Consumer medicine information

Ferriprox 500 mg Tablets

CMI for 500 mg Tablets

Deferiprone

BRAND INFORMATION

Brand name

Ferriprox

Active ingredient

Deferiprone

Schedule

What is in this leaflet

This leaflet answers some common questions about Ferriprox. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

if there is anything you do not understand in this leaflet,
if you are worried about taking your medicine, or
to obtain the most up-to-date information.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

If you have concerns about taking Ferriprox, ask your doctor.

Keep this leaflet with your medicine. You may want to read it again.

What Ferriprox is used for

Ferriprox contains the active ingredient deferiprone and is used for the treatment of iron overload in patients with thalassaemia major who are unable to take desferrioxamine or in whom desferrioxamine therapy has proven ineffective.

Ferriprox is a medicine that removes iron from the body.

In a disease such as thalassaemia major, there is accumulation of iron in the body in those patients who are dependent on blood transfusions. If not removed, the iron levels can reach a serious level in the body as a result of the accumulation. By removing the excess iron from the body, Ferriprox can reduce the serious effects of iron overload.

Ask your doctor if you have any questions about why Ferriprox has been prescribed for you. Your doctor may have prescribed this medicine for another use.

Ferriprox is not addictive.

This medicine is available only with a doctor's prescription.

Before you take this medicine

When you must not take it

Do not take Ferriprox if you or your child:

have a history of hypersensitivity (an allergy) to deferiprone or any of the other ingredients listed at the end of this leaflet. Signs of allergic reactions may include itchy skin, rash, shortness of breath and swelling of the face or tongue.
have a history of repeated episodes of neutropenia (low white blood cell count).
have a history of agranulocytosis (very low white blood cell count <0.5x10⁹/L).

Do not take this medication if you are breast-feeding, if you are pregnant, or if you are trying to become pregnant. This medication could seriously harm your baby. You must use effective contraception while you are taking deferiprone.

Ask your doctor which method is best for you. If you become pregnant while taking Ferriprox, stop taking the medicine immediately and tell your doctor.

Do not take Ferriprox if the packaging is torn or seems to have been opened.

Do not take Ferriprox after the expiry date printed on the bottle.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you are pregnant or intend to become pregnant or breast-feeding.

Tell your doctor if you have any of the following medical conditions:

hepatitis
HIV
liver or kidney disease
problems with your immune system.

Taking other medicines

Tell your doctor or pharmacist about all other medications that you are taking, even ones that you can buy without a prescription.

Do not take vitamin C or antacids containing aluminium at the same time as Ferriprox.

Do not take medicines which can cause neutropenia or agranulocytosis at the same time as Ferriprox. Your doctor can advise you on this and tell you which medicines you can safely take with Ferriprox.

How to take this medicine

It is important to follow the directions that your doctor has given to you.

How much to take

How much of Ferriprox that you take will depend on your weight. The usual dose of Ferriprox is three (3) times per day. Your doctor will advise you on how much to take.

Do not take more than the dose your doctor has recommended.

When to take it

Take your first dose in the morning. Take your second dose midday. Take your third dose in the evening.

You do not have to take this medicine with food. However, you may find it easier to remember to take your medicine, if you take it with your meals. If you experience nausea or vomiting, it may help to take your Ferriprox with some food.

How long to take it for

Do not stop taking Ferriprox unless your doctor tells you to.

If Ferriprox has been successfully reducing the levels of iron in your body, stopping Ferriprox will cause the iron levels in your body to rise again and the risk of problems with excess body iron may return.

If you forget to take it

Ferriprox will be most effective if you do not miss any doses.

If you forget to take a dose of Ferriprox, leave out that dose completely. Take your next dose at the normal time it is due.

Do not take a double dose to make up for missed doses.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Australia: 13 11 26 or New Zealand: 0800 POISON or 0800 764766) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Make sure that all of your doctors and pharmacists know about your use of Ferriprox. Remind them if any new medicines are about to be started.

Be sure to keep all of your doctor’s appointments so your progress can be checked.

