By Zosia Chustecka
Medscape Medical News
Tamoxifen.jpg 

May 5, 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.

There are usually alternatives within each given drug class, and consideration should be given to a drug with the least amount of CYP2D6 inhibition, the authors write.

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.

In addition to the drug classes listed above, many drugs that fall into the antihistamine category (available by prescription and over the counter) are intermediate inhibitors of CYP2D6, the authors note. Alternative options that have little inhibition include chlorpheniramine, cetrizine, and loratadine.

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.

 

作者:Zosia Chustecka 出處:WebMD醫學新聞
  【24drs.com】May 5, 2010 — 5月3日線上版臨床腫瘤期刊(Journal of Clinical Oncology)的一篇回顧,列出服用tamoxifen來預防乳癌(不論是初發或復發)的婦女應避免使用的藥品。
  
  這些新建議擴大了之前Medscape Oncology所報導的服用tamoxifen時應避免使用的藥物(paroxetine和fluoxetine)範圍,新納入了一些抗精神病藥物、心臟用藥、感染症用藥等。
  
  使用tamoxifen者應避免哪些藥物呢?作者們在回顧中指出,在臨床實務上,每天都有病患和醫師提出這個問題,這些研究者都來自明尼蘇達州羅徹斯特梅約診所,資深作者是Matthew Goetz醫師。
  
  該團隊率先研究指出tamoxifen在細胞色素P450 (cytochrome P450)中,主要是由速率限定酵素CYP2D6代謝。這有臨床重要性,因為此藥物透過活性代謝物(endoxifen)發揮效用,任何會干擾tamoxifen代謝的因素都會導致血中濃度降低且減少抗乳癌效果。
  
  之前,該團隊使用CYP2DP基因定型分析來辨識tamoxifen的不佳或良好代謝,藉以對應哪些人對於tamoxifen治療有不佳或良好的反應,當時由Medscape Oncology報導。
  
  【應避免的藥物】
  現在,該團隊回顧了CYP2D6之強力抑制劑的藥物文獻;這些藥物不應和tamoxifen同時處方,因為它們會干擾其代謝而導致活性代謝物的血中濃度降低。
  
  作者們指出,我們建議,服用tamoxifen的婦女應避免強力CYP2D6 抑制劑,此篇研究為此建議增添強力證據。
  
  作者們列出中度到強度的CYP2D6 抑制劑如下:
  * 選擇性血清素再吸收抑制劑(SSRIs)或選擇性正腎上腺素再吸收抑制劑(SNRIs)等抗憂鬱藥物— paroxetine、fluoxetine、bupropion以及duloxetine
  * 抗精神病藥物 — thioridazine、perphenazine以及 pimozide
  * 心臟用藥 — quinidine以及 ticlopidine
  * 感染症用藥 — terfenadine以及quinidine
  * 其他藥物 — cinacalcet
  
  作者們寫道,通常用該類的其他替代藥物取代這些品項,並考量CYP2D6抑制效果最低的藥物。
  
  他們列出體內抑制活性較低的替代藥物:
  * 抗憂鬱藥物 (SSRIs/SNRIs) — venlafaxine、desvenlafaxine、reboxetine、escitalopram以及mirtazapine
  * 抗精神病藥物— thiothixene、clozapine、risperidone、olanzapine、ziprasidone以及 quetiapine
  * 心臟用藥— diltiazem
  * 感染症用藥— indinavir、saquinavir、nelfinavir、delavirdine、nevirapine以及 efavirenz
  * 其他藥物— gabapentin
  
  作者們指出,除了避免上列藥物之外,許多抗組織胺藥物(處方藥與成藥)屬於CYP2D6中度抑制劑,抑制強度較低的替代品項包括chlorpheniramine、cetrizine以及loratadine。
  
  此外,在組織胺H2-阻斷劑中,cimetidine是CYP2D6中度抑制劑,ranitidine的抑制強度較小,所以應優先考慮使用。
  
  【檢測時的不確定性】
  梅約診所的研究者在此次回顧中重申他們的立場,對於基因型的病患,tamoxifen治療有相當充足的知識證據。
  
  Goetz醫師曾經向Medscape Oncology表示,梅約診所落實在開立tamoxifen之前檢測CYP2D6的政策已經達3年以上,他表示,這是相當有道理的,特別是停經後婦女,使用替代治療(芳香胺 酶抑制劑)於證實對tamoxifen代謝不佳的婦女。
  
  不過,並非每個人都同意這一點,包括Medscape Oncology影片部落格主、印第安那大學醫學院的Kathy Miller醫師在上個月表示,目前而言,尚未準備好進行CYP2D6檢測。
  
  此外,最近在臨床腫瘤期刊(2010;28:1273-1275)的編輯評論指出,臨床實務上,CYP2D檢測尚嫌不足。來自波士頓大學醫學院的編輯Timothy Lash博士以及Carol Rosenberg醫師也指出,如同Medscape Oncology所報導的,尚未有任何臨床指引建議進行此類檢測。
  
  但是,編輯評論中也指出,在這所有的不確定性中,有一個實務建議已經達成— 避免使用抑制CYP2D6的藥物。
  
  在回應梅約診所研究團隊的建議中,編輯們鼓勵醫師在開立因為抑制CYP2D6而和tamoxifen有交互作用的藥物時須謹慎。
  
  Lash博士以及Rosenberg醫師指出,只要有治療上相似的藥物,就要謹慎使用抑制CYP2D6強度最小的藥物。
  
  這四位作者(以及梅約診所)列為有關tamoxifen和CYP2D6之應用的無條件性專利(Non-provisional Patent)的共同開發者,這項技術尚未獲得核准與專利權。
  
  J Clin Oncol.線上發表於2010年5月3日。


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