver
iron and serum ferritin levels and induce net iron balance in patients receiving infrequent transfusions
or exchange transfusions. Serum ferritin assessed by monthly monitoring reflected changes in liver
iron concentration indicating that trends in serum ferritin can be used to monitor response to therapy.
Limited clinical data (29 patients with normal cardiac function at baseline) using MRI indicate that
treatment with EXJADE 10-30 mg/kg/day for 1 year may also reduce levels of iron in the heart (on
average, MRI T2* increased from 18.3 to 23.0 milliseconds).
The principal analysis of the pivotal comparative study in 586 patients suffering from beta-
thalassaemia and transfusional iron overload did not demonstrate non-inferiority of EXJADE to
deferoxamine in the analysis of the total patient population. It appeared from a post-hoc analysis of
this study that, in the subgroup of patients with liver iron concentration ≥7 mg Fe/g dw treated with
EXJADE (20 and 30 mg/kg) or deferoxamine (35 to ≥50 mg/kg), the non-inferiority criteria were
achieved. However, in patients with liver iron concentration <7 mg Fe/g dw treated with EXJADE (5
and 10 mg/kg) or deferoxamine (20 to 35 mg/kg), non-inferiority was not established due to imbalance
in the dosing of the two chelators. This imbalance occurred because patients on deferoxamine were
34
allowed to remain on their pre-study dose even if it was higher than the protocol specified dose. Fifty-
six patients under the age of 6 years participated in this pivotal study, 28 of them receiving EXJADE.
It appeared from preclinical and clinical studies that EXJADE could be as active as deferoxamine
when used in a dose ratio of 2:1 (i.e. a dose of EXJADE that is numerically half of the deferoxamine
dose). However, this dosing recommendation was not prospectively assessed in the clinical trials.
In addition, in patients with liver iron concentration ≥7 mg Fe/g dw with various rare anaemias or
sickle cell disease, EXJADE up to 20 and 30 mg/kg produced a decrease in liver iron concentration
and serum ferritin comparable to that obtained in patients with beta-thalassaemia.
5.2 Pharmacokinetic properties
Absorption
Deferasirox is absorbed following oral administration with a median time to maximum plasma
concentration (t
max
) of about 1.5 to 4 hours. The absolute bioavailability (AUC) of deferasirox from
EXJADE tablets is about 70% compared to an intravenous dose. Total exposure (AUC) was
approximately doubled when taken along with a high-fat breakfast (fat content >50% of calories) and
by about 50% when taken along with a standard breakfast. The bioavailability (AUC) of deferasirox
was moderately (approx. 13–25%) elevated when taken 30 minutes before meals with normal or high
fat content.
Distribution
Deferasirox is highly (99%) protein bound to plasma proteins, almost exclusively serum albumin, and
has a small volume of distribution of approximately 14 litres in adults.
Biotransformation
Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion.
Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling)
is likely to occur: in a healthy volunteer study, the administration of cholestyramine after a single dose
of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC).
Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalysed
(oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). No inhibition of
deferasirox metabolism by hydroxyurea was observed
in vitro
.
Elimination
Deferasirox and its metabolites are primarily excreted in the faeces (84% of the dose). Renal excretion
of deferasirox and its metabolites is minimal (8% of the dose). The mean elimination half-life (t
1/2
)
ranged from 8 to 16 hours. The transporters MRP2 and MXR (BCRP) are involved in the biliary
excretion of deferasirox.
Linearity / non-linearity
The C
max
and AUC
0-24h
of deferasirox increase approximately linearly with dose under steady-state
conditions. Upon multiple dosing exposure increased by an accumulation factor of 1.3 to 2.3.
Characteristics in patients
Paediatric patients
The overall exposure of adolescents (12 to ≤17
years) and children (2 to <12 years) to deferasirox after
single and multiple doses was lower than that in adult patients. In children younger than 6 years old
exposure was about 50% lower than in adults. Since dosing is individually adjusted according to
response this is not expected to have clinical consequences.
