Methylfenidaat xr eg 40 mg

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SUMMARY OF PRODUCT CHARACTERISTICS
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1.
NAME OF THE MEDICINAL PRODUCT

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<PRODUCT NAME> 90 mg film-coated tablets
<PRODUCT NAME> 180 mg film-coated tablets
<PRODUCT NAME> 360 mg film-coated tablets

2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
<PRODUCT NAME> 90 mg film-coated tablets:
Each film-coated tablet contains 90 mg deferasirox.
<PRODUCT NAME>180 mg film-coated tablets:
Each film-coated tablet contains 180 mg deferasirox.
<PRODUCT NAME> 360 mg film-coated tablets:
Each film-coated tablet contains 360 mg deferasirox.
For the full list of excipients, see section 6.1.

3.
PHARMACEUTICAL FORM
Film-coated tablet
<PRODUCT NAME> 90 mg film-coated tablets
Light blue, ovaloid, biconvex, film-coated tablet with bevelled edges, debossed with `90' on one side
and plain on the other side. Approximate tablet dimensions 10.3 mm x 4.1 mm.
<PRODUCT NAME> 180 mg film-coated tablets
Medium blue, ovaloid, biconvex, film-coated tablet with bevelled edges, debossed with `180' on one
side and plain on the other side. Approximate tablet dimensions 13.4 mm x 5.4 mm.
<PRODUCT NAME> 360 mg film-coated tablets
Dark blue, ovaloid, biconvex, film-coated tablet with bevelled edges, debossed with `360' on one side
and plain on the other side. Approximate tablet dimensions 16.6 mm x 6.6 mm.

4.
CLINICAL PARTICULARS

4.1 Therapeutic indications

<PRODUCT NAME> 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.
<PRODUCT NAME> 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 paediatric patients with beta thalassaemia major with iron overload due to frequent blood
transfusions (7 ml/kg/month of packed red blood cells) aged 2 to 5 years,
-
in adult and paediatric patients with beta thalassaemia major with iron overload due to
infrequent blood transfusions (<7 ml/kg/month of packed red blood cells) aged 2 years and
older,
-
in adult and paediatric patients with other anaemias aged 2 years and older.
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<PRODUCT NAME> is also indicated for the treatment of chronic iron overload requiring chelation
therapy when deferoxamine therapy is contraindicated or inadequate in patients with non-transfusion-
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dependent thalassaemia syndromes aged 10 years and older.
4.2 Posology and method of administration

Treatment with <PRODUCT NAME> should be initiated and maintained by physicians experienced
in the treatment of chronic iron overload.
Posology
Transfusional iron overload

It is recommended that treatment be started after the transfusion of approximately 20 units (about 100
ml/kg) of packed red blood cells (PRBC) 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.
Caution should be taken during chelation therapy to minimise the risk of overchelation in all patients
(see section 4.4).
Deferasirox film-coated tablets demonstrate higher bioavailability compared to deferasirox dispersible
tablet formulations (see section 5.2). In case of switching from dispersible tablets to film-coated
tablets, the dose of the film-coated tablets should be 30% lower than the dose of the dispersible
tablets, rounded to the nearest whole tablet. <Invented name> is not available in dispersible tablets.
For this pharmaceutical form, other medicinal products containing deferasirox should be used.

The corresponding doses for the different formulations are shown in the table below.
Table 1
Recommended doses for transfusional iron overload


Film-coated

Dispersible tablets

Transfusions



Serum ferritin

tablets/granules

Starting dose

14 mg/kg/day

20 mg/kg/day
After 20 units
or >1,000 g/l
(about 100
ml/kg) of
PRBC

Alternative
21 mg/kg/day
30 mg/kg/day
>14



starting doses
ml/kg/month of
PRBC
(approx. >4
units/month
for an adult)

7 mg/kg/day
10 mg/kg/day
<7


ml/kg/month of
PRBC
(approx. <2
units/month
for an adult)
For patients
One third of
Half of



well managed
deferoxamine
deferoxamine dose
on
dose
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deferoxamine
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Monitoring






Monthly
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Target range






500-1,000g/l
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Adjustment

Increase



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steps
3.5-7 mg/kg/day
5-10 mg/kg/day
>2,500 g/l
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(every 3-6
Up to 28
Up to 40
months)
mg/kg/day

mg/kg/day



Decrease



3.5-7 mg/kg/day
5-10 mg/kg/day

<2,500 g/l
In patients treated In patients
with doses
treated with
>21 mg/kg/day
doses
>30 mg/kg/day


