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Film Coated Tablets
100 X 500 mg
500 ml X 100 mg/ml
Deferiprone therapy should be initiated and maintained by a physician experienced in the treatment of patients with thalassaemia. 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. Dosage per kilogram body weight should be calculated to the nearest half tablet. Doses above 100 mg/kg/day are not recommended because of the potentially increased risk of adverse reactions; chronic administration of more than 2.5 times the maximum recommended dose has been associated with neurological disorders. 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. 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 patient’s absolute neutrophil count (ANC) is low, as well as when treating patients with renal insufficiency or hepatic dysfunction.
For full details see prescribing information.
Treatment of iron overload in patients over 6 years old with thalassemia major in whom deferoxamine therapy is contraindicated or inadequate.
Hypersensitivity to the active substance or to any of the excipients. History of recurrent episodes of neutropenia. History of agranulocytosis. Pregnancy or breast-feeding. Due to the unknown mechanism of deferiprone-induced neutropenia, patients should not take medicdbinal products known to be associated with neutropenia or those that can cause agranulocytosis.
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 Neutropenia and agranulocytosis resolved once therapy was withdrawn.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 1.5×109 /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 3 (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, a rechallenge is contraindicated.
Carcinogenicity/mutagenicity/effects on fertility: In view of the genotoxicity results, a carcinogenic potential of deferiprone cannot be excluded. No animal studies to evaluate the potential effects of deferiprone on fertility have been reported.
Serum ferritin concentration/plasma Zn2+ concentration: 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 µg/l. 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.
Chornic 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.
The most serious adverse reaction reported in clinical trials with deferiprone is agranulocytosis (neutrophils <0.5×109 /l), with an incidence of 1.1%( 0.6 cases per 100 patient-years of treatment). The observed incidence of the less severe form of neutropenia (neutrophils <1.5×109 /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. 5 Increased levels of serum liver enzymes have been reported in 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. 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 hyotonia) 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.
For full details see prescribing information.
Interactions between deferiprone and other medicinal products have not been reported. However, 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. Due to the unknown mechanism of deferiprone induced neutropenia, patients must not take medicinal products know to be associated with neutropenia or those that can cause agranulocytosis.
Pregnancy and Lactation
Pregnancy: there are no adequate data from the use of deferiprone in pregnant women. Studies in animals have shown reproductive toxicity. 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 counselled to take contraceptive measures and must be advised to immediately stop taking deferiprone if they become pregnant or plan to become pregnant.
Lactation: it is not known whether deferiprone is excreted in human milk. No prenatal and postnatal reproductive studies have been conducted in animals. Deferiprone should not be used by breast-feeding mothers. If treatment is unavoidable, breast feeding must be stopped.
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 children who had been voluntarily prescribed more then 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.