Gender
Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males.
Since dosing is individually adjusted according to response this is not expected to have clinical
consequences.
35
Elderly patients
The pharmacokinetics of deferasirox have not been studied in elderly patients (aged 65 or older).
Renal or hepatic impairment
The pharmacokinetics of deferasirox have not been studied in patients with renal or hepatic
impairment. The pharmacokinetics of deferasirox were not influenced by liver transaminase levels up
to 5 times the upper limit of the normal range.
5.3 Preclinical safety data
Preclinical data reveal no special hazard for patients with iron overload, based on conventional studies
of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential. The main
findings were kidney toxicity and lens opacity (cataracts). Similar findings were observed in neonatal
and juvenile animals. The kidney toxicity is considered mainly due to iron deprivation in animals that
were not previously overloaded with iron.
Tests of genotoxicity
in vitro
were either negative (Ames test, chromosomal aberration test) or positive
(V79 screen). Deferasirox caused formation of micronuclei
in vivo
in the bone marrow, but not liver,
of non-iron-loaded rats at lethal doses. No such effects were observed in iron-preloaded rats.
Deferasirox was not carcinogenic when administered to rats in a 2-year study and transgenic p53+/-
heterozygous mice in a 6-month study.
The potential for toxicity to reproduction was assessed in rats and rabbits. Deferasirox was not
teratogenic, but caused increased frequency of skeletal variations and stillborn pups in rats at high
doses that were severely toxic to the non-iron-overloaded mother. Deferasirox did not cause other
effects on fertility or reproduction.
6.
6.1 List of excipients
Lactose monohydrate
Crospovidone type A
Cellulose, microcrystalline
Povidone
Sodium lauryl sulphate
Silica, colloidal anhydrous
Magnesium stearate
6.2 Incompatibilities
Dispersion in carbonated drinks or milk is not recommended due to foaming and slow dispersion,
respectively.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from moisture.
36
6.5 Nature and contents of container
PVC/PE/PVDC/Aluminium blisters.
Packs containing 28, 84 or 252 dispersible tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/06/356/005
EU/1/06/356/006
EU/1/06/356/009
9.
28.08.2006
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
37
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
38
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Novartis Pharma GmbH
Roonstraße 25
D-90429 Nuremberg
Germany
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
The MAH shall set up a surveillance programme to collect information on the demographics of
patients prescribed Exjade, any adverse reactions and reasons for discontinuation of Exjade. The
formal protocols for the sentinel monitoring surveillance should be reviewed by the CHMP.
The MAH must ensure that, at launch, all physicians who are expected to prescribe Exjade are
provided with a physician information pack containing the following:
Product information
Physician information about Exjade (brochure and pocket card)
Patient information pack
The physician information about Exjade should contain the following key elements:
The need to monitor serum ferritin monthly
That Exjade causes rises in serum creatinine in some patients
o
The need to monitor serum creatinine
On two occasions prior to initiation of treatment
Every week during the first month of initiation of treatment or after therapy
modification
Monthly thereafter
o
The need to reduce by 10 mg/kg the dose if serum creatinine rises:
Adults: >33% above baseline and creatinine clearance <LLN (90 ml/min)
Paediatrics: either >ULN or creatinine clearance falls to <LLN at two
consecutive visits.
o
The need to consider renal biopsy:
When serum creatinine is elevated and if another abnormality has been
detected (eg. proteinuria, signs of Fanconi’s Syndrome).
39
o
The need to interrupt treatment after a dose reduction if serum creatinine rises:
Adults and Paediatrics: remain >33% above baseline or creatinine clearance
<LLN (90 ml/min)
The importance of measuring creatinine clearance
Brief overview of methods of measuring creatinine clearance
That rises in serum transaminases occur in patients treated with Exjade
o
The need for liver function tests prior to prescription, then at monthly intervals or
more often if clinically indicated
o
Not to prescribe to patients with pre-existing severe hepatic disease
o
The need to interrupt treatment if persistent and progressive increase in liver enzyme
were noted.
