TAMOXIFEN TABLETS BP 10 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Tamoxifen Tablets BP 10 mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablets contains 15.20 mg of tamoxifen citrate.

Excipient with known effect:

Each tablet contains 129.80 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

White, normal convex tablets printed with the company logo on one face and A388 on the other face.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Tamoxifen Tablets BP 10 mg is indicated for:

1. The treatment of breast cancer.

2. The treatment of anovulatory infertility.

3. 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

1. 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

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

2. Anovulatory 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. If unsatisfactory basal temperature or poor pre-ovulatory cervical mucus indicate that this initial course of treatment has been 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. If no signs of ovulation are demonstrable, 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.

3. 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.

Paediatric population

The use of tamoxifen is not recommended in children. The safety and efficacy of tamoxifen in children has not yet been established (see sections 5.1 and 5.2).

Method of administration

For oral use.

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

The warnings 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 premenopausal 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 Hormone replacement therapy (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.

Venous thromboembolism (VTE)

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 (see section 4.5). 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 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).

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 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).

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.

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

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 sections 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.

The use of tamoxifen for reduction of breast cancer risk has been associated with reduced bone density in premenopausal women. Whether this may result in an increased risk of fracture is not known. Pre-menopausal women taking tamoxifen for this reason should be advised regarding measures to maintain bone health.

Severe cutaneous adverse reactions (SCARs)

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.

Hereditary angioedema

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

4.5 Interaction with other medicinal products and other forms of interaction

Pregnancy

Tamoxifen tablets must not be given 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 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.

Breastfeeding

Limited data suggest that tamoxifen and its active metabolites are excreted and accumulate over time in human milk, and therefore the medicinal product is not recommended during breastfeeding. The decision either to discontinue nursing or discontinue tamoxifen should take into account the importance of the medicinal product to the mother.

4.7 Effects on ability to drive and use machines

Tamoxifen is unlikely to impair the ability of patients 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

The following definitions apply to the incidence of undesirable effects: Frequencies are defined as: 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), not known (cannot be estimated from the available data).

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.

Table 1 – Adverse Drug Reactions (ADR) by System Organ Class (SOC) and Frequency.

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’.

Side effects can be classified as either due to the pharmacological action of the medicine, 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. 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 commonly hypersensitivity reactions including angioedema have been reported.

Uncommonly, patients with bony metastases have developed hypercalcaemia on initiation of therapy.

Cases of visual disturbances including rare reports of corneal changes, and common reports of retinopathy have been described, in patients receiving tamoxifen therapy. Cataracts have been reported commonly in association with the administration of tamoxifen.

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

Sensory disturbances (including paraesthesia and dysgeusia) have been reported commonly in patients receiving tamoxifen.

Uterine fibroids, endometriosis and other endometrial changes including hyperplasia and polyps have been reported.

Uncommonly incidences of endometrial cancer and rare instances of uterine sarcoma

(mostly malignant mixed Mullerian tumours) has been reported in association with tamoxifen treatment.

Cystic ovarian swellings have occasionally been observed in 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, and rarely cases of agranulocytosis have been reported.

There is evidence of ischaemic cerebrovascular events and thromboembolic events, including deep vein thrombosis, microvascular 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 and myalgia have been reported commonly in patients receiving tamoxifen.

Uncommonly, cases of interstitial pneumonitis have been reported.

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).

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

Vaginal polyps have rarely been observed in women receiving tamoxifen.

Cutaneous lupus erythematosus has been observed very-rarely in patients receiving tamoxifen.

Porphyria cutanea tarda has been observed very-rarely in patients receiving tamoxifen.

Fatigue has been reported very commonly in patients taking tamoxifen.

Radiation Recall has been observed very rarely in patients receiving tamoxifen.

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 (RR 1.19, 95% CI 0.53–2.65; p=0.6). Similarly, women 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

5   PHARMACOLOGICAL PROPERTIES

5.1   Pharmacodynamic properties

5.2 Pharmacokinetic properties

Absorption

After oral administration, tamoxifen is absorbed rapidly with maximum serum concentrations attained within 4–7 hours. Steady state concentrations (about 300 ng/ml) are achieved after four weeks treatment with 40 mg daily.

Distribution

The active substance is highly protein bound to serum albumin (>99%).

Biotransformation

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.

Elimination

Excretion occurs primarily via the faeces and an elimination half-life of approximately seven days has been calculated for the active substance itself, whereas that for N-desmethyltamoxifen, the principal circulating metabolite, is 14 days.

Paediatric population

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.

CYPD26 polymorphism

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

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate

Cellulose, microcrystalline

Povidone

Carmellose sodium

Magnesium stearate

6.2 Incompatibilities

None reported.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store in the original package in order to protect from heat, light and moisture.

6.5 Nature and contents of container

The product is packed in blister packaging (10 tablets/strip) in aluminium foil, subsequently packed in printed boxboard carton in pack sizes of 28, 30, 42, 50, 56,

60, 84, 90, 100, 112 and 250 tablets. The product is also packed in aluminium foil, dull side laminated to plain 25 mu nylon and bright side lacquer laminated to 60 mu UPVC for all pack sizes.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

None.

7 MARKETING AUTHORISATION HOLDER

Crescent Pharma Ltd

Units 3 and 4, Quidhampton Business Units

Polhampton Lane

Overton

Hampshire

RG25 3ED

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 20416/0224

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

Date of first authorisation: 10 March 2009