- When target is reached



500-1,000 g/l

Maximum

28 mg/kg/day

40mg/kg/day




dose
Consider






<500 g/l

interruption
Starting dose
The recommended initial daily dose of <PRODUCT NAME> film-coated tablets is 14 mg/kg body
weight.
An initial daily dose of 21 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).
An initial daily dose of 7 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 deferasirox
film-coated tablets that is numerically one third 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 14 mg/kg/day of deferasirox film-coated tablets). When this
results in a daily dose less than 14 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).
Dose adjustment
It is recommended that serum ferritin be monitored every month and that the dose of deferasirox be
adjusted, if necessary, every 3 to 6 months based on the trends in serum ferritin. Dose adjustments
may be made in steps of 3.5 to 7 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 21 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 28 mg/kg may be considered. The availability of long-term
efficacy and safety data from clinical studies conducted with deferasirox dispersible tablets 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 21 mg/kg, a further
increase (to a maximum of 28 mg/kg) may not achieve satisfactory control, and alternative treatment
options may be considered. If no satisfactory control is achieved at doses above 21 mg/kg, treatment
at such doses should not be maintained and alternative treatment options should be considered
whenever possible. Doses above 28 mg/kg are not recommended because there is only limited
experience with doses above this level (see section 5.1).
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In patients treated with doses greater than 21 mg/kg, dose reductions in steps of 3.5 to 7 mg/kg should
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be considered when control has been achieved (e.g. serum ferritin levels persistently below 2,500 µg/l
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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 3.5 to 7 mg/kg should be
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considered to maintain serum ferritin levels within the target range and to minimise the risk of
overchelation. If serum ferritin falls consistently below 500 µg/l, an interruption of treatment should
be considered (see section 4.4).
Non-transfusion-dependent thalassaemia syndromes

Chelation therapy should only be initiated when there is evidence of iron overload (liver iron
concentration [LIC] 5 mg Fe/g dry weight [dw] or serum ferritin consistently >800 µg/l). LIC is the
preferred method of iron overload determination and should be used wherever available. Caution
should be taken during chelation therapy to minimise the risk of overchelation in all patients (see
section 4.4).
Deferasirox film-coated tablets demonstrate higher bioavailability compared to deferasirox dispersible
tablet formulations (see section 5.2). In case of switching from dispersible tablets to film-coated
tablets, the dose of the film-coated tablets should be 30% lower than the dose of the dispersible
tablets, rounded to the nearest whole tablet.
The corresponding doses for the different formulations are shown in the table below.
Table 2
Recommended doses for non-transfusion-dependent thalassaemia syndromes


Film-coated
Dispersible
Liver iron

Serum
tablets/granules
tablets
concentration
ferritin
(LIC)*
Starting dose
7 mg/kg/day
10 mg/kg/day
5 mg Fe/g dw
or
>800 g/l
Monitoring Monthly
Adjustment
Increase
7 mg Fe/g dw
or
>2,000 g/l
steps
3.5 -7 mg/kg/day 5-10 mg/kg/day


(every 3-6
Decrease
<7 mg Fe/g dw
or
2,000 g/l
months)
3.5 - 7 mg/kg/day 5-10 mg/kg/day



Maximum
14 mg/kg/day
20 mg/kg/day



dose

7 mg/kg/day
10 mg/kg/day




For adults
not assessed
and 2,000 g/l
For paediatric patients

Interruption


<3 mg Fe/g dw
or
<300 g/l
Retreatment Not recommended
*LIC is the preferred method of iron overload determination.
Starting dose
The recommended initial daily dose of deferasirox film-coated tablets in patients with non-
transfusion-dependent thalassaemia syndromes is 7 mg/kg body weight.
Dose adjustment
It is recommended that serum ferritin be monitored every month to assess the patient's response to
therapy and to minimise the risk of overchelation (see section 4.4). After every 3 to 6 months of
treatment, a dose increase in increments of 3.5 to 7 mg/kg should be considered if the patient's LIC is
7 mg Fe/g dw, or if serum ferritin is consistently > 2,000 µg/l and not showing a downward trend,
and the patient is tolerating the medicinal product well. Doses above 14 mg/kg are not recommended
because there is no experience with doses above this level in patients with non-transfusion-dependent
thalassaemia syndromes.
In patients in whom LIC was not assessed and serum ferritin is 2,000 µg/l, dosing should not exceed
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7 mg/kg.
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For patients in whom the dose was increased to >7 mg/kg, dose reduction to 7 mg/kg or less is
recommended when LIC is <7 mg Fe/g dw or serum ferritin is 2,000 µg/l.
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Treatment cessation
Once a satisfactory body iron level has been achieved (LIC <3 mg Fe/g dw or serum ferritin <300
µg/l), treatment should be stopped. There are no data available on the retreatment of patients who
reaccumulate iron after having achieved a satisfactory body iron level and therefore retreatment
cannot be recommended.
Special populations