Your doctor will ask you to come in for tests to monitor body iron load. As a precaution, your doctor may have your blood, liver and kidney tested regularly during treatment with Ferriprox. Some blood tests may be done as often as once a week to avoid side effects.

In addition, he or she also might ask you to undergo liver biopsies.

Things you must not do

Do not use Ferriprox to treat any complaint other than that directed by your doctor. It may not be safe to use Ferriprox for another complaint.

Do not give Ferriprox to someone else even if their symptoms are the same. It may not be safe for another person to use Ferriprox.

Things to be careful of

Ferriprox should not affect your ability to drive or use machinery. However, be careful driving, operating machinery or doing jobs that require you to be alert until you know how this medicine affects you.

Possible side effects

Tell your doctor as soon as possible if you feel unwell while you are taking Ferriprox. Like all medicines, Ferriprox may have some side effects. Most side effects are mild and patients often find that these wear off after a few weeks.

Your urine may become a reddish/brown colour. This is the most common side effect of Ferriprox and it is not harmful.

Tell your doctor immediately if you notice any symptoms of infection such as fever, sore throat or flu-like symptoms. The most serious side effect of deferiprone is the occurrence of a very low white blood cell count. This condition, known as severe neutropenia or agranulocytosis, has occurred in about 1.0% of people who have taken deferiprone in clinical studies. Because white blood cells help to fight infection, a low white blood cell count may place you at risk of developing a serious infection. If an infection of this nature is not discovered and treated early, it could cause death.

Tell your doctor if you notice any of the following:

joint pain and swelling
abdominal pain
diarrhoea
nausea
vomiting
increase in appetite
headache.

These effects generally disappear after a few days to a few weeks of continued treatment.

If these events persist, you should consult your doctor.

Neurological disorders (such as tremors, walking disorders, double vision, involuntary muscle contractions, problems with movement coordination) have been reported in children who had been voluntarily prescribed more than double the maximum recommended dose of 100 mg/kg/day for several months and have also been observed in children with standard doses of deferiprone. The children recovered from these symptoms after Ferriprox discontinuation.

Other side effects not listed above may also occur in some patients.

Tell your doctor if you notice anything else that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Storage and disposal

Storage

Keep Ferriprox 500 mg tablets in their bottle until it is time to take your dose. If you take them out of their container, they may not keep well.
Keep Ferriprox 500 mg tablets in a cool dry place where the temperature stays below 25°C.
Do not store it or any other medicine in the bathroom or near a sink. Do not leave it in the car. Heat, cold and dampness can destroy some medicines.
Keep Ferriprox where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

Return any unused medicine to your pharmacist.

Product description

What Ferriprox 500 mg Tablets look like

Ferriprox 500 mg tablets are white to off-white, capsule-shaped, film-coated, scored and imprinted “APO” bisect “500” on one side, and plain on the other side. The tablets are breakable in half.

Ingredients

Each tablet contains 500 mg of deferiprone as the active ingredient.

It also contains the following inactive ingredients:

microcrystalline cellulose
magnesium stearate
silicon dioxide
hypromellose
macrogol 3350
titanium dioxide.

Australian Registration Numbers

Ferriprox 500 mg tablets (bottle): AUST R 93946.

Sponsor

In Australia:

Chiesi Australia Pty Ltd
Suite 3, 22 Gillman Street
Hawthorn East, VIC 3123

In New Zealand:

Chiesi New Zealand Ltd
Bellingham Wallace Ltd
Suite 1, 470 Parnell Road
Parnell
Auckland 1052

Distributed in New Zealand by:

Healthcare Logistics
58 Richard Pearse Drive
Airport Oaks
Mangere
Auckland 2022

Email: [email protected]
Website: www.chiesi.com.au

This leaflet was last updated in
July 2022.

Published by MIMS October 2022

BRAND INFORMATION

Brand name

Ferriprox

Active ingredient

Deferiprone

Schedule

1 Name of Medicine

Deferiprone.

2 Qualitative and Quantitative Composition

Ferriprox 500 mg film-coated tablet.

