From MedscapeCME Clinical Briefs
Drugs to Avoid in Women Taking Tamoxifen
May 13, 2010 — Medications that should be avoided by women who are taking tamoxifen for the prevention of breast cancer, either primary or recurrence, are listed in a review published online May 3 in the Journal of Clinical Oncology.These new recommendations extend previous work that singled out paroxetine and fluoxetine as drugs to avoid in women who are already taking tamoxifen, as reported by Medscape Oncology, and they include certain antipsychotics, cardiac drugs, and medications for infectious diseases.
Which medications should be avoided in the setting of tamoxifen? This important clinical question is asked by physicians and patients on a daily basis in clinical practice, say the authors of the review. They are all from the Mayo Clinic, in Rochester, Minnesota; the senior author is Matthew Goetz, MD.
This team has been at the forefront of research into tamoxifen metabolism, which occurs in the cytochrome P450 system, primarily by the rate-limiting enzyme CYP2D6. It is clinically important because the drug exerts its beneficial effects through its active metabolite (endoxifen), and any interference with the metabolism of tamoxifen leads to lower blood levels and less protection against breast cancer.
Previously, this team used CYP2DP genotyping to identify poor and good metabolizers of tamoxifen, who respond, correspondingly, either poorly or well to treatment with tamoxifen, as previously reported by Medscape Oncology
Medications to Avoid
Now the team has reviewed the medical literature for evidence of drugs that are strong inhibitors of CYP2D6; these should not be prescribed with tamoxifen because they interfere with its metabolism and result in lower blood levels of the active metabolite."We recommend that potent CYP2D6 inhibitors be avoided in women receiving tamoxifen," the authors state, adding that there is "strong" evidence to support this recommendation.
The authors list the following drugs as moderate to potent inhibitors of CYP2D6:
- antidepressants that act as selective serotonin reuptake inhibitors (SSRIs) or selective noradrenergic reuptake inhibitors (SNRIs) — paroxetine, fluoxetine, bupropion, and duloxetine
- antipsychotics — thioridazine, perphenazine, and pimozide
- cardiac drugs — quinidine and ticlopidine
- medications for infectious disease — terfenadine and quinidine
- miscellaneous medication — cinacalcet.
They list the alternative drugs that are expected to have little in vivo inhibition:
- antidepressants (SSRIs/SNRIs) — venlafaxine, desvenlafaxine, reboxetine, escitalopram, and mirtazapine
- antipsychotics — thiothixene, clozapine, risperidone, olanzapine, ziprasidone, and quetiapine
- cardiac drugs — diltiazem
- medications for infectious diseases — indinavir, saquinavir, nelfinavir, delavirdine, nevirapine, and efavirenz
- miscellaneous medication — gabapentin.
Also, among the histamine H2-blockers, cimetidine is an intermediate inhibitor of CYP2D6, whereas ranitidine has little inhibition and is therefore preferable.
Uncertainty Over Testing
In their review, the Mayo researchers reiterate their position that recommendations for tamoxifen therapy "are best made with knowledge regarding the patients' CYP2D6 genotype."
Dr. Goetz previously told Medscape Oncology that the Mayo Clinic has been testing for CYP2D6 before prescribing tamoxifen for more than 3 years. He said that it is a reasonable thing to do, particularly in the postmenopausal setting, where there is an alternative treatment (aromatase inhibitors) that can be offered to women who are found to be poor metabolizers of tamoxifen.
However, not everyone agrees with this, including Medscape Oncology video blogger Kathy Miller, MD, from Indiana University School of Medicine in Indianapolis, who said last month that CYP2D6 testing is not ready for prime time.
In addition, a recent editorial in the Journal of Clinical Oncology (2010;28:1273-1275) reported that there is hesitancy and uncertainty about CYP2D6 testing in clinical practice. The editorialists, Timothy Lash, MD, PhD, and Carol Rosenberg, MD, from Boston University School of Health in Massachusetts, also noted that such testing is not recommended in any clinical guidelines, as reported by Medscape Oncology.
