DEFERIPRONE LIPOMED 500mg tablets medication leaflet

Deferiprone Lipomed 500 mg film-coated tablets

Each film-coated tablet contains 500 mg deferiprone.

For the full list of excipients, see section 6.1.

Film-coated tablet.

White to off-white, glossy surface, oval film-coated tablet. The tablet is 8.2 mm x 17.2 mm x 6.7 mmand scored. The tablet can be divided into equal doses.

Deferiprone Lipomed monotherapy is indicated for the treatment of iron overload in patients withthalassaemia major when current chelation therapy is contraindicated or inadequate.

Deferiprone Lipomed in combination with another chelator (see section 4.4) is indicated in patientswith thalassaemia major when monotherapy with any iron chelator is ineffective, or when preventionor treatment of life-threatening consequences of iron overload (mainly cardiac overload) justifies rapidor intensive correction (see section 4.2).

Deferiprone therapy should be initiated and maintained by a physician experienced in the treatment ofpatients with thalassaemia.

Deferiprone is usually given as 25 mg/kg body weight, orally, three times a day for a total daily doseof 75 mg/kg body weight. Dose per kilogram body weight should be calculated to the nearest halftablet. 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 tablesfor the body weight of the patient. Sample body weights at 10 kg increments are listed.

Dose table for Deferiprone Lipomed 500 mg film-coated tablets

Body weight Total daily dose Dose Number of tablets(kg) (mg) (mg, three times/day) (three times/day)20 1 500 500 1.030 2 250 750 1.540 3 000 1 000 2.050 3 750 1 250 2.560 4 500 1 500 3.070 5 250 1 750 3.580 6 000 2 000 4.090 6 750 2 250 4.5

A total daily dose above 100 mg/kg body weight is not recommended because of the potentiallyincreased risk of adverse reactions (see sections 4.4, pct. 4.8, and 4.9).

The effect of Deferiprone Lipomed in decreasing the body iron is directly influenced by the dose andthe degree of iron overload. After starting Deferiprone Lipomed therapy, it is recommended that serumferritin concentrations, or other indicators of body iron load, be monitored every two to three monthsto assess the long-term effectiveness of the chelation regimen in controlling the body iron load. Doseadjustments should be tailored to the individual patient’s response and therapeutic goals (maintenanceor reduction of body iron burden). Interruption of therapy with deferiprone should be considered ifserum ferritin falls below 500 µg/l.

Dose adjustments when used with other iron chelators

In patients for whom monotherapy is inadequate, Deferiprone Lipomed may be used withdeferoxamine 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 Lipomed at 75-100 mg/kg/day should be addedto deferoxamine therapy. The product information of deferoxamine should be consulted.

Concurrent use of iron chelators is not recommended in patients whose serum ferritin falls below500 µg/l due to the risk of excessive iron removal (see section 4.4).

Dose adjustment is not required in patients with mild, moderate, or severe renal impairment (seesection 5.2). The safety and pharmacokinetics of Deferiprone Lipomed in patients with end stage renaldisease are unknown.

Dose adjustment is not required in patients with mildly or moderately impaired hepatic function (seesection 5.2). The safety and pharmacokinetics of Deferiprone Lipomed in patients with severe hepaticimpairment are unknown.

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.

For oral use.

* 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 takemedicinal products known to be associated with neutropenia or those that can causeagranulocytosis (see section 4.5).

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 deferipronehas not been interrupted during the first year of therapy due to any decrease in the neutrophilcount, the frequency of ANC monitoring may be extended to the patient’s blood transfusioninterval (every 2 - 4 weeks) after one year of deferiprone therapy.

The change from weekly ANC monitoring, to monitoring at the time of transfusion visits after12 months of deferiprone therapy should be considered on an individual patient basis, according to thephysician’s assessment of the patient’s understanding of the risk minimization measures requiredduring therapy (see section 4.4 below).

