ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Ferriprox 500 mg film-coated tablets
2.
Each tablet contains 500 mg deferiprone.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
White to off-white, capsule-shaped, film-coated tablets imprinted “APO” bisect “500” on one side,
plain on the other. The tablet is scored. The tablet can be divided into equal halves.
4.
Ferriprox is indicated for the treatment of iron overload in patients with thalassaemia major when
deferoxamine therapy is contraindicated or inadequate.
Deferiprone therapy should be initiated and maintained by a physician experienced in the treatment of
patients with thalassaemia.
Posology
Deferiprone is usually given as 25 mg/kg body weight, orally, three times a day for a total daily dose
of 75 mg/kg body weight. Dose per kilogram body weight should be calculated to the nearest half
tablet. See table below for recommended doses for body weights at 10 kg increments.
Dose table
To obtain a dose of about 75 mg/kg/day, use the number of tablets suggested in the following table for
the body weight of the patient. Sample body weights at 10 kg increments are listed.
Body weight
(kg)
Total daily dose
(mg)
Dose
(mg, three times/day)
Number of tablets
(three times/day)
20
1500
500
1.0
30
2250
750
1.5
40
3000
1000
2.0
50
3750
1250
2.5
60
4500
1500
3.0
70
5250
1750
3.5
80
6000
2000
4.0
90
6750
2250
4.5
A total daily dose above 100 mg/kg body weight is not recommended because of the potentially
increased risk of adverse reactions (see sections 4.4, 4.8, and 4.9).
The effect of Ferriprox in decreasing the body iron is directly influenced by the dose and the degree of
iron overload. After starting Ferriprox therapy, it is recommended that serum ferritin concentrations,
2
or other indicators of body iron load, be monitored every two to three months to assess the long-term
effectiveness of the chelation regimen in controlling the body iron load. Dose adjustments should be
tailored to the individual patient’s response and therapeutic goals (maintenance or reduction of body
iron burden). Interruption of therapy with deferiprone should be considered if serum ferritin
measurements fall below 500 g/l.
Paediatric population
There are limited data available on the use of deferiprone in children between 6 and 10 years of age,
and no data on deferiprone use in children under 6 years of age.
Method of administration
For oral use
- Hypersensitivity to the active substance or to any of the excipients.
- History of recurrent episodes of neutropenia.
- History of agranulocytosis.
- Pregnancy (see section 4.6).
- Breastfeeding (see section 4.6).
- Due to the unknown mechanism of deferiprone-induced neutropenia, patients must not take
medicinal products known to be associated with neutropenia or those that can cause
agranulocytosis (see section 4.5).
Neutropenia/Agranulocytosis
Deferiprone has been shown to cause neutropenia, including agranulocytosis. The patient’s
neutrophil count should be monitored every week.
In clinical trials, weekly monitoring of the neutrophil count has been effective in identifying cases of
neutropenia and agranulocytosis. Neutropenia and agranulocytosis resolved once therapy was
withdrawn. If the patient develops an infection while on deferiprone, therapy should be interrupted and
the neutrophil count monitored more frequently. Patients should be advised to report immediately to
their physician any symptoms indicative of infection such as fever, sore throat and flu-like symptoms.
Suggested management of cases of neutropenia is outlined below. It is recommended that such a
management protocol be in place prior to initiating any patient on deferiprone treatment.
Treatment with deferiprone should not be initiated if the patient is neutropenic.
The risk of
agranulocytosis and neutropenia is higher if the baseline absolute neutrophil count (ANC) is less than
1.5x10
9
/l.
In the event of neutropenia:
Instruct the patient to immediately discontinue deferiprone and all other medicinal products with a
potential to cause neutropenia. The patient should be advised to limit contact with other individuals in
order to reduce the risk of infection. Obtain a complete blood cell (CBC) count, with a white blood
cell (WBC) count, corrected for the presence of nucleated red blood cells, a neutrophil count, and a
platelet count immediately upon diagnosing the event and then repeat daily. It is recommended that
following recovery from neutropenia, weekly CBC, WBC, neutrophil and platelet counts continue to
be obtained for three consecutive weeks, to ensure that the patient recovers fully. Should any evidence
of infection develop concurrently with the neutropenia, the appropriate cultures and diagnostic
procedures should be performed and an appropriate therapeutic regimen instituted.
3
In the event of severe neutropenia or agranulocytosis:
Follow the guidelines above and administer appropriate therapy such as granulocyte colony
stimulating factor, beginning the same day that the event is identified; administer daily until the
condition resolves. Provide protective isolation and if clinically indicated, admit patient to the hospital.
Limited information is available regarding rechallenge. Therefore, in the event of neutropenia,
rechallenge is not recommended. In the event of agranulocytosis, rechallenge is contraindicated.
Carcinogenicity/mutagenicity
In view of the genotoxicity results, a carcinogenic potential of deferiprone cannot be excluded (see
section 5.3).
Plasma Zn
2+
concentration
Monitoring of plasma Zn
2+
concentration, and supplementation in case of a deficiency, is
recommended.
HIV positive or other immune compromised patients
No data are available on the use of deferiprone in HIV positive or in other immune compromised
patients. Given that deferiprone can be associated with neutropenia and agranulocytosis, therapy in
immune compromised patients should not be initiated unless potential benefits outweigh potential
risks.
Renal or hepatic impairment and liver fibrosis
There are no data available on the use of deferiprone in patients with renal or hepatic impairment.
Since deferiprone is eliminated mainly via the kidneys, there may be an increased risk of
complications in patients with impaired renal function. Similarly, as deferiprone is metabolised in the
liver
,
caution must be exercised in patients with hepatic dysfunction. Renal and hepatic function
should be monitored in this patient population during deferiprone therapy. If there is a persistent
increase in serum alanine aminotransferase (ALT), interruption of deferiprone therapy should be
considered.
In thalassaemia patients there is an association between liver fibrosis and iron overload and/or
hepatitis C. Special care must be taken to ensure that iron chelation in patients with hepatitis C is
optimal. In these patients careful monitoring of liver histology is recommended.
Discoloration of urine
Patients should be informed that their urine may show a reddish/brown discoloration due to the
excretion of the iron-deferiprone complex.
Chronic overdose and neurological disorders
Neurological disorders have been observed in children treated with 2.5 to 3 times the recommended
dose for several years. Prescribers are reminded that the use of doses above 100 mg/kg/day are not
recommended (see sections 4.8 and 4.9).
Due to the unknown mechanism of deferiprone-induced neutropenia, patients must not take medicinal
products known to be associated with neutropenia or those that can cause agranulocytosis (see section
4.3).
Interactions between deferiprone and other medicinal products have not been reported. However, since
deferiprone binds to metallic cations, the potential exists for interactions between deferiprone and
trivalent cation-dependent medicinal products such as aluminium-based antacids. Therefore, it is not
recommended to concomitantly ingest aluminium-based antacids and deferiprone.
4
The safety of concurrent use of deferiprone and vitamin C has not been formally studied. Based on the
reported adverse interaction that can occur between deferoxamine and vitamin C, caution should be
used when administering deferiprone and vitamin C concurrently.
Pregnancy
There are no adequate data from the use of deferiprone in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Women of childbearing potential must be advised to avoid pregnancy due to the clastogenic and
teratogenic properties of the medicinal product. These women should be advised to take contraceptive
measures and must be advised to immediately stop taking deferiprone if they become pregnant or plan
to become pregnant (see section 4.3).
Breastfeeding
It is not known whether deferiprone is excreted in human milk. No prenatal and postnatal reproductive
studies have been conducted in animals. Deferiprone must not be used by breast-feeding mothers. If
treatment is unavoidable, breast-feeding must be stopped (see section 4.3).
Fertility
No effects on fertility or early embryonic development were noted in animals (see section 5.3).
Not relevant.
The most common adverse reactions reported during therapy with deferiprone in clinical trials were
nausea, vomiting, abdominal pain, and chromaturia, which were reported in more than 10% of
patients. The most serious adverse reaction reported in clinical trials with deferiprone was
agranulocytosis, defined as an absolute neutrophil count less than 0.5 x 10
9
/l, which occurred in
approximately 1% of patients. Less severe episodes of neutropenia were reported in approximately 5%
of patients.
Adverse reaction frequencies: Very common (≥1/10), Common (≥1/100 to <1/10).
SYSTEM ORGAN CLASS VERY COMMON (≥1/10) COMMON (≥1/100 to
<1/10)
Blood and lymphatic system disorders
Neutropenia
Agranulocytosis
Metabolism and nutrition disorders
Increased Appetite
Nervous system disorders
Headache
Gastrointestinal disorders
Nausea
Abdominal Pain
Vomiting
Diarrhoea
Musculoskeletal and connective tissue
disorders
Arthralgia
Renal and urinary disorders
Chromaturia
General disorders and administration
site conditions
Fatigue
Investigations
Increased liver enzymes
The most serious adverse reaction reported in clinical trials with deferiprone is agranulocytosis
(neutrophils <0.5x10
9
/l), with an incidence of 1.1% (0.6 cases per 100 patient-years of treatment) (see
section 4.4). The observed incidence of the less severe form of neutropenia (neutrophils <1.5x10
9
/l) is
5
4.9% (2.5 cases per 100 patient-years). This rate should be considered in the context of the underlying
elevated incidence of neutropenia in thalassaemia patients, particularly in those with hypersplenism.
Episodes of diarrhoea, mostly mild and transient, have been reported in patients treated with
deferiprone. Gastrointestinal effects are more frequent at the beginning of therapy and resolve in most
patients within a few weeks without the discontinuation of treatment. In some patients it may be
beneficial to reduce the dose of deferiprone and then scale it back up to the former dose. Arthropathy
events, which ranged from mild pain in one or more joints to severe arthritis with effusion and
significant disability, have also been reported in patients treated with deferiprone. Mild arthropathies
are generally transient.
Increased levels of serum liver enzymes have been reported in some patients taking deferiprone. In the
majority of these patients, the increase was asymptomatic and transient, and returned to baseline
without discontinuation or decreasing the dose of deferiprone (see section 4.4).
Some patients experienced progression of fibrosis associated with an increase in iron overload or
hepatitis C.
Low plasma zinc levels have been associated with deferiprone in a minority of patients. The levels
normalised with oral zinc supplementation.
Neurological disorders (such as cerebellar symptoms, diplopia, lateral nystagmus, psychomotor
slowdown, hand movements and axial hypotonia) have been observed in children who had been
voluntarily prescribed more than 2.5 times the maximum recommended dose of 100 mg/kg/day for
several years. The neurological disorders progressively regressed after deferiprone discontinuation
(see sections 4.4 and 4.9).
No cases of acute overdose have been reported. However, neurological disorders (such as cerebellar
symptoms, diplopia, lateral nystagmus, psychomotor slowdown, hand movements and axial
hypotonia) have been observed in children who had been voluntarily prescribed more than 2.5 times
the maximum recommended dose of 100 mg/kg/day for several years. The neurological disorders
progressively regressed after deferiprone discontinuation.