Elderly patients ( 65 years of age)
The dosing recommendations for elderly patients are the same as described above. In clinical studies,
elderly patients experienced a higher frequency of adverse reactions than younger patients (in
particular, diarrhoea) and should be monitored closely for adverse reactions that may require a dose
adjustment.
Paediatric population
Transfusional iron overload:
The dosing recommendations for paediatric patients aged 2 to 17 years with transfusional iron
overload are the same as for adult patients (see section 4.2). It is recommended that serum ferritin be
monitored every month to assess the patient's response to therapy and to minimise the risk of
overchelation (see section 4.4). Changes in weight of paediatric patients over time must be taken into
account when calculating the dose.
In children with transfusional iron overload 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.
Non-transfusion-dependent thalassaemia syndromes:
In paediatric patients with non-transfusion-dependent thalassaemia syndromes, dosing should not
exceed 7 mg/kg. In these patients, closer monitoring of LIC and serum ferritin is essential to avoid
overchelation (see section 4.4). In addition to monthly serum ferritin assessments, LIC should be
monitored every three months when serum ferritin is 800 g/l.
Children from birth to 23 months:
The safety and efficacy of deferasirox in children from birth to 23 months of age have not been
established. No data are available.

Patients with renal impairment
Deferasirox 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).
Patients with hepatic impairment
Deferasirox is not recommended in patients with severe hepatic impairment (Child-Pugh Class C). In
patients with moderate hepatic impairment (Child-Pugh Class B), the dose should be considerably
reduced followed by progressive increase up to a limit of 50% (see sections 4.4 and 5.2), and
deferasirox must be used with caution in such patients. 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.
The film-coated tablets should be swallowed whole with some water. For patients who are unable to
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swallow whole tablets, the film-coated tablets may be crushed and administered by sprinkling the full
dose onto soft food, e.g. yogurt or apple sauce (pureed apple). The dose should be immediately and
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completely consumed, and not stored for future use.
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The film-coated tablets should be taken once a day, preferably at the same time each day, and may be
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taken on an empty stomach or with a light meal (see sections 4.5 and 5.2).
4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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.
4.4 Special warnings and precautions for use

Renal function
Deferasirox has been studied only in patients with baseline serum creatinine within the age-
appropriate normal range.
During clinical studies, 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. In some cases, only a stabilisation of the
serum creatinine values has been observed after dose reduction. Cases of acute renal failure have been
reported following post-marketing use of deferasirox (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
deferasirox 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 of deferasirox dispersible tablets to doses above 30 mg/kg in clinical studies, an increased
risk of renal adverse events with deferasirox film-coated tablet doses above 21 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
prior to therapy, weekly in the first month after initiation or modification of therapy with
deferasirox (including switch of formulation), 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.
There have been post-marketing reports of metabolic acidosis occurring during treatment with
deferasirox. The majority of these patients had renal impairment, renal tubulopathy (Fanconi
syndrome) or diarrhoea, or conditions where acid-base imbalance is a known complication. Acid-base
balance should be monitored as clinically indicated in these populations. Interruption of deferasirox
therapy should be considered in patients who develop metabolic acidosis.
Post-marketing cases of severe forms of renal tubulopathy (such as Fanconi syndrome) and renal
failure associated with changes in consciousness in the context of hyperammonaemic encephalopathy
have been reported in patients treated with deferasirox, mainly in children. It is recommended that
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hyperammonaemic encephalopathy be considered and ammonia levels measured in patients who
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develop unexplained changes in mental status while on deferasirox therapy.
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Table 3
Dose adjustment and interruption of treatment for renal monitoring

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Serum creatinine

Creatinine clearance
Before initiation of
Twice (2x)
and
Once (1x)
therapy
Contraindicated

<60 ml/min
Monitoring

-
First month after
Weekly
and
Weekly
start of therapy or dose

modification (including


switch of formulation)

-
Thereafter

Monthly
and
Monthly
Reduction of daily dose by 7 mg/kg/day (film-coated tablet formulation),
if following renal parameters are observed at
two consecutive visits and cannot be attributed to
other causes
Adult patients
>33% above pre-
and
Decreases <LLN* (<90 ml/min)
treatment average

