indication

For the treatment of breast cancer.

pharmacology

Tamoxifen belongs to a class of drugs called selective estrogen receptor modulators (SERMs), which have both estrogenic and antiestrogenic effects. Tamoxifen has the same nucleus as diethylstilbestrol but possesses an additional side chain (trans isomer) which accounts for its antiestrogenic activity.

mechanism of action

Tamoxifen binds to estrogen receptors (ER), inducing a conformational change in the receptor. This results in a blockage or change in the expression of estrogen dependent genes. The prolonged binding of tamoxifen to the nuclear chromatin of these results in reduced DNA polymerase activity, impaired thymidine utilization, blockade of estradiol uptake, and decreased estrogen response. It is likely that tamoxifen interacts with other coactivators or corepressors in the tissue and binds with different estrogen receptors, ER-alpha or ER-beta, producing both estrogenic and antiestrogenic effects.

toxicity

Signs observed at the highest doses following studies to determine LD₅₀ in animals were respiratory difficulties and convulsions.

biotransformation

Hepatic. Tamoxifen is extensively metabolized after oral administration. N-Desmethyl-tamoxifen is the major metabolite found in plasma. N-Desmethyl-tamoxifen activity is similar to tamoxifen. 4-hydroxy-tamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. 4-Hydroxy-tamoxifen formation is catalyzed mainly by cytochrome P450 (CYP) 2D6, and also by CYP2C9 and 3A4. At high tamoxifen concentrations, CYP2B6 also catalyzes 4-hydroxylation of the parent drug. 4-Hydroxy-tamoxifen possesses 30- to 100-times greater affinity for the estrogen receptor and 30- to 100-times greater potency at inhibiting estrogen-dependent cell proliferation compared to tamoxifen.

half life

Distribution t_1/2=7 to 14 hours; Elimination t_1/2=5 to 7 days; Elimination t_1/2 of N-desmethyl-tamoxifen=9-14 days.

route of elimination

The drug is excreted mainly as polar conjugates, with unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal radioactivity.

drug interactions

Acenocoumarol: Tamoxifen may increase the serum concentration of Acenocoumarol increasing the risk of bleeding. Concomitant therapy should be avoided.

Aminoglutethimide: Aminoglutethimide may increase Tamoxifen clearance decreasing its therapeutic effect. Consider alternate therapy or monitor for changes in Tamoxifen effects when Aminoglutethimide is initiated, discontinued or dose changed.

Amiodarone: Amiodarone may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Amprenavir: Amprenavir may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen.

Atazanavir: Atazanavir may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen.

Capecitabine: Capecitabine may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Capecitabine is initiated, discontinued or dose changed.

Chloroquine: Chloroquine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Chlorpromazine: Chlorpromazine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Concomitant therapy should be avoided.

Cimetidine: Cimetidine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Cinacalcet: Cinacalcet may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Concomitant therapy should be avoided.

Clarithromycin: Clarithromycin may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen.

Clomipramine: Clomipramine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Clozapine: Clozapine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Cocaine: Cocaine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Concomitant therapy should be avoided.

Conivaptan: Conivaptan may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen.

Darifenacin: Darifenacin may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Darunavir: Darunavir may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen.

Delavirdine: Delavirdine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Concomitant therapy should be avoided.

Desipramine: Desipramine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Diphenhydramine: Diphenhydramine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Duloxetine: Duloxetine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Floxuridine: Floxuridine may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Floxiridine is initiated, discontinued or dose changed.

Fluconazole: Fluconzole may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Fluconazole is initiated, discontinued or dose changed.

Fluorouracil: Fluorouracil may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Fluorouracil is initiated, discontinued or dose changed.

Fluoxetine: Fluoxetine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Concomitant therapy should be avoided.

Flurbiprofen: Flurbiprofen may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Flurbiprofen is initiated, discontinued or dose changed.

Fosamprenavir: Fosmprenavir may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen.

Gemfibrozil: Gemfibrozil may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Gemfibrozil is initiated, discontinued or dose changed.

Haloperidol: Haloperidol may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Ibuprofen: Ibuprofen may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Ibuprofen is initiated, discontinued or dose changed.

Imatinib: Imatinib may increase the serum concentration of Tamoxifen by decreasing its metabolism and clearance. Imatinib may also decrease the therapeutic effect of Tamoxifen by decreasing active metabolite production. Monitor for changes in the therapeutic/adverse effects of Tamoxifen if Imatinib is initiated, discontinued or dose changed.

Imipramine: Imipramine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Indinavir: Indinavir may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen.