In clinical trials, weekly monitoring of the neutrophil count has been effective in identifying cases ofneutropenia and agranulocytosis. Agranulocytosis and neutropenia usually resolve upondiscontinuation of deferiprone, but fatal cases of agranulocytosis have been reported. If the patientdevelops an infection while on deferiprone, therapy should be immediately interrupted, and an ANCobtained without delay. The neutrophil count should then be monitored more frequently.

Patients should be aware to contact their physician if they experience any symptoms indicativeof infection (such as fever, sore throat and flu-like symptoms). Immediately interruptdeferiprone if the patient experiences infection.

Suggested management of cases of neutropenia is outlined below. It is recommended that such amanagement 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 ofagranulocytosis and neutropenia is higher if the baseline ANC is less than 1.5 x 109/l.

For neutropenia events (ANC < 1.5 x 109/l and > 0.5 x 109/l)

Instruct the patient to immediately discontinue deferiprone and all other medicinal products with apotential to cause neutropenia. The patient should be advised to limit contact with other individuals inorder to reduce the risk of infection. Obtain a complete blood cell (CBC) count, with a white bloodcell (WBC) count, corrected for the presence of nucleated red blood cells, a neutrophil count, and aplatelet count immediately upon diagnosing the event and then repeat daily. It is recommended thatfollowing recovery from neutropenia, weekly CBC, WBC, neutrophil and platelet counts continue tobe obtained for three consecutive weeks, to ensure that the patient recovers fully. Should any evidenceof infection develop concurrently with the neutropenia, the appropriate cultures and diagnosticprocedures should be performed and an appropriate therapeutic regimen instituted.

For agranulocytosis (ANC < 0.5 x 109/l)

Follow the guidelines above and administer appropriate therapy such as granulocyte colonystimulating factor, beginning the same day that the event is identified; administer daily until thecondition resolves. Provide protective isolation and if clinically indicated, admit patient to the hospital.

Limited information is available regarding re-challenge. Therefore, in the event of neutropenia, re-challenge is not recommended. In the event of agranulocytosis, re-challenge is contraindicated.

Carcinogenicity/mutagenicity

In view of the genotoxicity results, a carcinogenic potential of deferiprone cannot be excluded (seesection 5.3).

Plasma Zn2+ concentration

Monitoring of plasma Zn2+ concentration, and supplementation in case of a deficiency, isrecommended.

HIV positive or other immunocompromised patients

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

Given that deferiprone can be associated with neutropenia and agranulocytosis, therapy inimmunocompromised patients should not be initiated unless potential benefits outweigh potentialrisks.

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 severehepatic impairment (see section 5.2). Caution must be exercised in patients with end stage renaldisease or severe hepatic dysfunction. Renal and hepatic function should be monitored in these patientpopulations during deferiprone therapy. If there is a persistent increase in serum alanineaminotransferase (ALT), interruption of deferiprone therapy should be considered.

In thalassaemia patients there is an association between liver fibrosis and iron overload and/orhepatitis C. Special care must be taken to ensure that iron chelation in patients with hepatitis C isoptimal. In these patients careful monitoring of liver histology is recommended.

Discolouration of urine

Patients should be informed that their urine may show a reddish/brown discolouration due to theexcretion of the iron-deferiprone complex.

Neurological disorders

Neurological disorders have been observed in children treated with more than 2.5 times the maximumrecommended 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 is not recommended. Deferiproneuse 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 therapyshould be assessed periodically, and the occurrence of adverse events closely monitored. Fatalities andlife-threatening situations (caused by agranulocytosis) have been reported with deferiprone incombination with deferoxamine. Combination therapy with deferoxamine is not recommended whenmonotherapy with either chelator is adequate or when serum ferritin falls below 500 µg/l. Limited dataare available on the combined use of deferiprone and deferasirox, and caution should be applied whenconsidering the use of such combination.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet and that is to sayessentially ‘sodium-free’.

