Source: Υπουργείο Υγείας (CY) Revision Year: 2021 Publisher: Remedica Ltd, Aharnon Street, Limassol Industrial Estate, 3056 Limassol, Cyprus, EU
Pharmacotherapeutic group: Endocrine therapy; hormone antagonists and related agents
ATC Code: L02BA01
Tamoxifen is a non-steroidal, triphenylethylene-based drug which displays a complex spectrum of oestrogen antagonist and oestrogen agonist-like pharmacological effects in different tissues. In breast cancer patients, at the tumour level, tamoxifen acts primarily as an antiestrogen, preventing oestrogen binding to the oestrogen receptor. In the clinical situation, it is recognized that tamoxifen leads to reduction in levels of blood total cholesterol and low density lipoproteins in postmenopausal women of the order of 1020%. Tamoxifen does not adversely affect bone mineral density.
An uncontrolled trial was undertaken in a heterogeneous group of 28 girls aged 2 to 10 years with McCune Albright Syndrome (MAS), who received 20 mg once a day for up to 12 months duration. Among the patients who reported vaginal bleeding during the pre-study period, 62% (13 out of 21 patients) reported no bleeding for a 6-month period and 33% (7 out of 21 patients) reported no vaginal bleeding for the duration of the trial. Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. While this finding is in line with the pharmacodynamic properties of tamoxifen, a causal relationship has not been established (see section 4.4). There are no long-term safety data in children. In particular, the long-term effects of tamoxifen on growth, puberty and general development have not been studied.
CYP2D6 polymorphism status may be associated with variability in clinical response to tamoxifen. The poor metabolizer status may be associated with reduced response. The consequences of the findings for the treatment of CYP2D6 poor metabolizers have not been fully elucidated (see sections 4.4, 4.5 and 5.2)
Available clinical data suggest that patients who are homozygote for nonfunctional CYP2D6 alleles, may experience reduced effect of tamoxifen in the treatment of breast cancer.
The available studies have mainly been performed in postmenopausal women (see sections 4.4 and 5.2).
After oral administration, tamoxifen is absorbed rapidly with maximum serum concentrations attained within 4-7 hours. Steady state concentrations (about 300 ng/ml) are achieved after four weeks treatment with 40 mg daily. The drug is highly protein bound to serum albumin (>99%). Metabolism is by hydroxylation, demethylation and conjugation, giving rise to several metabolites which have a similar pharmacological profile to the parent compound and thus contribute to the therapeutic effect. Excretion occurs primarily via the faeces and an elimination half-life of approximately seven days has been calculated for the drug itself, whereas that for N-desmethyltamoxifen, the principal circulating metabolite, is 14 days.
In a clinical study where girls between 2 and 10 years with McCune Albright Syndrome (MAS) received 20 mg tamoxifen once a day for up to 12 months duration, there was an age-dependent decrease in clearance and an increase in exposure (AUC), (with values up to 50% higher in the youngest patients) compared with adults.
Tamoxifen is metabolized mainly via CYP3A4 to N-desmethyltamoxifen, which is further metabolized by CYP2D6 to another active metabolite endoxifen. In patients who lack the enzyme CYP2D6 endoxifen concentrations are approximately 75% lower than in patients with normal CYP2D6 activity. Administration of strong CYP2D6 inhibitors reduces endoxifen circulating levels to a similar extent.
Tamoxifen was not mutagenic in a range of in-vitro and in-vivo mutagenicity tests. Tamoxifen was genotoxic in some in-vitro and in-vivo genotoxicity tests in rodents. Gonadal tumours in mice and liver tumours in rats receiving tamoxifen have been reported in long-term studies. The clinical relevance of these findings has not been established.
Tamoxifen is a drug on which extensive clinical experience has been obtained. Relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.
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