Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:

Tamoxifen and several of its metabolites are thought to act as estrogen antagonists, by competitively binding to estrogen receptors on tumour and other tissue targets, producing a nuclear complex that decreases DNA synthesis.2,3 This mechanism appears to have cytostatic effects, causing cells to accumulate in G0 and G1 phases.2

Tamoxifen may also have cytotoxic activity; tamoxifen may induce apoptosis independent of estrogen receptor expression.4,5 It is also recognized that tamoxifen acts as an estrogen agonist on endometrium, bone and lipids.3

PHARMACOKINETICS:

SPECIAL PRECAUTIONS:

Mutagenicity: Not mutagenic in Ames test and in the mammalian in vivo mutation test.24 It is not known if tamoxifen is clastogenic.25

Fertility: Tamoxifen may cause disturbances of menstrual cycle, including infrequent or light menstruation and amenorrhea.3 Tamoxifen does not induce menopause. Premenopausal women should be advised not to become pregnant while taking tamoxifen.3 Tamoxifen has been used to treat infertility.26-30 Tamoxifen has caused impotence in men.31

Pregnancy: FDA Pregnancy Category D.2 There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Breastfeeding is not recommended due to the potential secretion into breast milk.32 Tamoxifen may inhibit lactation.32

Special populations: The risk of serious adverse events is higher in patients older than 50 years of age.6 Women of childbearing potential should initiate tamoxifen during menstruation; barrier or nonhormonal contraceptives should be used and pregnancy avoided for 2 months after tamoxifen is discontinued.2 Porphyric patients must

avoid tamoxifen, as tamoxifen has been associated with acute attacks of porphyria.8

SIDE EFFECTS:

The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be

clinically important.33 When placebo-controlled trials are available, adverse events are included if the incidence is > 5% higher in the treatment group.