Each film-coated tablet contains 500 mg deferiprone as the active ingredient.

Ferriprox 1000 mg film-coated tablet.

Each film-coated tablet contains 1000 mg deferiprone as the active ingredient.

Ferriprox 100 mg/mL oral solution.

Each mL of oral solution contains 100 mg deferiprone as the active substance. The 250 mL bottle contains a total dose of 25 g of deferiprone and the 500 mL bottle contains a total dose of 50 g of deferiprone.

Excipients with known effect.

Sucralose (oral solution only).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

500 mg film-coated tablet.

Ferriprox tablets are white to off white, capsule-shaped, film-coated, scored and imprinted "APO" bisect "500" on one side, and plain on the other side. The tablets are breakable in half.

1000 mg film-coated tablet.

Ferriprox tablets are white to off-white, capsule-shaped, film-coated, scored and imprinted "APO" bisect "1000" on one side, and plain on the other side. The tablets are breakable in half.

100 mg/mL oral solution.

Ferriprox oral solution is a clear, reddish orange solution with a peppermint and cherry-flavoured aroma.

4 Clinical Particulars

4.1 Therapeutic Indications

Ferriprox is indicated for the treatment of iron overload in patients with thalassaemia major who are unable to take desferrioxamine or in whom desferrioxamine therapy has proven ineffective.

4.2 Dose and Method of Administration

Method of administration.

For oral administration.
Therapy with Ferriprox should be initiated and maintained by a physician experienced in the treatment of patients with transfusional haemosiderosis.

Dosage.

The effect of Ferriprox in decreasing the body iron is influenced by the dose and degree of iron overload. Ferriprox is given as 25 mg/kg to 33 mg/kg body weight, orally, three times a day for a total daily dose of 75 mg/kg to 100 mg/kg body weight. The recommended initial total daily dose of Ferriprox is 75 mg/kg body weight. After starting Ferriprox 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 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 Ferriprox therapy should be considered if serum ferritin falls below 500 microgram/L.
Doses above 100 mg/kg/day are not recommended because of the limited experience with these higher doses of Ferriprox.
Dosage per kilogram body weight should be calculated to the nearest half tablet or to the nearest 2.5 mL. See dosage tables.

Dosage tables for 75 mg/kg/day.

To obtain a dose of about 75 mg/kg/day, use the dose suggested in Tables 1, 2 and 3 for the body weight of the patient.

Dosage tables for 100 mg/kg/day.

To obtain a dose of about 100 mg/kg/day, use the dose suggested in Tables 4, 5 and 6 for the body weight of the patient.

Due to the nature of the serious adverse events which can occur with the use of Ferriprox, special monitoring is required for all patients. Treatment with Ferriprox should not be initiated if the baseline absolute neutrophil count (ANC) is low. Caution must be used when treating patients with renal insufficiency or hepatic dysfunction (see Section 4.4 Special Warnings and Precautions for Use).

Dosage adjustment in renal and hepatic impairment.

Currently there are no available data in patients with renal impairment and limited data on the use of Ferriprox in patients with hepatic impairment. Caution must be used when treating patients with renal insufficiency or hepatic dysfunction (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Ferriprox is contraindicated in patients who:
have demonstrated hypersensitivity to the active substance or any of the excipients;
have a history of recurrent episodes of neutropenia;
have a history of agranulocytosis;
are pregnant or breastfeeding.

4.4 Special Warnings and Precautions for Use

Neutropenia/ agranulocytosis.