In case of overdose, close clinical supervision of the patient is required.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Iron chelating agents, ATC code:
V03AC02
Mechanism of action
The active substance is deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), a bidentate ligand which
binds to iron in a 3:1 molar ratio.
Pharmacodynamic effects
Clinical studies have demonstrated that Ferriprox is effective in promoting iron excretion and that a
dose of 25 mg/kg three times per day can prevent the progression of iron accumulation as assessed by
serum ferritin, in patients with transfusion-dependent thalassaemia. However, chelation therapy may
not necessarily protect against iron-induced organ damage.
Clinical efficacy and safety
Studies LA16-0102, LA-01 and LA08-9701 compared the efficacy of Ferriprox with that of
deferoxamine in controlling serum ferritin in transfusion-dependent thalassemia patients. Ferriprox
6
and deferoxamine were equivalent in promoting a net stabilization or reduction of body iron load,
despite the continuous transfusional iron administration in those patients (no difference in proportion
of patients with a negative trend in serum ferritin between the two treatment groups by regression
analysis; p >0.05).
A magnetic resonance imaging (MRI) method, T2*, was also used to quantify myocardial iron load.
Iron overload causes concentration-dependent MRI T2* signal loss, thus, increased myocardial iron
reduces myocardial MRI T2* values. Myocardial MRI T2* values of less than 20 milliseconds
represent iron overload in the heart. An increase in MRI T2* on treatment indicates that iron is being
removed from the heart. A positive correlation between MRI T2* values and cardiac function (as
measured by Left Ventricular Ejection Fraction (LVEF)) has been documented.
Study LA16-0102 compared the efficacy of Ferriprox with that of deferoxamine in decreasing cardiac
iron overload and in improving cardiac function (as measured by LVEF) in transfusion-dependent
thalassemia patients. Sixty-one patients with cardiac iron overload, previously treated with
deferoxamine, were randomized to continue deferoxamine (average dose 43 mg/kg/day; N=31) or to
switch to Ferriprox (average dose 92 mg/kg/day N=29). Over the 12-month duration of the study,
Ferriprox was superior to deferoxamine in decreasing cardiac iron load. There was an improvement in
cardiac T2* of more than 3 milliseconds in patients treated with Ferriprox compared with a change of
about 1 millisecond in patients treated with deferoxamine. At the same time point, LVEF had
increased from baseline by 3.07 ± 3.58 absolute units (%) in the Ferriprox group and by
0.32 ± 3.38 absolute units (%) in the deferoxamine group (difference between groups; p=0.003).
Study LA12-9907 compared survival, incidence of cardiac disease, and progression of cardiac disease
in 129 patients with thalassemia major treated for at least 4 years with Ferriprox (N=54) or
deferoxamine (N=75). Cardiac endpoints were assessed by echocardiogram, electrocardiogram, the
New York Heart Association classification and death due to cardiac disease. There was no significant
difference in percentage of patients with cardiac dysfunction at first assessment (13% for Ferriprox vs.
16% for deferoxamine). Of patients with cardiac dysfunction at first assessment, none treated with
deferiprone compared with four (33%) treated with deferoxamine had worsening of their cardiac status
(p=0.245). Newly diagnosed cardiac dysfunction occurred in 13 (20.6%) deferoxamine-treated
patients and in 2 (4.3%) Ferriprox-treated patients who were cardiac disease-free at the first
assessment (p=0.013). Overall, fewer Ferriprox-treated patients than deferoxamine-treated patients
showed a worsening of cardiac dysfunction from first assessment to last assessment (4% vs. 20%,
p=0.007).
Data from the published literature are consistent with the results from the Apotex studies,
demonstrating less heart disease and/or increased survival in Ferriprox-treated patients than in those
treated with deferoxamine.
5.2 Pharmacokinetic properties
Absorption
Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract. Peak serum
concentration is reported to occur 45 to 60 minutes following a single dose in fasted patients. This may
be extended to 2 hours in fed patients.
Following a dose of 25 mg/kg, lower peak serum concentrations have been detected in patients in the
fed state (85 mol/l) than in the fasting state (126 mol/l), although there was no decrease in the
amount of deferiprone absorbed when it was given with food.
Biotransformation
Deferiprone is metabolised predominantly to a glucuronide conjugate. This metabolite lacks
iron-binding capability due to inactivation of the 3-hydroxy group of deferiprone. Peak serum
concentrations of the glucuronide occur 2 to 3 hours after administration of deferiprone.
7
Elimination
In humans, deferiprone is eliminated mainly via the kidneys; 75% to 90% of the ingested dose is
reported as being recovered in the urine in the first 24 hours, in the form of free deferiprone, the
glucuronide metabolite and the iron-deferiprone complex. A variable amount of elimination via the
faeces has been reported. The elimination half-life in most patients is 2 to 3 hours.
5.3 Preclinical safety data
Non-clinical studies have been conducted in animal species including mice, rats, rabbits, dogs and
monkeys.
The most common findings in non-iron-loaded animals at doses of 100 mg/kg/day and above were
hematologic effects such as bone marrow hypocellularity, and decreased WBC, RBC and/or platelet
counts in peripheral blood.
Atrophy of the thymus, lymphoid tissues, and testis, and hypertrophy of the adrenals, were reported at
doses of 100 mg/kg/day or greater in non-iron-loaded animals.
No carcinogenicity studies in animals have been conducted with deferiprone. The genotoxic potential
of deferiprone was evaluated in a set of
in vitro
and
in vivo
tests. Deferiprone did not show direct
mutagenic properties; however, it did display clastogenic characteristics in
in vitro
assays and
in vivo
in animals.
Deferiprone was teratogenic and embryotoxic in reproductive studies in non-iron-loaded pregnant rats
and rabbits at doses at least as low as 25 mg/kg/day. No effects on fertility or early embryonic
development were noted in non-iron-loaded male and female rats that received deferiprone orally at
doses of up to 75 mg/kg twice daily for 28 days (males) or 2 weeks (females) prior to mating and until
termination (males) or through early gestation (females). In females, an effect on the oestrous cycle
delayed time to confirmed mating at all doses tested.
No prenatal and postnatal reproductive studies have been conducted in animals.
6.
6.1 List of excipients
Tablet core
Microcrystalline cellulose
Magnesium stearate
Colloidal silicon dioxide
Coating
Hypromellose
Macrogol
Titanium dioxide
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
5 years.
8
6.4 Special precautions for storage
Do not store above 30ºC.
6.5 Nature and contents of container
High density polyethylene (HDPE) bottles with child resistant closure (polypropylene).
Each pack contains one bottle of 100 tablets.
6.6 Special precautions for disposal
No special requirements.
7.
Apotex Europe B.V.
Darwinweg 20
2333 CR Leiden
Netherlands
8.
EU/1/99/108/001
9.
Date of first authorisation: 25/08/1999
Date of latest renewal: 25/08/2009
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
9
1.
Ferriprox 100 mg/ml oral solution
2.
Each ml of oral solution contains 100 mg deferiprone (25 g deferiprone in 250 ml and 50 g deferiprone
in 500 ml).
Excipient:
Each ml of oral solution contains 0.4 mg Sunset Yellow (E110).
For a full list of excipients, see section 6.1.
3.
Oral solution.
Clear, reddish orange coloured liquid.
4.
Ferriprox is indicated for the treatment of iron overload in patients with thalassaemia major when
deferoxamine therapy is contraindicated or inadequate.
Deferiprone therapy should be initiated and maintained by a physician experienced in the treatment of
patients with thalassaemia.
Posology
Deferiprone is usually given as 25 mg/kg body weight, orally, three times a day for a total daily dose
of 75 mg/kg body weight. Dose per kilogram body weight should be calculated to the nearest 2.5 ml.
See table below for recommended doses for body weights at 10 kg increments.
Dose table
To obtain a dose of about 75 mg/kg/day, use the volume of oral solution suggested in the following
table for the body weight of the patient. Sample body weights at 10 kg increments are listed.
Body weight
(kg)
Total daily dose
(mg)
Dose
(mg, three times/day)
ml of oral solution
(three times/day)
20
1500
500
5.0
30
2250
750
7.5
40
3000
1000
10.0
50
3750
1250
12.5
60
4500
1500
15.0
70
5250
1750
17.5
80
6000
2000
20.0
90
6750
2250
22.5
A total daily dose above 100 mg/kg body weight is not recommended because of the potentially
increased risk of adverse reactions (see sections 4.4, 4.8, and 4.9).
10
The effect of Ferriprox in decreasing the body iron is directly influenced by the dose and the degree of
iron overload. After starting Ferriprox therapy, it is recommended that serum ferritin concentrations,
or other indicators of body iron load, be monitored every two to three months to assess the long-term
effectiveness of the chelation regimen in controlling the body iron load. Dose adjustments should be
tailored to the individual patient’s response and therapeutic goals (maintenance or reduction of body
iron burden). Interruption of therapy with deferiprone should be considered if serum ferritin
measurements fall below 500 g/l.
Paediatric population
There are limited data available on the use of deferiprone in children between 6 and 10 years of age,
and no data on deferiprone use in children under 6 years of age.
Method of administration
For oral use.
- Hypersensitivity to the active substance or to any of the excipients.
- History of recurrent episodes of neutropenia.
- History of agranulocytosis.
- Pregnancy (see section 4.6).
- Breastfeeding (see section 4.6).
- Due to the unknown mechanism of deferiprone-induced neutropenia, patients must not take
medicinal products known to be associated with neutropenia or those that can cause
agranulocytosis (see section 4.5).
Neutropenia/Agranulocytosis
Deferiprone has been shown to cause neutropenia, including agranulocytosis. The patient’s
neutrophil count should be monitored every week.
In clinical trials, weekly monitoring of the neutrophil count has been effective in identifying cases of
neutropenia and agranulocytosis. Neutropenia and agranulocytosis resolved once therapy was
withdrawn. If the patient develops an infection while on deferiprone, therapy should be interrupted and
the neutrophil count monitored more frequently. Patients should be advised to report immediately to
their physician any symptoms indicative of infection such as fever, sore throat and flu-like symptoms.
Suggested management of cases of neutropenia is outlined below. It is recommended that such a
management protocol be in place prior to initiating any patient on deferiprone treatment.
Treatment with deferiprone should not be initiated if the patient is neutropenic.
The risk of
agranulocytosis and neutropenia is higher if the baseline absolute neutrophil count (ANC) is less than
1.5x10
9
/l.
In the event of neutropenia:
Instruct the patient to immediately discontinue deferiprone and all other medicinal products with a
potential to cause neutropenia. The patient should be advised to limit contact with other individuals in
order to reduce the risk of infection. Obtain a complete blood cell (CBC) count, with a white blood
cell (WBC) count, corrected for the presence of nucleated red blood cells, a neutrophil count, and a
platelet count immediately upon diagnosing the event and then repeat daily. It is recommended that
following recovery from neutropenia, weekly CBC, WBC, neutrophil and platelet counts continue to
be obtained for three consecutive weeks, to ensure that the patient recovers fully. Should any evidence
of infection develop concurrently with the neutropenia, the appropriate cultures and diagnostic
procedures should be performed and an appropriate therapeutic regimen instituted.
