4.1. Therapeutic indications

As an orally active anti-oestrogen in the treatment of breast cancer. Also used to stimulate ovulation in anovulatory infertility.

It is also indicated for the primary prevention of breast cancer in women at moderate or high risk (see section 5.1).

Women aged less than 30 years old were excluded from primary prevention trials so the efficacy and safety of tamoxifen treatment in these younger women is unknown.

4.2. Posology and method of administration

Posology

Adults:

I) Breast Cancer: 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.

II) Anovulatory Infertility: The possibility of pregnancy must be excluded before the commencement of treatment, whether initial or subsequent. In women with regular menstruation but with anovular cycles, treatment should commence with 20 mg daily in either one or two doses administered on the second, third, fourth and fifth days of the menstrual cycle. In unsuccessful cases, further courses may be given during subsequent menstrual periods, increasing the dosage to 20 mg then 40 mg twice daily.

In women with irregular menstruation, the commencement of treatment may take place on any day. If this initial course is not successful, then a further course may be initiated after an interval of 45 days with the higher dosage level (20 mg to 40 mg twice daily).

If a patient responds with menstruation, then the next course of treatment should be initiated on the second day of the cycle.

III) Primary prevention of breast cancer:

Tamoxifen treatment for the primary prevention of breast cancer should only be initiated by a medical practitioner experienced in prescribing for this indication, and as part of a shared care pathway arrangement, with appropriate patient identification, management and follow up.

The recommended dose is 20 mg daily for 5 years for those women at moderate or high risk. There are insufficient data to support a higher dose or longer period of use.

Before commencing treatment, an assessment of the potential benefits and risks is essential, including calculating a patient's risk of developing breast cancer according to local guidelines and risk assessment tools. Validated algorithms are available that calculate breast cancer risk based on features such as age, family history, genetic factors, reproductive factors and history of breast disease.

The use of Tamoxifen should be as part of a program including regular breast surveillance tailored to the individual woman, taking into account her risk of breast cancer.

Elderly

The adult dosage range has been used in elderly patients with breast cancer and in some of these patients it has been used as sole therapy.

Paediatric population

The use of tamoxifen is not recommended in children and adolescents, as safety and efficacy have not been established (see sections 5.1 and 5.2).

Method of administration

For oral administration (use) only.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

The use of tamoxifen is contraindicated:

• In pregnancy Pre-menopausal patients should have pregnancy excluded before treatment is commenced. (see also section 4.6).

• In concurrent anastrozole therapy (see section 4.5).

Treatment for infertility: Tamoxifen should not be used in patients with a personal or family history of confirmed idiopathic venous thromboembolic events or a known genetic defect.

Primary prevention of breast cancer

Tamoxifen should not be used in:

• Women with a history of deep vein thrombosis or pulmonary embolus.

• Women who require concomitant coumarin-type anticoagulant therapy (see sections 4.4 and 4.5).

4.4. Special warnings and precautions for use

The warning and precautions for use are different depending on the indication being treated. The specific warnings and precautions for the primary prevention of breast cancer can be found at the end of the section.

Suppression of menstruation

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

Endometrial changes

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.

There are several factors that influence the risk of developing endometrial cancer, with the majority of risk factors affecting oestrogen levels. Therefore, Tamoxifen treatment may increase the incidence of endometrial cancer. In addition, other risk factors include obesity, nulliparity, diabetes mellitus, polycystic ovary syndrome and oestrogen-only HRT. There is also the general risk for endometrial cancer with increasing age.

Any patient receiving or having previously received tamoxifen who report abnormal gynaecological symptoms, especially non-menstrual vaginal bleeding, or who presents with menstrual irregularities, vaginal discharge and symptoms such as pelvic pain or pressure should be promptly investigated.

Secondary tumours

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.

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in association with Tamoxifen treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, Tamoxifen should be withdrawn immediately, and an alternative treatment considered (as appropriate). If the patient has developed a serious reaction such as SJS or TEN with the use of Tamoxifen, treatment with Tamoxifen must not be restarted in this patient at any time.

Exacerbation of hereditary angioedema

In patients with hereditary angioedema, Tamoxifen may induce or exacerbate symptoms of angioedema.

Venous thromboembolism (VTE)

• A 2-3-fold increase in the risk for VTE has been demonstrated in healthy tamoxifen-treated women (see 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 (see also 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 (see section 4.5). 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 interrupted 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.

Complications during breast reconstruction

In delayed microsurgical breast reconstruction, tamoxifen may increase the risk of microvascular flap complications.

