SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Tamoxifen Tablets BP 40 mg.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablets contains 60.80mg of Tamoxifen Citrate BP.

3 PHARMACEUTICAL FORM

White, normal convex tablets printed with the company logo on one face and A390 on the other face.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

1.    The treatment of breast cancer.

2.    The treatment of anovulatory infertility.

4.2 Posology and method of administration

Breast Cancer

Adults : The recommended daily dose of tamoxifen is normally 20 mg. No additional benefit in terms of delayed recurrence or improved survival in patients has been demonstrated with higher doses. Substantive evidence supporting the use of treatment with 30-40 mg per day is not available although these doses have been used in some patients with advanced disease.

Elderly : The same dosage regimes of tamoxifen have been used in elderly patients with breast cancer and in some of these patients it has been used as sole therapy.

Infertility

The possibility of pregnancy must be excluded before commencing any course of treatment whether initial or subsequent.

The initial course of treatment in women menstruating regularly but with anovular cycles, consists of 20 mg of tamoxifen daily on the second, third, fourth and fifth days of the menstrual cycle. Should the initial course of treatment, as judged by basal temperature and preovulatory cervical mucus, prove unsuccessful, further courses of treatment may be given during subsequent menstrual periods, increasing the dosage to 40 mg and then 80 mg daily.

In women with irregular menstrual cycle, the initial course of treatment may begin on any day. Should there be no sign of ovulation, then a subsequent course of treatment may begin 45 days later with dosage increased to 40 mg and then 80 mg daily. If a patient responds with menstruation then the next course of treatment is commenced on the second day of the cycle.

Route of administration: oral.

4.3 Contraindications

Tamoxifen must not be given during pregnancy.

Premenopausal patients must be carefully examined before treatment for breast cancer or infertility to exclude the possibility of pregnancy (see section 4.6).

Tamoxifen should not be given to patients who have experienced hypersensitivity to the product or any of its ingredients.

Concurrent anastrozole therapy (see section 4.5).

Treatment for infertility: Patients with a personal or family history of confirmed idiopathic venous thromboembolic events or a known genetic defect.

4.4 Special warnings and precautions for use

Tamoxifen should not be used continuously in patients with existing leucopenia or thrombocytopenia.

Complete blood counts including platelet counts should be carried out periodically in patients receiving this drug.

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 of Tamoxifen.

Abnormal vaginal bleeding including menstrual irregularities, vaginal discharge and symptoms such as pelvic pain or pressure in patients who are receiving or have previously received tamoxifen should be promptly investigated.

Tamoxifen has been associated with changes in liver enzyme levels and rarely with more severe abnormalities including fatty liver, cholestasis and hepatitis.

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 (section 4.8).

•    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 (cross reference with section 4.5).

•    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 anticoagulant 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 anticoagulant treatment.

•    If any patient presents with VTE, tamoxifen should be stopped immediately and appropriate antithrombosis 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 (see section 5.2).

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 (see section 4.5 and 5.2).

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent use with oestrogens may interfere with tamoxifen's therapeutic effect.

When tamoxifen is used in combination with coumarin-type anticoagulants, significant increase in anticoagulant effect may occur. When such coadministration 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 (see sections 4.4 and 4.8). 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 (see section 4.4 and 5.2).

4.6 Fertility, Pregnancy and lactation

Tamoxifen tablets must not be given during pregnancy. Pre-menopausal patients must be carefully examined before treatment for breast cancer or infertility to exclude the possibility of 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 estradiol, ethinylestradiol, 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 and should use barrier or other non-hormonal contraceptive methods if sexually active. Women should be informed of the potential risks to the foetus, should they become pregnant whilst taking Tamoxifen or within two months of cessation of therapy.

It is not known if tamoxifen is excreted in human milk and therefore the drug is not recommended during lactation. The decision either to discontinue nursing or discontinue tamoxifen should take into account the importance of the drug to the mother

4.7 Effects on ability to drive and use machines

None reported.

4.8 Undesirable effects

Occasional adverse effects reported and attributed to the anti-oestrogenic action of tamoxifen include hot flushes, vaginal bleeding including menstrual irregularities, vaginal discharge, pruritus vulvae and alopecia

When side effects are severe, it may be possible to control them by a simple reduction of dosage (to not less than 20 mg/day) without loss of control of the disease. If side effects do not respond to this measure, it may be necessary to stop the treatment.

Skin rashes (including isolated reports of erythema multiforme, Stevens Johnson syndrome and bullous pemphigoid) and rare hypersensitivity reactions including angioedema have been reported.

Less frequently reported adverse reactions include gastro-intestinal intolerance, tumour flare, headache, light headedness and fluid retention. Suppression of menstruation has been reported in a proportion of premenopausal women receiving tamoxifen for the treatment of breast cancer. The administration of 40 mg of tamoxifen, twice daily for short periods, has occasionally caused reversible cystic ovarian swellings. Transient falls in platelet count, usually to 80,000-90,000 per cu mm but occasionally lower, have been reported in patients taking tamoxifen for breast cancer. No haemorrhagic tendency has been reported and the platelet counts have recovered even though treatment with the drug has continued.