11
In the event of severe neutropenia or agranulocytosis:
Follow the guidelines above and administer appropriate therapy such as granulocyte colony
stimulating factor, beginning the same day that the event is identified; administer daily until the
condition resolves. Provide protective isolation and if clinically indicated, admit patient to the hospital.
Limited information is available regarding rechallenge. Therefore, in the event of neutropenia,
rechallenge is not recommended. In the event of agranulocytosis, rechallenge is contraindicated.
Carcinogenicity/mutagenicity
In view of the genotoxicity results, a carcinogenic potential of deferiprone cannot be excluded (see
section 5.3).
Plasma Zn
2+
concentration
Monitoring of plasma Zn
2+
concentration, and supplementation in case of a deficiency, is
recommended.
HIV positive or other immune compromised patients
No data are available on the use of deferiprone in HIV positive or in other immune compromised
patients. Given that deferiprone can be associated with neutropenia and agranulocytosis, therapy in
immune compromised patients should not be initiated unless potential benefits outweigh potential
risks.
Renal or hepatic impairment and liver fibrosis
There are no data available on the use of deferiprone in patients with renal or hepatic impairment.
Since deferiprone is eliminated mainly via the kidneys, there may be an increased risk of
complications in patients with impaired renal function. Similarly, as deferiprone is metabolised in the
liver
,
caution must be exercised in patients with hepatic dysfunction. Renal and hepatic function
should be monitored in this patient population during deferiprone therapy. If there is a persistent
increase in serum alanine aminotransferase (ALT), interruption of deferiprone therapy should be
considered.
In thalassaemia patients there is an association between liver fibrosis and iron overload and/or
hepatitis C. Special care must be taken to ensure that iron chelation in patients with hepatitis C is
optimal. In these patients careful monitoring of liver histology is recommended.
Discoloration of urine
Patients should be informed that their urine may show a reddish/brown discoloration due to the
excretion of the iron-deferiprone complex.
Chronic overdose and neurological disorders
Neurological disorders have been observed in children treated with 2.5 to 3 times the recommended
dose for several years. Prescribers are reminded that the use of doses above 100 mg/kg/day are not
recommended (see sections 4.8 and 4.9).
Excipients
Ferriprox oral solution contains the colouring agent Sunset Yellow (E110) which may cause allergic
reactions.
Due to the unknown mechanism of deferiprone-induced neutropenia, patients must not take medicinal
products known to be associated with neutropenia or those that can cause agranulocytosis (see section
4.3).
Interactions between deferiprone and other medicinal products have not been reported. However, since
deferiprone binds to metallic cations, the potential exists for interactions between deferiprone and
12
trivalent cation-dependent medicinal products such as aluminium-based antacids. Therefore, it is not
recommended to concomitantly ingest aluminium-based antacids and deferiprone.
The safety of concurrent use of deferiprone and vitamin C has not been formally studied. Based on the
reported adverse interaction that can occur between deferoxamine and vitamin C, caution should be
used when administering deferiprone and vitamin C concurrently.
4.6
Pregnancy
There are no adequate data from the use of deferiprone in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Women of childbearing potential must be advised to avoid pregnancy due to the clastogenic and
teratogenic properties of the medicinal product. These women should be advised to take contraceptive
measures and must be advised to immediately stop taking deferiprone if they become pregnant or plan
to become pregnant (see section 4.3).
Breastfeeding
It is not known whether deferiprone is excreted in human milk. No prenatal and postnatal reproductive
studies have been conducted in animals. Deferiprone must not be used by breast-feeding mothers. If
treatment is unavoidable, breast-feeding must be stopped (see section 4.3).
Fertility
No effects on fertility or early embryonic development were noted in animals (see section 5.3).
Not relevant.
The most common adverse reactions reported during therapy with deferiprone in clinical trials were
nausea, vomiting, abdominal pain, and chromaturia, which were reported in more than 10% of
patients. The most serious adverse reaction reported in clinical trials with deferiprone was
agranulocytosis, defined as an absolute neutrophil count less than 0.5 x 10
9
/l, which occurred in
approximately 1% of patients. Less severe episodes of neutropenia were reported in approximately 5%
of patients.
Adverse reaction frequencies: Very common (≥1/10), Common (≥1/100 to <1/10).
SYSTEM ORGAN CLASS VERY COMMON (≥1/10) COMMON (≥1/100 to
<1/10)
Blood and lymphatic system disorders
Neutropenia
Agranulocytosis
Metabolism and nutrition disorders
Increased Appetite
Nervous system disorders
Headache
Gastrointestinal disorders
Nausea
Abdominal Pain
Vomiting
Diarrhoea
Musculoskeletal and connective tissue
disorders
Arthralgia
Renal and urinary disorders
Chromaturia
General disorders and administration
site conditions
Fatigue
Investigations
Increased liver enzymes
13
The most serious adverse reaction reported in clinical trials with deferiprone is agranulocytosis
(neutrophils <0.5x10
9
/l), with an incidence of 1.1% (0.6 cases per 100 patient-years of treatment) (see
section 4.4). The observed incidence of the less severe form of neutropenia (neutrophils <1.5x10
9
/l) is
4.9% (2.5 cases per 100 patient-years). This rate should be considered in the context of the underlying
elevated incidence of neutropenia in thalassaemia patients, particularly in those with hypersplenism.
Episodes of diarrhoea, mostly mild and transient, have been reported in patients treated with
deferiprone. Gastrointestinal effects are more frequent at the beginning of therapy and resolve in most
patients within a few weeks without the discontinuation of treatment. In some patients it may be
beneficial to reduce the dose of deferiprone and then scale it back up to the former dose. Arthropathy
events, which ranged from mild pain in one or more joints to severe arthritis with effusion and
significant disability, have also been reported in patients treated with deferiprone. Mild arthropathies
are generally transient.
Increased levels of serum liver enzymes have been reported in some patients taking deferiprone. In the
majority of these patients, the increase was asymptomatic and transient, and returned to baseline
without discontinuation or decreasing the dose of deferiprone (see section 4.4).
Some patients experienced progression of fibrosis associated with an increase in iron overload or
hepatitis C.
Low plasma zinc levels have been associated with deferiprone in a minority of patients. The levels
normalised with oral zinc supplementation.
Neurological disorders (such as cerebellar symptoms, diplopia, lateral nystagmus, psychomotor
slowdown, hand movements and axial hypotonia) have been observed in children who had been
voluntarily prescribed more than 2.5 times the maximum recommended dose of 100 mg/kg/day for
several years. The neurological disorders progressively regressed after deferiprone discontinuation
(see sections 4.4 and 4.9).
No cases of acute overdose have been reported. However, neurological disorders (such as cerebellar
symptoms, diplopia, lateral nystagmus, psychomotor slowdown, hand movements and axial
hypotonia) have been observed in children who had been voluntarily prescribed more than 2.5 times
the maximum recommended dose of 100 mg/kg/day for several years. The neurological disorders
progressively regressed after deferiprone discontinuation.
In case of overdose, close clinical supervision of the patient is required.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Iron chelating agents, ATC code:
V03AC02
Mechanism of action
The active substance is deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), a bidentate ligand which
binds to iron in a 3:1 molar ratio.
Pharmacodynamic effects
Clinical studies have demonstrated that Ferriprox is effective in promoting iron excretion and that a
dose of 25 mg/kg three times per day can prevent the progression of iron accumulation as assessed by
serum ferritin, in patients with transfusion-dependent thalassaemia. However, chelation therapy may
not necessarily protect against iron-induced organ damage.
14
Clinical efficacy and safety
Studies LA16-0102, LA-01 and LA08-9701 compared the efficacy of Ferriprox with that of
deferoxamine in controlling serum ferritin in transfusion-dependent thalassemia patients. Ferriprox
and deferoxamine were equivalent in promoting a net stabilization or reduction of body iron load,
despite the continuous transfusional iron administration in those patients (no difference in proportion
of patients with a negative trend in serum ferritin between the two treatment groups by regression
analysis; p >0.05).
A magnetic resonance imaging (MRI) method, T2*, was also used to quantify myocardial iron load.
Iron overload causes concentration-dependent MRI T2* signal loss, thus, increased myocardial iron
reduces myocardial MRI T2* values. Myocardial MRI T2* values of less than 20 milliseconds
represent iron overload in the heart. An increase in MRI T2* on treatment indicates that iron is being
removed from the heart. A positive correlation between MRI T2* values and cardiac function (as
measured by Left Ventricular Ejection Fraction (LVEF)) has been documented.
Study LA16-0102 compared the efficacy of Ferriprox with that of deferoxamine in decreasing cardiac
iron overload and in improving cardiac function (as measured by LVEF) in transfusion-dependent
thalassemia patients. Sixty-one patients with cardiac iron overload, previously treated with
deferoxamine, were randomized to continue deferoxamine (average dose 43 mg/kg/day; N=31) or to
switch to Ferriprox (average dose 92 mg/kg/day N=29). Over the 12-month duration of the study,
Ferriprox was superior to deferoxamine in decreasing cardiac iron load. There was an improvement in
cardiac T2* of more than 3 milliseconds in patients treated with Ferriprox compared with a change of
about 1 millisecond in patients treated with deferoxamine. At the same time point, LVEF had
increased from baseline by 3.07 ± 3.58 absolute units (%) in the Ferriprox group and by
0.32 ± 3.38 absolute units (%) in the deferoxamine group (difference between groups; p=0.003).
Study LA12-9907 compared survival, incidence of cardiac disease, and progression of cardiac disease
in 129 patients with thalassemia major treated for at least 4 years with Ferriprox (N=54) or
deferoxamine (N=75). Cardiac endpoints were assessed by echocardiogram, electrocardiogram, the
New York Heart Association classification and death due to cardiac disease. There was no significant
difference in percentage of patients with cardiac dysfunction at first assessment (13% for Ferriprox vs.
16% for deferoxamine). Of patients with cardiac dysfunction at first assessment, none treated with
deferiprone compared with four (33%) treated with deferoxamine had worsening of their cardiac status
(p=0.245). Newly diagnosed cardiac dysfunction occurred in 13 (20.6%) deferoxamine-treated
patients and in 2 (4.3%) Ferriprox-treated patients who were cardiac disease-free at the first
assessment (p=0.013). Overall, fewer Ferriprox-treated patients than deferoxamine-treated patients
showed a worsening of cardiac dysfunction from first assessment to last assessment (4% vs. 20%,
p=0.007).
Data from the published literature are consistent with the results from the Apotex studies,
demonstrating less heart disease and/or increased survival in Ferriprox-treated patients than in those
treated with deferoxamine.
