Deferiprone DOC 500 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Produktens egenskaper Produktens egenskaper (SPC)

20-04-2018

Aktiva substanser:
deferipron
Tillgänglig från:
DOC Generici Srl,
ATC-kod:
V03AC02
INN (International namn):
deferiprone
Dos:
500 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
deferipron 500 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 100 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
55996
Tillstånd datum:
2018-02-05

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Deferiprone DOC 500 mg film-coated tablets.

Deferiprone DOC 1000 mg film-coated tablets.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Deferiprone DOC 500 mg film-coated tablets

Each tablet contains 500 mg deferiprone.

Deferiprone DOC 1000 mg film-coated tablets

Each tablet contains 1000 mg deferiprone.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet.

Deferiprone DOC 500 mg film-coated tablets

White to off-white film coated tablets, debossed with ‘DL 500’ with a score line on one side and plain on the

other and with dimensions of 14.2 mm x 8.2 mm. The tablet can be divided into equal halves.

Deferiprone DOC 1000 mg film-coated tablets

White to off-white film coated tablets, debossed with ‘DH 1000’ with a score line on one side and plain on

the other and with dimensions of 19.2 mm x 9.2 mm. The tablet can be divided into equal halves.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Deferiprone DOC monotherapy is indicated for the treatment of iron overload in patients with thalassaemia

major when current chelation therapy is contraindicated or inadequate.

Deferiprone DOC in combination with another chelator (see section 4.4) is indicated in patients with

thalassaemia major when monotherapy with any iron chelator is ineffective, or when prevention or treatment

of life-threatening consequences of iron overload (mainly cardiac overload) justifies rapid or intensive

correction (see section 4.2).

4.2

Posology and method of administration

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 tables

below for recommended doses for body weights at 10 kg increments.

To obtain a dose of about 75 mg/kg/day, use the number of tablets suggested in the following tables for the

body weight of the patient. Sample body weights at 10 kg increments are listed.

Dose table for Deferiprone DOC 500 mg film-coated tablets

Body weight

(kg)

Total daily dose

(mg)

Dose

(mg, three times/day)

Number of tablets

(three times/day)

1500

2250

3000

1000

3750

1250

4500

1500

5250

1750

6000

2000

6750

2250

Dose table for Deferiprone DOC 1000 mg film-coated tablets

Bodyweight

(kg)

Total daily dose

(mg)

Number of 1000 mg tablets*

Morning

Midday

Evening

1500

2250

3000

3750

4500

5250

6000

6750

*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).

Dose adjustment

The effect of Deferiprone DOC in decreasing the body iron is directly influenced by the dose and the degree

iron

overload.

After

starting

Deferiprone

therapy,

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 falls

below 500 μg/l.

Dose adjustments when used with other iron chelators

In patients for whom monotherapy is inadequate, Deferiprone DOC may be used with deferoxamine at the

standard dose (75 mg/kg/day) but should not exceed 100 mg/kg/day.

In the case of iron-induced heart failure, Deferiprone DOC at 75-100 mg/kg/day should be added to

deferoxamine therapy. The product information of deferoxamine should be consulted.

Concurrent use of iron chelators is not recommended in patients whose serum ferritin falls below 500 µg/l

due to the risk of excessive iron removal.

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.

Renal impairment

Dose adjustment is not required in patients with mild, moderate, or severe renal impairment (see section 5.2).

The safety and pharmacokinetics of deferiprone in patients with end stage renal disease are unknown.

Hepatic impairment

Dose adjustment is not required in patients with mildly or moderately impaired hepatic function (see section

5.2). The safety and pharmacokinetics of deferiprone in patients with severe hepatic impairment are

unknown.

Method of administration

For oral use.

4.3

Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- History of recurrent episodes of neutropenia.

- History of agranulocytosis.

- Pregnancy (see section 4.6).

- Breast-feeding (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).

4.4

Special warnings and precautions for use

Neutropenia/Agranulocytosis

Deferiprone has been shown to cause neutropenia, including agranulocytosis (see section 4.8

‘Description of selected adverse reactions’). The patient’s absolute neutrophil count (ANC) should

be monitored every week

during the first year of therapy. For patients whose

Deferiprone DOC

has not been interrupted during the first year of therapy due to any decrease in the neutrophil

count, the frequency of ANC monitoring may be extended to the patient’s blood transfusion

interval (every 2-4 weeks) after one year of deferiprone therapy.

