Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Chiesi Farmaceutici S.p.A., Via Palermo 26/A, 43122, Parma, Italy
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.
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.
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.
In view of the genotoxicity results, a carcinogenic potential of deferiprone cannot be excluded (see section 5.3).
Monitoring of plasma Zn2+ concentration, and supplementation in case of a deficiency, is recommended.
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.
There are no data available on the use of deferiprone in patients with end stage renal disease or severe hepatic impairment (see section 5.2). Caution must be exercised in patients with end stage renal disease or severe 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.
Patients should be informed that their urine may show a reddish/brown discoloration due to the excretion of the iron-deferiprone complex.
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).
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.
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.
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).
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).
No effects on fertility or early embryonic development were noted in animals (see section 5.3).
Not relevant.
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 × 109/l, which occurred in approximately 1% of patients. Less severe episodes of neutropenia were reported in approximately 5% of patients.
Adverse reaction frequencies: Very common (≥1/10), Common (≥1/100 to <1/10), not known (cannot be estimated from the available data).
Common: Neutropenia, Agranulocytosis
Frequency not known: Hypersensitivity reactions
Common: Increased Appetite
Common: Headache
Very common: Nausea, Abdominal Pain, Vomiting
Common: Diarrhoea
Frequency not known: Rash, Urticaria
Common: Arthralgia
Very common: Chromaturia
Common: Fatigue
Common: Increased liver enzymes
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). Data from pooled clinical studies in patients with systemic iron overload show that 63% of the episodes of agranulocytosis occurred within the first six months of treatment, 74% within the first year and 26% after one year of therapy. The median time to onset of the first episode of agranulocytosis was 190 days (ranged 22 days-17.6 years) and median duration was 10 days in clinical trials. A fatal outcome was observed in 8.3% of the reported episodes of agranulocytosis from clinical trials and post-marketing experience.
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. Episodes of hypotonia, instability, inability to walk, and hypertonia with inability of limb movement, have been reported in children in the post-marketing setting with standard doses of deferiprone. 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). Evaluation of rate of reactions per 100 patient-years of exposure showed that only the rate of diarrhoea was significantly higher in children (11.1) than in adults (2.0, p=0.01).
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 the national reporting system listed in Appendix V.
Not applicable.
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