Gluconorm (repaglinide) - New Contraindication for Concomitant Use with Clopidogrel

Starting date:
July 31, 2015
Posting date:
July 31, 2015
Type of communication:
Dear Healthcare Professional Letter
Source of recall:
Health Canada
Important Safety Information
Healthcare Professionals
Identification number:


Family physicians, general practitioners, nurses, nurse practitioners, pharmacists, endocrinologists and cardiovascular clinics

Key messages

  • Co-administration of repaglinide and clopidogrel (a CYP2C8 inhibitor) may lead to a significant decrease in blood glucose levels due to a drug-drug interaction.
  • The concomitant use of repaglinide and clopidogrel is now contraindicated.
  • The prescriber information for GLUCONORM (repaglinide) has been updated. The prescriber information for PLAVIX (clopidogrel) is currently being updated. The prescriber information for the generic products will be updated (see Products affected).


Co-administration of repaglinide and clopidogrel (a known CYP2C8 inhibitor), may lead to a significant decrease in blood glucose levels due to a drug-drug interaction.


Repaglinide is an oral antidiabetic agent used for the treatment of type 2 diabetes mellitus. Clopidogrel is an oral antiplatelet agent used to prevent atherothrombotic events. Please refer to the GLUCONORM (repaglinide) and PLAVIX (clopidogrel) Canadian Product Monographs (CPMs) for full prescribing information.

Health Canada and Novo Nordisk Canada Inc. have reviewed the new safety information regarding repaglinide published in the Clinical Pharmacology and Therapeutics Journal. This information has now led to new prescribing information in the CPM for GLUCONORM (repaglinide). The CPM for PLAVIX (clopidogrel) is currently being updated. The CPMs for the generic versions will be updated (see Products affected listed below).

In a study conducted with healthy volunteers, co-administration of clopidogrel (300 mg on day 1, followed by 75 mg daily for 2 consecutive days), and repaglinide (single dose of 0.25 mg on day 1 and day 3) resulted in an increase in repaglinide systemic exposure (AUC0-∞) by 5.1-fold and 3.9-fold on day 1 and day 3 respectively. Hypoglycemia was noted in healthy volunteers on day 1 (3.3 mmol/L) and on day 3 (3.9 mmol/L).1

Products affected

  • Repaglinide:
  • Clopidogrel:

Who is affected

Information for consumers

Repaglinide (a medicine used to treat type 2 diabetes) and clopidogrel (a medicine used to prevent blood clots) are not to be used together. Repaglinide when taken by itself is intended to lower blood sugar to a normal level. However, when both medications are taken together, there is a greater risk of the blood sugar becoming too low, also known as hypoglycemia. Severe hypoglycemia can cause loss of consciousness, seizure, brain damage and even death.

If you are taking both medicines together, talk to your doctor or pharmacist before making any changes to your current therapy. Additional information for consumers is also provided in the Part III: Consumer Information section of the product information for GLUCONORM (repaglinide).

Information for health care professionals

The concomitant use of repaglinide and clopidogrel is now contraindicated. Combined use of repaglinide and clopidogrel may lead to hypoglycemia. Please refer to the GLUCONORM (repaglinide) and PLAVIX (clopidogrel) CPMs for full prescribing information.

Action taken by Health Canada

The CPM for GLUCONORM (repaglinide) has been updated to include this new safety information. The CPM for the PLAVIX (clopidogrel) is being updated. The CPMs for the generic versions will be updated.

Report health or safety concerns

Managing marketed health product-related side effects depends on health care professionals and consumers reporting them. Any case of serious hypoglycemia or other serious or unexpected side effects in patients receiving repaglinide and clopidogrel should be reported to the respective manufacturer of repaglinide prescribed as indicated below or to Health Canada.

GlucoNorm® (repaglinide)
Novo Nordisk Canada Inc.
300-2680 Skymark Avenue
Mississauga, ON, L4W 5L6
Telephone: 1-800-465-4334

ACT-Repaglinide (repaglinide)
Actavis Pharma Company
6733 Mississauga Road, Suite 400
Mississauga, ON, L5N 6J5
Telephone: 866-254-6111

APO-Repaglinide (repaglinide)
Apotex Inc.
150 Signet Drive
Toronto, ON, M9L 1T9
Telephone: 1-800-667-4708 or 416-401-7780
Fax: 1-866-429-9133 or 416-401-3819

pms-REPAGLINIDE (repaglinide)
Pharmascience Inc.
6111, Avenue Royalmount, Suite 100
Montreal, PQ, H4P 2T4
Telephone: 1-888-550-6060
Fax: 1-514-340-0164

Repaglinide (repaglinide)
Pro Doc Ltée
2925 Boulevard Industriel
Laval, PQ, H7L 3W9
Telephone: 1 800 361-8559
Fax: 450-668-0816

Sandoz Repaglinide (repaglinide)
Sandoz Canada Inc.
145 Jules-Léger Street
Boucherville, PQ, J4B 7K8
Telephone : 1-800-343-8839 ext : 4636
Fax:  1-888-243-6221

AURO-Repaglinide (repaglinide)
Auro Pharma Inc.
3700 Steeles Avenue West, Suite 402
Woodbridge ON, L4L 8K8
Tel: 905-856-8063 ext 223

To correct your mailing address or fax number, contact the manufacturer(s).

You can report any suspected adverse reactions associated with the use of health products to Health Canada by:

  • Calling toll-free at 1-866-234-2345; or
  • Visiting MedEffect Canada's Web page on Adverse Reaction Reporting for information on how to report online, by mail or by fax.

For other health product inquiries related to this communication, contact Health Canada at:

Marketed Health Products Directorate
Telephone: 613-954-6522
Fax: 613-952-7738

Original signed by

Dr. Mohamed Eid
Vice President, Clinical, Medical and Regulatory
Novo Nordisk Canada Inc.

Kent Major
Vice President, Regulatory Affairs
Actavis Pharma Company

Dr. Colin D’Cunha
Director Global Medical Affairs
Apotex Inc.

Ms. Rana Harb
Manager Regulatory Affairs
Auro Pharma Inc.

Len Neirinck, Ph.D.
Vice-president and Chief Scientific Officer, Scientific Affairs
Pharmascience Inc.

Jovette Deschênes,
Director, QC/QA and Regulatory Affairs
Pro Doc Ltée

Len Arsenault
Vice President, Scientific Affairs
Sandoz Canada Inc.


1. Tornio A, Filppula AM, Kailari O et al. Glucuronidation Converts Clopidogrel to a Strong Time-Dependent Inhibitor of CYP2C8: A Phase II Metabolite as a Perpetrator of Drug-Drug Interactions. Clin Pharmacol Ther 2014 Oct,96(4):498-507

For more information

The manufacturer advised Health Canada of the risk associated with this health product. Health Canada supports the actions taken by the manufacturer and as such a risk assessment was not required and a Summary Safety Review was not prepared.