Gyraxen

Each Film Coated tablet contains: Tamoxifen (as citrate), USP 30.4 mg (as Tamoxifen 20 mg).

Pharmacology: Pharmacodynamics: 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 antioestrogen, preventing oestrogen binding to the oestrogen receptor. However, clinical studies have shown some benefit in oestrogen receptor negative tumours, which may indicate other mechanisms of action. In the clinical situation, it is recognised that tamoxifen leads to reductions in levels of blood total cholesterol and low density lipoproteins in postmenopausal women of the order of 10 - 20%. Tamoxifen does not adversely affect bone mineral density.
An uncontrolled trial was undertaken in a heterogenous 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. 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 metaboliser status may be associated with reduced response. The consequences of the findings for the treatment of CYP2D6 poor metabolisers have not been fully elucidated.
CYP2D6 genotype: Available clinical data suggest that patients, who are homozygote for non-functional CYP2D6 alleles, may experience reduced effect of tamoxifen in the treatment of breast cancer.
The available studies have mainly been performed in postmenopausal women.
Pharmacokinetics: After oral administration, tamoxifen is absorbed rapidly with maximum serum concentrations attained within 4 - 7 hours. Steady state concentrations (about 300 mg/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 metabolised mainly via CYP3A4 to N-desmethyl-tamoxifen, which is further metabolised 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 is indicated for the treatment of advanced breast cancer in postmenopausal women.

One or two 20 mg tablets are administered twice a day (morning and evening) or as prescribed by the physician.

Acute overdosage in humans has not been reported. Signs observed at the highest doses following studies to determine LD50 in animals were respiratory difficulties and convulsions. No specific treatment for overdosage is known; treatment must be symptomatic.

Tamoxifen citrate must not be given during pregnancy. Pre-menopausal patients must undergo a careful examination to exclude any possibility of pregnancy before treatment with Tamoxifen citrate for breast cancer or infertility.

Suppression of menstruation has been observed in a proportion of pre-menopausal patients receiving Tamoxifen for the treatment of breast cancer. Reversible cystic ovarian swelling has occasionally been observed when such women have been treated with Tamoxifen 40 mg twice daily for short periods.
Hypercalcaemia has been reported in a small number of patients with bony metastases when treated with Tamoxifen. In such cases therapy should be stopped and the patient may be treated by rehydration, corticosteroids and if necessary mithramycin. There have been reports of serious potentiation of coumarin-type anticoagulants (Warfarin) by Tamoxifen. Patients taking coumarin-type anticoagulants require close monitoring on the introduction or withdrawal of Tamoxifen.
Menstruation is suppressed in a proportion of pre-menopausal women receiving Tamoxifen for the treatment of breast cancer.
An increased incidence of endometrial changes including hyperplasia, polyps, cancer and uterine sarcoma (mostly malignant mixed Mullerian tumours), has been reported in association with Tamoxifen treatment. The underlying mechanism is unknown but may be related to the oestrogen-like effect properties of Tamoxifen. Any patient receiving or having previously received Tamoxifen who report abnormal gynaecological symptoms, especially vaginal bleeding, or who presents with menstrual irregularities, vaginal discharge and symptoms such as pelvic pain or pressure should be promptly investigated.
A number of second primary tumours, occurring at sites other than the endometrium and the opposite breast, have been reported in clinical trials, following the treatment of breast cancer patients with tamoxifen. No causal link has been established and the clinical significance of these observations remains unclear.
Venous thromboembolism: A 2-3-fold increase in the risk for VTE has been demonstrated in healthy tamoxifen-treated women.
In patients with breast cancer, prescribers should obtain careful histories with respect to the patient's personal and family history of VTE. If suggestive of a prothrombotic risk, patients should be screened for thrombophilic factors. Patients who test positive should be counselled regarding their thrombotic risk. The decision to use tamoxifen in these patients should be based on the overall risk to the patient. In selected patients, the use of tamoxifen with prophylactic anticoagulation may be justified.
The risk of VTE is further increased by severe obesity, increasing age and all other risk factors for VTE. The risks and benefits should be carefully considered for all patients before treatment with tamoxifen. In patients with breast cancer, this risk is also increased by concomitant chemotherapy. Long-term anti-coagulant prophylaxis may be justified for some patients with breast cancer who have multiple risk factors for VTE.
Surgery and immobility: For patients being treated for infertility, tamoxifen should be stopped at least 6 weeks before surgery or long-term immobility (when possible) and re-started only when the patient is fully mobile. For patients with breast cancer, tamoxifen treatment should only be stopped if the risk of tamoxifen-induced thrombosis clearly outweighs the risks associated with interrupting treatment. All patients should receive appropriate thrombosis prophylactic measures and should include graduated compression stockings for the period of hospitalisation, early ambulation, if possible, and anti-coagulant treatment.
If any patient presents with VTE, tamoxifen should be stopped immediately and appropriate anti-thrombosis measures initiated. In patients being treated for infertility, tamoxifen should not be re-started unless there is a compelling alternative explanation for their thrombotic event. In patients receiving tamoxifen for breast cancer, the decision to re-start tamoxifen should be made with respect to the overall risk for the patient. In selected patients with breast cancer, the continued use of tamoxifen with prophylactic anticoagulation may be justified.
All patients should be advised to contact their doctors immediately if they become aware of any symptoms of VTE.
In an uncontrolled trial in 28 girls aged 2–10 years with McCune Albright Syndrome (MAS), who received 20 mg once a day for up to 12 months duration, 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.
In the literature it has been shown that CYP2D6 poor metabolisers have a lowered plasma level of endoxifen, one of the most important active metabolites of tamoxifen.
Concomitant medications that inhibit (CYPD2D6 may lead to reduced concentrations of the active metabolite endoxifen. Therefore, potent inhibitors of CYP2D6 (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should whenever possible be avoided during tamoxifen treatment.