Due to the unknown mechanism of deferiprone-induced neutropenia, patients must not take medicinalproducts known to be associated with neutropenia or those that can cause agranulocytosis (see section4.3).

Since deferiprone binds to metallic cations, the potential exists for interactions between deferiproneand trivalent cation-dependent medicinal products such as aluminium-based antacids. Therefore, it isnot 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 thereported adverse interaction that can occur between deferoxamine and vitamin C, caution should beused when administering deferiprone and vitamin C concurrently.

Women of childbearing potential/contraception in men and women

Due to the genotoxic potential of deferiprone (see section 5.3), women of childbearing potential arerecommended to use effective contraceptive measures and avoid becoming pregnant while beingtreated with Deferiprone Lipomed and for 6 months following the completion of treatment.

Men are recommended to use effective contraceptive measures and to not father a child whilereceiving Deferiprone Lipomed and for 3 months following completion of treatment.

There are no adequate data from the use of deferiprone in pregnant women. Studies in animals haveshown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Pregnant women must be advised to immediately stop taking deferiprone (see section 4.3).

It is not known whether deferiprone is excreted in human milk. No prenatal and postnatal reproductivestudies have been conducted in animals. Deferiprone must not be used by breast-feeding mothers. Iftreatment 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).

This medicinal product has no or negligible influence on the ability to drive and use machinery.

The most common adverse reactions reported during therapy with deferiprone in clinical trials werenausea, vomiting, abdominal pain, and chromaturia, which were reported in more than 10% ofpatients. The most serious adverse reaction reported in clinical trials with deferiprone wasagranulocytosis, defined as an absolute neutrophil count less than 0.5 x 109/l, which occurred inapproximately 1% of patients. Less severe episodes of neutropenia were reported in approximately 5%of patients.

The adverse reactions are listed below by system organ class (SOC) and by frequency, with thefollowing frequency grouping: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon(≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot beestimated from the available data).

Within each frequency grouping, adverse reactions are presented in the order of decreasingseriousness.

System organ class Very common Common Frequency notknown

Blood and lymphatic system Agranulocytosisdisorders Neutropenia

Immune system disorders Hypersensitivityreactions

Metabolism and nutrition Increased appetitedisorders

Nervous system disorders Headache

Gastrointestinal disorders Vomiting Diarrhoea

Nausea

Abdominal pain

Skin and subcutaneous tissue Rashdisorders Urticaria

Musculoskeletal and Arthralgiaconnective tissue disorders

Renal and urinary disorders Chromaturia

General disorders and Fatigueadministration site conditions

Investigations Increased liverenzymes

The most serious adverse reaction reported in clinical trials with deferiprone is agranulocytosis(neutrophils <0.5 x 109/l), with an incidence of 1.1% (0.6 cases per 100 patient-years of treatment)(see section 4.4). Data from pooled clinical trials in patients with systemic iron overload show that63% of the episodes of agranulocytosis occurred within the first six months of treatment, 74% withinthe first year and 26% after one year of therapy. The median time to onset of the first episode ofagranulocytosis was 190 days (ranged 22 days- 17.6 years) and median duration was 10 days inclinical trials. A fatal outcome was observed in 8.3% of the reported episodes of agranulocytosis fromclinical trials and post-marketing experience.

The observed incidence of the less severe form of neutropenia (neutrophils <1.5 x 109/l) is 4.9% (2.5cases per 100 patient-years). This rate should be considered in the context of the underlying elevatedincidence of neutropenia in thalassaemia patients, particularly in those with hypersplenism.

Episodes of diarrhoea, mostly mild and transient, have been reported in patients treated withdeferiprone. Gastrointestinal effects are more frequent at the beginning of therapy and resolve in mostpatients within a few weeks without the discontinuation of treatment. In some patients it may bebeneficial to reduce the dose of deferiprone and then scale it back up to the former dose. Arthropathyevents, which ranged from mild pain in one or more joints to severe arthritis with effusion andsignificant disability, have also been reported in patients treated with deferiprone. Mild arthropathiesare generally transient.

