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1. Tamoxifen 40mg Film-Coated Tablets
2. Tamoxifen 40mg Film-Coated Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Tamoxifen 40mg Film-Coated Tablets

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Tamoxifen Citrate BP 60.8 mg equivalent to 40mg of tamoxifen.

For excipients, see 6.1.

3.    PHARMACEUTICAL FORM Film-coated tablets

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Tamoxifen tablets are used for the treatment of breast carcinoma, particularly in oestrogen receptor positive patients and for the treatment of anovulatory infertility.

4.2 Posology and method of administration

Breast carcinoma: The recommended daily dose of tamoxifen is normally 20mg. 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 - 40mg per day is not available, although these doses have been used in some patients with advanced disease.

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

Anovulatory infertility: Before commencing any course of treatment, whether initial or subsequent, the possibility of pregnancy must be excluded. In women with regular menstruation but anovular cycles, treatment should be initiated with 20mg daily given on the second, third, fourth and fifth days of the menstrual cycle. If treatment is unsuccessful (unsatisfactory basal temperature records or poor pre-ovulatory cervical mucus), further courses may be given during subsequent menstrual periods, increasing the dosage to 40mg and then 80mg daily.

In women with irregular menstruation, treatment may be initiated on any day. If no signs of ovulation are apparent, a subsequent course of treatment may be commenced 45 days later with dosage increased as above. If the patient responds with menstruation, the next course of treatment should start on the second day of the cycle.

4.3    Contraindications

Tamoxifen must not be administered during pregnancy. Pre-menopausal patients must be carefully examined before treatment for breast cancer or infertility to exclude the possibility of pregnancy (see also Section 4.6).

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

Tamoxifen should not be administered concomitantly with anastrozole therapy.

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

4.4    Special warnings and precautions for use

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 risk of endometrial cancer is increased with higher daily doses and prolonged therapy. The underlying mechanism is unknown but may be related to the oestrogen-like properties of tamoxifen. Any patient receiving or having previously received tamoxifen who reports abnormal gynaecological symptoms, especially abnormal 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.

Menstruation is suppressed in a proportion of premenopausal women receiving tamoxifen for the treatment of breast cancer.

Tamoxifen is considered unsafe for use in porphyria, and may trigger acute attacks in inherited prophyria.

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).

Venous thromboembolism (VTE)

•    A two- to three-fold increase in the risk for VTE has been demonstrated in healthy tamoxifen-treated women (see section 4.8).

•    The risk of VTE is further increased by severe obesity, increasing age, concomitant chemotherapy and all other risk factors for VTE. The risks and benefits should be carefully considered for all patients before treatment with tamoxifen. Long-term prophylactic anticoagulation may be justified in some patients with breast cancer who have multiple risk factors for VTE.

•All patients should be advised to contact their doctors immediately if they become aware of any symptoms of VTE.

Breast cancer treatment & VTE Prior to starting treatment with tamoxifen

•    Obtain a careful 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 risk of VTE is increased in breast cancer patients receiving concomitant chemotherapy.

•    The decision to treat should be based on the overall risk to the patient.

•    Use of prophylactic anticoagulant may be justified.

Surgery/immobility

•    Do not stop tamoxifen treatment before surgery or long-term immobility unless the risk of tamoxifen-induced thrombosis clearly outweighs the risk

of interrupting treatment.

•    This decision should take into account the possible duration of treatment interruption, the stage and grade of cancer, the clinical response of the patient to tamoxifen therapy and the stage of the treatment regimen at which interruption occurs.

•    All patients should receive appropriate thrombosis prophylactic measures.

Occurrence of VTE

•    Stop tamoxifen immediately and initiate anti-thrombosis measures.

•    The decision to re-start tamoxifen should be made with respect to the overall risk:benefit balance for the patient.

•    Anti-coagulation measures should beconsidered if the patient is to be restarted on tamoxifen.

Anovulatory infertility treatment & VTE Prior to starting treatment with tamoxifen

•    Tamoxifen is contraindicated in patients with a known personal or family history of confirmed, idiopathic VTE or known genetic defect predisposing to thrombosis.

Surgery / immobility

•    Stop tamoxifen treatment at least 6 weeks before surgery or long-term

immobility and re-start only when the patient is fully mobile.

•    All patients should receive appropriate thrombosis prophylactic measures.

Occurrence of VTE

•    Stop tamoxifen immediately and initiate appropriate anti-thrombosis measures.

•    Do not re-start tamoxifen unless there is a compelling alternative explanation for the thrombotic event.

Periodic complete blood counts and liver function tests are recommended during tamoxifen therapy.

4.5 Interaction with other medicinal products and other forms of interaction

Antibacterials: As tamoxifen is metabolised by cytochrome P450 isoenzyme CYP 3A4, care is required when co-administering with drugs, known to induce this enzyme such as rifampicin, because tamoxifen levels may be reduced.

Anticoagulants: When tamoxifen is 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.

Other Hormone Antagonists: Tamoxifen may reduce letrozole plasma concentrations. The use of tamoxifen in combination with anastrozole as adjuvant therapy has not shown improved efficacy compared with tamoxifen alone.’

Cytotoxics: Haemolytic anaemia, thrombocytopenia and renal dysfunction, leading to potentially fatal haemolytic uraemic syndrome, can occur in patients given tamoxifen with, or shortly after, mitomycin. Concomitant use of tamoxifen with cytotoxic agents may increase the risk of thromboembolic events. Thrombosis prophylactic measures should be considered in patients taking tamoxifen during periods of concomitant chemotherapy.

