BackgroundThe incidence of factor IX inhibitor development in congenital haemophilia B is low (3–5% depending on the population) and usually occurs in the first days of treatment. Guidelines suggest that, after 150 days exposed to the drug (ED), testing is only required if clinically indicated. But we detected two cases in which the inhibitors developed on long term treatments.PurposeTo describe all worldwide reported cases in which patients developed inhibitors when they were treated with Nonacog alfa. We focused on the time it took to develop the inhibitors since the treatment started.Material and methodsWe searched on VigiBase and FEDRA (global and Spanish pharmacovigilance databases, respectively), including all spontaneous reports in patients with Nonacog alfa who developed inhibitors in the past 20 years. All patients who did not have laboratory confirmation were excluded. Age, gender, reporting country, Nonacog alfa treatment starting date, EDs and confirmation inhibitor testing date were recorded.Results52 cases of inhibitor development were reported globally: 29 in the USA, 8 in Japan and 15 in Europe. They were primarily in men (45/52) and gender was unknown in 5 cases. Their ages ranged from 9 months to 50 years (age was unknown in 19 cases). It was not possible to confirm the EDs in any of the cases. Half of the notifications (26/52) did not correctly record the chronology of inhibitor development. Of the remainder, 19 notifications were made in the first year of treatment (12 in the first 100 days), 2 notifications between the first and second year, 1 notification between the second and third year, 1 notification between the third and fourth year, 2 notifications between the fourth and fifth year and 1 notification between the sixth and seventh year.ConclusionThese results show that patients treated for several years are also susceptible, although to a lesser extent, to developing inhibitors. Despite the major limitations of this study, it is not wrong to think that patients with longer treatments have been exposed to more doses which might even exceed 150 ED. Hence it is important to monitor all haemophilia B patients throughout all of their treatment.No conflict of interest

BackgroundSpironolactone is widely used in paediatrics for cardiovascular disease despite being an off-label treatment. After detecting a case of severe gynaecomastia in a 4-month-old child with spironolactone and no other likely causes, it was decided to make a more thorough review of the cases globally reported.PurposeTo describe worldwide reported cases in which the paediatric population developed breast disorders (BD) associated with spironolactone treatment. We focused on the time it took to develop the disorder since the treatment started. We also focused on whether there was another reason which could have induced the condition.Material and methodsA search was conducted on Vigibase and FEDRA (Global and Spanish Pharmacovigilance Database, respectively), including all spontaneous reports performed in patients >18 years of age with BD treated with spironolactone. We calculated how long the BD appeared after treatment had started. We also checked the product information to determine if concomitant medication could produce this adverse drug reaction (ADR). We included as BD: gynaecomastia, breast enlargement, galactorrhoea and nipple pain. Age, gender, reporting country, spironolactone treatment starting date, date of diagnosis of BD and list of concomitant medications were recorded.Results14 cases of BD were reported globally: 7 in Asia, 5 in Europe, 1 in Australia and 1 in the USA. They were 11 boys and 3 girls. Median age was 2 years (21 days–17 years). 7 cases developed BD early (in the first month of treatment), 2 cases developed it late (more than 4 years after treatment) and in the other cases (5) the time it took for BD to appear could not be correctly identified. Regarding possible causes of BD, 10 cases could be attributed to spironolactone and 4 cases to concomitant medication. The drugs involved were digoxin, ramipril and domperidone.ConclusionReported cases occurred after a few days of treatment with spironolactone, especially in infants. Despite the off-label use, this draws attention to the low incidence of notifications in a drug widely used in paediatrics. This may be because this ADR is well known, and ADR notifications in paediatrics is generally low.No conflict of interest