The need for annual auditory and ophthalmic testing
The need for a guidance table highlighting pre-treatment measurements of serum creatinine,
creatinine clearance, proteinuria, hepatic enzymes, ferritin, such as:
Before initiating treatment
Serum creatinine at Day - X Value 1
Serum creatinine at Day - Y Value 2
X and Y are the days (to be determined) when pre-treatment measurements should be performed.
That the safety database of Exjade is limited and physicians are encouraged to enrol patients
in a surveillance programme (sentinel site monitoring and paediatric registry) to increase
knowledge about the incidence of important ADRs.
The information collected should include:
o
Anonymised patient details – age, sex, weight
o
Transfusion history and requirements
o
Initial dose of Exjade and subsequent changes in dose
o
Concomitant medications
o
Record of measurements of serum creatinine, creatinine clearance, proteinuria, hepatic
enzymes, ferritin
o
Renal histology, if available
o
Reason for discontinuation
o
ADRs
The educational programme should prompt doctors to report serious ADRs and certain
selected ADRs as below:
All serious ADRs
Persistent and progressive increase in hepatic enzymes
Increase in serum creatinine levels (>33% above baseline) or clearance
creatinine decrease (<90 ml/min)
Significant changes found in auditory or ophthalmological testing
Gallstones
Unexpected ADRs according to the SPC.
40
The Patient information pack should include the following information:
o
Patient information leaflet
o
Information on the need for regular monitoring, and when it should be carried out, of
serum creatinine, creatinine clearance, proteinuria, hepatic enzymes, ferritin
o
Information that renal biopsy may be considered if significant renal abnormalities
occur
o
Patient booklet where the physician can record the results of the above along with the
dose of Exjade
o
Reminder card for dates of tests
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, 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 perform the studies and additional pharmacovigilance activities detailed in the
Pharmacovigilance Plan.
The MAH must inform the European Medicines Agency and the CHMP of the status and results of the
surveillance programme in each Member State within 6 months of the Decision and at each update of
the EU Risk Management Plan. This report shall also provide the details of the ADRs as specified
above.
As well as the requirements in the legislation, the following serious ADRs should be forwarded on an
expedited basis to the appropriate competent authority as well as summarised in the above reports:
o
Increase in hepatic enzymes >10xULN
o
Serious rise in creatinine
o
Results of renal biopsies, if available
o
Cataracts
o
Hearing loss
o
Gallstones
An updated Risk Management Plan should be provided as per the CHMP Guideline on Risk
Management Systems for medicinal products for human use.
41
ANNEX III
LABELLING AND PACKAGE LEAFLET
42
A. LABELLING
43
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
EXJADE 125 mg dispersible tablets
Deferasirox
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each dispersible tablet contains 125 mg of deferasirox.
3.
LIST OF EXCIPIENTS
Contains lactose. See leaflet for further information.
4.
28 dispersible tablets
84 dispersible tablets
252 dispersible tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use. Read the package leaflet before use.
Take this medicine on an empty stomach.
Disperse tablets in water or fruit juice before swallowing. Do not swallow whole or chew.
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
Use only as directed by a doctor.
8.
EXPIRY DATE
EXP
44
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/06/356/001
28 dispersible tablets
EU/1/06/356/002
84 dispersible tablets
EU/1/06/356/007
252 dispersible tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
EXJADE 125 mg
45
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
EXJADE 125 mg dispersible tablets
Deferasirox
2.
Novartis Europharm Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
46
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
EXJADE 250 mg dispersible tablets
Deferasirox
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each dispersible tablet contains 250 mg of deferasirox.
3.
LIST OF EXCIPIENTS
Contains lactose. See leaflet for further information.
4.
28 dispersible tablets
84 dispersible tablets
252 dispersible tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use. Read the package leaflet before use.
Take this medicine on an empty stomach.
Disperse tablets in water or fruit juice before swallowing. Do not swallow whole or chew.