Paediatric patients
> age appropriate ULN** and/or
Decreases <LLN* (<90 ml/min)
After dose reduction, interrupt treatment, if
Adult and paediatric
Remains >33% above
and/or
Decreases <LLN* (<90 ml/min)
pre-treatment average
*LLN: lower limit of the normal range
**ULN: upper limit of the normal range
Treatment may be reinitiated depending on the individual clinical circumstances.
Dose reduction or interruption may be also considered if abnormalities occur in levels of markers
of renal tubular function and/or as clinically indicated:
Proteinuria (test should be performed prior to therapy and monthly thereafter)
Glycosuria in non-diabetics and low levels of serum potassium, phosphate, magnesium or
urate, phosphaturia, aminoaciduria (monitor as needed).
Renal tubulopathy has been mainly reported in children and adolescents with beta-
thalassaemia treated with deferasirox.
Patients should be referred to a renal specialist, and further specialised investigations (such as
renal biopsy) may be considered if the following occur despite dose reduction and interruption:
Serum creatinine remains significantly elevated and
· Persistent abnormality in another marker of renal function (e.g. proteinuria, Fanconi
Syndrome).

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Hepatic function

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Liver function test elevations have been observed in patients treated with deferasirox. Post-marketing
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cases of hepatic failure, some of which were fatal, have been reported. Severe forms associated with
changes in consciousness in the context of hyperammonaemic encephalopathy, may occur in patients
treated with deferasirox, particularly in children. It is recommended that hyperammonaemic
encephalopathy be considered and ammonia levels measured in patients who develop unexplained
changes in mental status while on Ddeferasirox therapy. Care should be taken to maintain adequate
hydration in patients who experience volume-depleting events (such as diarrhoea or vomiting),
particularly in children with acute illness. Most reports of hepatic failure involved patients with
significant morbiditiescomorbidities including pre-existing chronic liver conditions (including
cirrhosis and hepatitis C) and multi-organ failure. However, theThe role of deferasirox 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, deferasirox 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.
Deferasirox is not recommended in patients with severe hepatic impairment (Child-Pugh Class C)
(see section 5.2).
Table 4
Summary of safety monitoring recommendations

Test
Frequency
Serum creatinine
In duplicate prior to therapy.
Weekly during first month of therapy or after
dose modification (including switch of
formulation).
Monthly thereafter.
Creatinine clearance and/or plasma
Prior to therapy.
cystatin C
Weekly during first month of therapy or after
dose modification (including switch of
formulation).
Monthly thereafter.
Proteinuria
Prior to therapy.
Monthly thereafter.
Other markers of renal tubular function
As needed.
(such as glycosuria in non-diabetics
and low levels of serum potassium,
phosphate, magnesium or urate,
phosphaturia, aminoaciduria)
Serum transaminases, bilirubin, alkaline Prior to therapy.
phosphatase
Every 2 weeks during first month of
therapy.
Monthly thereafter.
Auditory and ophthalmic testing
Prior to therapy.
Annually thereafter.
Body weight, height and sexual
Prior to therapy.
development
Annually in paediatric patients.
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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 deferasirox might be limited
and may be inferior to risks. As a consequence, treatment with deferasirox is not recommended in
these patients.
Caution should be used in elderly patients due to a higher frequency of adverse reactions (in particular,
diarrhoea).
Data in children with non-transfusion-dependent thalassaemia are very limited (see section 5.1). As a
consequence, deferasirox therapy should be closely monitored to detect adverse reactions and to
follow iron burden in the paediatric population. In addition, before treating heavily iron-overloaded
children with non-transfusion-dependent thalassaemia with deferasirox, the physician should be aware
that the consequences of long-term exposure in such patients are currently not known.
Gastrointestinal disorders
Upper gastrointestinal ulceration and haemorrhage have been reported in patients, including children
and adolescents, receiving deferasirox. Multiple ulcers have been observed in some patients (see
section 4.8). There have been reports of ulcers complicated with digestive perforation. Also, there
have been reports of fatal gastrointestinal haemorrhages, especially in elderly patients who had
haematological malignancies and/or low platelet counts. Physicians and patients should remain alert
for signs and symptoms of gastrointestinal ulceration and haemorrhage during deferasirox therapy. In
case of gastrointestinal ulceration or haemorrhage, deferasirox should be discontinued and promptly
initiate additional evaluation and treatment must be propmptly initiated.if a serious gastrointestinal
adverse reaction is suspected. Caution should be exercised in patients who are taking deferasirox 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/mm3 (50 x 109/l) (see section 4.5).
Skin disorders
Skin rashes may appear during deferasirox 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. Severe cutaneous
adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis
(TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-
threatening or fatal, have been reported. If any SCAR is suspected, deferasirox should be discontinued
immediately and should not be reintroduced. At the time of prescription, patients should be advised of
the signs and symptoms of severe skin reactions, and be closely monitored.
Hypersensitivity reactions
Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported
in patients receiving deferasirox, 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, deferasirox should be
discontinued and appropriate medical intervention instituted. Deferasirox should not be reintroduced
in patients who have experienced a hypersensitivity reaction due to the risk of anaphylactic shock (see
section 4.3).
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) and of aggravated anaemia in patients treated with deferasirox. Most
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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 and to avoid overchelation (see section 4.2). Dose reduction or closer monitoring of renal and
hepatic function, and serum ferritin levels are recommended during periods of treatments with high
doses and when serum ferritin levels are close to the target range. If serum ferritin falls consistently
below 500 µg/l (in transfusional iron overload) or below 300 µg/l (in non-transfusion-dependent
thalassaemia syndromes), 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.
In two clinical studies, growth and sexual development of paediatric patients treated with deferasirox
for up to 5 years were not affected (see section 4.8). 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 prior to therapy and 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 deferasirox.
4.5 Interaction with other medicinal products and other forms of interaction

