Acute pancreatitis and serious hypersensitivity reactions reported with saxagliptin

HSA would like to highlight recent overseas post-market cases of acute pancreatitis and serious hypersensitivity reactions reported in patients treated with saxagliptin (Onglyza®, Kombiglyze®, Bristol-Myers Squibb) from July 2009 to September 2011.

Saxagliptin belongs to the class of antidiabetic drugs known as dipeptidyl peptidase-4 (DPP-4) inhibitors. DPP-4 inhibitors work by inhibiting the enzyme DPP-4, which slows down the inactivation of incretin hormones such as glucose-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This results in prolongation of the actions of these hormones in glucose homeostasis. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by DPP-4 enzymes within minutes.

Locally, saxagliptin has been licensed since November 2010, under the brand name Onglyza®. It was recently approved in February 2012 for use as a combination product with metformin under the brand name Kombiglyze®.

Overseas post-marketing reports of acute pancreatitis and serious hypersensitivity reactions

Fifty-six cases of overseas post-marketing reports of acute pancreatitis associated with saxagliptin have been received between July 2009 and September 2011 while 70 cases of angioedema and 11 cases of anaphylactic responses have been received from July 2009 to January 2011 and February 2011 respectively.

In the cases where pancreatitis was reported, more than half of these had resolved or were resolving at the time of reporting. There were, however, two fatal reports - one patient with a history of cholelithiasis and who was subsequently diagnosed with pancreatic carcinoma; and the other with a history of hypercholesterolemia where the cause of death was recorded as sepsis, acute pancreatitis and acute cholescystitis.

With regard to hypersensitivity reactions, the adverse reactions reported included anaphylaxis, angioedema, and exfoliative skin conditions. The onset of these reactions occurred within the first three months after initiating saxagliptin, with some reports occurring after the first dose. Some of these cases also had confounding factors which included pre-existing medical conditions or concomitant medications. There was one report of a fatal anaphylactic reaction, in which hypersensitivity to saxagliptin could not be ruled out.

Local situation and HSA's advisory

To date, HSA has not received any local reports of acute pancreatitis and serious hypersensitivity reactions associated with saxagliptin use.

A Dear Healthcare Professional Letter was issued on 5 March 2012 to inform healthcare professionals on the risk of acute pancreatitis and serious hypersensitivity reactions reported in patients treated with saxagliptin.¹ The local package inserts for Onglyza® and Kombiglyze® have also been updated to include these warnings.

HSA would like to remind healthcare professionals that the safety concern of acute pancreatitis is not restricted to saxagliptin. There have been overseas post-marketing reports of pancreatitis observed with the use of other DPP-4 inhibitors like sitagliptin and vildagliptin, indicating the possibility that pancreatitis could be a class effect of DPP-4 inhibitors.^2-4

Physicians are reminded to monitor their patients carefully for acute pancreatitis and hypersensitivity reactions. Onset of the hypersensitivity reactions were reported to occur within first three months of initiating saxagliptin therapy in some of the overseas reports. Some signs and symptoms of acute pancreatitis include persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting. Serious hypersensitivity reactions include anaphylaxis, angioedema or exfoliative skin conditions.

Healthcare professionals are also encouraged to report adverse drug reactions suspected to be associated with the use of DPP-4 inhibitors to the Vigilance Branch of HSA.

References

1. HSA website. Dear Healthcare Professional Letters (DHCPL) , 5 March 2012 

2. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm183764.htm

3. HSA ADR News Bulletin. April 2010, Vol 12; No1

4. Endocr Pract 2011; Vol 17(3): 334-6.