Increased levels of serum liver enzymes have been reported in some patients taking deferiprone. In themajority of these patients, the increase was asymptomatic and transient, and returned to baselinewithout discontinuation or decreasing the dose of deferiprone (see section 4.4).

Some patients experienced progression of fibrosis associated with an increase in iron overload orhepatitis C.

Low plasma zinc levels have been associated with deferiprone in a minority of patients. The levelsnormalised with oral zinc supplementation.

Neurological disorders (such as cerebellar symptoms, diplopia, lateral nystagmus, psychomotorslowdown, hand movements and axial hypotonia) have been observed in children who had beenvoluntarily prescribed more than 2.5 times the maximum recommended dose of 100 mg/kg/day forseveral years. Episodes of hypotonia, instability, inability to walk, and hypertonia with inability oflimb movement have been reported in children in the post-marketing setting with standard doses ofdeferiprone. The neurological disorders progressively regressed after deferiprone discontinuation (seesections 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 characterised formonotherapy.

Data from the pooled safety database from clinical trials (1 343 patient-years exposure to deferipronemonotherapy and 244 patient-years exposure to deferiprone and deferoxamine) showed statisticallysignificant (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 urinarydisorders”. The incidences of “Musculoskeletal and connective tissue disorders” and “Renal andurinary disorders” were lower during combination therapy than monotherapy, whereas the incidenceof “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 thehigher 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 combinationtherapy were not significantly different between the two age groups except in the incidence ofarthropathy (11.1% in children vs. none in adults, p=0.02). Evaluation of rate of reactions per100 patient-years of exposure showed that only the rate of diarrhoea was significantly higher inchildren (11.1) than in adults (2.0, p=0.01).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No cases of acute overdose have been reported. However, neurological disorders (such as cerebellarsymptoms, diplopia, lateral nystagmus, psychomotor slowdown, hand movements and axialhypotonia) have been observed in children who had been voluntarily prescribed more than 2.5 timesthe maximum recommended dose of 100 mg/kg/day for several years. The neurological disordersprogressively regressed after deferiprone discontinuation.

In case of overdose, close clinical supervision of the patient is required.

Pharmacotherapeutic group: All other therapeutic products, iron chelating agents, ATCcode: V03AC02

The active substance is deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), a bidentate ligand whichbinds iron in a 3:1 molar ratio.

Clinical trials have demonstrated that deferiprone is effective in promoting iron excretion and that adose of 25 mg/kg three times per day can prevent the progression of iron accumulation as assessed byserum ferritin, in patients with transfusion-dependent thalassaemia. Data from the published literatureon iron balance studies in patients with thalassaemia major show that the use of deferiproneconcurrently with deferoxamine (co-administration of both chelators during the same day, eithersimultaneously or sequentially, e.g., deferiprone during the day and deferoxamine during the night),promotes greater iron excretion than either medicinal product alone. Doses of deferiprone in thosestudies 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.

Studies LA16-0102, LA-01 and LA08-9701 compared the efficacy of deferiprone with that ofdeferoxamine in controlling serum ferritin in transfusion-dependent thalassaemia patients. Deferiproneand 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 proportionof patients with a negative trend in serum ferritin between the two treatment groups by regressionanalysis; 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 ironreduces myocardial MRI T2* values. Myocardial MRI T2* values of less than 20 ms represent ironoverload in the heart. An increase in MRI T2* on treatment indicates that iron is being removed fromthe 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 decreasingcardiac 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 withdeferoxamine, were randomized to continue deferoxamine (average dose 43 mg/kg/day; N=31) or toswitch 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 improvementin cardiac T2* of more than 3 ms in patients treated with deferiprone compared with a change of about1 ms in patients treated with deferoxamine. At the same time point, LVEF had increased from baselineby 3.07 ± 3.58 absolute units (%) in the deferiprone group and by 0.32 ± 3.38 absolute units (%) in thedeferoxamine group (difference between groups; p=0.003).

