Special Warning : אזהרת שימוש

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 Ferriprox 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 at the time of transfusion visits after 12 months of Ferriprox 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 Ferriprox, 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 be then 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 experience 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 1.5x109/l.

For neutropenia events (ANC < 1.5x109/l and > 0.5x109/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 < 0.5x109/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 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 immunocompromised patients
No data are available on the use of deferiprone in HIV positive or in 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 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 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.

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.

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 are not recommended. Deferiprone use should be discontinued if neurological disorders are observed (see sections 4.8 and 4.9).

Effects on Driving

4.7   Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.