The change from weekly ANC monitoring to at the time of transfusion visits after 12 months of

Deferiprone DOC therapy, should be considered on an individual patient basis, according to the

physician’s assessment of the patient’s understanding of the risk minimization measures required during

therapy (see section 4.4 below).

In clinical trials, weekly monitoring of the neutrophil count has been effective in identifying cases of

neutropenia and agranulocytosis. Agranulocytosis and neutropenia usually resolve upon discontinuation

of Deferiprone DOC, but fatal cases of agranulocytosis have been reported. If the patient develops an

infection while on deferiprone, therapy should be

immediately interrupted, and an ANC obtained

without delay. The neutrophil count should be then monitored more frequently.

Patients should be aware to contact their physician if they experience any symptoms indicative of

infection (such as fever, sore throat and flu-like symptoms).

Immediately interrupt deferiprone if

the patient experience infection.

Suggested

management

cases

neutropenia

outlined

below.

recommended

that

such

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 ANC is less than 1.5x10

For neutropenia

events (ANC < 1.5x109/l and > 0.5x10

/l):

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

event

then

repeat

daily.

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.

For agranulocytosis (ANC < 0.5x10

/l):

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

concentration

Monitoring of plasma Zn

concentration, and supplementation in case of a deficiency, is recommended.

HIV positive or other immunocompromised patients

No data are available on the use of deferiprone in HIV positive or in other immunocompromised patients.

Given

that

deferiprone

associated

with

neutropenia

agranulocytosis,

therapy

immunocompromised 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 end stage renal disease or severe

hepatic impairment (see section 5.2). Caution must be exercised in patients with end stage renal disease or

severe hepatic dysfunction. Renal and hepatic function should be monitored in these patient populations

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.

Neurological disorders

Neurological disorders have been observed in children treated with more than 2.5 times the maximum

recommended dose for several years but have also been observed with standard doses of deferiprone.

Prescribers are reminded that the use of doses above 100 mg/kg/day are not recommended.

Deferiprone use should be discontinued if neurological disorders are observed (see sections 4.8 and

4.9).

Combined use with other iron chelators

The use of combination therapy should be considered on a case-by-case basis. The response to therapy

should be assessed periodically, and the occurrence of adverse events closely monitored. Fatalities and

life-

threatening situations (caused by agranulocytosis) have been reported with deferiprone in combination with

deferoxamine. Combination therapy with deferoxamine is not recommended when monotherapy with either

chelator is adequate or when serum ferritin falls below 500 µg/l. Limited data

are available on the

combined use of deferiprone and deferasirox, and caution should be applied when considering the use of

such combination.

4.5

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).

Since deferiprone binds to metallic cations, the potential exists for interactions between deferiprone and

trivalent

cation-dependent

medicinal

products

such

aluminium-based

antacids.

Therefore,

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

Fertility, pregnancy and lactation

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).

4.7

Effects on ability to drive and use machines

Not relevant.

4.8

Undesirable effects

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 10

/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).

SYSTEM ORGAN CLASS

VERY COMMON

(≥1/10)

COMMON

(≥1/100 to <1/10)

FREQUENCY NOT

KNOWN

Blood and lymphatic system

disorders

Neutropenia

Agranulocytosis

Immune system disorders

Hypersensitivity

reactions

Metabolism

nutrition

disorders

Increased Appetite

Nervous system disorders

Headache

Gastrointestinal disorders

Nausea

Abdominal Pain

Vomiting

Diarrhoea

Skin and subcutaneous tissue

disorders

Rash

Urticaria

Musculoskeletal and

connective tissue disorders

Arthralgia

Renal and urinary disorders

Chromaturia

General disorders and

administration site conditions

Fatigue

Investigations

Increased liver

enzymes

Description of selected adverse reactions

The most serious adverse reaction reported in clinical trials with deferiprone is agranulocytosis (neutrophils

<0.5x10

/l), with an incidence of 1.1% (0.6 cases per 100 patient-years of treatment) (see section 4.4). Data

from pooled clinical studies in patients with systemic iron overload show that 63% of the episodes of

agranulocytosis occurred within the first six months of treatment, 74% within the first year and 26% after

one year of therapy. The median time to onset of the first episode of agranulocytosis was 190 days (ranged

22 days- 17.6 years) and median duration was 10 days in clinical trials. A fatal outcome was observed in

8.3% of the reported episodes of agranulocytosis from clinical trials and post-marketing experience.