ORGAN SITE	SIDE EFFECT
Clinically important side effects are in bold, italics
allergy/immunology	hypersensitivity reactions ( < 3%) 2,24,34
allergy/immunology	vasculitis 6,35
blood/bone marrow/ febrile neutropenia	myelosuppression; anemia, 3,34 leukopenia, 34,36 neutropenia, 24 thrombocytopenia 24 ; transient 6 ( < 10%) 2,34,37,38
cardiovascular (arrhythmia)	QT prolongation 39,40
cardiovascular (general)	cardiovascular events (4%, severe 1%) 41
cardiovascular (general)	hypertension (7-11%) 37-39
ORGAN SITE	SIDE EFFECT
Clinically important side effects are in bold, italics
	ischemic heart disease (1-3%, severe 0.6%) 38,41,42
	thromboembolic events (2-5%, severe 1-2%) 38,39,41-44
constitutional symptoms	fatigue (4-24%, severe 2%) 2,39,42,43
	sweating (6-18%, severe 3%) 37,43,44
	weight gain (8-9%) 37,39
	weight loss (23%) 2
dermatology/skin	alopecia (<5%) 2,44
	cutaneous lupus erythematosus 45
	nail changes (3%) 38
	porphyria cutanea tarda 46 ; has occurred after years on treatment 46
	radiation recall 47-49
	rash (<13%) 2,24,37,39
	skin changes (6-19%) 2
	Stevens-Johnson syndrome, erythema multiforme, bullous pemphigoid (<1%) 2
endocrine	hot flashes (25-81%, severe 4%) 2,3,6,41-43
gastrointestinal	anorexia (1-3%) 2,44
	constipation (1-8%) 2,37,39,44
	diarrhea (2-7%, severe 0.04%) 37-39,43
	dyspepsia (6%) 37
	dry mouth (2%) 38
	nausea (5-26%, severe 0.7%) 2,3,37,39,42-44
	vomiting (2%) 44
hemorrhage	hemorrhage 6
hemorrhage	vaginal bleeding (2-23%, severe 0.1-0.3%) 2,37,39,41-43
hepatobiliary/pancreas	cholestasis ( < 0.1%) 34
	gallstones; generally occurs after 2-3 years of treatment 50
	pancreatitis (<1%) 2,6,34
	liver dysfunction, hepatitis (<1%) 2,34,38
infection	urinary tract infection (10%) 37,38
infection	vulvovaginal candidiasis 51 (4%) 38
lymphatics	peripheral edema (8-11%) 37,39
metabolic/laboratory	elevated creatinine 6
	hypercalcemia (<1%) 2 ; with metastatic disease; generally occurs shortly after starting treatment 3,6
	altered lipid profile; decreased total and LDL cholesterol, decreased HDL cholesterol, 6 hypercholestremia (3%) 38 , increased triglycerides ( < 1%) 6,34,52,53 ; onset may be delayed months or years 6,52,53
ORGAN SITE	SIDE EFFECT
Clinically important side effects are in bold, italics
	elevated liver function tests 6,24 ( < 1%) 34
musculoskeletal	arthritis (14%) 37
	arthrosis (4%) 39
	favorable effect on bone mass 54-56
	fractures (4-8%) 37,38,41,42
	osteoporosis (6-7%) 37,38,43
neurology	anxiety (6%) 37
	depression (4-12%, severe 0.2%) 37,43
	dizziness (8-12%, severe 0.6%) 37,43
	ischemic cerebrovascular events (1-3%, severe 1%) 39,41,42
	insomnia (6-17%, severe 1%) 37,39,43
	paresthesia (5%) 37,38
ocular/visual	cataracts (<7%) 2,24,34,37,39,42,43
	corneal changes ( < 0.1%) 34
	retinopathy ( < 1%) 2,24,34 ; can occur within weeks-years 57
	vision changes (6%, severe 0.4%) 43
pain	abdominal pain (7-9%) 37
	arthralgia/myalgia (4-29%, severe 0.4-0.9%) 41-43
	back pain (10%) 37
	bone pain (6%) 42 ; generally occurs shortly after starting treatment 3,6
	breast pain (6%) 37
	chest pain (5%) 37
	cramps (4%, severe 0.2%) 43
	headache (2-16, severe 0.8%) 37,39,43,44
	pain not specified (16%) 37
	tumour pain; generally occurs shortly after starting treatment 3
pulmonary	cough (4-10%) 2,6,37,39
	pharyngitis ( < 14%) 37,39
	pneumonitis (<1%) 2
renal/genitourinary	endometrial polyps, hyperplasia, endometriosis ( < 1%) 2,34
	ovarian cysts (<3%) 2,6,34,58,59
	pruritus vulvae (<1%) 2 , vulvovaginitis (5%) 37
	urinary incontinence (4%) 38
	uterine fibroids ( < 1%) 2,24,34
	non-infectious vaginal discharge, leukorrhea (9-13%) 37,42,43
	vaginal dryness (<3%) 2,39
ORGAN SITE	SIDE EFFECT
Clinically important side effects are in bold, italics
secondary malignancy	endometrial cancer (0.8%) 38,42 ; uterine sarcoma
sexual/reproductive function	impotence (<1%) 2
	menstrual dysfunction
	priapism 6
syndromes	flu syndrome (6%) 37
syndromes	tumour flare (<10%) 34 ; generally occurs shortly after starting treatment 3

Adapted from standard reference3 unless specified otherwise.

Hot flashes are one of the most common adverse events reported in women taking tamoxifen, but are rarely severe.6 If severe, they may be controlled in some patients by a decreased or divided dose. Patients who have their sleep interrupted by drenching night sweats may benefit by taking their tamoxifen in the morning.33 Several

medications have been shown to decrease the frequency and severity of hot flashes (See BC Cancer Agency Breast Tumour Group/Cancer Management Guidelines/Breast/Follow-up/Post-menopausal Replacement Therapy).60,61 Occasionally tamoxifen must be discontinued due to severe hot flashes which significantly decrease quality of life.33

Tamoxifen flare response: A transient increase in bone pain, local disease flare (increase in size of preexisting lesions, swelling and redness) and/or hypercalcemia may occur at the initiation of therapy in patients with metastatic disease.3 Serum calcium should be evaluated in any patient with extensive bony metastases on tamoxifen who have symptoms suggestive of hypercalcemia.33 The so-called tamoxifen flare response may be a favourable sign,3 although hypercalcemia may require treatment.

Endometrial changes: Tamoxifen has a stimulant effect on the endometrium, possibly by acting as a partial estrogenic agonist.6 Tamoxifen use has been associated with an increased incidence of endometrial changes, including hyperplasia, polyps, uterine fibroids, and endometriosis.

