Medical Summary
This is an open, randomized, two-period crossover bioequivalence study. Nolvadex (tamoxifen citrate), is a potent nonsteroidal anti-estrogen used for the treatment of breast cancer. The efficacy has already been established. Adjuvant breast cancer studies with Nolvadex have consistently shown prolongation of disease-free survival and in some studies an overall survival benefit has been seen. The safety profile is equally well established . Nolvadex is well tolerated by breast cancer patients. The acute adverse events are related to NolvadexÕs anti-estrogenic properties (eg. hot flushes and vaginal dryness) but these are usually well tolerated. Several studies have reported a reduction in second contralateral breast tumors with Nolvadex treatment as compared to the control group. In the adjuvant setting, survival was substantially improved in women with ER positive tumors and tumors of unknown ER status. Clinical trial results have supported the use of Nolvadex for both advanced disease and for adjuvant use. Pharmacokinetics of Nolvadex suggest that this agent could be taken once a day. The objective of this study is to compare the bioequivalence of two 20 mg Nolvadex tablet formulations taken once a day. The two formulations differ in that the US formulation contains mannitol and the UK formulation contains lactose. This bioequivalence study will be undertaken to confirm that the dosing of the US formulated 20 mg (once daily) Nolvadex tablet and the UK formulated 20 mg (once daily) Nolvadex tablets result in equivalent blood levels. In this study, post menopausal women who have been prescribed tamoxifen therapy and whose disease is not likely to progress in 6 months will be randomized into one of two treatment sequences. One group will receive a 20 mg Nolvadex tablet (F6293) taken once daily for 3 months and then will receive a 20 mg Nolvadex tablet (F12061) taken once a day for 3 months. The other group will first receive a 20 mg Nolvadex tablet (F12061) taken once a day for 3 months and then a 20 mg Nolvadex tablet (F6293) taken once daily for 3 months. After the first treatment period of 3 months, subjects will have pharmacokinetic assessments performed. Subjects will then be crossed over into the alternative treatment for 3 months of treatment. At the end of the second 3 month period, pharmacokinetic assessments will be repeated.

References:

1. Fisher, B. et al., A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 320:479-484, 1989.
2. Baum, M., et al., Controlled trial of tamoxifen as single adjuvant agent in management of early breast cancer. Lancet 1:836-840, 1985.
3. Peto, R. et al., Tamoxifen for early breast cancer; an overview of randomised trials. Lancet 351:1451, 1998.

Lay Summary
This study is designed to test whether the two different formulations of tamoxifen made by Zeneca are equivalent with respect to absorption, blood levels, your bodyÕs metabolism of it, etc. Patients who are otherwise on tamoxifen for either prevention or cancer therapy, are asked to take one of the two formulations for 3 months as they usually do. After that, they are asked to spend one night in our clinical research unit, during which a small catheter will be placed in a vein, and blood samples willbe taken at various times, in order to measure the drug. After this, they will be switched to the other tamoxifen formulation for three months, and the procedure will be repeated in the Clinical research unit one more time. Patients who volunteer will have their time compensated for.

Throughout the study participants will be carefully monitored .

Eligibility Criteria

1. Postmenopausal women (defined as aged 50 or over and whose last menstrial period was 1 or more years prior to entry to the study) and
2. who have been prescribed tamoxifen therapy for at least 4 weeks, and whose disease is not likely to progress in 6 months and
3. whose life expectancy is greater than six months as assessed by the investigator

1. Subjects who have had cytotoxic therapy within 1 month or other hormonal therapy within three months of baseline
2. Abnormal liver function tests; SGOT, SGPT, alkaline phosphate or bilirubin greater than 1.5 times the upper limits of the normal range or albumin below the normal limit.
3. Normal kidney function.
4. Subjects who for whatever reason (e.g. confusion, infirmity, alcoholism) are likely to strictly comply with the study instructions.
5. History of significant hepatic, renal, hematologic, endocrine, cardiovascular, gastrointestinal, metabolic, neurologic or chronic resppiratory disease, or other concomitant disease which in the doctorÕs opinion puts the subject at risk or which would make completion of the study unlikely.
6. Blood donation within eight weeks of the start of the study. Participation in another drug study within 30 days prior to the start of this study.
7. Subjects unwilling to provide written informed consent
8. Subjects currently taking warfarin, barbiturates, or other drugs affecting liver drug metabolizing enzymes
9. Risk of transmitting through blood the agents responsible for transmission of Hepatitis B or C and AIDS.