SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Deferiprone 1000 mg Film-coated Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains 1000mg deferiprone.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet.

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.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Deferiprone is indicated for the treatment of iron overload in patients with thalassaemia major when deferoxamine therapy is contraindicated or inadequate.

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 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.

Body weight	Total daily dose	Number of 1000 mg tablets		*
(kg)	(mg)	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 100mg/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 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 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.

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)

-    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)

4.4    Special warnings and precautions for use

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 1.5x 10⁹/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.

Carcinogenicity/mutagenicity

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

Plasma Zn²+ concentration

2+

Monitoring of plasma Zn 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 and 4.9).

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).

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.

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 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).

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 and 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 <0.5x10⁹/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 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 Yellow Card Scheme website: www.mhra.gov.uk/yellowcard.

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 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.

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 to 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 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; 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 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).

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 25mg/kg, lower peak serum concentrations have been detected in patients in the fed state (85pmol/l) than in the fasting state (126pmol/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.

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 100mg/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 100mg/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 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-iron-loaded 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 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 (partially)

Magnesium stearate

Film coating

Hypromellose

Hydroxypropylcellulose

Titanium dioxide

Macrogol 6000

Incompatibilities

Not applicable

6.3    Shelf life

30 months

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 the blister.

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5    Nature and contents of container

PVC/PE/PVdC/Aluminium blisters containing 50 tablets.

High density polyethylene (HDPE) bottle, with a plastic child resistant cap, containing 50 or 100 tablets.

Not all pack presentations and pack sizes may be marketed.

6.6    Special precautions for disposal

Any unused medicinal product or waster material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Focus Pharmaceuticals Ltd Capital House,

85 King William Street,

London

EC4N 7BL, UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 20046/0280

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

15/04/2016

10    DATE OF REVISION OF THE TEXT

15/04/2016