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Ferriprox 500 mg and 1000mg film-coated tablets
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Ferriprox®（去铁酮）Swedish孤儿Biovitrum公司分布在英国和爱尔兰，西班牙，葡萄牙，马耳他，瑞士，法国，比利时，卢森堡，荷兰，丹麦，挪威，瑞典，芬兰，爱沙尼亚，拉脱维亚，立陶宛和该产品阿尔及利亚上市。
最新研究的结果显示，利用口服铁螯合剂 Ferriprox（TM）治疗不仅能够预防由铁引发的心脏病，而且能够明显降低需定期输血治疗的海洋性贫血患者过早心脏死亡的风险。
海洋性贫血是一种影响人体红血球细胞制造功能的遗传疾病。海洋性贫血是一种长期病症，需要患者每两到四周接受一次输血治疗，因而造成了人体内各器官（心脏、肝脏和内腺）毒性铁的大量沉积。数据显示，与目前的治疗标准 DFO（去铁胺）相比，Ferriprox 能够对心脏提供更好的保护。尽管 DFO已降低了海洋性贫血患者的死亡率，然而心脏病依然是最常见的致死原因。接受DFO治疗的患者中有70%的人死于心脏病，年龄一般在20或30年龄段上。
铁螯合剂是从心脏中去除过量铁的唯一有效疗法。直到最近，DFO还是唯一的螯合剂。该药物必须在患者皮下注射8到12个小时（每星期5到7个晚上）。Ferriprox是第一种口服铁螯合剂，目前已在包括欧盟在内的48个国家和地区获得了批准，主要治疗铁负荷过重的重型海洋性贫血患者（不适于用 DFO治疗）或用DFO治疗呈现严重毒性的患者。
使用 Ferriprox 治疗的患者最常见的不良反应是短暂的胃肠症状（恶心、呕吐或腹部疼痛）。这些症状通常在治疗的第一周出现，而在停止或减少药量后的三天内缓解。
Ferriprox 500 mg and 1000mg film-coated tablets
1. Name of the medicinal product
Ferriprox 500 mg film-coated tablets
Ferriprox 1000 mg film-coated tablets
2. Qualitative and quantitative composition
Ferriprox 500 mg film-coated tablets
Each tablet contains 500 mg deferiprone.
Ferriprox 1000 mg film-coated tablets
Each tablet contains 1000 mg deferiprone.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Film-coated tablet.
Ferriprox 500 mg film-coated tablets
White to off-white, capsule-shaped, film-coated tablets imprinted “APO” bisect “500” on one side, plain on the other. The tablet is scored. The tablet can be divided into equal halves.
Ferriprox 1000 mg film-coated tablets
White to off-white, capsule-shaped, film-coated tablets imprinted “APO” bisect “1000” on one side, plain on the other. The tablet is scored. The tablet can be divided into equal halves.
4. Clinical particulars
4.1 Therapeutic indications
Ferriprox monotherapy is indicated for the treatment of iron overload in patients with thalassaemia major when current chelation therapy is contraindicated or inadequate.
Ferriprox 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 Ferriprox 500 mg film-coated tablets
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Body weight
(kg)
|
Total daily dose
(mg)
|
Dose
(mg, three times/day)
|
Number of tablets
(three times/day)
|
|
20
|
1500
|
500
|
1.0
|
|
30
|
2250
|
750
|
1.5
|
|
40
|
3000
|
1000
|
2.0
|
|
50
|
3750
|
1250
|
2.5
|
|
60
|
4500
|
1500
|
3.0
|
|
70
|
5250
|
1750
|
3.5
|
|
80
|
6000
|
2000
|
4.0
|
|
90
|
6750
|
2250
|
4.5
|
Dose table for Ferriprox 1000 mg film-coated tablets
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Body weight
(kg)
|
Total daily dose
(mg)
|
Number of 1000 mg tablets*
|
|
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 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 Ferriprox in decreasing the body iron is directly influenced by the dose and the degree of iron overload. 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 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, Ferriprox 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, Ferriprox at 75-100 mg/kg/day should be added to deferoxamine therapy. The product information of deferoxamine should be consulted.
Concurrent use of iron chelators is not recommended in patients whose serum ferritin falls below 500 µg/l due to the risk of excessive iron removal.
Paediatric population
There are limited data available on the use of deferiprone in children between 6 and 10 years of age, and no data on deferiprone use in children under 6 years of age.
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. The patient's neutrophil count should be monitored every week.
In clinical trials, weekly monitoring of the neutrophil count has been effective in identifying cases of neutropenia and agranulocytosis. Neutropenia and agranulocytosis resolved once therapy was withdrawn. If the patient develops an infection while on deferiprone, therapy should be interrupted and the neutrophil count monitored more frequently. Patients should be advised to report immediately to their physician any symptoms indicative of infection such as fever, sore throat and flu-like symptoms.