5.2 Pharmacokinetic properties
Absorption
Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract. Peak serum
concentration is reported to occur 45 to 60 minutes following a single dose in fasted patients. This may
be extended to 2 hours in fed patients.
Following a dose of 25 mg/kg, lower peak serum concentrations have been detected in patients in the
fed state (85 mol/l) than in the fasting state (126 mol/l), although there was no decrease in the
amount of deferiprone absorbed when it was given with food.
15
Biotransformation
Deferiprone is metabolised predominantly to a glucuronide conjugate. This metabolite lacks
iron-binding capability due to inactivation of the 3-hydroxy group of deferiprone. Peak serum
concentrations of the glucuronide occur 2 to 3 hours after administration of deferiprone.
Elimination
In humans, deferiprone is eliminated mainly via the kidneys; 75% to 90% of the ingested dose is
reported as being recovered in the urine in the first 24 hours, in the form of free deferiprone, the
glucuronide metabolite and the iron-deferiprone complex. A variable amount of elimination via the
faeces has been reported. The elimination half-life in most patients is 2 to 3 hours.
5.3
Preclinical safety data
Non-clinical studies have been conducted in animal species including mice, rats, rabbits, dogs and
monkeys.
The most common findings in non-iron-loaded animals at doses of 100 mg/kg/day and above were
hematologic effects such as bone marrow hypocellularity, and decreased WBC, RBC and/or platelet
counts in peripheral blood.
Atrophy of the thymus, lymphoid tissues, and testis, and hypertrophy of the adrenals, were reported at
doses of 100 mg/kg/day or greater in non-iron-loaded animals.
No carcinogenicity studies in animals have been conducted with deferiprone. The genotoxic potential
of deferiprone was evaluated in a set of
in vitro
and
in vivo
tests. Deferiprone did not show direct
mutagenic properties; however, it did display clastogenic characteristics in
in vitro
assays and
in vivo
in animals.
Deferiprone was teratogenic and embryotoxic in reproductive studies in non-iron-loaded pregnant rats
and rabbits at doses at least as low as 25 mg/kg/day. No effects on fertility or early embryonic
development were noted in non-iron-loaded male and female rats that received deferiprone orally at
doses of up to 75 mg/kg twice daily for 28 days (males) or 2 weeks (females) prior to mating and until
termination (males) or through early gestation (females). In females, an effect on the oestrous cycle
delayed time to confirmed mating at all doses tested.
No prenatal and postnatal reproductive studies have been conducted in animals.
6.
6.1 List of excipients
Purified water
Hydroxyethylcellulose
Glycerol
Hydrochloric acid, concentrated
Artificial cherry flavour
Peppermint oil
Sunset Yellow (E110)
Sucralose (E955)
6.2 Incompatibilities
Not applicable.
16
6.3 Shelf life
2 years.
After first opening use within 35 days.
6.4 Special precautions for storage
Do not store above 30ºC. Store in the original package in order to protect from light.
6.5 Nature and contents of container
Amber polyethylene terephthalate (PET) bottles with child resistant closure (polypropylene), and a
graduated measuring cup (polypropylene).
Each pack contains one bottle of 250 ml or 500 ml oral solution.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Apotex Europe B.V.
Darwinweg 20
2333 CR Leiden
Netherlands
8.
EU/1/99/108/002
EU/1/99/108/003
9.
Date of first authorisation: 25/08/1999
Date of latest renewal: 25/08/2009
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
17
1.
Ferriprox 1000 mg film-coated tablets
2.
Each tablet contains 1000 mg deferiprone.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
White to off-white, capsule-shaped, film-coated tablets imprinted “APO” bisect “1000” on one side,
plain on the other. The tablet is scored. The tablet can be divided into equal halves.
4.
Ferriprox is indicated for the treatment of iron overload in patients with thalassaemia major when
deferoxamine therapy is contraindicated or inadequate.
Deferiprone therapy should be initiated and maintained by a physician experienced in the treatment of
patients with thalassaemia.
Posology
Deferiprone is usually given as 25 mg/kg body weight, orally, three times a day for a total daily dose
of 75 mg/kg body weight. Dose per kilogram body weight should be calculated to the nearest half
tablet. See table below for recommended doses for body weights at 10 kg increments.
Dose table
To obtain a dose of about 75 mg/kg/day, use the number of tablets suggested in the following table for
the body weight of the patient. Sample body weights at 10 kg increments are listed.
Body weight
(kg)
Total daily dose
(mg)
Number of 1000 mg tablets*
Morning
Midday
Evening
20
1500
0.5
0.5
0.5
30
2250
1.0
0.5
1.0
40
3000
1.0
1.0
1.0
50
3750
1.5
1.0
1.5
60
4500
1.5
1.5
1.5
70
5250
2.0
1.5
2.0
80
6000
2.0
2.0
2.0
90
6750
2.5
2.0
2.5
*number of tablets rounded to nearest half tablet
A total daily dose above 100 mg/kg body weight is not recommended because of the potentially
increased risk of adverse reactions (see sections 4.4, 4.8, and 4.9).
18
The effect of Ferriprox in decreasing the body iron is directly influenced by the dose and the degree of
iron overload. After starting Ferriprox therapy, it is recommended that serum ferritin concentrations,
or other indicators of body iron load, be monitored every two to three months to assess the long-term
effectiveness of the chelation regimen in controlling the body iron load. Dose adjustments should be
tailored to the individual patient’s response and therapeutic goals (maintenance or reduction of body
iron burden). Interruption of therapy with deferiprone should be considered if serum ferritin
measurements fall below 500 g/l.
Paediatric population
There are limited data available on the use of deferiprone in children between 6 and 10 years of age,
and no data on deferiprone use in children under 6 years of age.
Method of administration
For oral use
- Hypersensitivity to the active substance or to any of the excipients.
- History of recurrent episodes of neutropenia.
- History of agranulocytosis.
- Pregnancy (see section 4.6).
- Breastfeeding (see section 4.6).
- Due to the unknown mechanism of deferiprone-induced neutropenia, patients must not take
medicinal products known to be associated with neutropenia or those that can cause
agranulocytosis (see section 4.5).
Neutropenia/Agranulocytosis
Deferiprone has been shown to cause neutropenia, including agranulocytosis. The patient’s
neutrophil count should be monitored every week.
In clinical trials, weekly monitoring of the neutrophil count has been effective in identifying cases of
neutropenia and agranulocytosis. Neutropenia and agranulocytosis resolved once therapy was
withdrawn. If the patient develops an infection while on deferiprone, therapy should be interrupted and
the neutrophil count monitored more frequently. Patients should be advised to report immediately to
their physician any symptoms indicative of infection such as fever, sore throat and flu-like symptoms.
Suggested management of cases of neutropenia is outlined below. It is recommended that such a
management protocol be in place prior to initiating any patient on deferiprone treatment.
Treatment with deferiprone should not be initiated if the patient is neutropenic.
The risk of
agranulocytosis and neutropenia is higher if the baseline absolute neutrophil count (ANC) is less than
1.5x10
9
/l.
In the event of neutropenia:
Instruct the patient to immediately discontinue deferiprone and all other medicinal products with a
potential to cause neutropenia. The patient should be advised to limit contact with other individuals in
order to reduce the risk of infection. Obtain a complete blood cell (CBC) count, with a white blood
cell (WBC) count, corrected for the presence of nucleated red blood cells, a neutrophil count, and a
platelet count immediately upon diagnosing the event and then repeat daily. It is recommended that
following recovery from neutropenia, weekly CBC, WBC, neutrophil and platelet counts continue to
be obtained for three consecutive weeks, to ensure that the patient recovers fully. Should any evidence
of infection develop concurrently with the neutropenia, the appropriate cultures and diagnostic
procedures should be performed and an appropriate therapeutic regimen instituted.
19
In the event of severe neutropenia or agranulocytosis:
Follow the guidelines above and administer appropriate therapy such as granulocyte colony
stimulating factor, beginning the same day that the event is identified; administer daily until the
condition resolves. Provide protective isolation and if clinically indicated, admit patient to the hospital.
Limited information is available regarding rechallenge. Therefore, in the event of neutropenia,
rechallenge is not recommended. In the event of agranulocytosis, rechallenge is contraindicated.
Carcinogenicity/mutagenicity
In view of the genotoxicity results, a carcinogenic potential of deferiprone cannot be excluded (see
section 5.3).
Plasma Zn
2+
concentration
Monitoring of plasma Zn
2+
concentration, and supplementation in case of a deficiency, is
recommended.
HIV positive or other immune compromised patients
No data are available on the use of deferiprone in HIV positive or in other immune compromised
patients. Given that deferiprone can be associated with neutropenia and agranulocytosis, therapy in
immune compromised patients should not be initiated unless potential benefits outweigh potential
risks.
Renal or hepatic impairment and liver fibrosis
There are no data available on the use of deferiprone in patients with renal or hepatic impairment.
Since deferiprone is eliminated mainly via the kidneys, there may be an increased risk of
complications in patients with impaired renal function. Similarly, as deferiprone is metabolised in the
liver
,
caution must be exercised in patients with hepatic dysfunction. Renal and hepatic function
should be monitored in this patient population during deferiprone therapy. If there is a persistent
increase in serum alanine aminotransferase (ALT), interruption of deferiprone therapy should be
considered.
In thalassaemia patients there is an association between liver fibrosis and iron overload and/or
hepatitis C. Special care must be taken to ensure that iron chelation in patients with hepatitis C is
optimal. In these patients careful monitoring of liver histology is recommended.
Discoloration of urine
Patients should be informed that their urine may show a reddish/brown discoloration due to the
excretion of the iron-deferiprone complex.
Chronic overdose and neurological disorders
Neurological disorders have been observed in children treated with 2.5 to 3 times the recommended
dose for several years. Prescribers are reminded that the use of doses above 100 mg/kg/day are not
recommended (see sections 4.8 and 4.9).
Due to the unknown mechanism of deferiprone-induced neutropenia, patients must not take medicinal
products known to be associated with neutropenia or those that can cause agranulocytosis (see section
4.3).
Interactions between deferiprone and other medicinal products have not been reported. However, since
deferiprone binds to metallic cations, the potential exists for interactions between deferiprone and
trivalent cation-dependent medicinal products such as aluminium-based antacids. Therefore, it is not
recommended to concomitantly ingest aluminium-based antacids and deferiprone.
20
The safety of concurrent use of deferiprone and vitamin C has not been formally studied. Based on the
reported adverse interaction that can occur between deferoxamine and vitamin C, caution should be
used when administering deferiprone and vitamin C concurrently.
Pregnancy
There are no adequate data from the use of deferiprone in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Women of childbearing potential must be advised to avoid pregnancy due to the clastogenic and
teratogenic properties of the medicinal product. These women should be advised to take contraceptive
measures and must be advised to immediately stop taking deferiprone if they become pregnant or plan
to become pregnant (see section 4.3).