Pharmacokinetic interaction with CYP2D6 inhibitors, showing 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 Pregnancy and Lactation

Pregnancy

Tamoxifen must not be administered during pregnancy. There have been a small number of reports of spontaneous abortions in women treated for infertility, 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. However, studies in rats have demonstrated reversible, non-teratogenic, developmental skeletal changes, an increased foetal death rate and intrauterine growth retardation, with slower learning behaviour in survivors. Abortions and premature delivery have occurred in rabbits.

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 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 or within two months of cessation of therapy.

Lactation

As tamoxifen may inhibit lactation and it is not known if tamoxifen is excreted in human milk, 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

Patients should be warned that visual disturbances, including reduced visual acuity and blurred vision, may occur with tamoxifen therapy and may affect their ability to drive or operate machinery.

4.8 Undesirable effects

During long term treatment side-effects are generally mild.

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.

Cerebrovascular accident: Some reports show Tamoxifen to be associated with an increased risk of cerebrovascular accidents.

Eye: A number of cases of visual disturbance (including reports of blurred vision, reduced visual acuity, optic neuritis, corneal changes and retinopathy) and an increased incidence of cataracts, have been described in patients receiving tamoxifen therapy. Cases of optic neuropathy and optic neuritis have been reported in patients receiving tamoxifen and, in a small number of cases, blindness has occurred.

Gastroinestinal: gastrointestinal intolerance. May cause nausea and vomiting.

General: Fatigue, Leg cramps have been reported commonly in patients receiving tamoxifen.

Haematological: Falls in platelet count, usually to 80,000-90,000 per cu mm but occasionally lower, have been reported in patients receiving tamoxifen for breast carcinoma. 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.

Hepatobiliary: Tamoxifen has been associated with changes in liver enzyme levels and rarely with more severe liver abnormalities including, cholestasis, hepatitis., non-alcoholic steatohepatitis and cirrhosis. The potential for tamoxifen to precipitate non-alcoholic steatohepatitis and cirrhosis is associated with the following risk factors: Being overweight or obese, insulin resistance, diabetes, hyperlipidaemia. Non-alcoholic steatohepatitis is reversible on withdrawal of tamoxifen

Immunological: Rare hypersensitivity reactions, including angioedema, have been reported.

Metabolic: Weight gain, fluid retention. A small number of patients with bony metastases have developed hypercalcaemia on initiation of therapy. Rarely, elevation of serum triglyceride levels, in some cases with pancreatitis, may be associated with the use of tamoxifen.

Neoplasms benign, malignant and unspecified (incl. Cysts and polyps): Tumour flare and pain. An increased incidence of endometrial cancer and uterine sarcoma (mostly malignant mixed Mullerian tumours) has been reported in association with tamoxifen treatment. The risk of endometrial cancer is increased with higher daily doses and prolonged therapy.

Nervous system disorders: Headaches, light-headedness

Psychiatric: Confusion, depression.

Reproductive: Vaginal bleeding, vaginal discharge, pruritus vulvae. Menstruation is suppressed in a proportion of pre-menopausal women receiving tamoxifen for the treatment of breast cancer. Uterine fibroids, endometriosis and other endometrial changes including hyperplasia and polyps have been reported. Cystic ovarian swellings have occasionally been observed in pre-menopausal women receiving tamoxifen.

Respiratory: Very rarely, cases of interstitial pneumonitis have been reported.

Skin: Rashes (including isolated reports of erythema multiforme, Stevens-Johnson syndrome and bullous pemphigoid), dry skin, alopecia. In rare instances, radiation recall dermatitis may occur.

Vascular Disorders: Hot flushes, Cases of deep vein thrombosis and pulmonary embolism have been reported during tamoxifen therapy (see section 4.4). When tamoxifen is used in combination with cytotoxic agents, there is an increased risk of thromboembolic events

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

a)    Symptoms

In theory, overdosage causes antioestrogenic side-effects. In animals extremely high doses (greater than 100 times the recommended dosage) have caused oestrogenic effects.

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.

b)    Treatment

Treatment is symptomatic, as there is no specific antidote.

5    PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 results 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.

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

Peak plasma concentrations of tamoxifen occur four to seven hours after an oral dose. Steady state concentrations (about 300ng/ml) are achieved after four weeks of treatment with 40mg daily. It is extensively 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.

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

A small number of cases of endometrial polyps and endometrial carcinoma have been reported in association with tamoxifen treatment. A definitive relationship to tamoxifen therapy has not been established.

Tamoxifen was not mutagenic in a range of in vitro and in vivo mutagenicity tests. 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.

6.1 List of excipients

Lactose Maize starch

Pregelatinised maize starch Magnesium stearate Water

Film Coat

Methylhydroxypropylcellulose Propylene glycol

Opaspray M-l-7111B (E171, E464) Water

6.2    Incompatibilities

None known

6.3    Shelf life

Three years.

6.4    Special precautions    for storage

Do not store above 25°C.

Store in the original container in order to protect from light and moisture.

6.5    Nature and contents of container

Packs of tablets in polypropylene or polyethylene containers with child resistant closures or amber glass bottles.

Blister packs of white PVC and aluminium foil coated with PVC/PVDC film.

6.6    Instructions for use/handling

The tablets are administered orally. Take the tablets with a glass of water.

7.    MARKETING AUTHORISATION HOLDER

Wockhardt UK Limited Ash Road North Wrexham