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 1.5x109/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
Monitoring of plasma Zn2+ 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 100 mg/kg/day are not recommended (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 Ferriprox and deferasirox, and caution should be applied when considering the use of such combination.
4.5 Interaction with other medicinal products and other forms of interaction
Due to the unknown mechanism of deferiprone-induced neutropenia, patients must not take medicinal products known to be associated with neutropenia or those that can cause agranulocytosis (see section 4.3).
Since deferiprone binds to metallic cations, the potential exists for interactions between deferiprone and trivalent cation-dependent medicinal products such 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).
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
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 100 mg/kg/day for several years. The neurological disorders progressively regressed after deferiprone discontinuation (see sections 4.4 and 4.9).
The safety profile of combination therapy (deferiprone and deferoxamine) observed in clinical trials, post-marketing experience or published literature was consistent with that characterized for monotherapy.
Data from the pooled safety database from clinical trials (1343 patient-years exposure to Ferriprox monotherapy and 244 patient-years exposure to Ferriprox 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).
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). eva luation of rate of reactions per 100 patient-years of exposure showed that only the rate of diarrhoea was significantly higher in children (11.05) than in adults (2.01, 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:
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: medsafety@hpra.ie
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.
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 Ferriprox is effective in promoting iron excretion and that a dose of 25 mg/kg three times per day can prevent the progression of iron accumulation as assessed by serum ferritin, in patients with transfusion-dependent thalassaemia. Data from the published literature on iron balance studies in patients with thalassaemia major show that the use of Ferriprox concurrently with deferoxamine (coadministration of both chelators during the same day, either simultaneously or sequentially, e.g., Ferriprox during the day and deferoxamine during the night), promotes greater iron excretion than either drug alone. Doses of Ferriprox in those studies ranged from 50 to 100 mg/kg/day and doses of deferoxamine from 40 to 60 mg/kg/day. However, chelation therapy may not necessarily protect against iron-induced organ damage.
Clinical efficacy and safety
Studies LA16-0102, LA-01 and LA08-9701 compared the efficacy of Ferriprox with that of deferoxamine in controlling serum ferritin in transfusion-dependent thalassaemia patients. Ferriprox 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 Ferriprox with that of deferoxamine in decreasing cardiac iron overload and in improving cardiac function (as measured by LVEF) in transfusion-dependent thalassaemia patients. Sixty-one patients with cardiac iron overload, previously treated with deferoxamine, were randomized to continue deferoxamine (average dose 43 mg/kg/day; N=31) or to switch to Ferriprox (average dose 92 mg/kg/day N=29). Over the 12-month duration of the study, Ferriprox 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 Ferriprox 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 Ferriprox group and by 0.32 ± 3.38 absolute units (%) in the deferoxamine group (difference between groups; p=0.003).
Study LA12-9907 compared survival, incidence of cardiac disease, and progression of cardiac disease in 129 patients with thalassaemia major treated for at least 4 years with Ferriprox (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 Ferriprox 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%) Ferriprox-treated patients who were cardiac disease-free at the first assessment (p=0.013). Overall, fewer Ferriprox-treated patients than deferoxamine-treated patients showed a worsening of cardiac dysfunction from first assessment to last assessment (4% vs. 20%, p=0.007).
Data from the published literature are consistent with the results from the Apotex studies, demonstrating less heart disease and/or increased survival in Ferriprox-treated patients than in those treated with deferoxamine.
A randomized, placebo-controlled, double-blind trial eva luated the effect of concurrent therapy with Ferriprox and deferoxamine in patients with thalassaemia major, who previously received the standard chelation monotherapy with subcutaneous deferoxamine and had mild to moderate cardiac iron loading (myocardial T2* from 8 to 20 ms). Following randomization, 32 patients received deferoxamine (43.4 mg/kg/day for 5 days/week) and Ferriprox (75 mg/kg/day) and 33 patients received deferoxamine monotherapy (34.9 mg/kg/day for 5 days/week). After one year of study therapy, patients on concurrent chelation therapy had experienced a significantly greater reduction in serum ferritin (1574 µg/l to 598 µg/l with concurrent therapy vs. 1379 µg/l to 1146 µg/l with deferoxamine monotherapy, p<0.001), significantly greater reduction in myocardial iron overload, as assessed by an increase in MRI T2* (11.7 ms to 17.7 ms with concurrent therapy vs. 12.4 ms to 15.7 ms with deferoxamine monotherapy, p=0.02) and significantly greater reduction in liver iron concentration, also assessed by an increase in MRI T2* (4.9 ms to 10.7 ms with concurrent therapy vs. 4.2 ms to 5.0 ms with deferoxamine monotherapy, p< 0.001).