Breastfeeding
It is not known whether deferiprone is excreted in human milk. No prenatal and postnatal reproductive
studies have been conducted in animals. Deferiprone must not be used by breast-feeding mothers. If
treatment is unavoidable, breast-feeding must be stopped (see section 4.3).
Fertility
No effects on fertility or early embryonic development were noted in animals (see section 5.3).
Not relevant.
The most common adverse reactions reported during therapy with deferiprone in clinical trials were
nausea, vomiting, abdominal pain, and chromaturia, which were reported in more than 10% of
patients. The most serious adverse reaction reported in clinical trials with deferiprone was
agranulocytosis, defined as an absolute neutrophil count less than 0.5 x 10
9
/l, which occurred in
approximately 1% of patients. Less severe episodes of neutropenia were reported in approximately 5%
of patients.
Adverse reaction frequencies: Very common (≥1/10), Common (≥1/100 to <1/10).
SYSTEM ORGAN CLASS VERY COMMON (≥1/10) COMMON (≥1/100 to
<1/10)
Blood and lymphatic system disorders
Neutropenia
Agranulocytosis
Metabolism and nutrition disorders
Increased Appetite
Nervous system disorders
Headache
Gastrointestinal disorders
Nausea
Abdominal Pain
Vomiting
Diarrhoea
Musculoskeletal and connective tissue
disorders
Arthralgia
Renal and urinary disorders
Chromaturia
General disorders and administration
site conditions
Fatigue
Investigations
Increased liver enzymes
The most serious adverse reaction reported in clinical trials with deferiprone is agranulocytosis
(neutrophils <0.5x10
9
/l), with an incidence of 1.1% (0.6 cases per 100 patient-years of treatment) (see
section 4.4). The observed incidence of the less severe form of neutropenia (neutrophils <1.5x10
9
/l) is
21
4.9% (2.5 cases per 100 patient-years). This rate should be considered in the context of the underlying
elevated incidence of neutropenia in thalassaemia patients, particularly in those with hypersplenism.
Episodes of diarrhoea, mostly mild and transient, have been reported in patients treated with
deferiprone. Gastrointestinal effects are more frequent at the beginning of therapy and resolve in most
patients within a few weeks without the discontinuation of treatment. In some patients it may be
beneficial to reduce the dose of deferiprone and then scale it back up to the former dose. Arthropathy
events, which ranged from mild pain in one or more joints to severe arthritis with effusion and
significant disability, have also been reported in patients treated with deferiprone. Mild arthropathies
are generally transient.
Increased levels of serum liver enzymes have been reported in some patients taking deferiprone. In the
majority of these patients, the increase was asymptomatic and transient, and returned to baseline
without discontinuation or decreasing the dose of deferiprone (see section 4.4).
Some patients experienced progression of fibrosis associated with an increase in iron overload or
hepatitis C.
Low plasma zinc levels have been associated with deferiprone in a minority of patients. The levels
normalised with oral zinc supplementation.
Neurological disorders (such as cerebellar symptoms, diplopia, lateral nystagmus, psychomotor
slowdown, hand movements and axial hypotonia) have been observed in children who had been
voluntarily prescribed more than 2.5 times the maximum recommended dose of 100 mg/kg/day for
several years. The neurological disorders progressively regressed after deferiprone discontinuation
(see sections 4.4 and 4.9).
No cases of acute overdose have been reported. However, neurological disorders (such as cerebellar
symptoms, diplopia, lateral nystagmus, psychomotor slowdown, hand movements and axial
hypotonia) have been observed in children who had been voluntarily prescribed more than 2.5 times
the maximum recommended dose of 100 mg/kg/day for several years. The neurological disorders
progressively regressed after deferiprone discontinuation.
In case of overdose, close clinical supervision of the patient is required.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Iron chelating agents, ATC code:
V03AC02
Mechanism of action
The active substance is deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), a bidentate ligand which
binds to iron in a 3:1 molar ratio.
Pharmacodynamic effects
Clinical studies have demonstrated that Ferriprox is effective in promoting iron excretion and that a
dose of 25 mg/kg three times per day can prevent the progression of iron accumulation as assessed by
serum ferritin, in patients with transfusion-dependent thalassaemia. However, chelation therapy may
not necessarily protect against iron-induced organ damage.
Clinical efficacy and safety
Studies LA16-0102, LA-01 and LA08-9701 compared the efficacy of Ferriprox with that of
deferoxamine in controlling serum ferritin in transfusion-dependent thalassemia patients. Ferriprox
22
and deferoxamine were equivalent in promoting a net stabilization or reduction of body iron load,
despite the continuous transfusional iron administration in those patients (no difference in proportion
of patients with a negative trend in serum ferritin between the two treatment groups by regression
analysis; p >0.05).
A magnetic resonance imaging (MRI) method, T2*, was also used to quantify myocardial iron load.
Iron overload causes concentration-dependent MRI T2* signal loss, thus, increased myocardial iron
reduces myocardial MRI T2* values. Myocardial MRI T2* values of less than 20 milliseconds
represent iron overload in the heart. An increase in MRI T2* on treatment indicates that iron is being
removed from the heart. A positive correlation between MRI T2* values and cardiac function (as
measured by Left Ventricular Ejection Fraction (LVEF)) has been documented.
Study LA16-0102 compared the efficacy of Ferriprox with that of deferoxamine in decreasing cardiac
iron overload and in improving cardiac function (as measured by LVEF) in transfusion-dependent
thalassemia patients. Sixty-one patients with cardiac iron overload, previously treated with
deferoxamine, were randomized to continue deferoxamine (average dose 43 mg/kg/day; N=31) or to
switch to Ferriprox (average dose 92 mg/kg/day N=29). Over the 12-month duration of the study,
Ferriprox was superior to deferoxamine in decreasing cardiac iron load. There was an improvement in
cardiac T2* of more than 3 milliseconds in patients treated with Ferriprox compared with a change of
about 1 millisecond in patients treated with deferoxamine. At the same time point, LVEF had
increased from baseline by 3.07 ± 3.58 absolute units (%) in the Ferriprox group and by
0.32 ± 3.38 absolute units (%) in the deferoxamine group (difference between groups; p=0.003).
Study LA12-9907 compared survival, incidence of cardiac disease, and progression of cardiac disease
in 129 patients with thalassemia major treated for at least 4 years with Ferriprox (N=54) or
deferoxamine (N=75). Cardiac endpoints were assessed by echocardiogram, electrocardiogram, the
New York Heart Association classification and death due to cardiac disease. There was no significant
difference in percentage of patients with cardiac dysfunction at first assessment (13% for Ferriprox vs.
16% for deferoxamine). Of patients with cardiac dysfunction at first assessment, none treated with
deferiprone compared with four (33%) treated with deferoxamine had worsening of their cardiac status
(p=0.245). Newly diagnosed cardiac dysfunction occurred in 13 (20.6%) deferoxamine-treated
patients and in 2 (4.3%) Ferriprox-treated patients who were cardiac disease-free at the first
assessment (p=0.013). Overall, fewer Ferriprox-treated patients than deferoxamine-treated patients
showed a worsening of cardiac dysfunction from first assessment to last assessment (4% vs. 20%,
p=0.007).
Data from the published literature are consistent with the results from the Apotex studies,
demonstrating less heart disease and/or increased survival in Ferriprox-treated patients than in those
treated with deferoxamine.
5.2 Pharmacokinetic properties
Absorption
Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract. Peak serum
concentration is reported to occur 45 to 60 minutes following a single dose in fasted patients. This may
be extended to 2 hours in fed patients.
Following a dose of 25 mg/kg, lower peak serum concentrations have been detected in patients in the
fed state (85 mol/l) than in the fasting state (126 mol/l), although there was no decrease in the
amount of deferiprone absorbed when it was given with food.
Biotransformation
Deferiprone is metabolised predominantly to a glucuronide conjugate. This metabolite lacks
iron-binding capability due to inactivation of the 3-hydroxy group of deferiprone. Peak serum
concentrations of the glucuronide occur 2 to 3 hours after administration of deferiprone.
23
Elimination
In humans, deferiprone is eliminated mainly via the kidneys; 75% to 90% of the ingested dose is
reported as being recovered in the urine in the first 24 hours, in the form of free deferiprone, the
glucuronide metabolite and the iron-deferiprone complex. A variable amount of elimination via the
faeces has been reported. The elimination half-life in most patients is 2 to 3 hours.
5.3 Preclinical safety data
Non-clinical studies have been conducted in animal species including mice, rats, rabbits, dogs and
monkeys.
The most common findings in non-iron-loaded animals at doses of 100 mg/kg/day and above were
hematologic effects such as bone marrow hypocellularity, and decreased WBC, RBC and/or platelet
counts in peripheral blood.
Atrophy of the thymus, lymphoid tissues, and testis, and hypertrophy of the adrenals, were reported at
doses of 100 mg/kg/day or greater in non-iron-loaded animals.
No carcinogenicity studies in animals have been conducted with deferiprone. The genotoxic potential
of deferiprone was evaluated in a set of
in vitro
and
in vivo
tests. Deferiprone did not show direct
mutagenic properties; however, it did display clastogenic characteristics in
in vitro
assays and
in vivo
in animals.
Deferiprone was teratogenic and embryotoxic in reproductive studies in non-iron-loaded pregnant rats
and rabbits at doses at least as low as 25 mg/kg/day. No effects on fertility or early embryonic
development were noted in non-iron-loaded male and female rats that received deferiprone orally at
doses of up to 75 mg/kg twice daily for 28 days (males) or 2 weeks (females) prior to mating and until
termination (males) or through early gestation (females). In females, an effect on the oestrous cycle
delayed time to confirmed mating at all doses tested.
No prenatal and postnatal reproductive studies have been conducted in animals.
6.
6.1 List of excipients
Tablet core
Methylcellulose USP A15LV
Crospovidone
Magnesium stearate
Coating
Hypromellose 2910 USP/EP
Hydroxypropyl cellulose
Macrogol
Titanium dioxide
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
For the bottle: After first opening use within 50 days.
24
6.4 Special precautions for storage
Do not store above 30ºC.
For the bottle: Keep the bottle tightly closed in order to protect from moisture.
For the blister: Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
High density polyethylene (HDPE) bottle with a child resistant polypropylene cap and a desiccant.
Pack size of 50 tablets.
High density polyethylene (HDPE) bottle with a polypropylene screw cap and a desiccant.
Pack size of 100 tablets.
Perforated unit dose aluminium blisters.
Pack size of 50 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Apotex Europe B.V.
Darwinweg 20
2333 CR Leiden
Netherlands
8.
EU/1/99/108/004
EU/1/99/108/005
EU/1/99/108/006
9.
Date of first authorisation: 25/08/1999
Date of latest renewal: 25/08/2009
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
25
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
26
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Apotex Nederland B.V.
Bio Science Park
Archimedesweg 2
2333 CN Leiden
Netherlands
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 should provide a patient/carer reminder card in each pack, the text of which is included in
the Package Leaflet.
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 02 presented in
Module 1.8.1 of the Marketing Authorisation, is in place and functioning before and whilst the product
is on the market.