The safety of deferasirox 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).
Interaction with food
The Cmax of deferasirox film-coated tablets was increased (by 29%) when taken with a high-fat meal.
<PRODUCT NAME> film-coated tablets may be taken either on an empty stomach or with a light
meal, preferably at the same time each day (see sections 4.2 and 5.2).
Agents that may decrease deferasirox systemic exposure
Deferasirox metabolism depends on UGT enzymes. In a healthy volunteer study, the concomitant
administration of deferasirox (single dose of 30 mg/kg, dispersible tablet formulation) 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 deferasirox with potent UGT
inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, ritonavir) may result in a decrease
in deferasirox efficacy. The patient's serum ferritin should be monitored during and after the
combination, and the dose of deferasirox adjusted if necessary.
Cholestyramine significantly reduced the deferasirox exposure in a mechanistic study to determine the
degree of enterohepatic recycling (see section 5.2).
Interaction with midazolam and other agents metabolised by CYP3A4
In a healthy volunteer study, the concomitant administration of deferasirox dispersible tablets 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).
Interaction with repaglinide and other agents metabolised by CYP2C8
In a healthy volunteer study, the concomitant administration of deferasirox as a moderate CYP2C8
inhibitor (30 mg/kg daily, dispersible tablet formulation), with repaglinide, a CYP2C8 substrate, given
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as a single dose of 0.5 mg, increased repaglinide AUC and Cmax 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.
Interaction with theophylline and other agents metabolised by CYP1A2
In a healthy volunteer study, the concomitant administration of deferasirox as a CYP1A2 inhibitor
(repeated dose of 30 mg/kg/day, dispersible tablet formulation) 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 Cmax was not affected, but an increase of theophylline Cmax is expected
to occur with chronic dosing. Therefore, the concomitant use of deferasirox with theophylline is not
recommended. If deferasirox and theophylline are used concomitantly, monitoring of theophylline
concentration and theophylline dose reduction should be considered. An interaction between
deferasirox 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
Other information
The concomitant administration of deferasirox 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 deferasirox tablets with aluminium-containing antacid preparations.
The concomitant administration of deferasirox 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 deferasirox with anticoagulants may also increase the risk of gastrointestinal
haemorrhage. Close clinical monitoring is required when deferasirox is combined with these
substances.
Concomitant administration of deferasirox and busulfan resulted in an increase of busulfan exposure
(AUC), but the mechanism of the interaction remains unclear. If possible, evaluation of the
pharmacokinetics (AUC, clearance) of a busulfan test dose should be performed to allow dose
adjustment.
4.6 Fertility, pregnancy and lactation

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 deferasirox is not used during pregnancy unless clearly
necessary.
Deferasirox may decrease the efficacy of hormonal contraceptives (see section 4.5). Women of
childbearing potential are recommended to use additional or alternative non-hormonal methods of
contraception when using deferasirox.
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 deferasirox is not recommended.
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Fertility
No fertility data is available for humans. In animals, no adverse effects on male or female fertility
were found (see section 5.3).
4.7 Effects on ability to drive and use machines

Deferasirox has minor influence on the ability to drive and use machines. Patients experiencing the
uncommon adverse reaction of dizziness should exercise caution when driving or operating machines
(see section 4.8).
4.8 Undesirable effects