Study LA37-1111 was conducted to eva luate the effect of single therapeutic (33 mg/kg) and supratherapeutic (50 mg/kg) oral doses of deferiprone on the cardiac QT interval duration in healthy subjects. The maximum difference between the LS means of the therapeutic dose and placebo was 3.01 msec (95% one-sided UCL: 5.01 msec), and between the LS means of the supratherapeutic dose and placebo was 5.23 msec (95% one-sided UCL: 7.19 msec). Ferriprox was concluded to produce no significant prolongation of the QT interval.
5.2 Pharmacokinetic properties
Absorption
Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract. Peak serum concentration occurs 45 to 60 minutes following a single dose in fasted patients. This may be extended to 2 hours in fed patients.
Following a dose of 25 mg/kg, lower peak serum concentrations have been detected in patients in the fed state (85 μmol/l) than in the fasting state (126 μmol/l), although there was no decrease in the amount of deferiprone absorbed when it was given with food.
Biotransformation
Deferiprone is metabolised predominantly to a glucuronide conjugate. This metabolite lacks iron-binding capability due to inactivation of the 3-hydroxy group of deferiprone. Peak serum concentrations of the glucuronide occur 2 to 3 hours after administration of deferiprone.
Elimination
In humans, deferiprone is eliminated mainly via the kidneys; 75% to 90% of the ingested dose is reported as being recovered in the urine in the first 24 hours, in the form of free deferiprone, the glucuronide metabolite and the iron-deferiprone complex. A variable amount of elimination via the faeces has been reported. The elimination half-life in most patients is 2 to 3 hours.
5.3 Preclinical safety data
Non-clinical studies have been conducted in animal species including mice, rats, rabbits, dogs and monkeys.
The most common findings in non-iron-loaded animals at doses of 100 mg/kg/day and above were hematologic effects such as bone marrow hypocellularity, and decreased WBC, RBC and/or platelet counts in peripheral blood.
Atrophy of the thymus, lymphoid tissues, and testis, and hypertrophy of the adrenals, were reported at doses of 100 mg/kg/day or greater in non-iron-loaded animals.
No carcinogenicity studies in animals have been conducted with deferiprone. The genotoxic potential of deferiprone was eva luated 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 non-iron-loaded pregnant rats and rabbits at doses at least as low as 25 mg/kg/day. No effects on fertility or early embryonic development were noted in non-iron-loaded male and female rats that received deferiprone orally at doses of up to 75 mg/kg twice daily for 28 days (males) or 2 weeks (females) prior to mating and until termination (males) or through early gestation (females). In females, an effect on the oestrous cycle delayed time to confirmed mating at all doses tested.
No prenatal and postnatal reproductive studies have been conducted in animals.
6. Pharmaceutical particulars
6.1 List of excipients
Ferriprox 500 mg film-coated tablets
Tablet core
Microcrystalline cellulose
Magnesium stearate
Colloidal silicon dioxide
Coating
Hypromellose
Macrogol
Titanium dioxide
Ferriprox 1000 mg film-coated tablets
Tablet core
Methylcellulose USP A15LV
Crospovidone
Magnesium stearate
Coating
Hypromellose 2910 USP/EP
Hydroxypropyl cellulose
Macrogol
Titanium dioxide
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Ferriprox 500 mg film-coated tablets
5 years.
Ferriprox 1000 mg film-coated tablets
3 years.
For the bottle: After first opening use within 50 days.
6.4 Special precautions for storage
Ferriprox 500 mg film-coated tablets
Do not store above 30°C.
Ferriprox 1000 mg film-coated tablets
Do not store above 30°C.
For the bottle: Keep the bottle tightly closed in order to protect from moisture.
For the blister: Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Ferriprox 500 mg film-coated tablets
High density polyethylene (HDPE) bottles with child resistant closure (polypropylene).
Each pack contains one bottle of 100 tablets.
Ferriprox 1000 mg film-coated tablets
High density polyethylene (HDPE) bottle with a child resistant polypropylene cap and a desiccant.
Pack size of 50 tablets.
High density polyethylene (HDPE) bottle with a polypropylene screw cap and a desiccant.
Pack size of 100 tablets.
Perforated unit dose aluminium blisters.
Pack size of 50 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Apotex Europe B.V.
Darwinweg 20
2333 CR Leiden
Netherlands
8. Marketing authorisation number(s)
Ferriprox 500 mg film-coated tablets
EU/1/99/108/001
Ferriprox 1000 mg film-coated tablets
EU/1/99/108/004
EU/1/99/108/005
EU/1/99/108/006
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 25 August 1999
Date of latest renewal: 25 August 2009
10. Date of revision of the text
26.05.2016
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. |
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