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
Use only as directed by a doctor.
8.
EXPIRY DATE
EXP
47
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/06/356/003
28 dispersible tablets
EU/1/06/356/004
84 dispersible tablets
EU/1/06/356/008
252 dispersible tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
EXJADE 250 mg
48
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
EXJADE 250 mg dispersible tablets
Deferasirox
2.
Novartis Europharm Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
49
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
EXJADE 500 mg dispersible tablets
Deferasirox
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each dispersible tablet contains 500 mg of deferasirox.
3.
LIST OF EXCIPIENTS
Contains lactose. See leaflet for further information.
4.
28 dispersible tablets
84 dispersible tablets
252 dispersible tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use. Read the package leaflet before use.
Take this medicine on an empty stomach.
Disperse tablets in water or fruit juice before swallowing. Do not swallow whole or chew.
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
Use only as directed by a doctor.
8.
EXPIRY DATE
EXP
50
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
EU/1/06/356/005
28 dispersible tablets
EU/1/06/356/006
84 dispersible tablets
EU/1/06/356/009
252 dispersible tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
EXJADE 500 mg
51
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
EXJADE 500 mg dispersible tablets
Deferasirox
2.
Novartis Europharm Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
52
B. PACKAGE LEAFLET
53
PACKAGE LEAFLET: INFORMATION FOR THE USER
EXJADE 125 mg dispersible tablets
EXJADE 250 mg dispersible tablets
EXJADE 500 mg dispersible tablets
Deferasirox
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed only for you or your child. Do not give it to anyone else or
use it for any other illnesses.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What EXJADE is and what it is used for
3.
How to take EXJADE
4.
Possible side effects
5.
How to store EXJADE
6.
Further information
1.
WHAT EXJADE IS AND WHAT IT IS USED FOR
What EXJADE is
EXJADE contains an active substance called deferasirox. It is an
iron chelator
which is a medicine
used to remove the excess iron from the body (also called iron overload).
What EXJADE is used for
EXJADE is used to treat iron overload caused by blood transfusions.
Repeated blood transfusions may be necessary in patients with various types of anaemia (for example
thalassaemia, sickle cell disease or myelodysplastic syndromes). However, repeated blood transfusions
can cause a build-up of excess iron. This is because blood contains iron and your body does not have a
natural way to remove the excess iron you get with your blood transfusions. Over time, the excess iron
can damage important organs such as the liver and heart. Medicines called
iron chelators
are used to
remove the excess iron and reduce the risk of it causing organ damage.
EXJADE is used to treat chronic iron overload caused by frequent blood transfusions in patients with
beta thalassaemia major aged 6 years and older.
EXJADE is also used when deferoxamine therapy is contraindicated or inadequate in patients with
beta thalassaemia major with iron overload caused by infrequent blood transfusions, in patients with
other types of anaemias, and in children aged 2 to 5 years.
How EXJADE works
EXJADE traps and removes excess iron which is then excreted mainly in the stools.
Monitoring your EXJADE treatment
You will have regular blood and urine tests during treatment. These will monitor the amount of iron in
your body (blood level of
ferritin
) to see how well EXJADE is working. The tests will also monitor
your kidney function (blood level of creatinine, presence of protein in the urine) and liver function
(blood level of transaminases). Your doctor will take these tests into consideration when deciding on
the dose of EXJADE most suitable for you.
54
-
Keep this leaflet. You may need to read it again.
2.
Before you take EXJADE
You will get a booklet from your doctor which will help you to track your response to EXJADE. Your
doctor will write your blood tests in this booklet at each visit. Keep the booklet safe and bring it with
you each time you visit your doctor.
Your eyesight and hearing will be tested each year during treatment as a precautionary measure.
If you have any questions about how EXJADE works or why this medicine has been prescribed for
you, ask your doctor.
2.
BEFORE YOU TAKE EXJADE
Follow all the doctor’s instructions carefully. They may differ from the general information in this
leaflet.