Paediatric population

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 (see section 5.1).

Tamoxifen at the recommended dose, may prolong the QTc interval on the electrocardiogram (ECG).

ECG and electrolyte monitoring are recommended in patients with underlying risks of QT prolongation and cardiac comorbidities such as:

• Long QT syndrome

• Clinically significant or uncontrolled heart disease, such as congestive heart failure, recent myocardial infarction, and cardiac conduction and repolarisation abnormalities

• Concomitant use of QT prolonging medicines

• Electrolyte abnormalities

ECG should be assessed before initiating treatment and follow-up ECG should be repeated once tamoxifen has reached steady state concentrations (at least 4 weeks). ECG monitoring thereafter should be done as clinically indicated for patient‑specific risk factors, i.e. introduction or dose changes of QT prolonging medicines, electrolyte abnormalities, new symptoms (e.g. palpitations, dizziness, syncope).

Appropriate monitoring of serum electrolytes (including potassium, magnesium, calcium, phosphate) should be performed before initiating treatment and during treatment as clinically indicated. Any abnormalities should be corrected prior to initiating tamoxifen and during treatment.

CYP2D6 poor metabolisers/interactions

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 CYP2D6 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 sections 4.5 and 5.2).

Radiation recall has been reported very rarely in patients on tamoxifen who have received prior radiotherapy. The reaction is usually reversible upon temporary cessation of therapy and re-challenge may result in a milder reaction. Treatment with tamoxifen was continued in most cases.

Additional precautions relating to primary reduction of breast cancer risk

Tamoxifen therapy for this indication has uncommonly been associated with serious side effects such as pulmonary embolus and uterine cancer (both endometrial adenocarcinoma and uterine sarcoma). In trials comparing tamoxifen to placebo for reduction of the incidence of breast cancer in women at increased risk of breast cancer, the use of tamoxifen was associated with an increased risk of serious and sometimes fatal adverse events including endometrial cancer (approximately 4 cases per 1000 women over 5 years of use) and thromboembolic events (including deep vein thrombosis and pulmonary embolism). Less serious side effects such as hot flushes, vaginal discharge, menstrual irregularities and gynaecological conditions may also occur. Non-gynaecological conditions such as cataracts were also increased (see section 4.8). Whether the benefits of treatment are considered to outweigh the risks depends on the woman's age, health history, and level of breast cancer risk (see sections 4.4, 4.8 and 5.1).

In the primary prevention studies, due to the limited number of patients with a confirmed BRCA mutation there is uncertainty about the absolute benefit in these patients treated with tamoxifen for primary prevention of breast cancer.

Benign gynaecological conditions (including endometrial polyps, endometriosis, and ovarian cysts) and gynaecological procedures (including hysteroscopy, dilation and curettage, and hysterectomy) were also found to occur more frequently with tamoxifen use.

Any women receiving or having previously received Tamoxifen for risk reduction should be promptly investigated if any abnormal gynaecological symptoms develop, especially non-menstrual vaginal bleeding.

The risks of Tamoxifen therapy are generally lower in younger women than in older women. In the primary prevention trials, in contrast to women aged 50 years or older, women younger than 50 years did not have an increased risk of endometrial cancer or pulmonary embolism and the increased risk of deep vein thrombosis was small and restricted to the treatment period.

When considered for primary reduction of breast cancer risk, Tamoxifen is contraindicated in women who require concomitant coumarin-type anticoagulant therapy or in women with a history of deep vein thrombosis or pulmonary embolus (see section 4.3 and 4.5). In women who do not have a history of thromboembolic events, but who are at increased risk of thromboembolic events, the benefits and risks of Tamoxifen for the primary reduction of breast cancer risk should be carefully considered. Risk factors for thromboembolic events include smoking, immobility and a family history of venous thrombosis; an additional risk factor, is concomitant oral contraceptive or hormone replacement therapy, which is not recommended in women taking Tamoxifen. In women receiving Tamoxifen for primary reduction of breast cancer risk, Tamoxifen should be stopped approximately 6 weeks before undergoing elective surgery to reduce the risk of thromboembolic events. Consideration should also be given to discontinuing Tamoxifen during periods of immobility.

Studies in premenopausal women who were treated with tamoxifen for reduction of breast cancer risk or in the management of breast cancer have reported decreases in bone mineral density. Premenopausal women taking Tamoxifen should be advised regarding measures to maintain bone health, according to local clinical guidelines.