Indomethacin: Indomethacin may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Indomethacin is initiated, discontinued or dose changed.

Isoniazid: Isoniazid may increase the serum concentration of Tamoxifen by decreasing its metabolism and clearance. Isoniazid may also decrease the therapeutic effect of Tamoxifen by decreasing active metabolite production. Monitor for changes in the therapeutic/adverse effects of Tamoxifen if Isoniazid is initiated, discontinued or dose changed.

Itraconazole: Itraconazole may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen.

Ketoconazole: Ketoconazole may increase the serum concentration of Tamoxifen by decreasing its metabolism and clearance. Ketoconazole may also decrease the therapeutic effect of Tamoxifen by decreasing active metabolite production. Monitor for changes in the therapeutic/adverse effects of Tamoxifen if Ketoconazole is initiated, discontinued or dose changed.

Lidocaine: Lidocaine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Lopinavir: Lopinavir may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Concomitant therapy should be avoided.

Lumefantrine: Lumefantrine, a moderate CYP2D6 inhibitor, may decrease the formation of highly potent tamoxifen metabolites. Concomitant therapy may decrease the effectiveness of tamoxifen. Consider alternate therapy.

Mefenamic acid: Mefenamic acid may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Mefenamic acid is initiated, discontinued or dose changed.

Methadone: Methadone may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Methimazole: Methimazole may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Miconazole: Miconazole may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Concomitant therapy should be avoided.

Nefazodone: Nefazodone may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen.

Nelfinavir: Nelfinavir may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen.

Nicardipine: Nicardipine may increase the serum concentration of Tamoxifen by decreasing its metabolism and clearance. Nicardipine may also decrease the therapeutic effect of Tamoxifen by decreasing active metabolite production. Monitor for changes in the therapeutic/adverse effects of Tamoxifen if Nicardipine is initiated, discontinued or dose changed.

Nilotinib: Nilotinib may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Paroxetine: Paroxetine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Concomitant therapy should be avoided.

Pergolide: Pergolide may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Concomitant therapy should be avoided.

Pioglitazone: Pioglitazone may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Piroxicam: Piroxicam may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Piroxicam is initiated, discontinued or dose changed.

Posaconazole: Posaconazole may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen.

Pyrimethamine: Pyrimethamine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Quinidine: Quinidine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Concomitant therapy should be avoided.

Quinine: Quinine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Quinupristin: This combination presents an increased risk of toxicity

Ranolazine: Ranolazine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Rifabutin: The rifamycin decreases the effect of anti-estrogen

Rifampin: The rifamycin decreases the effect of anti-estrogen

Ritonavir: Ritonavir may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Concomitant therapy should be avoided.

Rivaroxaban: Tamoxifen may increase serum concentrations of Rivaroxaban increasing the risk of bleeding. Concomitant therapy should be avoided.

Saquinavir: Saquinavir may increase the serum concentration of Tamoxifen by decreasing its metabolism. Monitor for increased adverse/toxic effects of Tamoxifen.

Sertraline: Sertraline may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Sitaxentan: Sitaxsentan may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Sitaxsentan is initiated, discontinued or dose changed.

Sulfadiazine: Sulfadiazine may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Sulfadiazine is initiated, discontinued or dose changed.

Sulfisoxazole: Sulfisoxazole may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Sulfisoxazole is initiated, discontinued or dose changed.

Telithromycin: Telithromycin may reduce clearance of Tamoxifen. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Tamoxifen if Telithromycin is initiated, discontinued or dose changed.

Terbinafine: Terbinafine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Concomitant therapy should be avoided.

Thioridazine: Thioridazine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Ticlopidine: Ticlopidine may decrease the therapeutic effect of tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Tolbutamide: Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tamoxifen. Consider alternate therapy or monitor for changes in Tamoxifen therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.

Topotecan: The p-glycoprotein inhibitor, Tamoxifen, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.

Tranylcypromine: The CYP2D6 inhibitor, Tranylcypromine, may decrease the efficacy of Tamoxifen by reducing active metabolite production. Consider alternate therapy.

Trazodone: Trazodone may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Tretinoin: The moderate CYP2C8 inhibitor, Tamoxifen, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Tamoxifen is initiated, discontinued to dose changed.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of tamoxifen by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of tamoxifen if voriconazole is initiated, discontinued or dose changed.

Warfarin: Tamoxifen, a CYP2C9 inhibitor, may increase the serum concentration of warfarin by decreasing its metabolism. Concomitant therapy is contraindicated due to significant increase in bleed risk.