Do not take EXJADE
-
if you are allergic (hypersensitive) to deferasirox or any of the other ingredients of EXJADE
listed in section 6 of this leaflet. If this applies to you,
tell your doctor before taking
EXJADE
. If you think you may be allergic, ask your doctor for advice.
-
if you have kidney disease.
-
if you are currently taking another iron chelator medication.
EXJADE is not recommended
-
if you are at an advanced stage of myelodysplastic syndrome (MDS) or have advanced cancer.
Take special care with EXJADE
- if you have a liver problem.
- if you have a cardiac problem due to iron overload.
- if you notice a marked decrease in your urine output (sign of kidney problem).
- if you develop a severe rash, or difficulty breathing and dizziness or swelling mainly of the face
and throat (signs of severe allergic reaction).
- if you develop a rash, reddening of the skin, blistering of lips, eyes or mouth, skin peeling, sore
throat (signs of severe skin reaction).
- if you experience a combination of drowsiness, upper right abdominal pain, yellowing or
increased yellowing of your skin or eyes and dark urine (signs of liver problems).
- if you vomit blood and/or have black stools.
- if you experience frequent abdominal pain, particularly after eating or taking EXJADE.
- if you experience frequent heartburn.
- if you are taking or have recently taken certain painkillers, anti-inflammatory medicines or oral
bisphosphonates (see “Taking other medicines”).
- if you are taking or have recently taken anticoagulant medication (see “Taking other
medicines”).
- if you have a low level of platelets in your blood test.
If any of these apply to you, tell your doctor straight away.
Taking other medicines
Antacids (medicines used to treat heartburn) containing aluminium should not be taken at the same
time of day as EXJADE.
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription. This includes in particular:
-
ciclosporin (used to prevent the body rejecting a transplanted organ or for other conditions, such
as rheumatoid arthritis or atopic dermatitis),
-
simvastatin (used to lower cholesterol),
-
certain painkillers or anti-inflammatory medicines (e.g. aspirin, ibuprofen, corticosteroids),
-
oral bisphosphonates (used to treat osteoporosis),
55
-
anticoagulant medicines (used to prevent or treat blood clotting),
-
hormonal contraceptive agents (birth control medicines),
-
repaglinide (used to treat diabetes),
-
rifampicin (used to treat tuberculosis),
-
phenytoin, phenobarbital, carbamazepine (used to treat epilepsy),
-
ritonavir (used in the treatment of HIV infection),
-
paclitaxel (used in cancer treatment),
-
theophylline (used to treat respiratory diseases such as asthma),
-
clozapine (used to treat psychiatric disorders such as schizophrenia),
-
tizanidine (used as a muscle relaxant).
Additional tests may be required to monitor the blood levels of some of these medicines.
Older people (age 65 years and over)
EXJADE can be used by people aged 65 years and over at the same dose as for other adults. Elderly
patients may experience more side effects than younger patients. They should be monitored closely by
their doctor for side effects that may require a dose adjustment.
Children and adolescents (age 2 years to 17 years)
EXJADE can be used in adolescents and children aged 2 years and over. As the patient grows the
doctor will adjust the dose.
Pregnancy and breast-feeding
EXJADE is not recommended during pregnancy unless clearly necessary. If you are pregnant or think
that you may be, tell your doctor who will discuss with you whether you can take EXJADE during
your pregnancy.
Breast-feeding is not recommended during treatment with EXJADE. Tell your doctor if you are breast-
feeding.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
If you feel dizzy after taking EXJADE, do not drive or operate any tools or machines until you are
feeling normal again.
Important information about some of the ingredients of EXJADE
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor
before taking this medicine.
3.
HOW TO TAKE EXJADE
Always take EXJADE exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
How much EXJADE to take
The dose of EXJADE is related to body weight for all patients. Your doctor will calculate the dose you
need and tell you how many tablets to take each day.
The usual daily dose at the start of the treatment is 20 mg per kilogram body weight. A higher
or lower starting dose may be recommended by your doctor based on your individual treatment
needs.