Summary of the safety profile
The most frequent reactions reported during chronic treatment in clinical studies conducted with
deferasirox dispersible tablets in adult and paediatric patients include gastrointestinal disturbances
(mainly nausea, vomiting, diarrhoea or abdominal pain) and skin rash. Diarrhoea is reported more
commonly in paediatric patients aged 2 to 5 years and in the elderly. These reactions are dose-
dependent, mostly mild to moderate, generally transient and mostly resolve even if treatment is
continued
During clinical studies dose-dependent increases in serum creatinine occurred in about 36% of
patients, though most remained within the normal range. Decreases in mean creatinine clearance have
been observed in both paediatric and adult patients with beta-thalassemia and iron overload during the
first year of treatment, but there is evidence that this does not decrease further in subsequent years of
treatment. Elevations of liver transaminases have been reported. Safety monitoring schedules for renal
and liver parameters are recommended. Auditory (decreased hearing) and ocular (lens opacities)
disturbances are uncommon, and yearly examinations are also recommended (see section 4.4).
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic
epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS)
have been reported with the use of deferasirox (see section 4.4).
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 5
Blood and lymphatic system disorders
Not known:
Pancytopenia1, thrombocytopenia1, anaemia aggravated1, neutropenia1

Immune system disorders
Not known:
Hypersensitivity reactions (including anaphylactic reactions and
angioedema)1

Metabolism and nutrition disorders
Not known:
Metabolic acidosis1

Psychiatric disorders
Uncommon:
Anxiety, sleep disorder

Nervous system disorders
Common:
Headache
Uncommon:
Dizziness
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Eye disorders
Uncommon:
Cataract, maculopathy
Rare:
Optic neuritis

Ear and labyrinth disorders
Uncommon:
Deafness

Respiratory, thoracic and mediastinal disorders
Uncommon:
Laryngeal 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
Not known:
Gastrointestinal perforation1, acute pancreatitis1

Hepatobiliary disorders
Common:
Transaminases increased
Uncommon:
Hepatitis, cholelithiasis
Not known:
Hepatic failure1,2

Skin and subcutaneous tissue disorders
Common:
Rash, pruritus
Uncommon:
Pigmentation disorder
Rare:
Drug reaction with eosinophilia and systemic symptoms (DRESS)
Not known:
Stevens-Johnson syndrome1, hypersensitivity vasculitis1, urticaria1, erythema
multiforme1, alopecia1, toxic epidermal necrolysis (TEN)1

Renal and urinary disorders
Very common:
Blood creatinine increased
Common:
Proteinuria
Uncommon:
Renal tubular disorder
2 (acquired Fanconi syndrome), glycosuria
Not known:
Acute renal failure1,2, tubulointerstitial nephritis1, nephrolithiasis1, renal
tubular necrosis1

General disorders and administration site conditions
Uncommon:
Pyrexia, oedema, fatigue
1 Adverse reactions reported during post-marketing 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.
2 Severe forms associated with changes in consciousness in the context of hyperammonaemic encephalopathy
have been reported.
Description of selected adverse reactions
Gallstones and related biliary disorders were reported in about 2% of patients. Elevations of liver
transaminases were reported as an adverse 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 post-marketing experience, hepatic failure, sometimes fatal, has been reported with the
deferasirox dispersible tablet formulation, especially in patients with pre-existing liver cirrhosis (see
section 4.4). There have been post-marketing reports of metabolic acidosis. The majority of these
patients had renal impairment, renal tubulopathy (Fanconi syndrome) or diarrhoea, or conditions
where acid-base imbalance is a known complication (see section 4.4). Cases of serious acute
pancreatitis were observed without documented underlying biliary conditions. As with other iron
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chelator treatment, high-frequency hearing loss and lenticular opacities (early cataracts) have been
uncommonly observed in patients treated with deferasirox (see section 4.4).
Creatinine clearance in transfusional iron overload
In a retrospective meta-analysis of 2,102 adult and paediatric beta-thalassaemia patients with
transfusional iron overload treated with deferasirox dispersible tablets in two randomised and four
open label studies of up to five years' duration, a mean creatinine clearance decrease of 13.2% in
adult patients (95% CI: -14.4% to -12.1%; n=935) and 9.9% (95% CI: -11.1% to -8.6%; n=1,142) in
paediatric patients was observed during the first year of treatment. In 250 patients who were followed
for up to five years, no further decrease in mean creatinine clearance levels was observed.
Clinical study in patients with non-transfusion-dependent thalassaemia syndromes
In a 1-year study in patients with non-transfusion-dependent thalassaemia syndromes and iron
overload (dispersible tablets at a dose of 10 mg/kg/day), diarrhoea (9.1%), rash (9.1%), and nausea
(7.3%) were the most frequent study drug-related adverse events. Abnormal serum creatinine and
creatinine clearance values were reported in 5.5% and 1.8% of patients, respectively. Elevations of
liver transaminases greater than 2 times the baseline and 5 times the upper limit of normal were
reported in 1.8% of patients.
Paediatric population
In two clinical studies, growth and sexual development of paediatric patients treated with deferasirox
for up to 5 years were not affected (see section 4.4).
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 deferasirox. In post-marketing reports, a high proportion of cases of metabolic acidosis occurred
in children in the context of Fanconi syndrome.
Acute pancreatitis has been reported, particularly in children and adolescents.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via the national reporting system
listed in Appendix V.*
4.9 Overdose

