| Section 4.2
Addition of Text:
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).
Deletion of text:
Due to the serious nature of agranulocytosis, that can occur with the use of deferiprone, special monitoring is required for all patients. Caution must be used when the patients’ absolute neutrophil count (ANC) is low, as well as when treating patients with renal insufficiency or hepatic dysfunction. (see section 4.4).
Section 4.4
No animal studies to evaluate the potential effects of deferiprone on fertility have been reported.
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. Interruption of therapy with deferiprone should be considered if serum ferritin measurements fall below 500 mg/l.
Section 4.6 (Addition)
Fertility
No effects on fertility or early embryonic development were noted in animals (see section 5.3).
section 4.7
No studies on the effects on the ability to drive and use machines have been performed.
Not relevant.
Section 4.8
Addition:
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.
Section 5.1
Deferiprone has been investigated in 247 patients in two phase III trials and a compassionate use programme. Serum ferritin was chosen as the primary efficacy criterion in the studies. In one study of two‑year duration deferiprone was compared to deferoxamine. The mean serum ferritin levels were not significantly different in the two treatment groups, but mean hepatic iron concentration in deferiprone treated patients seems to increase more than in deferoxamine treated patients. Therefore deferiprone at the recommended dose could be less effective than deferoxamine.
The other study was a supportive open, non‑comparative study. In this study patients maintained serum ferritin values at pre‑study levels. The primary end‑point was the incidence of agranulocytosis, which occurred at a frequency of 1.2%.
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 thalassemia 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 thalassemia 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 thalassemia 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.
Section 5.3
rats and rabbits at doses at least as low as 25 mg/kg/day. 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.
Section 9
Date of latest renewal: 23/0925/08/2009
Section 10
2330/09/20092010
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