Uterine malignancies associated with tamoxifen are typically adenocarcinomas of the endometrium; uterine sarcomas, an endometrial cancer with poor prognosis, have also been rarely reported.6,62 The relative risk of

endometrial cancer increases with duration of tamoxifen therapy; this relative risk is small, and must be weighed against the potential benefits of tamoxifen.8 Women receiving or who have received tamoxifen should have routine gynecological care and should be advised to report any abnormal gynecologic symptoms, such as menstrual

irregularities, abnormal vaginal bleeding or discharge, or pelvic pain and pressure immediately.6 Imaging, including endovaginal ultrasound and/or endometrial biopsy may be necessary to rule out malignancy.33

Ocular changes (retinopathy, corneal opacities, decreased visual acuity) have been reported in patients receiving tamoxifen.3,63 A modest increase in the risk of developing cataracts has been associated with tamoxifen treatment.64,65 The relationship between tamoxifen dose and cataract formation is not known.64 Cataract formation may be due to inhibition of chloride channels in the lens by tamoxifen.66 Macular degeneration does not appear to

predispose patients to tamoxifen-related ocular toxicity, nor does tamoxifen accelerate progression of macular degeneration.63 Patients receiving or who have received tamoxifen should be questioned about symptoms of ocular toxicity during follow-up and should seek prompt medical attention for changes in vision.6,63

Thromboembolic events, including deep vein thrombosis, stroke, and pulmonary embolism are increased with tamoxifen.3 Use tamoxifen with caution in individuals with a history of thromboembolic events,2 particularly those not receiving systemic anticoagulation therapy.

Hepatotoxicity usually consists of transient asymptomatic elevation of hepatic enzymes.3 However, more serious liver abnormalities, including fatty liver, cholestasis, and hepatitis, have occurred infrequently; 3 rarely fatalities have been reported.57

Lipid profile: Tamoxifen favorably affects lipid profiles by decreasing total and low-density lipoprotein cholesterol concentrations6; this effect does not translate to a reduced risk of ischemic heart disease.6,65,67 Less favorably, tamoxifen appears to moderately decrease high-density lipoprotein cholesterol concentrations and increase

triglyceride levels.3,6 Rarely, cases of pancreatitis have occurred.3 Periodic monitoring of plasma cholesterol and

triglyceride concentrations is advised for patients taking tamoxifen who have preexisting hyperlipidemias or other clinical indications.

6,18,19

Myelosuppression has been reported with tamoxifen.3 Temporary decreases in platelet and leukocyte counts may occurr.3 Hemorrhagic tendencies are uncommon, and platelet counts have returned to normal without treatment interruption.3 If myelosuppression is suspected, monitor complete blood counts.3,18,19 Use tamoxifen with caution in patients with thrombocytopenia or leukopenia.3

Bone mass: Tamoxifen generally has a favorable effect on bone mass. Tamoxifen reduces bone resorption and decreases bone turnover as manifested by reductions in bone turnover markers and increases in bone density.6 Tamoxifen acts mainly on trabecular bone, such as lumbar spine, and has little effect on cortical bone.6 The effect of tamoxifen on bone density may depend on menopausal status, as premenopausal women have demonstrated a loss

of bone mineral density of the lumbar spine and hip.6 Further information is needed to evaluate the long-term effects of tamoxifen on the risk of osteoporosis and fracture.6

INTERACTIONS:

Tamoxifen, N-desmethyltamoxifen, and 4-hydroxytamoxifen are inhibitors of cytochrome P450 mixed function oxidases, (isoenzymes 2B6, 2C8/9 and 3A4).2,6 The effect of tamoxifen on medications that require mixed function oxidases for activation is unknown.6 CYP3A4, CYP2D6 and, CYP 2C8/9 inhibitors may decrease metabolism and increase tamoxifen plasma concentrations.2,31 Tamoxifen active metabolite concentrations may be affected.86 The clinical impact of this interaction is not known. CYP3A4, CYP2D6, and CYP 2C8/9 inducers may increase metabolism and decrease tamoxifen plasma concentrations.

2,31Tamoxifen active metabolite concentrations may be affected.86 The clinical impact of this interaction is not known.

