Visits: 2
The drug Tamoxifen, a non-steroidal anti-oestrogen medicine, is commonly used to treat the oestrogen receptor positive (ER+ve) breast cancers as well as to prevent the incidence of breast cancer in high risk populations. Let us know some facts here about the medicine.
Molecular Formula: C26H29NO. It was granted FDA approval on 30 December 1977.
Some available brand names of Tamoxifen is listed below:
Adifen (Medicamerc) / Adopan (Sawai Seiyaku) /Bilem (Teva Int’l) / Caditam (Cadila) / Citofen /
Crisafeno (LKM) / Doctamoxifene (Docpharma) / Ebefen (Ebewe) / Fenahex (Sandoz) /
Genox (Merck Serono) / Gynatam (Biogalenic) / Istubal (AstraZeneca) /
Mammonex (CP Pharmaceuticals) / Neophedan (Aspen Pharmacare) /
Nolvadex-D (AstraZeneca) / Novofen (Remedica) / Oncomox (Sun) / Tadex (Orion) /
Tamifen (Medochemie) / Tamizam (Mithra) / Tamofen (Sanofi-Aventis) /
Tamoneprin (Actavis) / Tamoplex (Pharmachemie) / Tamoxen (Ascent) /
Tamoxilon (Celon) / Tamtero (Hetero) / Tecnotax (Zodiac) / Tomifen (Alkem).
Chemistry of drug: Tamoxifen is a substituted tri-phenyl ethylene anti-oestrogen. The crystallographic structure of tamoxifen (carbon = white, oxygen = red, nitrogen = blue) complexed with ligand-binding domain of oestrogen receptor alpha (ERα) (cyan ribbon).
Mechanisms of action: Tamoxifen competitively inhibits oestrogen binding to its receptor, which is crucial for the activity of it specifically in breast cancer cells. Tamoxifen leads to a decrease in Tumour Growth Factor α (TGF – α) and insulin-like growth factor 1 (ILGF-1), and an increase in sex hormone binding globulin. The increase in sex hormone binding globulin limits the amount of freely available oestradiol. These changes reduce levels of factors that stimulate the tumour growth. It has also been shown to induce apoptosis in oestrogen receptor positive cells. This action is thought to be the result of inhibition of protein kinase C, which prevents DNA synthesis. Alternate theories for the apoptotic effect of tamoxifen comes from the approximately 3-fold increase in intra-cellular and mitochondrial calcium ion levels after administration or the induction of tumour growth factor β (TGF- β).
The anti-oestrogen activity of the compound has been attributed to its metabolism to active 4-hydroxy derivative and the avid binding of the active metabolite to the oestrogen receptor. Receptor binding of the anti-oestrogen alters the transcriptional activity that is normally attributed to the oestradiol-bound oestrogen receptor. So, tamoxifen acts as a selective oestrogen receptor modulator, or as a partial agonist of the oestrogen receptors (ERs). The dual action is a function of the oestrogen receptor complex present in a particular cell or tissue. If a cell type requires activating factors 1 and 2 of the oestrogen receptor to be functioning concurrently, tamoxifen acts as antagonist. However, if a cell or tissue requires only activating factor 1 to interact with transcription factors at the promoter, tamoxifen has agonist effect. The implication is that one must understand the fundamental biology of the oestrogen receptor complex in a tissue context before predicting the tissue activity of tamoxifen.
The main mechanism of action of tamoxifen is as selective oestrogen receptor modulator. Its pro- and anti-oestrogenic actions are mediated by its competitive binding to the oestrogen receptors (ERα and/or β) which then undergo a conformational change. The nuclear complexes that form change the expression of oestrogen-dependent genes to generate multiple growth-promoting signals both inside and outside the nucleus.
Half life and excretion: Tamoxifen has a long duration of action. The terminal elimination half-life of tamoxifen is 5 – 7 days, But the active metabolite N-desmethyl tamoxifen has a half-life of approximately 14 days (2 weeks). It has a narrow therapeutic index as higher doses can lead to breathing difficulty or convulsions. Long time Tamoxifen administration is also linked with an increased incidence of uterine malignancies. Tamoxifen is mainly eliminated in the faeces and remaining through urine.
Common Indications of Tamoxifen: After careful history and examination, the clear indication of use of this drug is to be proven before its administration. The common indications are –
Dysmenorrhea (used effectively to improve uterine blood flow, reduce uterine contractility and pain in dysmenorrhea cases)
Breast cancer – both early and locally advanced oestrogen receptor-positive (ER+) breast cancer in pre-menopausal women and post-menopausal women; also used in metastatic breast cancers and for prevention of breast cancer in high risk groups.
Infertility
Gynecomastia
Peripheral precocious puberty.
Usual dosage:
Usually for breast cancer, Tamoxifen is to be taken for 5 years or 10 years. The usual dose is usually 10 or 20 mg per day. The treating physician or oncologist will suggest exactly about the dose and duration based on findings and purpose of prescribing the medicine. The medicine should be taken as a single dose in a day and preferably a fixed time in every day.
If a dose is missed, that should be taken immediately whenever remembered. Then the usual dose to be continued. If several dose are missed, it is better to consult the treating physician. For larger than 20mg doses, twice daily dose has been advocated.
Drug interactions: There are very significant interactions of different drugs if taken concomitantly with Tamoxifen. It is better to ask the doctor about use of other drugs.
About Pregnancy and lactation: It is important not to become pregnant or father a child while you are having treatment with this drug and for at least 2 months afterwards as this drug may harm a baby developing in the womb. No significant data on use of Tamoxifen during lactation is available yet.
Adverse effects of Tamoxifen:
Common: (1-10%)
Headache
Hot flush
Night sweats
Edema
Leg cramps
Fatigue (Weakness, tiredness, lack of energy)
Irregular menstrual periods or spotting (uterine bleeding)
Vaginal dryness or itching or Vaginal discharge in female
Loss of libido / sex drive in either sex
Impotence in male
GI upset (nausea, vomiting) and Bowel habit changes (Diarrhoea, constipation)
Less common / Rare: (Less than 1%)
Thrombo-embolism like – deep venous thrombosis (DVT), pulmonary embolism
Stroke
Cataract, retinopathy
Skin rash, dry skin and itching
Thinning of hair and hair loss
Bone loss in pre-menopausal women.
Uterine or endometrial cancer
Psychological upset
Brain fog (mental fogginess, impairment in thinking clearly)
Liver failure, Coma, Convulsions if toxicity