NPC Archive Item: Tamoxifen effectiveness reduced by CYP2D6 liver enzyme inhibitors

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27 September 2011

According to a public assessment report published by the MHRA there is growing evidence that drugs that strongly inhibit the liver enzyme CYP2D6, including some SSRIs such as paroxetine, may interact with tamoxifen resulting in a poorer clinical outcome for women taking tamoxifen for breast-cancer treatment.

Based on this evidence the following recommendations have been made to health care professionals:

Concomitant use of medicines that are potent inhibitors of the CYP2D6 enzyme should be avoided whenever possible in patients treated with tamoxifen for breast cancer. Examples of such drugs include:

  • Paroxetine
  • Fluoxetine
  • Bupropion
  • Quinidine
  • Cinacalcet

Current data for the impact of CYP2D6 genetic polymorphisms (i.e. individuals who vary in their natural level of CYP2D6 function) on the effectiveness of tamoxifen are insufficient to support recommending genotyping of patients.

What is the pharmacokinetic basis for this interaction?
Tamoxifen is a prodrug, and the formation of the active metabolite, endoxifen, is mediated by the CYP2D6 liver enzyme. Therefore, factors that affect CYP2D6 enzymatic activity have the potential to impact on the effectiveness of tamoxefin. Potential factors are:

  • Drugs that inhibit CYP2D6, such as SSRIs;
  • CYP2D6 polymorphism

So what are the clinical ramifications?
After consideration of current available data, the European Expert Working Group and MHRA concluded that there is sufficient evidence to suggest a strong association between reduced enzyme activity of CYP2D6 and the risk of lowered tamoxifen response. They concluded that although the study by Kelly et al, 2010 has important limitations, it adds to the evidence in favour of a clinical impact for interactions between CYP2D6 inhibitors and tamoxifen

The MHRA report states that the evidence for an association between CYP2D6 genetic polymorphism and clinical outcome in patients treated with tamoxifen is mixed and inconclusive. Patients treated with tamoxifen for breast cancer who have naturally reduced levels of CYP2D6 activity do not, on the whole, demonstrate worse clinical outcomes than patients treated with tamoxifen who have normal CYP2D6 activity.

A discussion of this information was included in an article within the November 2010 issue of Drug Safety Update.

Further information relating to tamoxifen can be found on NHS Evidence and in the breast cancer e-learning section of the NPC website.

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