Ferriprox (L1) Warning Document

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Offline Andy Battaglia

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Ferriprox (L1) Warning Document
« on: January 03, 2007, 03:09:47 AM »
Dear Health Care Professional,
ApoPharma Inc. would like to remind you, in conjunction with the European authorities, of the special
warnings, precautions and dosing instructions when using Ferriprox.
Ferriprox is indicated for the treatment of iron overload in patients with thalassaemia major when
deferoxamine therapy is contra-indicated or inadequate. The full Summary of Products Characteristics
(SPC) is attached to this letter for your convenience.
Risk of agranulocytosis:
Agranulocytosis (neutrophils<0.5  109/l) is a potentially fatal adverse reaction that is recognized for
the use of Ferriprox. Clinical findings suggest that Ferriprox-induced agranulocytosis is
idiosyncratic and not dose-related. Moreover, the onset was extremely variable (from a few weeks up
to 9 years).
The reported incidence in clinical trials is 0.5 cases per 100 patient-years of treatment whereas the
observed incidence of neutropenia (neutrophils <1.5  109/l), which is a predictive factor of
agranulocytosis occurrence, is 2.5 cases per 100 patient-years.
Since marketing authorisation in 1999, postmarketing surveillance activities have identified 46 cases
of agranulocytosis associated with the use of Ferriprox. Of these, nine were fatal cases and four of
these fatal cases occurred since September 2005. Some aspects of the reports of these cases indicate
that advice given in the SPC has not been followed. In all fatal cases, data on weekly White Blood
Cell count (WBC) monitoring were missing. Moreover, in 3/9 cases, Ferriprox was stopped from 2 to
7 days after the occurrence of neutropenia or agranulocytosis. Five of the fatal cases occurred in
patients who were prescribed Ferriprox for an off-label indication.
Thus, we would like to remind you of the absolute necessity of following the SPC guidance for the
prevention and treatment of agranulocytosis in patients with Thalassaemia Major treated with
• Treatment with Ferriprox should not be initiated in neutropenic patient.
• All patients treated with Ferriprox
should have weekly monitoring of neutrophil counts. Therapy
should be interrupted at the first sign of neutropenia (absolute neutrophil count < 1.5 109/L) and
appropriate therapeutic measures taken.
• If the patient develops an infection while on Ferriprox, therapy should be interrupted and the
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 flulike
•Concomitant treatment with other drugs that could increase the risk of agranulocytosis should be
• In the event of neutropenia:
- Deferiprone and all other medications with a potential to cause neutropenia should be
immediately discontinued;
- 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.
- rechallenge is not recommended.
• 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.
- Rechallenge is contraindicated.
Risk of neurological disorders :
Two cases of chronic overdosing with Ferriprox have been lately reported in two children aged 7 and
9 years-old who were prescribed long term therapy time (one and two years respectively) with more
than 2.5 times the recommended dose of 100 mg/kg/day.
These patients experienced neurological disorders such as nystagmus, walking disorders, ataxia,
dystonia and one developed impairment of psychomotor skills.
In both cases, neurological symptoms progressively reversed following discontinuation of Ferriprox.
Section 4.9 “Overdose” of the SPC warns of neurological disorders following chronic overdose with
Ferriprox and a further update is being discussed with the EMEA.
We would like to remind you that :
• Deferiprone is most commonly given as 25 mg/kg body weight, orally, three times a day for a total
daily dose of 75 mg/kg body weight.
• Doses above 100 mg/kg/day are not recommended because of the potentially increased risk of
adverse reactions.
You are reminded to closely observe the special warnings and precautions for the prevention and
treatment of agranulocytosis and the dosing instructions in the SPC when using Ferriprox.
ApoPharma would also like to take this opportunity to remind you that any suspected adverse
reactions should be reported to the local Health Regulatory Agency and/or the local representative of
the Marketing Authorisation Holder (see attached contact information below) according to the national
spontaneous reporting system.


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