Ferriprox has been shown to cause neutropenia, including agranulocytosis, which may lead to the development of a serious and potentially life-threatening infection. It is recommended that a patient's neutrophil count be monitored every week.
The most serious adverse event of therapy reported in clinical trials with Ferriprox is agranulocytosis (absolute neutrophil count < 0.5 x 10⁹/L) with an incidence of 1.9% (0.9 cases per 100 patient years of treatment). The observed incidence of the less severe form of neutropenia (absolute neutrophil count < 1.5 x 10⁹/L but > 0.5 x 10⁹/L) is 6.4% (3.6 cases per 100 patient years). This rate should be considered in context of the underlying elevated incidence of neutropenia in thalassaemia patients, particularly in those with hypersplenism.
Based on clinical trials, it is recommended that the absolute neutrophil count be monitored weekly to enable prompt detection of neutropenia and agranulocytosis. In the event of neutropenia or agranulocytosis, Ferriprox treatment should be stopped (see below for guidelines on re-initiating treatment).
If the patient develops an infection, Ferriprox therapy should be interrupted and the absolute neutrophil count should be monitored more frequently. Patients should be advised to report immediately to their physician any symptoms indicative of infection such as: fever, sore throat or flu-like symptoms.
Suggested management for cases of neutropenia is outlined below. It is recommended that such a management protocol be in place prior to initiating any patient on Ferriprox treatment.
Treatment with Ferriprox should not be initiated if the patient is neutropenic.

In the event of neutropenia.

Instruct the patient to immediately discontinue Ferriprox and all other medications with a potential to cause medicinal product associated neutropenia. The patient should be advised to limit contact with other individuals in order to reduce the risk of potential infection. Obtain a complete blood cell count immediately upon diagnosing the event and then repeat daily. It is recommended that following recovery of the absolute neutrophil count, weekly complete blood cell count continue to be obtained for three consecutive weeks, to ensure that the patient recovers fully. Should any evidence of infection develop concurrent with the neutropenia, the appropriate cultures and diagnostic procedures should be performed and an appropriate antibiotic 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 absolute neutrophil count recovers. Provide protective isolation and if clinically indicated, admit patient to hospital.
Limited data are available regarding rechallenge. Therefore in the event of neutropenia rechallenge is not recommended. In the event of agranulocytosis a rechallenge is contraindicated.

HIV positive or other immune compromised patients.

No data are available on the use of Ferriprox in HIV positive or in other immune compromised patients. Given that Ferriprox is associated with neutropenia and agranulocytosis, therapy in immune compromised patients should not be initiated unless potential benefits outweigh potential risks.

Allergic reactions.

Ferriprox oral solution contains the colouring agent sunset yellow FCF which may cause allergic reactions.

QT prolongation.

No significant inhibition of hERG K⁺ channels was seen at deferiprone concentrations up to 3,000 microM, and no effect on QT interval or other cardiovascular and electrocardiographic parameters were noted in iron loaded and non-iron loaded monkeys that received deferiprone for up to 12 months. However, the tested concentrations and doses were low, limiting the predictive value of negative findings. One episode of Torsade de pointes during therapy with Ferriprox was observed in a patient with a history of QT prolongation. Ferriprox should be administered with caution to patients who may be at increased risk of prolongation of the cardiac QT interval (e.g. those with congestive heart failure, bradycardia, use of a diuretic, cardiac hypertrophy, hypokalemia or hypomagnesemia). Any patient taking Ferriprox who experiences symptoms suggestive of an arrhythmia (such as palpitations, dizziness, lightheadedness, syncope, or seizures) should seek medical attention immediately.

Discolouration of urine.

Patients should be informed that a reddish/brown discolouration of the urine is commonly associated with Ferriprox use; the discolouration is due to the excretion of the iron-Ferriprox complex, which is a chromophore.

Neurological disorders.

Neurological disorders have been observed in children treated with more than 2.5 times the maximum recommended dose for several months but have also been observed with standard doses of deferiprone in patients with mild or normal iron load. Prescribers are reminded that the dose should be adjusted to the severity of the iron load and that the use of doses above 100 mg/kg/day is not recommended. Deferiprone use should be discontinued if neurological disorders are observed (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.9 Overdose).

Use in hepatic impairment.

There are limited data on the safety and efficacy of Ferriprox in patients with hepatic impairment. Ferriprox is metabolised by the liver and therefore caution should be exercised in such patients and hepatic function should be monitored.
In thalassaemia patients there is an association between liver fibrosis and 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.
Ferriprox has been associated with hepatotoxicity (increased ALT) in some patients. If there is a persistent increase in serum ALT, interruption of Ferriprox therapy should be considered.