Depending on how you respond to treatment, your doctor may later adjust your treatment to a
higher or lower dose.
The maximum recommended daily dose is 40 mg per kilogram body weight.
56
-
bepridil, ergotamine,
When to take EXJADE
Take EXJADE once a day, every day, at about the same time each day.
Take the tablets on an empty stomach.
Then wait at least 30 minutes before eating any food.
Taking EXJADE at the same time each day will help you remember when to take your tablets.
How to take EXJADE
:
Drop
the tablet(s) into a glass of water, or apple or orange juice
(100 to 200 ml).
Stir
until the tablet(s) dissolve completely. The liquid in the glass
will look cloudy.
Drink
everything in the glass. Then add a little water or juice to
what is left in the glass and drink that too.
Do not dissolve the tablets in fizzy drinks or milk.
Do not chew, break or crush the tablets.
Do not swallow the tablets whole.
How long to take EXJADE
Continue taking EXJADE every day for as long as your doctor tells you.
This is a long-term
treatment, possibly lasting for months or years. Your doctor will regularly monitor your condition to
check that the treatment is having the desired effect (see also section 1: “Monitoring your EXJADE
treatment”).
If you have questions about how long to take EXJADE, talk to your doctor.
If you take more EXJADE than you should
If you have taken too much EXJADE, or if someone else accidentally takes your tablets, contact your
doctor or hospital for advice straight away. Show them the pack of tablets. Medical treatment may be
necessary.
If you forget to take EXJADE
If you miss a dose, take it as soon as you remember on that day. Take your next dose as scheduled. Do
not take a double dose on the next day to make up for the forgotten tablet(s).
If you stop taking EXJADE
Do not stop taking EXJADE unless your doctor tells you to. If you stop taking it, the excess iron will
no longer be removed from your body (see also above section “How long to take EXJADE”).
4.
POSSIBLE SIDE EFFECTS
Like all medicines, EXJADE can cause side effects, although not everybody gets them. Most of the
side effects are mild to moderate and will generally disappear after a few days to a few weeks of
treatment.
Do not be alarmed by this list of possible side effects. You may not experience any of them.
57
Some side effects could be serious and need immediate medical attention.
These side effects are uncommon or rare.
If you get a severe rash, or difficulty breathing and dizziness or swelling mainly of the face and
throat (signs of severe allergic reaction),
If you notice a marked decrease in your urine output (sign of kidney problem),
If you experience a combination of drowsiness, upper right abdominal pain, yellowing or
increased yellowing of your skin or eyes and dark urine (signs of liver problems),
If you vomit blood and/or have black stools,
If you experience frequent abdominal pain, particularly after eating or taking EXJADE,
If you experience frequent heartburn,
If you experience partial loss of vision,
tell your doctor straight away.
Some side effects could become serious.
These side effects are uncommon, that is they may affect less than 1 in every 100 patients.
If you get blurred or cloudy eyesight,
If you get reduced hearing,
tell your doctor as soon as possible.
Some side effects are very common.
These side effects may affect more than 1 in every 10 patients
.
Disturbance in renal function tests.
Some side effects are common.
These side effects may affect between 1 and 10 in every 100 patients
.
Gastrointestinal disorders, such as nausea, vomiting, diarrhoea, pain in the abdomen, bloating,
constipation, indigestion
Rash
Headache
If any of these affects you severely, tell your doctor.
Other side effects are uncommon.
These side effects may affect less than 1 in every 100 patients.
Dizziness
Fever
Sore throat
Swelling of arms or legs
Change in the colour of the skin
Anxiety
Sleep disorder
Tiredness
If any of these affects you severely, tell your doctor.
Frequency not known
(cannot be estimated from the available data).
A decrease in the number of cells involved in blood clotting (thrombocytopenia), or in all kinds
of blood cells (pancytopenia)
Hair loss
Rash, reddening of the skin, blistering of lips, eyes or mouth, skin peeling, sore throat (signs of
severe skin reaction)
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
58
5.
HOW TO STORE EXJADE
Keep out of the reach and sight of children.
Do not use EXJADE after the expiry date which is stated on the blister and the carton. The
expiry date refers to the last day of that month.
Store in the original package in order to protect from moisture.
Do not use any pack that is damaged or shows signs of tampering.
6.
FURTHER INFORMATION
What EXJADE contains
The active substance is deferasirox.
Each tablet of EXJADE 125 mg contains 125 mg deferasirox.
Each tablet of EXJADE 250 mg contains 250 mg deferasirox.
Each tablet of EXJADE 500 mg contains 500 mg deferasirox.
The other ingredients are lactose monohydrate, crospovidone type A, povidone, sodium lauryl
sulphate, microcrystalline cellulose, colloidal anhydrous silica and magnesium stearate.
What EXJADE looks like and contents of the pack
EXJADE is supplied as dispersible tablets. The tablets are off-white, round and flat. Each tablet
contains 125 mg, 250 mg or 500 mg deferasirox:
EXJADE 125 mg tablets are stamped on each tablet with “J 125”.
EXJADE 250 mg tabletsare stamped on each tablet with “J 250”.
EXJADE 500 mg tablets are stamped on each tablet with “J 500”.
Each blister pack contains 28, 84 or 252 dispersible tablets.
Not all pack sizes or strengths may be available in your country.
Marketing Authorisation Holder
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
Manufacturer
Novartis Pharma GmbH
Roonstraße 25
D-90429 Nuremberg
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11
Luxembourg/Luxemburg
Novartis Pharma GmbH
Tél/Tel: +49 911 273 0
България
Novartis Pharma Services Inc.
Тел.: +359 2 489 98 28
Magyarország
Novartis Hungária Kft. Pharma
Tel.: +36 1 457 65 00
59
Česká republika
Novartis s.r.o.
Tel: +420 225 775 111
Malta
Novartis Pharma Services Inc.
Tel: +356 2298 3217
Danmark
Novartis Healthcare A/S
Tlf: +45 39 16 84 00
Nederland
Novartis Pharma B.V.
Tel: +31 26 37 82 111
Deutschland
Novartis Pharma GmbH
Tel: +49 911 273 0
Norge
Novartis Norge AS
Tlf: +47 23 05 20 00
Eesti
Novartis Pharma Services Inc.
Tel: +372 66 30 810
Österreich
Novartis Pharma GmbH
Tel: +43 1 86 6570
Ελλά
Novartis (Hellas) A.E.B.E.
Τηλ: +30 210 281 17 12
Polska
Novartis Poland Sp. z o.o.
Tel.: +48 22 550 8888
España
Novartis Farmacéutica, S.A.
Tel: +34 93 306 42 00
Portugal
Novartis Farma - Produtos Farmacêuticos, S.A.
Tel: +351 21 000 8600
France
Novartis Pharma S.A.S.
Tél: +33 1 55 47 66 00
România
Novartis Pharma Services Inc.
Tel: +40 21 31299 01
Ireland
Novartis Ireland Limited
Tel: +353 1 260 12 55
Slovenija
Novartis Pharma Services Inc.
Tel: +386 1 300 75 50
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Novartis Slovakia s.r.o.
Tel: +421 2 5542 5439
Italia
Novartis Farma S.p.A.
Tel: +39 02 96 54 1
Suomi/Finland
Novartis Finland Oy
Puh/Tel: +358 (0)10 6133 200
Κύπρς
Novartis Pharma Services Inc.
Τηλ: +357 22 690 690
Sverige
Novartis Sverige AB
Tel: +46 8 732 32 00
Latvija
Novartis Pharma Services Inc.
Tel: +371 67 887 070
United Kingdom
Novartis Pharmaceuticals UK Ltd.
Tel: +44 1276 698370
60
Lietuva
Novartis Pharma Services Inc.
Tel: +370 5 269 16 50
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
61
Source: European Medicines Agency
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