*Estrogen use with tamoxifen: While hormone replacement therapy is not recommended following estrogen receptor positive breast cancer or while on tamoxifen, postmenopausal symptoms can cause considerable distress to patients; replacement therapy may be considered if other treatment options fail.60 If estrogen is used, prescribe

the lowest dose to relieve symptoms, monitor patient carefully and consider short term use.60 For vaginal complaints such as dyspareunia, dryness and sexual dysfunction, REPLENS(r), a long-lasting vaginal moisturizer can be tried.33 If ineffective, low dose topical estrogen may then be considered.33,60 ESTRING(r) produces a local effect with

systemic levels measurable only for the first 24 hours of the three month ring.33 PREMARIN(r) cream can be used but may have variable systemic levels related to the absorption through the vaginal tissues. The potential risks and benefits should be discussed, the lowest dose to relieve symptoms should be used, and treatment should be

+Grapefruit juice and tamoxifen: Grapefruit juice inhibits the CYP 3A4 metabolism of tamoxifen in the intestine and may increase tamoxifen plasma levels.78 The clinical significance of a low rate of intestinal metabolism to active metabolites is unknown. Monitor for tamoxifen toxicity.

++Antidepressant use with tamoxifen: The metabolism of tamoxifen to active 4-hydroxy-N-desmethyl-tamoxifen (endoxifen) metabolites is inhibited by paroxetine, a potent inhibitor of CYP2D6.84 Other Selective Serotonin Reuptake Inhibitors (SSRI's) that inhibit CYP2D6 also inhibit the metabolism of tamoxifen.84 The magnitude of

reduction in endoxifen plasma concentration associated with CYP 2D6 inhibitors also depends on variations in CYP 2D6 genotypes.9,10,84 The minimally active levels of tamoxifen and its active metabolites are not known.89 The clinical significance of a low rate of hydroxylation to endoxifen is not known; the potential benefit of antidepressant use must

be weighed against the potential risk.9,10,13,90 Antidepressants that are weak inhibitors or do not inhibit CYP 2D6 may be considered.84

SUPPLY AND STORAGE:

Tablets: Apotex, Genpharm, and Novopharm supply tamoxifen as 10 mg or 20 mg tablets. AstraZeneca supplies tamoxifen as a 20 mg tablet. Selected non-medicinal ingredients: lactose.

Aventis Pharma supplies tamoxifen as 10 mg or 20 mg tablets. Selected non-medicinal ingredients: lactose. Store tamoxifen at room temperature and protect from light.3

DOSAGE GUIDELINES:

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.

Dosage in hepatic failure: adjustment required, no details found93; dosing may be based on serum levels of tamoxifen and its active metabolites94

REFERENCES:

