Tamoxifen, SSRIs, and Breast Cancer Recurrence
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In this issue: Tamoxifen and CYP2D6 inhibitors, FDA Actions, and FDA Warnings.
Tamoxifen and CYP2D6 Inhibitors
Two papers presented at the recent American Society of Clinical Oncology (ASCO) have brought to light to potential serious drug interaction between tamoxifen and several commonly used SSRI antidepressants. Tamoxifen is an estrogen receptor blocker commonly used in patients with hormone receptor-positive breast cancer. Many women taking tamoxifen are also taking SSRIs for the treatment of hot flashes or depression. Tamoxifen is extensively metabolized by cytochrome P450 enzymes to its active metabolites, which are primarily responsible for many effects of the drug. Some SSRIs, particularly paroxetine and fluoxetine, are potent inhibitors of CYP2D6, the main enzyme responsible for conversion of tamoxifen to its active form. The studies presented at ASCO revealed some conflicting results, but at least one suggested a near doubling of breast cancer recurrence when tamoxifen was administered with a CYP2D6 inhibitor, findings that agree with some previous studies.
Experts who discussed these findings at ASCO are now generally advising patients who are taking tamoxifen to avoid strong CYP2D6 inhibitors including paroxetine, fluoxetine, sertraline, and even drugs such as bupropion and duloxetine. Options for women taking tamoxifen include citalopram, escitalopram, fluvoxamine, mirtazapine, nefazodone, and venlafaxine. Alternatively, postmenopausal women can be treated with an aromatase inhibitor rather than tamoxifen, as these drugs are not affected by CYP2D6 (J Clin Oncol 2009;27(15S):Abstract CRA 508; J Clin Oncol 2009;27(15S):Abstract CRA 509).
FDA Actions: New Oral Antiplatelet Agent
The FDA has approved prasugrel, a new oral antiplatelet agent for use in preventing thrombosis in patients with acute coronary syndrome who are to be managed by angioplasty. The approval was based on a head-to-head trial with clopidogrel (Plavix®) in patients with a threatened heart attack or who had undergone angioplasty (TRITON-TIMI 38 trial). In the 13,608 patients studied, the rate of nonfatal heart attacks was 7.3% with prasugrel vs 9.5% for clopidogrel. The composite outcome of cardiovascular death, MI, and stroke was 9.9% with prasugrel vs 12.1% with clopidogrel (19% relative risk reduction, P < 0.001); however, major bleeding events were more common with prasugrel than clopidogrel (2.4% vs 1.8%). The rate of recurrent stroke was also slightly higher with prasugrel, prompting the FDA to state that prasugrel should not be used in patients with a history of transient ischemic attacks or stroke. It also should not be used in patients with pathological bleeding or an urgent need for surgery. Whether prasugrel is affected by concomitant administration of a proton pump inhibitor, a problem that has recently come to light with clopidogrel, is currently being investigated. Prasugrel will be marketed in partnership with Lilly and Daiichi Sankyo under the trade name Effient™.
Plan B One-Step
The FDA has approved a single-dose formulation of Plan B, the emergency contraceptive previously available in a two-tablet dose. Marketed as Plan B One-Step, the FDA will allow it to be sold over the -counter to consumers age 17 or older, while those younger than 17 will need a prescription. Plan B One-Step is indicated for prevention of pregnancy when taken within 72 hours of unprotected sex or contraceptive failure.
Dronedarone Approved
The anti-arrhythmic dronedarone has been approved by the FDA for maintenance of normal sinus rhythm in patients with a history of atrial fibrillation or atrial flutter. It is indicated for patients who have returned to sinus rhythm or who will be undergoing cardioversion. Dronedarone, which is closely related to amiodarone, was approved after a large trial showed that the drug reduced cardiovascular hospitalization or death from any cause by 24% when compared to placebo. This is the second time that the FDA has considered dronedarone. The drug was rejected in 2006 because of safety concerns in patients with heart failure, and the new approval carries a box warning cautioning against use in patients with severe heart failure. As opposed to amiodarone, dronedarone does not have an iodine moiety and also is less lipophilic, potentially resulting in less thyroid and neurologic toxicity. Dronedarone will be marketed by Sanofi-Aventis as Multaq®.
FDA Warnings
The FDA has recently issued stronger warnings on a number of commonly used drugs:
Propoxyphene and Overdose Risk
Propoxyphene-containing pain medications including Darvon® and Darvocet® have been a focus of the FDA because of data linking propoxyphene to fatal overdoses. The FDA is requiring a new box warning emphasizing the potential for overdose and is requiring manufacturers to provide a medication guide for patients stressing the importance of using the drugs as directed. The agency is particularly concerned about use of propoxyphene in the elderly and is planning on studying the safety profile of propoxyphene vs other pain relievers in this group. At the same time, the FDA denied a petition from the public interest group Public Citizen requesting a phased withdrawal of pro-poxyphene from the market. In January, an FDA subcommittee narrowly approved a recommendation to ban propoxyphene outright, a step that the European Medicines Agency, Europe's equivalent of the FDA, took in June. Still the FDA feels that propoxyphene has a role and is useful enough to remain on the market, at least for now.
Omalizumab for Allergic Asthma
The FDA announced in July that it is evaluating interim safety findings from an ongoing study of omalizumab (Xolair®), which is used to treat adults and adolescents with moderate-to-severe persistent allergic asthma not adequately controlled on inhaled steroids. Interim data from a study of 5000 treated patients presented to the FDA suggest a disproportionate increase in ischemic heart disease, arrhythmias, cardiomyopathy and cardiac failure, pulmonary hypertension, cerebrovascular disorders, and embolic, thrombotic, and thrombophlebitic events in patients treated with omalizumab compared with placebo. The FDA currently has no recommendations on changing prescriber information and is not advising patients to stop using the drug at this time.
Smoking Cessation and Psychiatric Effects
The smoking cessation drugs varenicline (Chantix®) and bupropion (Zyban®, Wellbutrin®) must carry new box warnings regarding the risk of serious neuropsychiatric symptoms associated with use of the drugs. The FDA advises patients to stop taking these drugs immediately if they develop changes in behavior, hostility, agitation, depression, and suicidal thoughts or behavior. Patients with pre-existing psychiatric illness may be at particular risk.
This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: [email protected].
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