A small number of patients with bony metastases have developed hypercalcaemia on initiation of therapy.

A small number of cases of visual disturbances including infrequent reports of corneal changes, cataracts and retinopathy have been described, mainly in patients treated with exceptionally high doses of tamoxifen for long periods of time.

Cases of optic neuropathy and optic neuritis have been reported in patients receiving tamoxifen and, in a small number of cases, blindness has occurred.

Uterine fibroids, endometriosis and other endometrial changes including hyperplasia and polyps have been reported in association with tamoxifen treatment.

An increased incidence of endometrial cancer and uterine sarcoma (mostly malignant mixed Mullerian tumours) has been reported in association with Tamoxifen treatment.

Cystic ovarian swellings have occasionally been observed in premenopausal women receiving tamoxifen.

Leucopenia has been observed following the administration of Tamoxifen, sometimes in association with anaemia and/or thrombocytopenia. Neutropenia has been reported on rare occasions; this can sometimes be severe.

There is evidence of an increased incidence of ischaemic cerebrovascular events and thromboembolic events, including deep vein thrombosis and pulmonary embolism, during tamoxifen therapy (see sections 4.3, 4.4 and 4.5). When Tamoxifen is used in combination with cytotoxic agents, there is an increased risk of thromboembolic events occurring.

Leg cramps have been reported commonly in patients receiving Tamoxifen. Very rarely, cases of interstitial pneumonitis have been reported.

Tamoxifen has been associated with changes in liver enzyme levels and on rare occasions with a spectrum of more severe liver abnormalities including fatty liver, cholestasis and hepatitis.

Rarely, elevation of serum triglyceride levels, in some cases with pancreatitis, may be associated with the use of Tamoxifen.

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Overdosage in humans has not been reported. Theoretically an overdosage would be expected to cause enhancement of the anti-oestrogenic side effects as described above. Observations in animals show that extreme overdosage (100 - 200 times recommended daily dose) may produce oestrogenic effects. No specific treatment for overdosage is known and treatment must be symptomatic.

There have been reports in the literature that Tamoxifen given at several times the standard dose may be associated with prolongation of the QT interval of the ECG.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Tamoxifen citrate is the trans-isomer of a triphenylethylene derivative. The chemical name is Z-2[4-(1,2-dipheny 1-1-buteny 1)phenoxy]-N, N-dimethyl-ethanamine 2-hydroxy-1 ,2,3-propane-tricarboxylate (1:1).

It is a nonsteroidal agent which has demonstrated potent antioestrogenic properties in animal test systems. In mice, however, tamoxifen citrate behaves as an oestrogen. Its antioestrogenic effects may be related to its ability to compete with oestrogen for binding sites in target tissues such as breast and uterus.

Tamoxifen citrate inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA), and causes the regression of already established DMBA-induced tumours.

In this rat model, it appears to exert its antitumour effects by binding to oestrogen receptors. In cytosols derived from human endometrium and human breast and uterine adenocarcinomas, tamoxifen citrate competes with estradiol for estrogen receptor protein.

The dosage for the treatment of breast cancer is 20 to 40 mg given either

in divided doses twice daily or as a single dose once daily.

Tamoxifen may induce ovulation in anovulatory women, stimulating release of gonadotropin-releasing hormone from the hypothalamus, which in turn stimulates release of pituitary gonadotrophins.

The usual dose is 10 mg twice daily on days 2, 3, 4 and 5 of the menstrual cycle, increased if necessary in subsequent cycles, to 40 mg twice daily; alternatively single daily doses of 20 to 80 mg be employed on the same days.

Tamoxifen has a low order of acute toxicity when given orally or intravenously to mice, rats, rabbits, and marmoset monkeys. The acute oral LD 50 was greater than 1 g/kg in all species tested.

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 (see sections 4.4, 4.5 and 5.2).

CYP2D6 genotype

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).

5.2 Pharmacokinetic properties

Tamoxifen is metabolised mainly in the liver and the peak plasma concentrations after a single dose occur 4 to 7 hours after ingestion. Elimination is accomplished with an initial half-life of 7-14 hours, but with a long secondary half-life or more than 7 days. The majority of the compound is metabolised to conjugates and hydroxylated derivatives, which are likewise eliminated very slowly. It is excreted slowly in the faeces with only small amounts appearing in the urine.

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.

5.3 Preclinical safety data

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose BP

Microcrystalline Cellulose BP Povidone BP Carmellose Sodium BP Magnesium Stearate BP Potable Water HSE

6.2 Incompatibilities

None reported.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Protect from heat, light and moisture. Keep out of the reach of children.

6.5 Nature and contents of container

1.    The product is packed in blister packaging (10 tablets/strip) in 20 MU hard temper aluminium foil and white opaque 200MU PVC laminated with 60 G/M¹ PVC (35MU) in pack sizes of 28, 30, 42, 50, 56, 60, 84, 90, 100, 112 and 250 tablets. It is subsequently packed in printed box board cartons.

1

   The product is also blister packed (10 tablets per strip) in aluminium foil with the dull side laminated to the plain 25MU nylon and the bright side