Use in renal impairment.

Currently, there are no available data in patients with renal impairment. Since Ferriprox and its metabolites are excreted by the kidney, there may be an increased risk of complications in patients with impaired renal function. Caution must be used when treating patients with renal impairment.

Use in the elderly.

Currently, there are no available data in elderly patients.

Paediatric use.

The safety and efficacy of Ferriprox for paediatric use was evaluated in 220 children aged 1 to 15 years with transfusion dependent anaemias. The data show that Ferriprox was effective in decreasing body iron load as measured by serum ferritin concentrations and it was not associated with new health concerns in this patient population. The effects of Ferriprox on growth are unknown.

Effects on laboratory tests.

Serum ferritin concentrations.

It is recommended that serum ferritin concentrations be monitored regularly (every two to three months) to assess the long-term effectiveness of the chelation regimen in controlling the body iron load. Interruption of therapy with Ferriprox should be considered if serum ferritin measurements fall below 500 microgram/L.

Plasma Zn²⁺.

Monitoring of plasma Zn²⁺, and supplementation in case of a deficiency is recommended.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Due to the unknown mechanism of Ferriprox induced neutropenia, patients should not take medicinal products known to be associated with neutropenia or those that can cause agranulocytosis.
Interactions between Ferriprox and other medicinal products have not been reported. However, since this compound binds to some metallic cations, the potential exists for interactions between Ferriprox and trivalent cation dependent medicinal products such as aluminium based antacids. Therefore, it is not recommended to concomitantly ingest aluminium based antacids with Ferriprox.
The safety of concurrent use of Ferriprox and vitamin C has not been formally studied. Based on the reported adverse interaction that can occur between desferrioxamine and vitamin C, caution should be used when administering concurrent Ferriprox and vitamin C.
Studies in vitro and in animals suggest that Ferriprox does not increase the risk of opportunistic Yersinia infections in iron overload conditions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No effect on fertility or early embryonic development, and no effect on reproductive performance were noted in naive (non-iron loaded) male and female rats that received deferiprone orally at 75 mg/kg twice daily (0.3 times the clinical dose based on body surface area) for 28 days (males) or 2 weeks (females) prior to mating and until termination (males) or through early gestation (females).
Atrophy of the testis was reported at oral doses of greater than or equal to 400 mg/kg/day in non-iron loaded dogs, corresponding to about 3 times the recommended initial human dose of 75 mg/kg/day, based on body surface area.
(Category D)
Reproductive studies in non-iron loaded rats and rabbits have indicated that Ferriprox is teratogenic and embryotoxic at doses corresponding to human equivalent doses (on a body surface area basis) considerably below the recommended daily dose in patients.
Women of childbearing potential should be advised to avoid pregnancy due to the potential mutagenic, clastogenic and teratogenic properties identified in preclinical studies with Ferriprox. Women should be counselled to take contraceptive measures and should be advised to immediately stop taking Ferriprox should they become pregnant or plan to become pregnant.
There is no relevant data on the use of Ferriprox in nursing mothers. No perinatal/postnatal reproductive studies have been conducted in animals. Ferriprox should not be used in nursing mothers.

4.7 Effects on Ability to Drive and Use Machines

There is no evidence that Ferriprox affects the ability of patients to drive or use machines.

4.8 Adverse Effects (Undesirable Effects)

Adverse effect information for Ferriprox represents the pooled data collected from 590 subjects with chronic iron overload secondary to transfusion dependent anemias, primarily subjects with thalassaemia major, who participated in single arm or active controlled clinical studies. (See Table 7.)
Gastrointestinal effects are more frequent at the beginning of therapy with Ferriprox and most resolve within a few weeks without the discontinuation of treatment. In some patients it may be beneficial to reduce the dose of Ferriprox and then scale it back up to 25 mg/kg three times per day.
Arthropathy events ranged from mild pain in one or more joints to severe arthritis with effusion and significant disability. Mild arthropathies are generally transient.
Increased ALT levels have been reported in some patients taking Ferriprox. This increase, which occurred most frequently during the first 3 months of therapy, was generally mild, and resolved either without discontinuation or after decreasing the dosage of Ferriprox in the majority of patients.
Some patients experienced progression of liver fibrosis associated with an increase in iron overload 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.
Low plasma zinc levels have been associated with Ferriprox, 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 months. 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 Section 4.4 Special Warnings and Precautions for Use; Section 4.9 Overdose).