But among all this uncertainty, the editorial continued, there is one practice recommendation that can be made — avoid drugs that inhibit the CYP2D6 system.
In comments that echo the recommendations of the Mayo team, that editorial urges physicians "to be cautious about prescribing comedications that might interact with tamoxifen via CYP2D6 inhibition."
Where there are therapeutically similar drugs available, it is "prudent to prescribe medications that inhibit CYP2D6 very little," Drs. Lash and Rosenberg add.
Four of the authors are listed (along with Mayo Clinic) as coinventors for nonprovisional patent applications regarding tamoxifen and CYP2D6. The technology is not licensed and no royalties have accrued.
J Clin Oncol. Published online May 3, 2010. Abstract
Additional Resource
More information on use of tamoxifen is available on the National Cancer Institute's Web site.
Study Highlights
- The reviewers strongly recommend that potent CYP2D6 inhibitors be avoided in women receiving tamoxifen.
- When it is necessary for tamoxifen-treated women to receive a drug known to potently inhibit CYP2D6, clinicians should consider treating with the inhibitor for the shortest period possible (weak recommendation).
- No specific recommendations were made regarding discontinuation of weak to moderate CYP2D6 inhibitors in tamoxifen-treated women, because neither prospective data nor retrospective level 2 evidence exists regarding their effects on breast cancer recurrence.
- When alternative options are available within a given drug class, clinicians should consider prescribing a drug with the least amount of CYP2D6 inhibition to tamoxifen-treated women (weak recommendation).
- Recommendations for tamoxifen therapy and use of CYP2D6 inhibitors are best made by considering the patient's CYP2D6 genotype.
- Prospective studies have shown that low plasma endoxifen concentrations result from either genetic CYP2D6 variation or from the coadministration of potent CYP2D6 inhibitors.
- Discontinuing tamoxifen and starting alternative hormonal therapy (eg, an aromatase inhibitor) should be considered in postmenopausal women treated with tamoxifen in either the adjuvant or metastatic breast cancer setting, when it is necessary to use a drug known to potently inhibit CYP2D6, or when a patient is a known CYP2D6 poor metabolizer (weak recommendation).
- Moderate to potent inhibitors of CYP2D6 that should be avoided in tamoxifen-treated women and preferred choices to substitute if possible include the following:
- Avoid SSRI or SNRI antidepressants paroxetine, fluoxetine, bupropion, and duloxetine; substitute venlafaxine, desvenlafaxine, reboxetine, escitalopram, or mirtazapine.
- Avoid antipsychotics thioridazine, perphenazine, and pimozide; substitute thiothixene, clozapine, risperidone, olanzapine, ziprasidone, or quetiapine.
- Avoid cardiac drugs quinidine and ticlopidine, but diltiazem is acceptable.
- Avoid terfenadine and quinidine to treat infectious disease; substitute indinavir, saquinavir, nelfinavir, delavirdine, nevirapine, or efavirenz.
- Cinacalcet should be avoided, whereas gabapentin has little CYP2D6 inhibition.
- If possible, avoid prescription and over-the-counter antihistamines that are intermediate inhibitors of CYP2D6; preferable alternatives with little inhibition include chlorpheniramine, cetirizine, and loratadine.
- If possible, avoid the histamine H2-blocker cimetidine, which is an intermediate inhibitor of CYP2D6; substitute ranitidine, which has little inhibition.
Clinical Implications
- Evidence is growing for the possible harm of CYP2D6 inhibition in tamoxifen-treated women. Despite the absence of conclusive evidence in many settings, recommendations regarding the use of CYP2D6 inhibitors in tamoxifen-treated women can be made, given the relative safety of discontinuing these medications or substituting others in most, but not all, situations.
- Moderate to potent inhibitors of CYP2D6 should be avoided in tamoxifen-treated women, and preferred choices with less CYP2D6 inhibition should be substituted if possible. For example, the SSRI or SNRI antidepressants paroxetine, fluoxetine, bupropion, and duloxetine should be avoided and venlafaxine, desvenlafaxine, reboxetine, escitalopram, or mirtazapine substituted if possible.
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