Repchinsky C, editor. Compendium of Pharmaceuticals and Specialties Nolvadex-D. Ottawa: Canadian Pharmacists Association; 2006. p. 1455-1456. Baptista MZ, Prieto VG, Chon S, et al. Tamoxifen-related vasculitis. J Clin Oncol 2006; 24(21):3504-3505. Mike V, Currie VE, Gee TS. Fatal neutropenia associated with long-term tamoxifen therapy. Lancet 1994; 344(8921):541-2. AstraZeneca. Arimidex-adjuvant product monograph. Mississauga, Ontario; 16 June 2004. The ATAC Trialists Group. Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early- stage breast cancer: long-term safety analysis of the ATAC trial. Lancet Oncology 2006; 7(8):633-643. AstraZeneca. Arimidex product monograph. Mississauga, Ontario; 16 June 2004. De Ponti F, Poluzzi E, Cavalli A, et al. Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: An overview. Drug Safety 2002; 25(4):263-286. The Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005; 353(26):2747-2757. ATAC Trialists Group. Results of the ATAC (arimidex, tamoxifen, alone or in combination) trial after completion of 5 years' adjuvant treatment for breast cancer. The Lancet 2005; 365(9453):60-62. Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004; 350(11):1081-92. Novartis Pharmaceuticals. Letrozole product monograph. Dorval, Quebec; 22 March 2004. Fumal I, Danchin A, Cosserat F, et al. Subacute cutaneous lupus erythematosus associated with tamoxifen therapy: Two cases [8]. Dermatology 2005; 210(3):251-252. Agarwal R, Peters TJ, Coombes RC, et al. Tamoxifen-related porphyria cutanea tarda. Medical Oncology 2002; 19(2):121-123. Parry BR. Radiation recall induced by tamoxifen. Lancet 1992; 340(8810):49. Bostrom A, Sjolin-Forsberg G, Wilking N, et al. Radiation recall - Another call with tamoxifen. Acta Oncologica 1999; 38(7):955- 959. Extermann M, Vogt N, Forni M, et al. Radiation recall in a patient with breast cancer treated for tuberculosis. Eur J Clin Pharmacol 1995; 48(1):77-8. Akin ML, Uluutku H, Erenoglu C, et al. Tamoxifen and gallstone formation in postmenopausal breast cancer patients: retrospective cohort study. World J Surg 2003; 27(4):395-9. Sobel JD, Chaim W, Leaman D. Recurrent vulvovaginal candidiasis associated with long-term tamoxifen treatment in postmenopausal women. Obstetrics & Gynecology 1996; 88(4 II SUPPL. ):704-706. Colls BM, George PM. Severe hypertriglyceridaemia and hypercholesterolaemia associated with tamoxifen use. Clin Oncol (R Coll Radiol) 1998; 10(4):270-1. Kanel KT, Wolmark N, Thompson PD. Delayed severe hypertriglyceridemia from tamoxifen. N Engl J Med 1997; 337(4):281. Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992; 326(13):852-6. Love RR, Barden HS, Mazess RB, et al. Effect of tamoxifen on lumbar spine bone mineral density in postmenopausal women after 5 years. Arch Intern Med 1994; 154(22):2585-8. Grey AB, Stapleton JP, Evans MC, et al. The effect of the antiestrogen tamoxifen on bone mineral density in normal late postmenopausal women. Am J Med 1995; 99(6):636-41. USPDI(r) Drug Information for the Health Care Professional (database on the Internet). Tamoxifen (Systemic). Thomson MICROMEDEX(r), 2006. Available at: www.micromedex.com. Accessed 9 June 2006. Shushan A, Peretz T, Uziely B, et al. Ovarian cysts in premenopausal and postmenopausal tamoxifen-treated women with breast cancer. American Journal of Obstetrics & Gynecology 1996; 174(1):141-144. Mourits MJ, de Vries EG, Willemse PH, et al. Ovarian cysts in women receiving tamoxifen for breast cancer. Br J Cancer 1999; 79(11-12):1761-4. BC Cancer Agency Breast Tumour Group. Cancer Management Guidelines: Breast Follow-up - Hormone Replacement Therapy After a Diagnosis of Breast Cancer. Vancouver, British Columbia: BC Cancer Agency; 2006. Mom CH, Buijs C, Willemse PHB, et al. Hot flushes in breast cancer patients. Critical Reviews in Oncology-Hematology 2006; 57(1):63-77. Arenas M, Rovirosa A, Hernandez V, et al. Uterine sarcomas in breast cancer patients treated with tamoxifen. International Journal of Gynecological Cancer 2006; 16(2):861-865. Nayfield SG, Gorin MB. Tamoxifen-associated eye disease. A review. J Clin Oncol 1996; 14(3):1018-1026. Bradbury BD, Lash TL, Kaye JA, et al. Tamoxifen and cataracts: a null association. Breast Cancer Res Treat 2004; 87(2):189- 96. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. Journal of the National Cancer Institute. 