increased risk of thromboembolism especially during and immediately after major surgery or periods of immobility. Use of tamoxifen has been shown to slightly increase risk of deep vein thrombosis, pulmonary embolism, and stroke. Liver toxicity Tamoxifen has been associated with a number of cases of hepatotoxicity. Several different varieties of hepatotoxicity have been reported. Tamoxifen can also precipitate non-alcoholic fatty liver disease in obese and overweight women (not in normal weight women) at an average rate of 40% after a year use with 20 mg/day. Overdose Acute overdose of tamoxifen has not been reported in humans. In dose-ranging studies, tamoxifen was administered at very high doses in women (e.g., 300 mg/m2) and was found to produce acute neurotoxicity including tremor, hyperreflexia, unsteady gait, and dizziness. These symptoms occurred within three to five days of therapy and disappeared within two to five days of discontinuation of therapy. No indications of permanent neurotoxicity were observed. QT prolongation was also observed with very high doses of tamoxifen. There is no specific antidote for overdose of tamoxifen. Instead, treatment should be based on symptoms. Interactions Patients with variant forms of the gene CYP2D6 may not receive full benefit from tamoxifen because of too slow metabolism of the tamoxifen prodrug into its active metabolites. On 18 October 2006, the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert. Certain CYP2D6 variations in breast cancer patients lead to a worse clinical outcome for tamoxifen treatment. Genotyping therefore has the potential for identification of women who have these CYP2D6 phenotypes and for whom the use of tamoxifen is associated with poor outcomes. Recent research has shown that 7–10% of women with breast cancer may not receive the full medical benefit from taking tamoxifen due to their genetic make-up. DNA Drug Safety Testing can examine DNA variations in the CYP2D6 and other important drug processing pathways. More than 20% of all clinically used medications are metabolized by CYP2D6 and knowing the CYP2D6 status of a person can help the doctor with the future selection of medications. Other molecular biomarkers may also be used to select appropriate patients likely to benefit from tamoxifen. Recent studies suggest that taking the selective serotonin reuptake inhibitors (SSRIs) antidepressants paroxetine (Paxil), fluoxetine (Prozac), and sertraline (Zoloft) can decrease the effectiveness of tamoxifen, as these drugs compete for the CYP2D6 enzyme which is needed to metabolize