Pregnancy: Tamoxifen Tablets must not be administered during pregnancy. There have been a small number of reports of spontaneous abortions, birth defects and foetal deaths after women have taken tamoxifen, although no causal relationship has been established.
Reproductive toxicology studies in rats, rabbits and monkeys have shown no teratogenic potential.
In rodent models of foetal reproductive tract development, tamoxifen was associated with changes similar to those caused by oestradiol, ethynyloestradiol, clomiphene and diethylstilboestrol (DES). Although the clinical relevance of these changes is unknown, some of them, especially vaginal adenosis, are similar to those seen in young women who were exposed to DES in-utero and who have a 1 in 1000 risk of developing clear-cell carcinoma of the vagina or cervix. Only a small number of pregnant women have been exposed to tamoxifen. Such exposure has not been reported to cause subsequent vaginal adenosis or clear-cell carcinoma of the vagina or cervix in young women exposed in utero to tamoxifen.
Women should be advised not to become pregnant whilst taking Tamoxifen 10mg Tablets and should use barrier or other non-hormonal contraceptive methods if sexually active. Pre-menopausal patients must be carefully examined before treatment to exclude pregnancy. Women should be informed of the potential risks to the foetus, should they become pregnant whilst taking Tamoxifen 10mg Tablets or within two months of cessation of therapy.
Lactation: It is not known if Tamoxifen Tablets is excreted in human milk and therefore the drug is not recommended during lactation. The decision either to discontinue nursing or discontinue Tamoxifen Tablets should take into account the importance of the drug to the mother.

Side effects from long term treatment are mainly associated with the anti-oestrogenic action of the drug such as hot flushes, vaginal bleeding and pruritus vulvae. Other side effects which may occur are gastro-intestinal upsets, tumour pain, light headedness, dizziness, rashes and occasionally fluid retention.
These side effects may be controlled by reduction of dosage without loss of control of the disease but if they are not, then it may be necessary to stop treatment.
Transient falls in platelet count, to levels 80,000 to 90,000, but occasionally lower, have been reported in patients taking Tamoxifen for breast cancer. These have not been associated with a haemorrhagic tendency and the platelet counts have recovered notwithstanding continuing treatment.
Tamoxifen citrate should be used with caution in patients with factors predisposing them to thromboembolism. A small number of endometrial hyperplasia, endometrial polyps and endometrial carcinomas have been reported in association with Tamoxifen treatment. A definitive relationship to Tamoxifen therapy has not been established.
A number of cases of visual disturbance including corneal changes, cataracts and retinopathy have been described in patients receiving Tamoxifen therapy.
Use in Pregnancy: Tamoxifen citrate must not be given during pregnancy.

When Tamoxifen Tablets are used in combination with coumarin-type anticoagulants, a significant increase in anticoagulant effect may occur. Where such co-administration is initiated, careful monitoring of the patient is recommended.
When Tamoxifen is used in combination with cytotoxic agents for the treatment of breast cancer, there is increased risk of thromboembolic events occurring. Because of this increase in risk of VTE, thrombosis prophylaxis should be considered for these patients for the period of concomitant chemotherapy.
The use of tamoxifen in combination with anastrozole as adjuvant therapy has not shown improved efficacy compared with tamoxifen alone.
As tamoxifen is metabolised by cytochrome P450 3A4, care is required when co-administering with drugs, such as rifampicin, known to induce this enzyme as tamoxifen levels may be reduced. The clinical relevance of this reduction is unknown.
Pharmacokinetic interaction with CYP2D6 inhibitors, showing a 65-75% reduction in plasma levels of one of the more active forms of the drug, i.e. endoxifen, has been reported in the literature.
Reduced efficacy of tamoxifen has been reported with concomitant usage of some SSRI antidepressants (e.g. paroxetine) in some studies. As a reduced effect of tamoxifen cannot be excluded, co-administration with potent CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should whenever possible be avoided.

Store at temperatures not exceeding 25°C.

Cancer Hormone Therapy

L02BA01 - tamoxifen ; Belongs to the class of anti-estrogens. Used in treatment of neoplastic diseases.

Rx