Other safety alerts
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| Canada: Summary Safety Review - Direct-acting antivirals - Assessing the potential risk of abnormal blood sugar levels (dysglycemia) |
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Health Canada announces that it reviewed the potential risk of abnormal blood sugar (glucose) levels (dysglycemia) with the use of direct-acting antivirals (DAAs), including both high blood sugar levels (hyperglycemia) and low blood sugar levels (hypoglycemia). This assessment was triggered by updates made to the European product safety information for DAAs to include warnings about the use of these products in diabetic patients. These updates included recommendations to closely monitor glucose levels and modify patients' diabetic medications to prevent hypoglycemia.
DAAs are prescription drugs authorized for sale in Canada to treat chronic hepatitis C virus (HCV) infection. HCV infection can potentially decrease the liver's ability to perform its different roles, one of which is the control of blood sugar. A potential complication seen in patients with HCV infection is the loss of blood sugar control and higher levels of sugar in the blood, which can in turn lead to type II diabetes mellitus (T2DM). Patients with chronic HCV infection are 3.8 times more likely to have T2DM than non-infected individuals.
This review included the following products available in Canada: Daklinza (daclatasvir), Sovaldi (sofosbuvir), Harvoni (sofosbuvir, ledipasvir), Epclusa (sofosbuvir, velpatasvir), Vosevi (sofosbuvir, velpatasvir, voxilaprevir), Zepatier (grazoprevir, elbasvir) and Maviret (glecaprevir, pibrentasvir). These products may either contain a single DAA or multiple DAAs together.
At the time of the review, the Canadian Product Information for Daklinza (daclatasvir) already included the risk of dysglycemia in diabetic patients. Additionally, the Canadian Product Safety Information of sofosbuvir-containing products recommended the close monitoring of blood glucose levels in diabetic patients and suggested that the dose of diabetes medications may need to be adjusted during treatment.
Until 20 Feb 2019, Health Canada had received 564 Canadian cases reporting either hypoglycemia, hyperglycemia and/or new onset diabetes with the use of DAAs. Of these reports, 538 reports were excluded mainly for lack of information or because they were duplicates. Twenty-six (26) cases were retained. Health Canada also reviewed the scientific literature and found 10 additional international cases. Among a total of 36 case reports assessed, 24 case reports were related to hyperglycemia/new onset diabetes, 8 were related to hypoglycemia/improvement in diabetes, and 4 were reported as other [1 case reported blood sugars as abnormal, 2 cases reported loss of blood sugar control and 1 case reported both increased (hyperglycemia) and decreased (hypoglycemia) blood sugar levels]. One (1) case of hyperglycemia also reported death. 2 case reports were assessed twice because one case reported the use of 2 DAAs initiated at different times. The events of hyperglycemia and death were both assessed for a cause-and-effect relationship (causality). 27 (including the reported death) were found to be possibly linked with the use of a DAA, 3 cases were unlikely to be linked to DAA use, and 8 cases could not be assessed due to insufficient information.
A search in VigiBase, the World Health Organization's Adverse Drug Reaction Database, found 735 cases related to dysglycemia reported in patients treated with DAAs. Given that chronic HCV can itself be linked with glucose disorders and that the VigiBase case reports contained limited information, the data could not be used to confirm or rule out a link between the use of DAAs and dysglycemia-related events.
This safety review also looked at information from 26 published studies in the scientific literature. There were a small number of reports of hypoglycemic events in the studies reviewed; no events related to hyperglycemia were reported. Diabetic patients were more vulnerable to the adverse reaction of hypoglycemia. In conclusion, the literature reviewed supports the finding that DAA treatment is associated with the improvement of glucose metabolism. Monitoring of blood sugar levels during treatment is advised.
A decrease in the dosage or the use of diabetes medications may be required in order to prevent the occurrence of symptoms or signs of hypoglycemia. The review of the literature identified biological mechanisms to explain how DAAs could lead to hypoglycemia in diabetic patients. There was no clear process explaining how DAAs could promote the development of hyperglycemia or new-onset diabetes.
Health Canada's review has concluded that there is a link between the use of DAAs and the risk of dysglycemia. There have been reported cases of hyperglycemia/new onset diabetes in patients being treated with DAAs. However, there is stronger evidence that supports the development of hypoglycemia in diabetic patients treated with DAAs who experience high insulin sensitivity and a decreased need of diabetes medications.
Health Canada is working with the manufacturers to update the Canadian product safety information on DAAs to inform about the risk of dysglycemia in diabetic patients. Health Canada will continue to monitor safety information involving DAAs and dysglycemia and take appropriate and timely action if and when any new health risks are identified.
Please refer to the following website in Health Canada for details:
http://hpr-rps.hres.ca/../summary-safety-review-detail.php?lang=en&linkID=SSR00234
In Hong Kong, there are 8 registered pharmaceutical products which are direct-acting antivirals, namely, Sovaldi Tablets 400mg (containing sofosbuvir; HK-63501), Harvoni Tablets (containing sofosbuvir and ledipasvir; HK-63886), Epclusa Tablets 400mg/100mg (containing sofosbuvir and velpatasvir; HK-65046) and Vosevi Tablets (containing sofosbuvir, velpatasvir and voxilaprevir; HK-65775) which are registered by Gilead Sciences Hong Kong Limited; Maviret Tablets (containing glecaprevir and pibrentasvir; HK- 65653) which is registered by Abbvie Limited; Daklinza Tablets 60mg (containing daclatasvir; HK-64505) and Sunvepra Capsules 100mg (containing asunaprevir; HK-64506) which are registered by Bristol-Myers Squibb Pharma (HK) Ltd; and Zepatier Tablets (containing grazoprevir and elbasvir; HK-65571) which is registered by Merck Sharp & Dohme (Asia) Ltd. All products are prescription-only medicines. So far, the Department of Health (DH) has not received any case of adverse drug reaction related to dysglycemia of the above-mentioned direct-acting antivirals.
Related news on risk of hypoglycemia of direct-acting antivirals was previously issued by the United Kingdom Medicines and Healthcare products Regulatory Agency, and was posted on the Drug Office website on 19 Dec 2018. Letters to inform local healthcare professionals were issued by DH on the same day. In view of the above Health Canada’s announcement, letters to inform local healthcare professionals will be issued, and the matter will be discussed by the Registration Committee of the Pharmacy and Poisons Board.
Ends/Tuesday, Feb 18, 2020
Issued at HKT 16:00
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