Study LA12-9907 compared survival, incidence of cardiac disease, and progression of cardiac diseasein 129 patients with thalassaemia major treated for at least 4 years with deferiprone (N=54) ordeferoxamine (N=75). Cardiac endpoints were assessed by echocardiogram, electrocardiogram, the

New York Heart Association classification and death due to cardiac disease. There was no significantdifference in percentage of patients with cardiac dysfunction at first assessment (13% for deferipronevs. 16% for deferoxamine). Of patients with cardiac dysfunction at first assessment, none treated withdeferiprone 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-treatedpatients and in 2 (4.3%) deferiprone-treated patients who were cardiac disease-free at the firstassessment (p=0.013). Overall, fewer deferiprone-treated patients than deferoxamine-treated patientsshowed 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 studies, demonstrating lessheart disease and/or increased survival in deferiprone-treated patients than in those treated withdeferoxamine.

A randomized, placebo-controlled, double-blind trial evaluated the effect of concurrent therapy withdeferiprone and deferoxamine in patients with thalassaemia major, who previously received thestandard chelation monotherapy with subcutaneous deferoxamine and had mild to moderate cardiaciron loading (myocardial T2* from 8 to 20 ms). Following randomization, 32 patients receiveddeferoxamine (34.9 mg/kg/day for 5 days/week) and deferiprone (75 mg/kg/day) and 33 patientsreceived deferoxamine monotherapy (43.4 mg/kg/day for 5 days/week). After one year of studytherapy, patients on concurrent chelation therapy had experienced a significantly greater reduction inserum ferritin (1 574 μg/l to 598 μg/l with concurrent therapy vs. 1 379 μg/l to 1 146 μg/l withdeferoxamine monotherapy, p<0.001), significantly greater reduction in myocardial iron overload, asassessed by an increase in MRI T2* (11.7 ms to 17.7 ms with concurrent therapy vs. 12.4 ms to15.7 ms with deferoxamine monotherapy, p=0.02) and significantly greater reduction in liver ironconcentration, 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) andsupratherapeutic (50 mg/kg) oral doses of deferiprone on the cardiac QT interval duration in healthysubjects. The maximum difference between the least square (LS) means of the therapeutic dose andplacebo was 3.01 ms (95% one-sided upper confidence limit (UCL): 5.01 ms), and between the LSmeans of the supratherapeutic dose and placebo was 5.23 ms (95% one-sided UCL: 7.19 ms).

Deferiprone was concluded to produce no significant prolongation of the QT interval.

Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract. Peak serumconcentration occurs 45 to 60 minutes following a single dose in fasted patients. This may be extendedto 2 hours in fed patients.

Following a dose of 25 mg/kg, lower peak serum concentrations have been detected in patients in thefed state (85 µmol/l) than in the fasting state (126 µmol/l), although there was no decrease in theamount 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 serumconcentrations 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 isreported as being recovered in the urine in the first 24 hours, in the form of free deferiprone, theglucuronide metabolite and the iron-deferiprone complex. A variable amount of elimination via thefaeces has been reported. The elimination half-life in most patients is 2 to 3 hours.

An open-label, non-randomized, parallel group clinical study was conducted to evaluate the effect ofimpaired renal function on the safety, tolerability, and pharmacokinetics of a single 33 mg/kg oraldose of deferiprone. Subjects were categorized into 4 groups based on estimated glomerular filtrationrate (eGFR): healthy volunteers (eGFR ≥ 90 mL/min/1.73m2), mild renal impairment (eGFR60-89 mL/min/1.73m2), moderate renal impairment (eGFR 30-59 mL/min/1.73m2), and severe renalimpairment (eGFR 15-29 mL/min/1.73m2). Systemic exposure to deferiprone and to its metabolitedeferiprone 3-O-glucuronide was assessed by the pharmacokinetic (PK) parameters maximumconcentration (Cmax) and area under the curve (AUC).