The observed incidence of the less severe form of neutropenia (neutrophils <1.5x10

/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. Episodes of

hypotonia, instability, inability to walk, and hypertonia with inability of limb movement, have been reported

in children in the post-marketing setting with standard doses of deferiprone. The neurological disorders

progressively regressed after deferiprone discontinuation (see sections 4.4 and 4.9).

The safety profile of combination therapy (deferiprone and deferoxamine) observed in clinical trials post-

marketing experience or published literature was consistent with that characterized for monotherapy.

Data from the pooled safety database from clinical trials (1343 patient-years exposure to deferiprone

monotherapy

patient-years

exposure

deferiprone

deferoxamine)

showed

statistically

significant (p<0.05) differences in the incidence of adverse reactions based on System Organ Class for

“Cardiac disorders", "Musculoskeletal and connective tissue disorders” and "Renal and urinary disorders".

The incidences of “Musculoskeletal and connective tissue disorders” and "Renal and urinary disorders" were

lower during combination therapy than monotherapy, whereas the incidence of “Cardiac disorders" was

higher during combination therapy than monotherapy. The higher rate of “Cardiac disorders" reported during

combination therapy than monotherapy was possibly due to the higher incidence of pre-existing cardiac

disorders in patients who received combination therapy.

Careful monitoring of cardiac events in patients on combination therapy is warranted (see section 4.4).

The incidences of adverse reactions experienced by 18 children and 97 adults treated with combination

therapy were not significantly different between the two age groups except in the incidence of arthropathy

(11.1% in children vs. none in adults, p=0.02). Evaluation of rate of reactions per 100 patient-years of

exposure showed that only the rate of diarrhoea was significantly higher in children (11.1) than in adults

(2.0, p=0.01).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked

to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9

Overdose

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

children

been

voluntarily

prescribed

more

than

times

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.

PHARMACOLOGICAL PROPERTIES

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

iron in a 3:1 molar ratio.

Pharmacodynamic effects

Clinical studies have demonstrated that deferiprone 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. Data from the published literature on iron

balance studies in patients with thalassaemia major show that the use of deferiprone concurrently with

deferoxamine (coadministration of both chelators during the same day, either simultaneously or sequentially,

e.g., deferiprone during the day and deferoxamine during the night), promotes greater iron

excretion than

either drug alone. Doses of deferiprone in those studies ranged from 50 to 100 mg/kg/day and doses of

deferoxamine from 40 to 60 mg/kg/day. 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 thalassaemia 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 thalassaemia

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 deferiprone

(average dose 92 mg/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; p=0.003).

Study LA12-9907 compared survival, incidence of cardiac disease, and progression of cardiac disease in 129

patients with thalassaemia 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).

Data from the published literature are consistent with the results from the innovator’s studies, demonstrating

less heart disease and/or increased survival in deferiprone-treated patients than in those treated with

deferoxamine.

A randomized, placebo-controlled, double-blind trial evaluated the effect of concurrent therapy with

deferiprone and deferoxamine in patients with thalassaemia major, who previously received the standard

chelation monotherapy with subcutaneous deferoxamine and had mild to moderate cardiac iron loading

(myocardial T2* from 8 to 20 ms). Following randomization, 32 patients received deferoxamine (34.9

mg/kg/day for 5 days/week) and deferiprone (75 mg/kg/day) and 33 patients received deferoxamine

monotherapy (43.4 mg/kg/day for 5 days/week). After one year of study therapy, patients on concurrent

chelation therapy had experienced a significantly greater reduction in

serum ferritin (1574 µg/l to 598 µg/l

with concurrent therapy vs. 1379 µg/l to 1146 µg/l with deferoxamine monotherapy, p<0.001), significantly

greater reduction in myocardial iron overload, as

assessed by an increase in MRI T2* (11.7 ms to 17.7 ms

with concurrent therapy vs. 12.4 ms to 15.7 ms with deferoxamine monotherapy, p=0.02) and significantly

greater reduction in liver iron concentration, also assessed by an increase in MRI T2* (4.9 ms to 10.7 ms with

concurrent therapy vs. 4.2 ms to 5.0 ms with deferoxamine monotherapy, p< 0.001).

