Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
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.

Tabulated list of adverse reactions
Adverse reaction frequencies: Very common (≥1/10), Common (≥1/100 to <1/10), not known (cannot be estimated from the available data).

SYSTEM ORGAN CLASS                        VERY COMMON COMMON                          FREQUENCY (≥1/10)     (≥1/100 to <1/10)               NOT
KNOWN
Blood and lymphatic system disorders                            Neutropenia Agranulocytosis
Immune system disorders                                                               Hypersensitivity reactions
Metabolism and nutrition disorders                              Increased Appetite Nervous system disorders                                        Headache Gastrointestinal disorders                Nausea                Diarrhoea Abdominal Pain
Vomiting
Skin and subcutaneous tissue                                                          Rash disorders                                                                             Urticaria Musculoskeletal and connective tissue                           Arthralgia disorders
Renal and urinary disorders               Chromaturia
General disorders and administration                            Fatigue site conditions
Investigations                                                  Increased liver enzymes

Description of selected adverse reactions
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).

Reporting of suspected adverse reactions

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il