Postmarketing experience.

The following adverse experiences have been reported in patients receiving Ferriprox worldwide since its first market authorisation in 1999. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure.

Blood and lymphatic system disorders.

Agranulocytosis and mild/moderate neutropenia, febrile neutropenia, thrombocytopenia, thrombocythemia, leukopenia, granulocytopenia, pancytopenia.

Cardiac disorders.

Atrial fibrillation, cardiac disorder, cardiac failure, congestive cardiac failure, sinus tachycardia.

Congenital, familial and genetic disorders.

Congenital anomaly, hypospadias, nonacute porphyria.

Eye disorders.

Diplopia, papilloedema, eye movement disorder, periorbital oedema, retinal toxicity visual impairment.

Gastrointestinal disorders.

Cecitis, enterocolitis, rectal haemorrhage, gastric ulcer, vomiting, nausea, diarrhoea, abdominal pain, stomatitis, pancreatitis, dysphagia, parotid gland enlargement.

General disorders and administration site conditions.

Asthenia, chills, difficulty in walking, face oedema, hyperpyrexia, pyrexia, fatigue, oedema peripheral, multiorgan failure.

Hepatobiliary disorders.

Hepatic function abnormal, jaundice, hepatomegaly.

Immune system disorders.

Anaphylactic shock, hypersensitivity.

Infections and infestations.

Cryptococcal cutaneous infection, encephalitis enteroviral, neutropenic sepsis, parapharyngeal abscess, Yersinia infection, bacterial infection, septic shock, pneumonia, infection, sepsis, parapharyngeal abscess, furuncle, subcutaneous abscess, tonsillitis urinary tract infection.

Investigations.

Anti-HBs antibody positive, blood arsenic increased, blood bilirubin increase, haemoglobin decrease, alanine aminotransferase increased, aspartate aminotransferase increased, blood corticotrophin decreased, blood cortisol decreased, hepatic enzymes increased, neutrophil count decreased, urine colour abnormal.

Metabolism and nutrition disorders.

Metabolic disorders, dehydration.

Musculoskeletal and connective tissue disorders.

Arthralgia, arthritis, bone pain, joint effusion, joint swelling pain in extremity, chondropathy, osteoarthritis, myositis, polyarthritis.

Neoplasms benign, malignant and unspecified (including cysts and polyps).

Hepatic neoplasm malignant.

Nervous system disorders.

Cerebellar syndrome, cerebral haemorrhage, convulsion, coordination abnormal, dystonia, febrile convulsion, hypotonia, intracranial pressure increased, nystagmus, psychomotor skills impaired, headache, depressed level of consciousness, dizziness, balance disorder.

Pregnancy, puerperium and perinatal conditions.

Intrauterine death.

Psychiatric disorders.

Depression, obsessive compulsive disorder.

Renal and urinary disorders.

Renal failure, haemoglobinuria, glycosuria, chromaturia.

Reproductive system and breast disorders.

Balanitis.

Respiratory, thoracic and mediastinal disorders.

Respiratory acidosis, haemoptysis, dyspnoea, lung disorder, pulmonary embolism, epistaxis, oropharyngolaryngeal pain, pharyngeal erythema.

Skin, subcutaneous tissue disorders.

Photosensitivity reaction, pruritus, urticaria, rash erythematous, rash, Henoch-Schonlein purpura, rash maculopapular.

Vascular disorders.

Hypotension, hypertension.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Acute toxicity and symptoms.

There have been no reports of acute overdose with Ferriprox.
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 months. The neurological disorders progressively regressed after Ferriprox discontinuation.

Management and treatment.