Study LA37-1111 was conducted to evaluate the effect of single therapeutic (33 mg/kg) and

supratherapeutic (50 mg/kg) oral doses of deferiprone on the cardiac QT interval duration in healthy

subjects. The maximum difference between the LS means of the therapeutic dose and placebo was 3.01

msec (95% one-sided UCL: 5.01 msec), and between the LS means of the supratherapeutic dose and

placebo was 5.23 msec (95% one-sided UCL: 7.19 msec). Deferiprone was concluded to produce no

significant prolongation of the QT interval.

5.2

Pharmacokinetic properties

Absorption

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 25 mg/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.

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.

Renal impairment

An open-label, non-randomized, parallel group clinical study was conducted to evaluate the effect of

impaired renal function on the safety, tolerability, and pharmacokinetics of a single 33 mg/kg oral dose of

deferiprone. Subjects were categorized into 4 groups based on estimated glomerular filtration rate (eGFR):

healthy volunteers (eGFR ≥ 90 mL/min/1.73m

), mild renal impairment (eGFR 60-89 mL/min/1.73m

moderate renal impairment (eGFR 30–59 mL/min/1.73m

), and severe renal impairment (eGFR 15–29

mL/min/1.73m

). Systemic exposure to deferiprone and to its metabolite deferiprone 3-

O

-glucuronide was

assessed by the PK parameters C

and AUC.

Regardless of the degree of renal impairment, the majority of the dose of deferiprone was excreted in the

urine over the first 24 hours as deferiprone 3-

O

-glucuronide. No significant effect of renal impairment was

seen on systemic exposure to deferiprone. Systemic exposure to the inactive 3-

O

-glucuronide increased with

decreasing eGFR. Based on the results of this study, no adjustment of the deferiprone dosage regimen is

required in patients with impaired renal function. The safety and pharmacokinetics of deferiprone in patients

with end stage renal disease is unknown.

Hepatic impairment

An open-label, non-randomized, parallel group clinical study was conducted to evaluate the effect of

impaired hepatic function on the safety, tolerability, and pharmacokinetics of a single 33 mg/kg oral dose of

deferiprone. Subjects were categorized into 3 groups based on the Child-Pugh classification score: healthy

volunteers, mild hepatic impairment (Class A: 5– 6 points), and moderate hepatic impairment (Class B: 7– 9

points). Systemic exposure to deferiprone and to its metabolite deferiprone 3-

O

-glucuronide was assessed by

the PK parameters C

and AUC. Deferiprone AUCs did not differ between treatment groups, but C

decreased by 20% in mildly or moderately hepatically impaired subjects compared with healthy volunteers.

Deferiprone-3-

O

-glucuronide AUC was decreased by 10% and C

by 20% in mildly and moderately

impaired subjects compared with healthy volunteers. A serious adverse event of acute liver and renal injury

was seen in one subject with moderate hepatic impairment. Based on the results of this study, no adjustment

of the deferiprone dosage regimen is required in patients with mildly or moderately impaired hepatic

function.

The influence of severe hepatic impairment on the pharmacokinetics of deferiprone and deferiprone 3-

O

glucuronide has not been evaluated. The safety and pharmacokinetics of deferiprone in patients with severe

hepatic impairment is unknown.

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

in vivo

tests. Deferiprone did not show direct mutagenic

properties; however, it did display clastogenic characteristics in

in vitro

assays and 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.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core

(Maize) starch pregelatinised

Magnesium stearate

Coating

Hypromellose

Hydroxypropylcellulose

Titanium dioxide

Macrogol

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

5 years.

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container

500 mg tablets are supplied in white PVC/PE/PVDC/Aluminium blister packs of 100 tablets.

1000 mg tablets are supplied in white PVC/PE/PVDC/Aluminium blister packs of 50 tablets.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements.

7.

MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8.

MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: {DD month YYYY}

Date of latest renewal: {DD month YYYY}

[To be completed nationally]

10.

DATE OF REVISION OF THE TEXT

12 November 2020

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