4.5. Interaction with other medicinal products and other forms of interaction

When tamoxifen is used in combination with coumarin-type anticoagulants, such as warfarin, a significant increase in anticoagulant effect may occur. Patients taking coumarin-type anticoagulants will require careful monitoring, including initiation or withdrawal of tamoxifen.

Concurrent use with cytotoxic agents, for the treatment of breast cancer, increases the risk of thromboembolic events occurring (see also 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 reduction in plasma level of an active tamoxifen metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen), has been reported in the literature.

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 sections 4.4 and 5.2).

Primary prevention of breast cancer risk

In women receiving Tamoxifen for the primary prevention of breast cancer, the use of coumarin type anticoagulants is contraindicated (see sections 4.3 and 4.4).

There is some evidence that hormone replacement therapy may reduce the effectiveness of Tamoxifen, and the concomitant use of Tamoxifen and oral hormonal contraceptives is not recommended. Therefore, the use of hormone replacement therapy or oral hormonal contraceptives to manage Tamoxifen side effects is not recommended (see section 5.1).

Tamoxifen at the recommended dose may prolong the QTc interval on the electrocardiogram (ECG), and the concomitant use of Tamoxifen with other medicinal products known to prolong the QT interval may further potentiate QT prolongation. Therefore, caution is advised in case of such combination, and ECG and electrolyte monitoring are recommended in such patients (see section 4.4).

4.6. Fertility, pregnancy and lactation

Pregnancy

Tamoxifen is contra-indicated in 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, ethinylestradiol, clomifene and diethylstilbestrol (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 of childbearing potential

Women should be advised not to become pregnant whilst taking tamoxifen and for nine months following the cessation of therapy 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.

Breast-feeding

Limited data suggest that tamoxifen and its active metabolites are excreted and accumulate over time in human milk, therefore the drug is not recommended during breast-feeding. 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

Tamoxifen has no or negligible influence on the ability to drive or operate machinery. However, fatigue has been reported with the use of tamoxifen and caution should be observed when driving or using machinery while such symptoms persist.

4.8. Undesirable effects

Tabulated list of adverse reactions

Unless specified, the following frequency categories were calculated from the number of adverse events reported in a large phase III study conducted in 9366 postmenopausal women patients with operable breast cancer treated for 5 years and, unless specified, no account was taken of the frequency within the comparative treatment group or whether the investigator considered it to be related to study medication. The safety findings in the breast cancer prevention trials appeared consistent overall with the established safety profile of Tamoxifen.

Very common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to <1/100)

Rare

≥1/10,000 to <1/1,000)

Very rare

(<1/10,000) including isolated reports.

Not known (cannot be estimated from the available data)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Uterine fibroids

Endometrial cancer

Uterine sarcoma (mostly malignant mixed Mullerian tumours)a

Tumour flarea

Blood and lymphatic system disorders

Anaemia

Thrombocytopenia

Leucopenia, in association with anaemia and/or thrombocytopenia.

Neutropeniaa (this can sometimes be severe)

Agranulocytosisa

Transient falls in platelet counts usually between 80,000 - 90,000 per cu mm but occasionally lower have been reported in patients taking tamoxifen for breast cancer

The tendency towards thrombophlebitis may increase and transient thrombocytopenia may occur.

Immune system disorders

Hypersensitivity reactions

Metabolism and nutrition disorders

Fluid retention

Hypercalcaemia (in patients with bone metastases) on initiation of therapy

Nervous system disorders

Ischaemic cerebrovascular events

Headache

Light-headedness

Sensory disturbances (including paraesthesia and dysgeusia)

Optic neuritis*

Eye disorders

Cataracts$

Retinopathy$

Visual disturbance$

Corneal changes$

Optic neuropathya *

Vascular disorders

Hot flushes

Thrombo-embolic events (including deep vein thrombosis, microvascular thrombosis and pulmonary embolism). Risks are increased when tamoxifen is used in combination with cytotoxic agents

Respiratory thoracic and mediastinal disorders

Interstitial pneumonitis

Gastrointestinal disorders

Nausea

Vomiting

Diarrhoea

Constipation

Pancreatitis%

Hepatobiliary disorders

Changes in liver enzyme

Fatty liver&

Cirrhosis of the liver&

Cholestasisa &

Hepatitis &

Hepatic failurea &

Hepatocellular injurya &

Hepatic necrosisa &

Skin and subcutaneous tissue disorders

Skin rash

Alopecia

Angioedema

Stevens-Johnson syndromea

Cutaneous vasculitisa

Bullous pemphigoida

Erythema multiformea

Toxic epidermal necrolysisa

Cutaneous lupus erythematosusb

Exacerbation of hereditary angioedema

Musculoskeletal and connective tissue disorders

Leg cramp

Myalgia

Decreased Bone Mineral Density (premenopausal women)