Risk Management plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan as agreed in version 4 of the Risk Management Plan (RMP) presented in
Module 1.8.2 of the Marketing Authorisation and any subsequent updates of the RMP agreed by the
CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
When new information is received that may impact on the current Safety specification,
Pharmacovigilance Plan or risk minimisation activities
Within 60 says of an important (pharmacovigilance or risk minimisation) milestone being
reached
At the request of the European Medicines Agency.
PSURs:
the MAH will continue to provide Periodic Safety Update Reports every year.
27
ANNEX III
LABELLING AND PACKAGE LEAFLET
28
A. LABELLING
29
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
BOTTLE OF 100 TABLETS
1.
Ferriprox 500 mg film-coated tablets
deferiprone
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One tablet contains 500 mg deferiprone.
3.
LIST OF EXCIPIENTS
4.
100 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
30
Apotex Europe B.V.
Darwinweg 20
2333 CR Leiden
Netherlands
EU/1/99/108/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Ferriprox 500 mg
31
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
BOTTLES OF 250 ML AND 500 ML ORAL SOLUTION
Ferriprox 100 mg/ml oral solution
Deferiprone
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each ml of oral solution contains 100 mg deferiprone (25 g deferiprone in 250 ml).
Each ml of oral solution contains 100 mg deferiprone (50 g deferiprone in 500 ml).
3. LIST OF EXCIPIENTS
Contains Sunset Yellow (E110); see leaflet for further information.
250 ml oral solution
500 ml oral solution
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
After first opening use within 35 days.
32
9. SPECIAL STORAGE CONDITIONS
Do not store above 30C.
Store in the original package in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Apotex Europe B.V.
Darwinweg 20
2333 CR Leiden
Netherlands
EU/1/99/108/002
EU/1/99/108/003
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Ferriprox 100 mg/ml
33
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
BOTTLE OF 50 TABLETS
BOTTLE OF 100 TABLETS
BLISTER PACKS OF 50 TABLETS
1.
Ferriprox 1000 mg film-coated tablets
deferiprone
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One tablet contains 1000 mg deferiprone.
3.
LIST OF EXCIPIENTS
4.
50 tablets
100 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
For the bottle: After first opening use within 50 days.
34
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30C.
For the bottle: Keep the bottle tightly closed in order to protect from moisture.
For the blister: 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
Apotex Europe B.V.
Darwinweg 20
2333 CR Leiden
Netherlands
EU/1/99/108/004
bottle of 100 tablets
EU/1/99/108/006
blisters, package of 50 tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Ferriprox 1000 mg
35
EU/1/99/108/005
bottle of 50 tablets
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
Ferriprox 1000 mg film-coated tablets
deferiprone
2.
Apotex Europe B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
36
B. PACKAGE LEAFLET
37
PACKAGE LEAFLET: INFORMATION FOR THE USER
Ferriprox 500 mg film-coated tablets
Deferiprone
Read all of this leaflet carefully before you start taking this medicine.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or pharmacist.
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
If you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Attached to this leaflet you will find a patient/carer reminder card. You should detach,
complete, read the card carefully and carry it with you.
In this leaflet:
1. What Ferriprox is and what it is used for
2. Before you take Ferriprox
3. How to take Ferriprox
4. Possible side effects
5. How to store Ferriprox
6. Further information
1. WHAT FERRIPROX IS AND WHAT IT IS USED FOR
Ferriprox contains the active substance deferiprone. Ferriprox is a medicine that removes iron from the
body.
Ferriprox is used to treat iron overload caused by frequent blood transfusions in patients with
thalassaemia major when deferoxamine therapy is contraindicated or inadequate.
2. BEFORE YOU TAKE FERRIPROX
Do not take Ferriprox
if you are allergic (hypersensitive) to deferiprone or any of the other ingredients of Ferriprox.
if you have a history of repeated episodes of neutropenia (low white blood cell (neutrophil) count).
if you have a history of agranulocytosis (very low white blood cell (neutrophil) count).
if you are currently taking medicines known to cause neutropenia or agranulocytosis (see “Taking
other medicines”).
if you are pregnant or breastfeeding.
Take special care with Ferriprox
the most serious side effect that may occur while taking Ferriprox is a very low white blood cell
(neutrophil) count. This condition, known as severe neutropenia or agranulocytosis, has occurred
in 1 to 2 out of 100 people who have taken Ferriprox in clinical studies. Because white blood cells
help to fight infection, a low neutrophil count may place you at risk of developing a serious and
potentially life-threatening infection. To monitor for neutropenia, your doctor will ask you to have
a blood test (to check your white blood cell count) performed regularly, as frequently as every
week, while you are being treated with Ferriprox. It is very important for you to keep all of these
appointments. Please refer to the patient/carer reminder card attached to this leaflet. Report
immediately to your doctor any symptoms of infection such as fever, sore throat or flu-like
symptoms.
if you are HIV positive or if your kidney and liver function is impaired, your doctor may
recommend additional tests.
38
Your doctor will also ask you to come in for tests to monitor body iron load. In addition he or she also
might ask you to undergo liver biopsies.
Taking other medicines
Do not take medicines known to cause neutropenia or agranulocytosis (see “Do not take Ferriprox”).
Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Do not take aluminium-based antacids while taking Ferriprox.
Please consult with your doctor or pharmacist before taking vitamin C with Ferriprox.
Pregnancy and breastfeeding
Do not take this medicine if you are pregnant or if you are trying to become pregnant. This medicine
could seriously harm your baby. You must use effective contraception while you are taking Ferriprox.
Ask your doctor which method is best for you. If you become pregnant while taking Ferriprox, stop
taking the medicine immediately and tell your doctor.
Do not use Ferriprox if you are breast-feeding. Please refer to the patient/carer reminder card attached
to this leaflet.
Driving and using machines
Not relevant.
3. HOW TO TAKE FERRIPROX
Always take Ferriprox exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure. The amount of Ferriprox that you take will depend on your weight. The
usual dose is 25 mg/kg, 3 times per day, for a total daily dose of 75 mg/kg/day. The total daily dose
should not exceed 100 mg/kg/day. Take your first dose in the morning. Take your second dose
midday. Take your third dose in the evening. Ferriprox can be taken with or without food; however,
you may find it easier to remember to take Ferriprox if you take it with your meals.
If you take more Ferriprox than you should
There are no reports of acute overdose with Ferriprox. If you have accidentally taken more than the
prescribed dose, you should contact your doctor.
If you forget to take Ferriprox
Ferriprox will be most effective if you do not miss any doses. If you do miss one dose take it as soon
as you remember and take your next dose at its regularly scheduled time. If you miss more than one
dose do not take a double dose to make up for forgotten individual doses, just continue with your
normal schedule. Do not change your daily dose without first talking to your doctor.
4. POSSIBLE SIDE EFFECTS
Like all medicines, Ferriprox can have side effects, although not everybody gets them.
The most serious side effect of Ferriprox is a very low white blood cell (neutrophil) count. This
condition, known as severe neutropenia or agranulocytosis, has occurred in 1 to 2 out of 100 people
who have taken Ferriprox in clinical studies. A low white blood cell count can be associated with a
serious and potentially life-threatening infection. Report immediately to your doctor any symptoms of
infection such as: fever, sore throat or flu-like symptoms.
39
Very common side effects
(affects more than 1 user in 10):
-
abdominal pain
-
nausea
-
vomiting
-
reddish/brown discolouration of urine
If you experience nausea or vomiting, it may help to take your Ferriprox with some food. Discoloured
urine is a very common effect and is not harmful.
Common side effects
(affects 1 to 10 users in 100):
-
low white blood cell count (agranulocytosis and neutropenia)
-
headache
-
diarrhoea
-
increase in liver enzymes
-
fatigue
-
increase in appetite
Events of joint pain and swelling ranged from mild pain in one or more joints to severe disability. In
most cases, the pain disappeared while patients continued taking Ferriprox.
In post-marketing experience with Ferriprox, neurological disorders (such as tremors, walking
disorders, double vision, involuntary muscle contractions, problems with movement coordination)
have been reported in children who had been voluntarily prescribed more than double the maximum
recommended dose of 100 mg/kg/day for several years. They recovered from these symptoms after
Ferriprox discontinuation.
If you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
5. HOW TO STORE FERRIPROX
Keep out of the reach and sight of children.
Do not use Ferriprox after the expiry date which is stated on the carton and the label after EXP.
Do not store above 30ºC.
6. FURTHER INFORMATION
What Ferriprox contains
The active substance is deferiprone. Each tablet contains 500 mg deferiprone.
The other ingredients are:
Tablet core: Microcrystalline cellulose, Magnesium stearate, Colloidal silicon dioxide.
Coating: Hypromellose, Macrogol, Titanium dioxide.
What Ferriprox looks like and contents of the pack
Ferriprox tablets are white to off-white, capsule-shaped, film-coated tablets imprinted “APO” bisect
“500” on one side, plain on the other. The tablets are scored and breakable in half. Ferriprox is
packaged in bottles of 100 tablets.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Apotex Europe B.V.
Darwinweg 20
2333 CR Leiden
Netherlands
40
Manufacturing Authorisation Holder:
Apotex Nederland B.V.
Bio Science Park
Archimedesweg 2
2333 CN Leiden
Netherlands
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
SWEDISH ORPHAN INTERNATIONAL SARL
Tél/Tel: + 33 1 41 92 18 01
Luxembourg/Luxemburg
SWEDISH ORPHAN INTERNATIONAL SARL
Tél/Tel: + 33 1 41 92 18 01
България
ТП „Торекс Киези Фарма”
Тел.: +359 2 920 12 05
Magyarország
Torrex Chiesi Hungária Kereskedelmi Kft.
Tel.: + 36-1-429 1060
Česká republika
Apotex CR
Tel: +00420 234 705 700
Malta
Swedish Orphan International s.r.l.
Tel: + 39 0521 19111
Danmark
SWEDISH ORPHAN A/S
Tlf: + 45 32 96 68 69
Nederland
SWEDISH ORPHAN INTERNATIONAL LTD
Tel: +44 1638 72 23 80
Deutschland
SWEDISH ORPHAN INTERNATIONAL GmbH
Tel: +49 6103 20 26 90
Norge
SWEDISH ORPHAN AS
Tlf: + 47 66 82 34 00
Eesti
Oy SWEDISH ORPHAN Ab
Tel: +358 201 558 840
Österreich
SWEDISH ORPHAN INTERNATIONAL GmbH
Tel: +49 6103 20 26 90
Ελλά
DEMO ABEE
Τηλ: + 30 210 8161802
Polska
Apotex Inc. Korporacja
Przedstawicielstwo w Polsce
Tel.: + 48 22 812 10 02
España
Swedish Orphan International Spain S.L.
Tel: + 34 913 91 35 80
Portugal
SWEDISH ORPHAN INTERNATIONAL AB
Tel: + 351 21 383 08 91
France
Swedish Orphan International SARL
Tél: + 33 1 41 92 18 01
România
Torrex Chiesi Pharma GmbH
Tel: + 40 729 995 020
Ireland
SWEDISH ORPHAN INTERNATIONAL LTD
Tel: + 44 1638 72 23 80
Slovenija
Torrex Chiesi Slovenija, d.o.o.
Tel: + 386-1-43 00 901
Ísland
SWEDISH ORPHAN A/S
Sími: + 45 32 96 68 69
Slovenská republika
Torrex Chiesi Slovakia, s.r.o.
Tel: + 421-2-59 30 00 60
41
Italia
Chiesi Farmaceutici S.p.A
Tel: + 39 0521 2791
Suomi/Finland
Oy SWEDISH ORPHAN Ab
Puh/Tel: + 358 201 558 840
Κύπρς
The Star Medicines Importers Co. Ltd.
Τηλ: + 357 25 371056
Sverige
SWEDISH ORPHAN AB
Tel: + 46 8 412 98 00
Latvija
Oy SWEDISH ORPHAN Ab
Tel: + 358 201 558 840
United Kingdom
SWEDISH ORPHAN INTERNATIONAL LTD
Tel: + 44 1638 722380
Lietuva
Oy SWEDISH ORPHAN Ab
Tel: + 358 201 558 840
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
42
PACKAGE LEAFLET: INFORMATION FOR THE USER
Ferriprox 100 mg/ml oral solution
Deferiprone
Read all of this leaflet carefully before you start taking this medicine.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or pharmacist.
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
If you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Attached to this leaflet you will find a patient/carer reminder card. You should detach,
complete, read the card carefully and carry it with you.
In this leaflet:
1. What Ferriprox is and what it is used for
2. Before you take Ferriprox
3. How to take Ferriprox
4. Possible side effects
5. How to store Ferriprox
6. Further information
1. WHAT FERRIPROX IS AND WHAT IT IS USED FOR
Ferriprox contains the active substance deferiprone. Ferriprox is a medicine that removes iron from the
body.
Ferriprox is used to treat iron overload caused by frequent blood transfusions in patients with
thalassaemia major when deferoxamine therapy is contraindicated or inadequate.
2. BEFORE YOU TAKE FERRIPROX
Do not take Ferriprox
if you are allergic (hypersensitive) to deferiprone or any of the other ingredients of Ferriprox.
if you have a history of repeated episodes of neutropenia (low white blood cell (neutrophil) count).
if you have a history of agranulocytosis (very low white blood cell (neutrophil) count).
if you are currently taking medicines known to cause neutropenia or agranulocytosis (see “Taking
other medicines”).
if you are pregnant or breastfeeding.
Take special care with Ferriprox
the most serious side effect that may occur while taking Ferriprox is a very low white blood cell
(neutrophil) count. This condition, known as severe neutropenia or agranulocytosis, has occurred
in 1 to 2 out of 100 people who have taken Ferriprox in clinical studies. Because white blood cells
help to fight infection, a low neutrophil count may place you at risk of developing a serious and
potentially life-threatening infection. To monitor for neutropenia, your doctor will ask you to have
a blood test (to check your white blood cell count) performed regularly, as frequently as every
week, while you are being treated with Ferriprox. It is very important for you to keep all of these
appointments. Please refer to the patient/carer reminder card attached to this leaflet. Report
immediately to your doctor any symptoms of infection such as fever, sore throat or flu-like
symptoms.
if you are HIV positive or if your kidney and liver function is impaired, your doctor may
recommend additional tests.
43
Your doctor will also ask you to come in for tests to monitor body iron load. In addition he or she also
might ask you to undergo liver biopsies.
Taking other medicines
Do not take medicines known to cause neutropenia or agranulocytosis (see “Do not take Ferriprox”).
Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Do not take aluminium-based antacids while taking Ferriprox.
Please consult with your doctor or pharmacist before taking vitamin C with Ferriprox.
Pregnancy and breastfeeding
Do not take this medicine if you are pregnant or if you are trying to become pregnant. This medicine
could seriously harm your baby. You must use effective contraception while you are taking Ferriprox.
Ask your doctor which method is best for you. If you become pregnant while taking Ferriprox, stop
taking the medicine immediately and tell your doctor.
Do not use Ferriprox if you are breast-feeding. Please refer to the patient/carer reminder card attached
to this leaflet.
Driving and using machines
Not relevant.
Important information about some of the ingredients of Ferriprox
Ferriprox oral solution contains Sunset Yellow (E110) which may cause allergic reactions.
3. HOW TO TAKE FERRIPROX
Always take Ferriprox exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure. The amount of Ferriprox that you take will depend on your weight. The
usual dose is 25 mg/kg, 3 times per day, for a total daily dose of 75 mg/kg/day. The total daily dose
should not exceed 100 mg/kg/day. Use the measuring cup to measure the volume prescribed by your
doctor. Take your first dose in the morning. Take your second dose midday. Take your third dose in
the evening. Ferriprox can be taken with or without food however, you may find it easier to remember
to take Ferriprox if you take it with your meals.
If you take more Ferriprox than you should
There are no reports of acute overdose with Ferriprox. If you have accidentally taken more than the
prescribed dose, you should contact your doctor.
If you forget to take Ferriprox
Ferriprox will be most effective if you do not miss any doses. If you do miss one dose take it as soon
as you remember and take your next dose at its regularly scheduled time. If you miss more than one
dose do not take a double dose to make up for forgotten individual doses, just continue with your
normal schedule. Do not change your daily dose without first talking to your doctor.
4. POSSIBLE SIDE EFFECTS
Like all medicines, Ferriprox can have side effects, although not everybody gets them.
The most serious side effect of Ferriprox is a very low white blood cell (neutrophil) count. This
condition, known as severe neutropenia or agranulocytosis, has occurred in 1 to 2 out of 100 people
who have taken Ferriprox in clinical studies. A low white blood cell count can be associated with a
44
serious and potentially life-threatening infection. Report immediately to your doctor any symptoms of
infection such as: fever, sore throat or flu-like symptoms.
Very common side effects
(affects more than 1 user in 10):
-
abdominal pain
-
nausea
-
vomiting
-
reddish/brown discolouration of urine
If you experience nausea or vomiting, it may help to take your Ferriprox with some food. Discoloured
urine is a very common effect and is not harmful.
Common side effects
(affects 1 to 10 users in 100):
-
low white blood cell count (agranulocytosis and neutropenia)
-
headache
-
diarrhoea
-
increase in liver enzymes
-
fatigue
-
increase in appetite
Events of joint pain and swelling ranged from mild pain in one or more joints to severe disability. In
most cases, the pain disappeared while patients continued taking Ferriprox.
In post-marketing experience with Ferriprox, neurological disorders (such as tremors, walking
disorders, double vision, involuntary muscle contractions, problems with movement coordination)
have been reported in children who had been voluntarily prescribed more than double the maximum
recommended dose of 100 mg/kg/day for several years. They recovered from these symptoms after
Ferriprox discontinuation.
If you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
5. HOW TO STORE FERRIPROX
Keep out of the reach and sight of children.
Do not use Ferriprox after the expiry date which is stated on the carton and the label after EXP.
After first opening use within 35 days. Do not store above 30ºC.
Store in the original package in order to protect from light.
6. FURTHER INFORMATION
What Ferriprox contains
The active substance is deferiprone. Each ml of oral solution contains 100 mg deferiprone.
The other ingredients are: purified water; hydroxyethylcellulose; glycerol; hydrochloric acid,
concentrated; artificial cherry flavour; peppermint oil; Sunset Yellow (E110); sucralose (E955).
What Ferriprox looks like and contents of the pack
Ferriprox oral solution is a clear, reddish orange coloured liquid. It is packaged in bottles of 250 ml or
500 ml.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Apotex Europe B.V.
Darwinweg 20
2333 CR Leiden
Netherlands
45
Manufacturer:
Apotex Nederland B.V.
Archimedesweg 2
2333 CN Leiden
Netherlands
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
SWEDISH ORPHAN INTERNATIONAL SARL
Tél/Tel: + 33 1 41 92 18 01
Luxembourg/Luxemburg
SWEDISH ORPHAN INTERNATIONAL SARL
Tél/Tel: + 33 1 41 92 18 01
България
ТП „Торекс Киези Фарма”
Тел.: +359 2 920 12 05
Magyarország
Torrex Chiesi Hungária Kereskedelmi Kft.
Tel.: + 36-1-429 1060
Česká republika
Apotex CR
Tel: +00420 234 705 700
Malta
Swedish Orphan International s.r.l.
Tel: + 39 0521 19111
Danmark
SWEDISH ORPHAN A/S
Tlf: + 45 32 96 68 69
Nederland
SWEDISH ORPHAN INTERNATIONAL LTD
Tel: +44 1638 72 23 80
Deutschland
SWEDISH ORPHAN INTERNATIONAL GmbH
Tel: +49 6103 20 26 90
Norge
SWEDISH ORPHAN AS
Tlf: + 47 66 82 34 00
Eesti
Oy SWEDISH ORPHAN Ab
Tel: +358 201 558 840
Österreich
SWEDISH ORPHAN INTERNATIONAL GmbH
Tel: +49 6103 20 26 90
Ελλά
DEMO ABEE
Τηλ: + 30 210 8161802
Polska
Apotex Inc. Korporacja
Przedstawicielstwo w Polsce
Tel.: + 48 22 812 10 02
España
Swedish Orphan International Spain S.L.
Tel: + 34 913 91 35 80
Portugal
SWEDISH ORPHAN INTERNATIONAL AB
Tel: + 351 21 383 08 91
France
Swedish Orphan International SARL
Tél: + 33 1 41 92 18 01
România
Torrex Chiesi Pharma GmbH
Tel: + 40 729 995 020
Ireland
SWEDISH ORPHAN INTERNATIONAL LTD
Tel: + 44 1638 72 23 80
Slovenija
Torrex Chiesi Slovenija, d.o.o.
Tel: + 386-1-43 00 901
Ísland
SWEDISH ORPHAN A/S
Sími: + 45 32 96 68 69
Slovenská republika
Torrex Chiesi Slovakia, s.r.o.
Tel: + 421-2-59 30 00 60
46
Bio Science Park
Italia
Chiesi Farmaceutici S.p.A
Tel: + 39 0521 2791
Suomi/Finland
Oy SWEDISH ORPHAN Ab
Puh/Tel: + 358 201 558 840
Κύπρς
The Star Medicines Importers Co. Ltd.
Τηλ: + 357 25 371056
Sverige
SWEDISH ORPHAN AB
Tel: + 46 8 412 98 00
Latvija
Oy SWEDISH ORPHAN Ab
Tel: + 358 201 558 840
United Kingdom
SWEDISH ORPHAN INTERNATIONAL LTD
Tel: + 44 1638 722380
Lietuva
Oy SWEDISH ORPHAN Ab
Tel: + 358 201 558 840
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
47
PACKAGE LEAFLET: INFORMATION FOR THE USER
Ferriprox 1000 mg film-coated tablets
Deferiprone
Read all of this leaflet carefully before you start taking this medicine.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or pharmacist.
