Health Sciences Authority (HSA) issued an interim safety update on the potential risk of diabetic ketoacidosis (DKA) with sodium-glucose cotransporter-2 (SGLT2) inhibitors in the September 2015 after evaluating the safety signal. Subsequently, in February 2016, HSA issued a Dear Healthcare Professional Letter to communicate its benefit-risk assessment outcomes and recommendations. The following is a reminder to healthcare professionals on HSA’s recommendations to minimise the risk of SGLT2 inhibitor-associated DKA.
There are three SGLT2 inhibitor-containing products registered in Singapore since 2014. They are Invokana (canagliflozin, Johnson & Johnson Pte Ltd), Forxiga (dapagliflozin, AstraZeneca Singapore Pte Ltd) and Jardiance (empagliflozin, Boehringer Ingelheim Singapore Pte Ltd). These drugs are indicated as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes mellitus (T2DM), as monotherapy or as an add-on combination therapy with other glucose-lowering agents including insulin. Forxiga is also indicated as an initial combination therapy with metformin.
As of 1 February 2016, HSA has received five local cases of DKA and one case of ketonaemia associated with SGLT2 inhibitors use, all of which had resulted in the patients being hospitalised. Four cases were associated with canagliflozin and two cases were associated with dapagliflozin. Details of the cases can be found at the HSA website.
HSA has assessed that while the benefit-risk profile of SGLT2 inhibitors remains favourable for their approved indications, the possibility of SGLT2 inhibitors leading to an increased risk of DKA cannot be excluded, particularly in the presence of predisposing factors.
HSA noted that both the EMA and US FDA have completed their respective reviews on SGLT2 inhibitors. The EMA’s Pharmacovigilance Risk Assessment Committee advised healthcare professionals to be aware of possible euglycaemic DKA cases. The US FDA added a new warning to the US package inserts for SGLT2 inhibitors to warn of the risk of ketoacidosis. Manufacturers of SGLT2 inhibitors are also required by the US FDA to conduct post-marketing studies to collect and analyse spontaneous reports of ketoacidosis with SGLT2 inhibitors and follow-up data for a period of 5 years.
HSA’s review took into account the findings from scientific publications as well as information from local and overseas cases of DKA associated with SGLT2 inhibitors. HSA advised healthcare professionals on the following to minimise the risk of SGLT2 inhibitor-associated DKA:
• SGLT2 inhibitors should be used in accordance to its approved indications
• SGLT2 inhibitors should be used with caution in patients at risk of developing DKA. Predisposing factors for DKA include a low beta-cell function reserve resulting from pancreatic disorders (e.g. Type 1 diabetes mellitus, history of pancreatitis or pancreatic surgery), insulin dose reduction, reduced caloric intake or increased insulin requirements due to infections, illness or surgery, and alcohol abuse
• Patients should be advised on the possible signs and symptoms of metabolic acidosis, such as tachypnoea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy or mental status changes, and to seek medical attention promptly upon experiencing such symptoms
• Atypical or euglycaemic DKA presentations were observed in some patients (i.e. blood glucose levels lower than usually associated with DKA) while in other cases, no alternative explanation for metabolic acidosis could be identified
• Patients presenting with metabolic acidosis should be assessed for ketoacidosis and tested for blood ketones, even when the blood glucose levels are not high
• If ketoacidosis is suspected, treatment with SGLT2 inhibitor should be discontinued
HSA is working with the product licence holders to strengthen the local package inserts of the SGLT2 inhibitor products, to warn of the risk of developing DKA during treatment with these medications. HSA has also required the product licence holders to submit Periodic Benefit-Risk Evaluation Reports. HSA will continue to closely monitor the local and international developments regarding the risk of DKA with SGLT2 inhibitors use and will update healthcare professionals of any new significant findings.
Please refer to the following website in HSA for details:
http://www.hsa.gov.sg/content/hsa/../sodium-glucose-cotransporter2sglt2inhibitorsandriskofseriousdiab.html
In Hong Kong, there are two registered pharmaceutical products containing dapagliflozin, namely Forxiga Tablets 5mg (HK-63301) and 10mg (HK-63302) which are registered by AstraZeneca Hong Kong Ltd (Astra); two products containing canagliflozin, namely Invokana Tablets 100mg (HK-63499) and 300mg (HK-63500) which are registered by Johnson & Johnson (HK) Ltd (J&J); and six products containing empagliflozin, namely Jardiance Tablets 10mg (HK-64095) and 25mg (HK-64096), Jardiance Duo Tablets 12.5mg/850mg (HK-64240), 5mg/850mg (HK-64241), 12.5mg/1000mg (HK-64242) and 5mg/1000mg (HK-64243) which are registered by Boehringer Ingelheim (HK) Ltd (Boehringer). All products are prescription only medicines. Related news was previously issued by various overseas drug regulatory authorities, and was posted on the Drug Office website since 16 May 2015, with the last update posted on 17 May 2016.
On 9 July 2015, 10 July 2015 and 14 December 2015, J&J, Astra and Boehringer notified the Department of Health (DH) respectively that they had issued letters to inform local healthcare professionals on the risk of diabetic ketoacidosis with SGLT2 inhibitors. So far, DH has received two adverse drug reaction cases of ketoacidosis after taking SGLT2 inhibitors, involving dapagliflozin and canagliflozin respectively. As previously reported, the issue, together with the above HSA announcement, will be discussed by the Registration Committee of the Pharmacy and Poisons Board.
Ends/ Saturday, May 21, 2016
Issued at HKT 12:00
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