1998; 90(18):1371-88. Zhang JJ, Jacob TJ, Valverde MA, et al. Tamoxifen blocks chloride channels. A possible mechanism for cataract formation. J Clin Invest 1994; 94(4):1690-7. Reis SE, Costantino JP, Wickerham DL, et al. Cardiovascular effects of tamoxifen in women with and without heart disease: breast cancer prevention trial. J Natl Cancer Inst 2001; 93(1):16-21. Wolters Kluwer Health I. Tamoxifen. Drug Interaction Facts. St. Louis, MO: Drug Facts and Comparisons 4.0 [online]; 2006. Lien EA, Anker G, Lonning PE, et al. Decreased serum concentrations of tamoxifen and its metabolites induced by aminoglutethimide. Cancer Res 1990; 50(18):5851-7. DRUGDEX(r) Evaluations (database on the Internet). Tamoxifen. Thomson MICROMEDEX(r), 2006. Available at: www.micromedex.com. Accessed 29 June 2006. Dowsett M, Cuzick J, Howell A, et al. Pharmacokinetics of anastrozole and tamoxifen alone, and in combination, during adjuvant endocrine therapy for early breast cancer in postmenopausal women: a sub-protocol of the 'Arimidex and tamoxifen alone or in combination' (ATAC) trial. Br J Cancer 2001; 85(3):317-24. Dowsett M, Tobias JS, Howell A, et al. The effect of anastrozole on the pharmacokinetics of tamoxifen in post-menopausal women with early breast cancer. British Journal of Cancer 1999; 79(2):311-5. Eisai Inc. TARGRETIN(r) capsules Package Insert. Woodcliff Lake, New Jersey; January 2007. Rose BD editor. Bexarotene. UpToDate 15.3 ed. Waltham, Massachusetts: UpToDate(r); 2008. Esteva FJ, Glaspy J, Baidas S, et al. Multicenter Phase II Study of Oral Bexarotene for Patients With Metastatic Breast Cancer. J Clin Oncol 2003; 21(6):999-1006. Albain KS, Green SJ, Ravdin PM, et al. Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG-8814). Proceedings of the American Society of Clinical Oncology 2002; 21 (Part 1 of 2):37a (Abstract 143). Hutson PR, Love RR, Havighurst TC, et al. Effect of exemestane on tamoxifen pharmacokinetics in postmenopausal women treated for breast cancer. Clinical Cancer Research 2005; 11(24):8722-8727. Patel P. Cytochrome P450 Drug Interactions. Compendium of Pharamceuticals and Specialties. Ottawa, Ontario, Canada: Canadian Pharmacists Association; 2006. p. L76-L78. Crewe HK., Ellis SW., Lennard MS.,Tucker GT. Variable contribution of cytochromes P450 2D6 and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes. Biochemical Pharmacology 1997; 53(2)(Jan):171-8. Crewe HK., Notley LM., Wunsch RM., Lennard MS.,Gillam EM. Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes. Drug Metabolism and Disposition: The Biological Fate of Chemicals 2002; 30(8)(Aug):869-74. Dowsett M, Pfister C, Johnston SR, et al. Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer. Clinical Cancer Research 1999; 5(9):2338-43. Ingle JN, Suman VJ, Johnson PA, et al. Evaluation of tamoxifen plus letrozole with assessment of pharmacokinetic interaction in postmenopausal women with metastatic breast cancer. Clinical Cancer Research 1999; 5(7):1642-9. Goetz MP LC. A hot flash on tamoxifen metabolism. Journal of the National Cancer Institute 2003; 95(No. 23):1734-1735. Borges S, Desta Z, Li L, et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther 2006; 80(1):61-74. Wolters Kluwer Health I. Tamoxifen. Drug Facts and Comparisons. St. Louis, MO: Drug Facts and Comparisons 4.0 [online]; 2006. Kivisto KT, Villikka K, Nyman L, et al. Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin. Clinical Pharmacology & Therapeutics 1998; 64(6):648-654. Anker GB, Lonning PE, Aakvaag A, et al. Thyroid function in postmenopausal breast cancer patients treated with tamoxifen. Scandinavian Journal of Clinical & Laboratory Investigation 1998; 58(2):103-107. Zidan J, Rubenstein W. Effect of adjuvant tamoxifen therapy on thyroid function in postmenopausal women with breast cancer. Oncology 1999; 56(1):43-45. Ratliff B, Dietze EC, Bean GR, et al. Re: Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine (multiple letters) [1]. Journal of the National Cancer Institute 2004; 96(11):883-885. Lehmann D, Nelsen J, Ramanath V, et al. Lack of attenuation in the antitumor effect of tamoxifen by chronic CYP isoform inhibition. Journal of Clinical Pharmacology 2004; 44(8):861-865. Karen Gelmon MD. Personal Communication. BC Cancer Agency Breast Tumour Group; 2005. Sutherland CM, Sternson LA, Muchmore JH, et al. Effect of impaired renal function on tamoxifen. J Surg Oncol 1984; 27(4):222-3. Susan Halasi MSc Phm. Personal Communication. Genpharm Drug Information Pharmacist; 27 June 2006. Floren LC, Hebert MF, Venook AP, et al. Tamoxifen in liver disease: Potential exacerbation of hepatic dysfunction. Annals of Oncology 1998; 9(10):1123-1126.