Symptoms
Early signs of acute overdose are digestive effects such as abdominal pain, diarrhoea, nausea and
vomiting. Hepatic and renal disorders have been reported, including cases of liver enzyme and creatinine
increased with recovery after treatment discontinuation. An erroneously administered single dose of 90
mg/kg led to Fanconi syndrome which resolved after treatment.
Treatment
There is no specific antidote for deferasirox. Standard procedures for management of overdose may be
indicated as well as symptomatic treatment, as medically appropriate.

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Iron chelating agents, ATC code: V03AC03
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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, deferasirox at daily
doses of 10, 20 and 40 mg/kg (dispersible tablet formulation) induced the mean net excretion of 0.119,
0.329 and 0.445 mg Fe/kg body weight/day, respectively.
Clinical efficacy and safety
Clinical efficacy studies were conducted with deferasirox dispersible tablets.
Deferasirox 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 [MDS], Diamond-
Blackfan syndrome, aplastic anaemia and other very rare anaemias).
Daily treatment with the deferasirox dispersible tablet formulation 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. Deferasirox induced
similar responses in iron-overloaded patients with other anaemias. Daily doses of 10 mg/kg (dispersible
tablet formulation) 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 deferasirox 10-30 mg/kg/day (dispersible
tablet formulation) 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 deferasirox dispersible tablets 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
deferasirox dispersible tablets (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
deferasirox dispersible tablets (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 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 deferasirox dispersible tablets.
It appeared from preclinical and clinical studies that deferasirox dispersible tablets could be as active as
deferoxamine when used in a dose ratio of 2:1 (i.e. a dose of deferasirox dispersible tablets that is
numerically half of the deferoxamine dose). For deferasirox film-coated tablets, a dose ratio of 3:1 can
be considered (i.e. a dose of deferasirox film-coated tablets that is numerically one third of the
deferoxamine dose). However, this dosing recommendation was not prospectively assessed in the
clinical studies.
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In addition, in patients with liver iron concentration 7 mg Fe/g dw with various rare anaemias or sickle
cell disease, deferasirox dispersible tablets 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.
A placebo-controlled randomised study was performed in 225 patients with MDS (Low/Int-1 risk) and
transfusional iron overload. The results of this study suggest that there is a positive impact of deferasirox
on event-free survival (EFS, a composite endpoint including non-fatal cardiac or liver events) and
serum ferritin levels. The safety profile was consistent with previous studies in adult MDS patients.
In a 5-year observational study in which 267 children aged 2 to <6 years (at enrollment) with
transfusional haemosiderosis received deferasirox, there were no clinically meaningful differences in
the safety and tolerability profile of deferasirox in paediatric patients aged 2 to <6 years compared to
the overall adult and older paediatric population, including increases in serum creatinine of >33% and
above the upper limit of normal on 2 consecutive occasions (3.1%), and elevation of alanine
aminotransferase (ALT) greater than 5 times the upper limit of normal (4.3%). Single events of increase
in ALT and aspartate aminotransferase were reported in 20.0% and 8.3%, respectively, of the 145
patients who completed the study.
In a study to assess the safety of deferasirox film-coated and dispersible tablets, 173 adult and paediatric
patients with transfusion dependent thalassaemia or myelodysplastic syndrome were treated for 24
weeks. A comparable safety profile for film-coated and dispersible tablets was observed.
In patients with non-transfusion-dependent thalassaemia syndromes and iron overload, treatment with
deferasirox dispersible tablets was assessed in a 1-year, randomised, double-blind, placebo-controlled
study. The study compared the efficacy of two different deferasirox dispersible tablet regimens (starting
doses of 5 and 10 mg/kg/day, 55 patients in each arm) and of matching placebo (56 patients). The study
enrolled 145 adult and 21 paediatric patients. The primary efficacy parameter was the change in liver
iron concentration (LIC) from baseline after 12 months of treatment. One of the secondary efficacy
parameters was the change in serum ferritin between baseline and fourth quarter. At a starting dose of
10 mg/kg/day, deferasirox dispersible tablets led to reductions in indicators of total body iron. On
average, liver iron concentration decreased by 3.80 mg Fe/g dw in patients treated with deferasirox
dispersible tablets (starting dose 10 mg/kg/day) and increased by 0.38 mg Fe/g dw in patients treated
with placebo (p<0.001). On average, serum ferritin decreased by 222.0 µg/l in patients treated with
deferasirox dispersible tablets (starting dose 10 mg/kg/day) and increased by 115 µg/l in patients treated
with placebo (p<0.001).
5.2 Pharmacokinetic properties

