Risk of pancreatitis associated with the use of deferasirox in paediatric patients

HSA would like to inform healthcare professionals of overseas cases of pancreatitis reported in paediatric patients following treatment with deferasirox.

Deferasirox (Exjade®, Novartis (Singapore) Pte Ltd) is an orally active iron chelator that has been registered in Singapore since 2008. It is approved for the treatment of chronic iron overload, either due to frequent blood transfusions (≥ 7ml/kg/month of packed red blood cells) in patients aged 6 years and older with beta thalassaemia major, or in patients aged 10 years and older with non-transfusion-dependent thalassaemia syndromes. Exjade® is also approved for the treatment of chronic iron overload due to blood transfusions when deferoxamine therapy is contraindicated or inadequate in patients with other anaemias, in patients aged 2 to 5 years, as well as in patients with beta thalassaemia major with iron overload due to infrequent blood transfusions.

About drug-induced pancreatitis1,2

Acute pancreatitis is usually characterised by abdominal pain and an increase in pancreatic enzymes in the blood and urine, with an overall mortality of approximately 5%. Epidemiological studies suggest that drug-induced pancreatitis is relatively rare, with an estimated incidence of 0.1% to 2%. Although most cases of possible drug-induced pancreatitis are mild, some have been reported to be severe or even fatal.

Drugs that have been reported to be associated with acute pancreatitis include azathioprine, tetracycline, valproic acid, isoniazid, metronidazole, oestrogens, angiotensin-converting enzyme (ACE) inhibitors and statins. The management of drug-induced pancreatitis includes the discontinuation of suspected drugs to prevent further progression of any ongoing pancreatic injury, intravenous fluid replacement, and close monitoring of blood pressure, cardiac and pulmonary status. In more severe cases, parenteral or enteral nutrition may be required if patients are unable to tolerate oral intake.

Overseas reports of acute pancreatitis with deferasirox

Recently, overseas adverse reaction reports received through the World Health Organisation (WHO) VigiBase®* suggest a signal of pancreatitis associated with the use of deferasirox in paediatric patients.²

As of March 2015, 14 reports of pancreatitis associated with the use of deferasirox in children and adolescents, aged between 4 to 16 years old, have been identified from VigiBase®. Deferasirox was the only suspected drug in 11 of these 14 cases. The remaining three cases also included other suspected drugs, such as azithromycin, ceftriaxone, hydroxycarbamide, amoxicillin, clarithromycin, omeprazole and deferoxamine. The time to onset was reported in nine cases and ranged from 17 days to over five years (median 11 months). This time interval is relatively consistent with the time to onset of drug-induced pancreatitis that had been reported in literature with various drugs including valproic acid, oestrogen, sulindac, statins and ACE inhibitors.¹ In addition, a positive dechallenge was also noted in six cases, which is supportive of a drug-induced effect.

*VigiBase® is a global database maintained and developed by the Uppsala Monitoring Centre (UMC) on behalf of the WHO. It consists of reports of adverse reactions received from national pharmacovigilance centres in more than 120 countries, including Singapore, and acts as a reference source for signal strengthening and ad hoc investigations.

HSA’s advisory

HSA has not received any local reports of pancreatitis associated with the use of deferasirox. The local package insert for Exjade® is currently in the process of being strengthened to include warnings on the risk of acute pancreatitis.

Healthcare professionals are advised to take into consideration the potential risk of acute pancreatitis in patients who are prescribed deferasirox, and to monitor for signs and symptoms which could be suggestive of pancreatitis, such as abdominal pain, nausea, vomiting or tenderness of the abdomen to touch, particularly in paediatric patients.

References

1. Drug Safety 2008; 31: 823-37

2. Uppsala Monitoring Centre. SIGNAL newsletter, June 2015