Reproductive system and breast disorders

Vaginal bleeding

Vaginal discharge

Pruritus vulvae

Endometrial changes (including hyperplasia and polyps)

Suppression of menstruation in premenopausal women

Endometriosisa

Cystic ovarian swellinga

Vaginal polyps

Congenital, familial and genetic disorders

Porphyria cutanea tardab

General disorders and administration site conditions

Fatigue

Tumour pain

Investigations

Increase of serum triglyceride%

Electrocardiogram QT Prolonged

Injury, poisoning and procedural complications

Radiation Recallb

Psychiatric Disorders

Depression

a This adverse drug reaction was not reported in the tamoxifen arm (n= 3094) of the above study; however, it has been reported in other trials or from other sources. The frequency has been calculated using the upper limit of the 95% confidence interval for the point estimate (based on 3/X, where X represents the total sample size e.g. 3094). This is calculated as 3/3094 which equates to a frequency category of 'rare'.

b The event was not observed in other major clinical studies. The frequency has been calculated using the upper limit of the 95% confidence interval for the point estimate (based on 3/X, where X represents the total sample size of 13,357 patients in the major clinical studies). This is calculated as 3/13,357 which equates to a frequency category of 'very rare'.

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

& Tamoxifen has been associated with changes in liver enzyme levels and with a spectrum of more severe liver abnormalities which in some cases were fatal, including fatty liver, cholestasis and hepatitis, liver failure, cirrhosis, and, hepatocellular injury (including hepatic necrosis).

% Elevation of serum triglyceride levels, in some cases with pancreatitis, may be associated with the use of tamoxifen.

$ Visual disturbance such as cataracts, retinopathy and corneal changes, mainly in patients treated with exceptionally high doses for a long period of time.

Side effects can be classified as either due to the pharmacological action of the drug, e.g. hot flushes, vaginal bleeding, vaginal discharge, pruritus vulvae and tumour flare, or as more general side effects, e.g. gastrointestinal intolerance, headache, light-headedness and occasionally, fluid retention 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. Persistent side effects may necessitate the discontinuance of treatment.

Primary prevention of breast cancer risk

The most common adverse events reported from studies in women at increased risk of breast cancer, and occurring more frequently during treatment with Tamoxifen than with placebo, were those associated specifically with the pharmacological action of Tamoxifen such as vasomotor symptoms (hot flushes, night sweats), menstrual abnormalities\irregularities, vaginal discharge, and vaginal dryness.

In the primary prevention trials Tamoxifen significantly increased the incidence of endometrial cancer, deep vein thrombosis, and pulmonary embolism compared with placebo, but the absolute increase in risk was small. The risk of developing cataracts was also significantly increased with Tamoxifen.

Women under 50 years old

A meta-analysis of risk reduction trials stratified by age showed that while women over 50 years old at randomisation had a significantly increased risk of endometrial cancer compared with placebo (RR 3.32, 95% CI 1.95-5.67; p<0.0001), women aged under 50 years did not have a significantly increased risk of pulmonary embolism compared with placebo (RR 1.16, 95% CI 0.55-2.43; p=0.60) and their risk of deep vein thrombosis was only significantly increased during the active treatment phase (RR 2.30, 95% CI 1.23-4.31; p=0,009) but not after treatment had ended.

Gynaecological conditions and procedures

In placebo controlled trials of the use of Tamoxifen for the primary reduction of breast cancer risk, benign gynaecological conditions and procedures were more commonly reported with Tamoxifen. The IBIS-1 trial found that in 3573 women taking Tamoxifen compared to 3566 women on placebo, the following gynaecological conditions and procedures were more common in women taking Tamoxifen: abnormal bleeding (842 v 678, p<00001); endometrial polyps (130 v 65, p<0,0001); ovarian cysts (101 v 42, p<00001); hysteroscopy (228 v 138, P<0,0001); pelvic ultrasound (209 v 132, p<00001); dilation and curettage (178 v 94, p<00001); hysterectomy (154 v 104, p=0002) and oophorectomy (103 v 67, p=0006).

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

On theoretical grounds, an overdosage would be expected to cause enhancement of the pharmacological side effects mentioned above.

Animal studies have demonstrated that extreme overdosage (100 – 200 times the recommended daily dose) may produce 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 of the ECG.

Management

There is no specific antidote to overdosage, and treatment should be carried out symptomatically.