Deferasirox film-coated tablets demonstrate higher bioavailability compared to the deferasirox
dispersible tablet formulation. After adjustment of the strength, the film-coated tablet formulation (360
mg strength) was equivalent to deferasirox dispersible tablets (500 mg strength) with respect to the
mean area under the plasma concentration time curve (AUC) under fasting conditions. The Cmax was
increased by 30% (90% CI: 20.3% - 40.0%); however a clinical exposure/response analysis revealed
no evidence of clinically relevant effects of such an increase.
Absorption
Deferasirox (dispersible tablet formulation) is absorbed following oral administration with a median
time to maximum plasma concentration (tmax) of about 1.5 to 4 hours. The absolute bioavailability
(AUC) of deferasirox (dispersible tablet formulation) is about 70% compared to an intravenous dose.
The absolute bioavailability of the film-coated tablet formulation has not been determined.
Bioavailability of deferasirox film-coated tablets was 36% greater than that with dispersible tablets.
A food-effect study involving administration of the film-coated tablets to healthy volunteers under
fasting conditions and with a low-fat (fat content <10% of calories) or high-fat (fat content >50% of
calories) meal indicated that the AUC and Cmax were slightly decreased after a low-fat meal (by 11%
and 16%, respectively). After a high-fat meal, AUC and Cmax were increased (by 18% and 29%,
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respectively). The increases in Cmax due to the change in formulation and due to the effect of a high-fat
meal may be additive and therefore, it is recommended that the film-coated tablets should be taken
either on an empty stomach or with a light meal.
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 (t1/2)
ranged from 8 to 16 hours. The transporters MRP2 and MXR (BCRP) are involved in the biliary
excretion of deferasirox.
Linearity / non-linearity
The Cmax and AUC0-24h 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.
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 impairment. The
pharmacokinetics of deferasirox were not influenced by liver transaminase levels up to 5 times the
upper limit of the normal range.
In a clinical study using single doses of 20 mg/kg deferasirox dispersible tablets, the average exposure
was increased by 16% in subjects with mild hepatic impairment (Child-Pugh Class A) and by 76% in
subjects with moderate hepatic impairment (Child-Pugh Class B) compared to subjects with normal
hepatic function. The average Cmax of deferasirox in subjects with mild or moderate hepatic
impairment was increased by 22%. Exposure was increased 2.8-fold in one subject with severe hepatic
impairment (Child-Pugh Class C) (see sections 4.2 and 4.4).
5.3 Preclinical safety data
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Non-clinical data reveal no special hazard for humans 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 negative (Ames test, chromosomal aberration test) while
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.
PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:
Crospovidone (E1202)
Povidone (E1201)
Cellulose, microcrystalline (E460)
Magnesium stearate (E470b)
Poloxamer
Silica, colloidal anhydrous (E551)
Coating material:
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol (E1521)
Talc (E553b)
Indigo carmine aluminium lake (E132)
6.2 Incompatibilities

Not applicable.
6.3 Shelf life

3 years
6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container

Aluminium-PVC/PE/PVDC blisters.
Blisters containing 30 or 90 film-coated tablets, or multipacks containing 300 (10 packs of 30) film
coated tablets.
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Perforated unit-dose blisters containing 30x1 or 90x1 film-coated tablets, or multipacks containing
300x1 (10 packs of 30x1) film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal

No special requirements.

7.
MARKETING AUTHORISATION HOLDER
<[To be completed nationally]>

8.
MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<[To be completed nationally]>

10. DATE OF REVISION OF THE TEXT

<[To be completed nationally]>












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