4.1. Therapeutic indications

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

Deferiprone Lipomed 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 Lipomed 500 mg film-coated tablets

Body weight

(kg)

Total daily dose

(mg)

Dose

(mg, three times/day)

Number of tablets

(three times/day)

20

1 500

500

1.0

30

2 250

750

1.5

40

3 000

1 000

2.0

50

3 750

1 250

2.5

60

4 500

1 500

3.0

70

5 250

1 750

3.5

80

6 000

2 000

4.0

90

6 750

2 250

4.5

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

Dose adjustment

The effect of Deferiprone Lipomed in decreasing the body iron is directly influenced by the dose and the degree of iron overload. After starting Deferiprone Lipomed 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 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 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 Lipomed 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 (see section 4.4).

Special populations

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 Lipomed 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 Lipomed in patients with severe hepatic impairment are unknown.

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).

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 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 monitoring at the time of transfusion visits after 12 months of deferiprone 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, 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 then be 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 experiences infection.

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 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 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.

For agranulocytosis (ANC < 0.5 x 109/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 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 (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 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 in 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.

Discolouration of urine

Patients should be informed that their urine may show a reddish/brown discolouration 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 is 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.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet and that is to say essentially 'sodium-free'.

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 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

Women of childbearing potential/contraception in men and women

Due to the genotoxic potential of deferiprone (see section 5.3), women of childbearing potential are recommended to use effective contraceptive measures and avoid becoming pregnant while being treated 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 while receiving Deferiprone Lipomed and for 3 months following completion of treatment.

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.

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

Breast-feeding

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

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

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

The adverse reactions are listed below by system organ class (SOC) and by frequency, with the following 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 be estimated from the available data).

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

System organ class

Very common

Common

Frequency not known

Blood and lymphatic system disorders

Agranulocytosis

Neutropenia

Immune system disorders

Hypersensitivity reactions

Metabolism and nutrition disorders

Increased appetite

Nervous system disorders

Headache

Gastrointestinal disorders

Vomiting

Nausea

Abdominal pain

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 <0.5 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 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 <1.5 x 109/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 characterised for monotherapy.

Data from the pooled safety database from clinical trials (1 343 patient-years exposure to deferiprone monotherapy and 244 patient-years exposure to deferiprone and 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).

Paediatric population

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 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.