Regardless of the degree of renal impairment, the majority of the dose of deferiprone was excreted inthe urine over the first 24 hours as deferiprone 3-O-glucuronide. No significant effect of renalimpairment 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 thedeferiprone dose regimen is required in patients with impaired renal function. The safety andpharmacokinetics of deferiprone in patients with end stage renal disease is unknown.

An open-label, non-randomized, parallel group clinical study was conducted to evaluate the effect ofimpaired hepatic function on the safety, tolerability, and pharmacokinetics of a single 33 mg/kg oraldose of deferiprone. Subjects were categorized into 3 groups based on the Child-Pugh classificationscore: healthy volunteers, mild hepatic impairment (Class A: 5- 6 points), and moderate hepaticimpairment (Class B: 7- 9 points). Systemic exposure to deferiprone and to its metabolite deferiprone3-O-glucuronide was assessed by the PK parameters Cmax and AUC. Deferiprone AUCs did not differbetween treatment groups, but Cmax was decreased by 20% in mildly or moderately hepaticallyimpaired subjects compared with healthy volunteers. Deferiprone-3-O-glucuronide AUC wasdecreased by 10% and Cmax by 20% in mildly and moderately impaired subjects compared withhealthy volunteers. A serious adverse event of acute liver and renal injury was seen in one subject withmoderate hepatic impairment. Based on the results of this study, no adjustment of the deferiprone doseregimen is required in patients with mildly or moderately impaired hepatic function.

The influence of severe hepatic impairment on the pharmacokinetics of deferiprone and deferiprone3-O-glucuronide has not been evaluated. The safety and pharmacokinetics of deferiprone in patientswith severe hepatic impairment is unknown.

Non-clinical studies have been conducted in animal species including mice, rats, rabbits, dogs andmonkeys.

The most common findings in non-iron-loaded animals at doses of 100 mg/kg/day and above werehematologic effects such as bone marrow hypocellularity, and decreased WBC, red blood cell (RBC)and/or platelet counts in peripheral blood.

Atrophy of the thymus, lymphoid tissues, and testis, and hypertrophy of the adrenals, were reported atdoses of 100 mg/kg/day or greater in non-iron-loaded animals.

No carcinogenicity studies in animals have been conducted with deferiprone. The genotoxic potentialof deferiprone was evaluated in a set of in vitro and in vivo tests. Deferiprone did not show directmutagenic properties; however, it did display clastogenic characteristics in in vitro assays and inanimals.

Deferiprone was teratogenic and embryotoxic in reproductive studies in non-iron-loaded pregnant ratsand rabbits at doses at least as low as 25 mg/kg/day. No effects on fertility or early embryonicdevelopment were noted in non-iron-loaded male and female rats that received deferiprone orally atdoses of up to 75 mg/kg twice daily for 28 days (males) or 2 weeks (females) prior to mating and untiltermination (males) or through early gestation (females). In females, an effect on the oestrous cycledelayed time to confirmed mating at all doses tested.

No prenatal and postnatal reproductive studies have been conducted in animals.

Hypromellose

Croscarmellose sodium

Silica, colloidal anhydrous

Microcrystalline cellulose

Magnesium stearate

Hypromellose

Macrogol 6 000

Titanium dioxide

Not applicable.

5 years.

Do not store above 25°C.

Aluminium/PVC-PVDC blisters in cartons of 100 film-coated tablets.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Lipomed GmbH

Hegenheimer Strasse 279576 Weil am Rhein

Germany

Phone number: +49 7621 1693 472

Fax number: +49 7621 1693 474

Electronic mail: lipomed@lipomed.com

EU/1/18/1310/001

Date of first authorisation: 20 September 2018

Date of latest renewal:

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.