Interpatient variability	considerable variation in serum concentrations after single doses and at steady state; 6,7 genetic polymorphism may influence the efficacy and toxicity of tamoxifen and its metabolites 8-10
Oral Absorption	well absorbed 2
	time to peak plasma concentration	3-7h
Distribution	high concentrations found in uterus and breast tissue 2
	cross blood brain barrier?	yes 11
	volume of distribution 12	20 L/kg
	plasma protein binding 2	99%
Metabolism	metabolized by hepatic cytochrome 2 P450; major CYP3A4, 2C8/9, 2D6; minor 2A6, 2B6, 2E1
	active metabolite(s)	N-desmethyltamoxifen, 4-hydroxytamoxifen, and 4-hydroxy-N-desmethyltamoxifen (endoxifen) 8
	inactive metabolite(s)	yes
Excretion	extensive enterohepatic circulation 3,6
	urine 2	9-13%
	feces 2,3,6	26-65%, excreted into bile 13
	terminal half life	5-7 days, range 3-21 days; major metabolite 9-14 days 6
	clearance	no information found

Primary uses:	Other uses:
Brain tumours 14-16	Carcinoid tumour 6,17
*Breast cancer 3,18,19	Endometrial cancer 17,20,21
Melanoma 2,22	Pancreatic cancer 2
Soft tissue sarcoma 2,23

AGENT	EFFECT	MECHANISM	MANAGEMENT
aldesleukin 68	increased risk of hypersensitivity reactions	unknown	monitor for signs and symptoms of hypersensitivity reactions
aminoglutethimide 69,70	decreased tamoxifen and its active metabolites concentrations	increased metabolism of tamoxifen	avoid concurrent use
anastrozole	tamoxifen decreases plasma anastrozole level by 27%, but has no significant effect on estrogen suppression by anastrozole 71 ; anastrozole has no significant effects on the pharmacokinetics of tamoxifen 71,72
bexarotene 73-75	35% decrease in tamoxifen plasma concentrations	unknown; likely be due to induction of CYP 3A4 by bexarotene	clinical significance unclear; consider alternate agent(s)
bromocriptine 6	increased tamoxifen concentrations	decreased metabolism of tamoxifen	caution
cyclophosphamide 76	decreased cytotoxic effects of cyclophosphamide	unknown	avoid concurrent use; start adjuvant tamoxifen after chemotherapy is completed
cytotoxic agents 3	increased risk of thromboembolic events	unknown	caution
doxorubicin 76	decreased cytotoxic effects of doxorubicin	unknown	avoid concurrent use; start adjuvant tamoxifen after chemotherapy is completed
AGENT	EFFECT	MECHANISM	MANAGEMENT
estrogens 57	may interfere with therapeutic effect of tamoxifen	may counter the estrogen suppression effect of tamoxifen	*see below
exemestane 77	no significant effects on tamoxifen or exemestane pharmacokinetics
fluorouracil 76	decreased cytotoxic effects of fluorouracil	unknown	avoid concurrent use; start adjuvant tamoxifen after chemotherapy is completed
grapefruit juice 78	may affect bioavailability of tamoxifen and its active metabolites 79,80	may inhibit CYP3A4 metabolism of tamoxifen in the intestinal wall	+see below
letrozole	tamoxifen decreases plasma letrozole level by 38%, but has no significant effect on estrogen suppression by letrozole 81 ; letrozole has no effects on the pharmacokinetics of tamoxifen and its major metabolites 82
mitomycin 70	increased risk of hemolytic uremic syndrome	unknown	avoid concurrent use
paroxetine 10,83,84 and other selective serotonin inhibitors that inhibit cytochrome P450 2D6	reduced tamoxifen active metabolite concentrations	inhibits CYP2D6 metabolism of tamoxifen	++see below
rifamycins (e.g., rifabutin, rifampin, rifapentine) 34,85,86	delayed, moderate, suspected; reduced tamoxifen and active metabolite concentrations	induces CYP3A4 metabolism of tamoxifen	monitor clinical response; may be necessary to increase tamoxifen dose
thyroid function tests 6,87,88	elevated thyroid hormone levels (T 4 and T 3 )	increased thyroxine- binding globulin	none, thyroid function does not appear to be affected
warfarin 3,85	delayed, major, possible; increased anticoagulant effect	unknown	monitor prothrombin time, adjust warfarin dose accordingly

COMMON TRADE NAME(S): APO-TAMOX(r), GEN-TAMOXIFEN(r), NOLVADEX-D(r), NOVO-TAMOXIFEN(r), TAMOFEN(r)

CLASSIFICATION: