DEFERIPRONE 500 MG FILM-COATED TABLETS
Active substance(s): DEFERIPRONE
NAME OF THE MEDICINAL PRODUCT
Deferiprone 500 mg Film-coated Tablets
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 500mg deferiprone.
For the full list of excipients, see section 6.1.
White to off-white, film-coated tablets, with a score line on one side and plain
on the other.
The tablet can be divided into equal doses.
Deferiprone is indicated for the treatment of iron overload in patients with
thalassaemia major when deferoxamine therapy is contraindicated or
Posology and method of administration
Deferiprone therapy should be initiated and maintained by a physician
experienced in the treatment of patients with thalassaemia.
Deferiprone is usually given as 25mg/kg body weight, orally, three times a day
for a total daily dose of 75mg/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 10kg increments.
To obtain a dose of about 75mg/kg/day, use the number of tablets suggested in
the following table for the body weight of the patient. Sample body weights at
10kg increments are listed.
Total daily dose
Dose (mg, three
A total daily dose above 100mg/kg body weight is not recommended because
of the potentially increased risk of adverse reactions (see sections 4.4, 4.8, and
The effect of deferiprone in decreasing the body iron is directly influenced by
the dose and the degree of iron overload. After starting deferiprone 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 500μg/l.
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
Method of administration
For oral use.
- Hypersensitivity to the active substance or to any of the excipients listed in
- 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).
Special warnings and precautions for use
Deferiprone has been shown to cause neutropenia, including
agranulocytosis. The patient's neutrophil count should be monitored
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 1.5x109/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.
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.
In view of the genotoxicity results, a carcinogenic potential of deferiprone
cannot be excluded (see section 5.3).
Plasma Zn2+ concentration
Monitoring of plasma Zn2+ 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 100mg/kg/day are not recommended (see sections 4.8
Interaction with other medicinal products and other forms of interaction
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
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.
Fertility, pregnancy and lactation
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).
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).
No effects on fertility or early embryonic development were noted in animals
(see section 5.3).
Effects on ability to drive and use machines
Summary of the safety profile
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 109/l, which occurred in
approximately 1% of patients. Less severe episodes of neutropenia were
reported in approximately 5% of patients.
Tabulated list of adverse reactions
Adverse reaction frequencies: Very common (≥1/10), Common (≥1/100 to
<1/10), not known (cannot be estimated from the available data).
Renal and urinary
Description of selected adverse reactions
The most serious adverse reaction reported in clinical trials with deferiprone is
agranulocytosis (neutrophils <0.5x109/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 <1.5x109/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 100mg/kg/day for several
years. The neurological disorders progressively regressed after deferiprone
discontinuation (see sections 4.4 and 4.9).
Reporting of adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk
balance of the medicinal product. Healthcare professionals are asked to report
any suspected adverse reactions via the Yellow Card Scheme website:
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 100mg/kg/day for several years. The
neurological disorders progressively regressed after deferiprone
In case of overdose, close clinical supervision of the patient is required.
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.
Clinical studies have demonstrated that deferiprone is effective in promoting
iron excretion and that a dose of 25mg/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
deferiprone with that of deferoxamine in controlling serum ferritin in
transfusion-dependent thalassemia patients. Deferiprone 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 deferiprone 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
43mg/kg/day; N=31) or to switch to deferiprone (average dose 92mg/kg/day
N=29). Over the 12-month duration of the study, deferiprone 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 deferiprone
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 deferiprone group and by 0.32 ± 3.38
absolute units (%) in the deferoxamine group (difference between groups;
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 deferiprone (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 deferiprone 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%) deferiprone-treated
patients who were cardiac disease-free at the first assessment (p=0.013).
Overall, fewer deferiprone-treated patients than deferoxamine-treated patients
showed a worsening of cardiac dysfunction from first assessment to last
assessment (4% vs. 20%, p=0.007).
Deferiprone is rapidly absorbed from the upper part of the gastrointestinal
tract. Peak serum concentration occurs 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 25mg/kg, lower peak serum concentrations have been
detected in patients in the fed state (85 μmol/l) than in the fasting state (126
μmol/l), although there was no decrease in the amount of deferiprone absorbed
when it was given with food.
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.
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 irondeferiprone complex. A variable amount of elimination via the faeces has been
reported. The elimination half-life in most patients is 2 to 3 hours.
Preclinical safety data
Non-clinical studies have been conducted in animal species including mice,
rats, rabbits, dogs and monkeys.
The most common finding in non-iron-loaded animals at doses of
100mg/kg/day and above were hematologic effects such as bone marrow
hypocellularity, and decreased WBC, RBC and/or platelet counts in peripheral
Atrophy of the thymus, lymphoid tissues, and testis, and hypertrophy of the
adrenals, were reported at doses of 100mg/kg/day or greater in non-ironloaded 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 noniron-loaded pregnant rats and rabbits at doses at least as low as 25mg/kg/day.
No effects on fertility or early embryonic development were noted in non-ironloaded male and female rats that received deferiprone orally at doses of up to
75mg/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
No prenatal and postnatal reproductive studies have been conducted in
List of excipients
(Maize) starch, pregelatinised (partially)
For the HDPE bottle: Once opened use within 70 days.
For the blister strips: Half tablets to be used within 48 hours of removal from
Special precautions for storage
This medicinal product does not require any special storage conditions.
Nature and contents of container
PVC/PE/PVdC/Aluminium blisters containing 100 tablets.
High density polyethylene (HDPE) bottle, with a plastic child resistant cap,
containing 100 tablets.
Not all pack presentations and pack sizes may be marketed.
Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in
accordance with local requirements.
MARKETING AUTHORISATION HOLDER
Focus Pharmaceuticals Ltd
85 King William Street,
EC4N 7BL, UK
MARKETING AUTHORISATION NUMBER(S)
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
DATE OF REVISION OF THE TEXT