In case of overdosage, close clinical supervision of the patient is required.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Deferiprone is an orally active synthetic bidentate iron (III) chelator (pFe³⁺ = 19.4) that forms a 3:1 (deferiprone iron) complex. Deferiprone is uncharged at physiological pH and is rapidly absorbed from the gut. Deferiprone has been shown to mobilise iron from primary cultures of cells derived from organs affected clinically by iron overload, including cardiomyocytes, hepatocytes and reticuloendothelial cells.

Clinical trials.

In a randomised study (LA-01), the efficacy of Ferriprox (25 mg/kg three times per day) was compared with desferrioxamine (50 mg/kg/day, 4 to 7 times/week) in the treatment of iron overload in patients with thalassaemia major for about two years. There were 35 patients in the Ferriprox group and 36 in the desferrioxamine group. At the completion of the second year of the study, no significant change from baseline was observed in serum ferritin concentration or hepatic iron concentration of patients treated with either therapy. The power to detect a 20% difference in serum ferritin or hepatic iron concentration between groups was less than 80% due to the variability of the data and a relatively small sample size.
An uncontrolled multicentre prospective iron chelation study (LA-02) was performed in 187 transfusion dependent thalassaemia patients over a year. Patients were aged ≥ 10 years and had previously been regularly chelated with desferrioxamine. Ferriprox 25 mg/kg orally three times per day was not associated with an increase in body iron stores (as assessed by serum ferritin) after changing from desferrioxamine.
On completion of the study, 84 patients continued Ferriprox treatment in an extension study (LA-06) for a total treatment duration of 4 years. Ferriprox maintained stable body iron stores.
In a randomised, open label, parallel group trial (LA-16) in patients with thalassaemia major who had received chelation therapy with desferrioxamine for at least 5 years, 29 patients were switched to Ferriprox and 31 remained on desferrioxamine. Subjects were aged 18 to 35 years. The mean dose of Ferriprox was 92 mg/kg/day and desferrioxamine 43 mg/kg/day (mean 5.7 days per week in the case of desferrioxamine). After 12 months, there were no significant differences between Ferriprox and desferrioxamine in reduction in serum ferritin or liver iron concentration.

5.2 Pharmacokinetic Properties

Absorption.

Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract.
Peak serum concentration is reported to occur 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 micromol/L) than in the fasting state (126 micromol/L), although there was no decrease in the amount of substance absorbed when given with food.

Distribution.

The protein binding of deferiprone is low (< 10%). Following oral administration of deferiprone, the volume of distribution is at least 1.73 L/kg in thalassaemia patients.

Metabolism.

Deferiprone is cleared from plasma by metabolism, predominantly to a glucuronide metabolite. The rate of clearance has not been determined. The glucuronide metabolite lacks iron binding capacity because of inactivation of the 3-hydroxy group of deferiprone. Peak concentrations of the glucuronide metabolite occur 2 to 3 hours after administration of deferiprone.

Excretion.

In humans, deferiprone is eliminated mainly via the kidneys with reports of 75% to 90% of the ingested dose being recovered in the urine in the first 24 hours, mainly in the form of the glucuronide metabolite and the iron-deferiprone complex. Only 5% of an administered dose of deferiprone is excreted unchanged in the urine. A variable amount of elimination into the faeces has been reported. The elimination half-life in most patients is 2 to 3 hours.

5.3 Preclinical Safety Data

Genotoxicity.

The genotoxic potential of deferiprone was evaluated in a set of in vitro and in vivo tests. Deferiprone was shown to be clastogenic in mouse micronucleus assays, as well as mutagenic and clastogenic in vitro in mammalian cells. Deferiprone was nonmutagenic in the bacterial reverse mutation assay.
A comparative study on the assessment of lymphocyte clastogenicity in patients with thalassaemia treated with deferiprone or with desferrioxamine did not show a significant difference in chromosomal aberration frequency between the two therapies.

Carcinogenicity.

The carcinogenic potential of deferiprone has not been adequately investigated in long-term animal studies. In view of the genotoxicity results a carcinogenic potential of deferiprone cannot be excluded.

6 Pharmaceutical Particulars