Potential interaction of Proton Pump Inhibitors (PPIs) with Plavix (clopidogrel) - For Health Professionals

Starting date:

August 14, 2009

Posting date:

August 20, 2009

Type of communication:

Dear Healthcare Professional Letter

Subcategory:

Drugs

Source of recall:

Health Canada

Audience:

Healthcare Professionals

Identification number:

RA-170002103

This is duplicated text of a letter from sanofi-aventis Canada Inc. and Bristol-Myers Squibb Canada Co.

Contact the company for a copy of any references, attachments or enclosures.

Notice about Health Canada advisories

Health Canada Endorsed Important Safety Information on Plavix (clopidogrel)

August 14, 2009

Dear Healthcare Professional,

Subject: Potential interaction of Proton Pump Inhibitors (PPIs) with Plavix^® (clopidogrel)

Sanofi-aventis Canada Inc. and Bristol Myers Squibb Canada Co., in collaboration with Health Canada, wish to inform you of new safety information regarding the potential interaction of Proton Pump Inhibitors (PPIs) with Plavix^® (clopidogrel). This potential interaction could lead to a reduction in the level of clopidogrel's active metabolite and therefore, it is conceivable that the therapeutic response to clopidogrel may be affected.

• Clopidogrel is a prodrug metabolized by the liver, partly by cytochrome P450 2C19 (CYP2C19), before it can be biologically active in preventing atherothrombotic events. Healthcare professionals should be aware of a potential interaction between PPIs or other drugs that inhibit CYP2C19 and clopidogrel leading to a potential reduction in the clinical activity of clopidogrel.
• Administration of PPIs or of other drugs that inhibit CYP2C19 should be discouraged in patients taking Plavix^® (clopidogrel). The risk-benefit relationship of continuing treatment with a PPI should be considered by the prescribing physician taking into account that other gastro-protective agents are available.
• Healthcare professionals should continue to prescribe and patients should continue to take Plavix^® (clopidogrel) as directed, because Plavix^® (clopidogrel) has demonstrated benefits in preventing life-threatening atherothrombotic events that could lead to myocardial infarction or stroke.

PPIs are drugs used to prevent and treat peptic ulcer and gastroesophageal reflux and may inhibit, to some degree, the activity of CYP2C19. Recent reports in the literature (mainly for omeprazole) suggest a potential interaction with PPIs through CYP2C19 that may reduce the efficacy of clopidogrel. Although the evidence for CYP2C19 inhibition varies within the class, the effect is possibly related to all members of the PPI class.

Sanofi-aventis Canada Inc. and Bristol Myers Squibb Canada Co. are currently working with Health Canada on this topic to integrate the new safety information in the Canadian Product Monograph. In addition to updating the Product Monograph for Plavix^® (clopidogrel), sanofi-aventis and Bristol Myers Squibb are currently conducting studies to further characterize this potential interaction to provide additional information to healthcare professionals.

Managing marketed health product-related adverse reactions depends on healthcare professionals and consumers reporting them. Reporting rates determined on the basis of spontaneously reported post-marketing adverse reactions are generally presumed to underestimate the risks associated with health product treatments. Any case of serious drug interaction with a PPI or a drug known to inhibit CYP2C19 or other serious or unexpected adverse reactions in patients receiving Plavix^® (clopidogrel) should be reported to sanofi-aventis Canada Inc. or Health Canada at the following addresses:

Sanofi-aventis Canada Inc.

2150 St. Elzear Blvd. West

Laval, Quebec, H7L 4A8

Telephone: 1-800-265-7927

The Product Monograph and a copy of this Important Safety Information can be accessed online at sanofi-aventis Canada Inc. and at Bristol-Myers Squibb Canada Co. Web sites.

Any suspected adverse reaction can also be reported to:

Canada Vigilance Program

Marketed Health Products Directorate

Health Canada

Address Locator: 0701C

Ottawa, Ontario, K1A 0K9

Telephone: 613-957-0337 or Fax: 613-957-0335

To report an Adverse Reaction, consumers and health professionals may call toll free:

Telephone: 1-866-234-2345

Fax: 1-866-678-6789

CanadaVigilance@hc-sc.gc.ca

The Adverse Reaction Reporting Form and the Adverse Reaction Guidelines can be found on the Health Canada web site or in The Canadian Compendium of Pharmaceuticals and Specialties.

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

Marketed Health Products Directorate (MHPD)

E-mail: mhpd_dpsc@hc-sc.gc.ca

Telephone: 613-954-6522

Fax: 613-952-7738

original signed by

Laurent-Didier Jacobs, M.D.

Vice President, Medical Affairs

sanofi-aventis Canada Inc.

original signed by

H. Mitchell Shulman, MDCM, FRCPC, CSPQ

Vice President, Medical

Bristol Myers Squibb Canada Co.

References:

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2. Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdani MM. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009 Mar 31;180(7):713-8. Epub 2009 Jan 28. PubMed PMID: 19176635; PubMed Central PMCID: PMC2659819.
3. SCAI Statement on "A National Study of the Effect of Individual Proton Pump Inhibitors on Cardiovascular Outcomes in Patients Treated with Clopidogrel Following Coronary Stenting: The Clopidogrel Medco Outcomes Study" accessed on 2009-07-18
4. Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J. 2009 Jan;157(1):148.e1-5. Epub 2008 Nov 6. PubMed PMID: 19081411.
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6. Sibbing D, Morath T, Stegherr J, Braun S, Vogt W, Hadamitzky M, Schömig A, Kastrati A, von Beckerath N. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost. 2009 Apr;101(4):714-9. PubMed PMID: 19350116.
7. Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009 Mar 4;301(9):937-44. PubMed PMID: 19258584.