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Once again, Health Canada has acted more promptly than the Food and Drug Administration (FDA), its U.S. regulatory counterpart, in disseminating important new drug safety information to physicians and patients.
On July 31, Health Canada warned of the risk of dangerously low blood sugar levels when repaglinide-containing diabetes medications and the anti-platelet drug clopidogrel (PLAVIX) are taken together. Severe drops in blood sugar can cause loss of consciousness, seizures, brain...
Once again, Health Canada has acted more promptly than the Food and Drug Administration (FDA), its U.S. regulatory counterpart, in disseminating important new drug safety information to physicians and patients.
On July 31, Health Canada warned of the risk of dangerously low blood sugar levels when repaglinide-containing diabetes medications and the anti-platelet drug clopidogrel (PLAVIX) are taken together. Severe drops in blood sugar can cause loss of consciousness, seizures, brain damage and even death. The agency therefore warned against using the drugs together under any circumstances.[1]
Repaglinide and clopidogrel
Repaglinide is marketed, both on its own (PRANDIN) and in combination with the diabetes medication metformin (PRANDIMET), for the treatment of Type 2 diabetes. It is a member of the family of diabetes drugs known as meglitinides, which stimulate the release of insulin from cells in the pancreas.[2] Public Citizen's Health Research Group has designated repaglinide as Do Not Use because the drug offers no advantages over older oral diabetes drugs.
Clopidogrel is a widely used drug that decreases blood clot formation. It was approved by the FDA to reduce the long-term risk of a new heart attack, stroke or cardiovascular death in patients who have suffered a recent heart attack or stroke or have established peripheral vascular disease (for example, evidence of narrowed or blocked arteries in the legs or neck).
Clopidogrel also has been approved by the FDA for the immediate treatment of a condition known as acute coronary syndrome in patients who may be treated medically or surgically in order to reduce the chance of subsequent heart attack, stroke and cardiovascular death.[3] Acute coronary syndrome consists of new or worsening chest pain, typically occurring at rest or with minimal exertion, accompanied by changes in an electrocardiogram (EKG or ECG) that suggest a heart attack.
We have designated clopidogrel as Limited Use. The drug is lifesaving in the immediate or recent aftermath of a heart attack or stroke, but it is beneficial for only one year after placement of a coronary artery stent (a metal device placed in a coronary vessel to keep it open).[4]
Study Showing Risk
Health Canada based its recent warning on a study published in October 2014 in the medical journal Clinical Pharmacology & Therapeutics. Researchers in Finland studied nine healthy subjects who were given repaglinide with and without clopidogrel over separate three-day periods (drug interaction studies are often this small, but still valid).[5] They then measured blood levels of both repaglinide and sugar.
On average, adding clopidogrel increased the concentration of repaglinide in the blood to levels four to five times higher than when repaglinide was given alone. This resulted in a significant drop in blood sugar levels. The explanation for these findings, like many drug interactions, is that clopidogrel interferes with an enzyme in the liver responsible for breaking down repaglinide.
In addition to issuing its warning, Health Canada required that the Canadian product labels for both drugs be updated to reflect information about this dangerous drug interaction and to advise against taking the two drugs together under any circumstances.
The FDA has yet to follow suit with a warning of its own, and the FDA-approved labels for these drugs do not carry a warning of the interaction However, we agree with Health Canada’s more protective approach.
What You Can Do
Do not take repaglinide-containing medications and clopidogrel together. If you are currently on both medicines, see your doctor immediately to discuss switching from repaglinide to another diabetes medication. Do not stop taking either drug before seeing your doctor.
References
[1] Health Canada. Gluconorm (repaglinide) - New Contraindication for Concomitant Use with Clopidogrel. July 31, 2015. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2015/54454a-eng.php.Accessed August 31, 2015.
[2] WorstPills.org. Drug profile for repaglinide. Last reviewed December 31, 2014. /monographs/view/47. Accessed August 31, 2015.
[3] Drugs@FDA. Clopidogrel product label, updated July 2015. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed August 31, 2015.
[4] WorstPills.org. Drug profile for clopidogrel. Last reviewed December 31, 2014. /monographs/view/217. Accessed August 31, 2015.
[5] 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;96(4):498-507.
[6] Drugs@FDA. Repaglinide product label, updated March 2012. Clopidogrel product label, updated July 2015. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed August 31, 2015.