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
If you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Attached to this leaflet you will find a patient/carer reminder card. You should detach,
complete, read the card carefully and carry it with you.
In this leaflet:
1. What Ferriprox is and what it is used for
2. Before you take Ferriprox
3. How to take Ferriprox
4. Possible side effects
5. How to store Ferriprox
6. Further information
1. WHAT FERRIPROX IS AND WHAT IT IS USED FOR
Ferriprox contains the active substance deferiprone. Ferriprox is a medicine that removes iron from the
body.
Ferriprox is used to treat iron overload caused by frequent blood transfusions in patients with
thalassaemia major when deferoxamine therapy is contraindicated or inadequate.
2. BEFORE YOU TAKE FERRIPROX
Do not take Ferriprox
if you are allergic (hypersensitive) to deferiprone or any of the other ingredients of Ferriprox.
if you have a history of repeated episodes of neutropenia (low white blood cell (neutrophil)
count).
if you have a history of agranulocytosis (very low white blood cell (neutrophil) count).
if you are currently taking medicines known to cause neutropenia or agranulocytosis (see
“Taking other medicines”).
if you are pregnant or breastfeeding.
Take special care with Ferriprox
the most serious side effect that may occur while taking Ferriprox is a very low white blood cell
(neutrophil) count. This condition, known as severe neutropenia or agranulocytosis, has
occurred in 1 to 2 out of 100 people who have taken Ferriprox in clinical studies. Because white
blood cells help to fight infection, a low neutrophil count may place you at risk of developing a
serious and potentially life-threatening infection. To monitor for neutropenia, your doctor will
ask you to have a blood test (to check your white blood cell count) performed regularly, as
frequently as every week, while you are being treated with Ferriprox. It is very important for
you to keep all of these appointments. Please refer to the patient/carer reminder card attached to
this leaflet. Report immediately to your doctor any symptoms of infection such as fever, sore
throat or flu-like symptoms.
if you are HIV positive or if your kidney and liver function is impaired, your doctor may
recommend additional tests.
48
Your doctor will also ask you to come in for tests to monitor body iron load. In addition he or she also
might ask you to undergo liver biopsies.
Taking other medicines
Do not take medicines known to cause neutropenia or agranulocytosis (see “Do not take Ferriprox”).
Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Do not take aluminium-based antacids while taking Ferriprox.
Please consult with your doctor or pharmacist before taking vitamin C with Ferriprox.
Pregnancy and breastfeeding
Do not take this medicine if you are pregnant or if you are trying to become pregnant. This medicine
could seriously harm your baby. You must use effective contraception while you are taking Ferriprox.
Ask your doctor which method is best for you. If you become pregnant while taking Ferriprox, stop
taking the medicine immediately and tell your doctor.
Do not use Ferriprox if you are breast-feeding. Please refer to the patient/carer reminder card attached
to this leaflet.
Driving and using machines
Not relevant.
3. HOW TO TAKE FERRIPROX
Always take Ferriprox exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure. The amount of Ferriprox that you take will depend on your weight. The
usual dose is 25 mg/kg, 3 times per day, for a total daily dose of 75 mg/kg/day. The total daily dose
should not exceed 100 mg/kg/day. Take your first dose in the morning. Take your second dose
midday. Take your third dose in the evening. Ferriprox can be taken with or without food; however,
you may find it easier to remember to take Ferriprox if you take it with your meals.
If you take more Ferriprox than you should
There are no reports of acute overdose with Ferriprox. If you have accidentally taken more than the
prescribed dose, you should contact your doctor.
If you forget to take Ferriprox
Ferriprox will be most effective if you do not miss any doses. If you do miss one dose take it as soon
as you remember and take your next dose at its regularly scheduled time. If you miss more than one
dose do not take a double dose to make up for forgotten individual doses, just continue with your
normal schedule. Do not change your daily dose without first talking to your doctor.
4. POSSIBLE SIDE EFFECTS
Like all medicines, Ferriprox can have side effects, although not everybody gets them.
The most serious side effect of Ferriprox is a very low white blood cell (neutrophil) count. This
condition, known as severe neutropenia or agranulocytosis, has occurred in 1 to 2 out of 100 people
who have taken Ferriprox in clinical studies. A low white blood cell count can be associated with a
serious and potentially life-threatening infection. Report immediately to your doctor any symptoms of
infection such as: fever, sore throat or flu-like symptoms.
49
Very common side effects
(affects more than 1 user in 10):
-
abdominal pain
-
nausea
-
vomiting
-
reddish/brown discolouration of urine
If you experience nausea or vomiting, it may help to take your Ferriprox with some food. Discoloured
urine is a very common effect and is not harmful.
Common side effects
(affects 1 to 10 users in 100):
-
low white blood cell count (agranulocytosis and neutropenia)
-
headache
-
diarrhoea
-
increase in liver enzymes
-
fatigue
-
increase in appetite
Events of joint pain and swelling ranged from mild pain in one or more joints to severe disability. In
most cases, the pain disappeared while patients continued taking Ferriprox.
In post-marketing experience with Ferriprox, neurological disorders (such as tremors, walking
disorders, double vision, involuntary muscle contractions, problems with movement coordination)
have been reported in children who had been voluntarily prescribed more than double the maximum
recommended dose of 100 mg/kg/day for several years. They recovered from these symptoms after
Ferriprox discontinuation.
If you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
5. HOW TO STORE FERRIPROX
Keep out of the reach and sight of children.
Do not use Ferriprox after the expiry date which is stated on the carton and the label after EXP.
Do not store above 30ºC.
For the bottle: Keep the bottle tightly closed in order to protect from moisture. After first opening use
within 50 days.
For the blister: Store in the original package in order to protect from moisture.
6. FURTHER INFORMATION
What Ferriprox contains
The active substance is deferiprone.
Each 1000 mg tablet contains 1000 mg deferiprone.
Tablet core: Methylcellulose, crospovidone, magnesium stearate.
Coating: Hypromellose, hydroxypropyl cellulose, macrogol, titanium dioxide.
What Ferriprox looks like and contents of the pack
Ferriprox 1000 mg tablets are white to off-white, capsule-shaped, film-coated tablets imprinted “APO”
bisect “1000” on one side, plain on the other. The tablets are scored and breakable in half. Ferriprox is
packaged in bottles of 50 tablets, bottles of 100 tablets, and blister packs of 50 tablets.
50
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Apotex Europe B.V.
2333 CR Leiden
Netherlands
Manufacturing Authorisation Holder:
Apotex Nederland B.V.
Bio Science Park
Archimedesweg 2
2333 CN Leiden
Netherlands
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
SWEDISH ORPHAN INTERNATIONAL SARL
Tél/Tel: + 33 1 41 92 18 01
Luxembourg/Luxemburg
SWEDISH ORPHAN INTERNATIONAL SARL
Tél/Tel: + 33 1 41 92 18 01
България
ТП „Торекс Киези Фарма”
Тел.: +359 2 920 12 05
Magyarország
Torrex Chiesi Hungária Kereskedelmi Kft.
Tel.: + 36-1-429 1060
Česká republika
Apotex CR
Tel: +00420 234 705 700
Malta
Swedish Orphan International s.r.l.
Tel: + 39 0521 19111
Danmark
SWEDISH ORPHAN A/S
Tlf: + 45 32 96 68 69
Nederland
SWEDISH ORPHAN INTERNATIONAL LTD
Tel: +44 1638 72 23 80
Deutschland
SWEDISH ORPHAN INTERNATIONAL GmbH
Tel: +49 6103 20 26 90
Norge
SWEDISH ORPHAN AS
Tlf: + 47 66 82 34 00
Eesti
Oy SWEDISH ORPHAN Ab
Tel: +358 201 558 840
Österreich
SWEDISH ORPHAN INTERNATIONAL GmbH
Tel: +49 6103 20 26 90
Ελλά
DEMO ABEE
Τηλ: + 30 210 8161802
Polska
Apotex Inc. Korporacja
Przedstawicielstwo w Polsce
Tel.: + 48 22 812 10 02
España
Swedish Orphan International Spain S.L.
Tel: + 34 913 91 35 80
Portugal
SWEDISH ORPHAN INTERNATIONAL AB
Tel: + 351 21 383 08 91
France
Swedish Orphan International SARL
Tél: + 33 1 41 92 18 01
România
Torrex Chiesi Pharma GmbH
Tel: + 40 729 995 020
Ireland
SWEDISH ORPHAN INTERNATIONAL LTD
Tel: + 44 1638 72 23 80
Slovenija
Torrex Chiesi Slovenija, d.o.o.
Tel: + 386-1-43 00 901
51
Darwinweg 20
Ísland
SWEDISH ORPHAN A/S
Sími: + 45 32 96 68 69
Slovenská republika
Torrex Chiesi Slovakia, s.r.o.
Tel: + 421-2-59 30 00 60
Italia
Chiesi Farmaceutici S.p.A
Tel: + 39 0521 2791
Suomi/Finland
Oy SWEDISH ORPHAN Ab
Puh/Tel: + 358 201 558 840
Κύπρς
The Star Medicines Importers Co. Ltd.
Τηλ: + 357 25 371056
Sverige
SWEDISH ORPHAN AB
Tel: + 46 8 412 98 00
Latvija
Oy SWEDISH ORPHAN Ab
Tel: + 358 201 558 840
United Kingdom
SWEDISH ORPHAN INTERNATIONAL LTD
Tel: + 44 1638 722380
Lietuva
Oy SWEDISH ORPHAN Ab
Tel: + 358 201 558 840
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
52
PATIENT/CARER REMINDER CARD
((Front Cover))
((Back cover))
Important Safety Reminders for Patients
taking Ferriprox (deferiprone)
Do not take Ferriprox if you are pregnant or if
you are trying to become pregnant. If taken
during pregnancy, Ferriprox may seriously harm
the unborn baby.
Prescribing
doctor:________________________
You must use effective contraception while you
are taking Ferriprox. Ask your doctor which
method is best for you. If you become pregnant
while taking Ferriprox, stop taking the medicine
immediately and tell your doctor. Do not take
Ferriprox if you are breast-feeding.
Phone
No:_______________________________
((Inside 1))
((Inside 2))
MONITORING YOUR WHITE BLOOD
CELL COUNT WITH FERRIPROX
Make sure you do the following:
There is a small chance that you may develop
agranulocytosis (very low white blood cell
count) while taking Ferriprox, which may lead
to a serious infection. Even though
agranulocytosis only affects 1 to 2 out of 100
users, it is important to monitor your blood on
a regular basis.
1. Have your blood monitored on a weekly
basis.
2. Contact your doctor immediately if you
develop a fever, sore throat or flu-like
symptoms
53
FOR WOMEN OF CHILD BEARING AGE
Source: European Medicines Agency
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