Tamoxifen 20 Mg Tablets

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Tamoxifen 20 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 30.4 mg tamoxifen Citrate equivalent to tamoxifen 20 mg.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet.

The tablets are white, round, biconvex tablets marked TN|20 on one side and G on reverse with an approximate diameter of 9.5 mm.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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

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.

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).

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

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

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 (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 restart 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 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.

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 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).

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 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

Breast-feeding

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

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

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.

	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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps)		Uterine fibroids	Endometrial cancer	Uterine sarcoma (mostly malignant mixed Mullerian tumours)^a Tumour flare^a
Blood and lymphatic system disorders		Anaemia	Thrombocytopenia Leucopenia, in association with anaemia and/or thrombocytopenia.	Neutropenia^a (this can sometimes be severe) Agranulocytosis^a 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 neuropathy³ *
Vascular disorders	Hot flushes	Thrombo-embolic events (including deep vein thrombosis and microvascular thrombosis). Risks are increased when tamoxifen is used in combination with cytotoxic agents
Respiratory thoracic and mediastinal disorders		Thrombo-embolic events (including pulmonary embolism). Risk is increased when tamoxifen is used in combination with cytotoxic agents	Interstitial pneumonitis
Gastrointestinal disorders	Nausea	Vomiting Diarrhoea Constipation	Pancreatitis"⁰

Hepatobiliary disorders		Changes in liver enzyme Fatty liver^&	Cirrhosis of the liver^&	Cholestasis^a & Hepatitis ^& Hepatic failure^a & Hepatocellular injury^{a &} Hepatic necrosis^a &
Skin and subcutaneous tissue disorders	Skin rash	Alopecia		Angioedema Stevens-Johnson syndrome^a Cutaneous vasculitis^a Bullous pemphigoid^a Erythema multiforme^a	Cutaneous lupus erythematosus^b
Musculoskeletal and connective tissue disorders		Leg cramp Myalgia
Reproductive system and breast disorders	Vaginal bleeding Vaginal discharge	Pruritus vulvae Endometrial changes (including hyperplasia and polyps)		Suppression of menstruation in premenopausal women Endometriosis^a Cystic ovarian swelling^a Vaginal polyps
Congenital, familial and genetic disorders					Porphyria cutanea tarda^b
General disorders and administration site conditions	Fatigue	Tumour pain
Investigations		Increase of serum triglyceride"⁰
Injury, poisoning and procedural complications					Radiation Recall^b

^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 therapeutic effect. Persistent side effects may necessitate the discontinuance of treatment.

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

An overdosage would be expected to cause enhancement of the antioestrogenic side effects.

Animal studies have demonstrated that extremely high dosage (greater than 100 times the recommended daily dose) may cause 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 an ECG.

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

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Hormone antagonists and related agents, anti-oestrogens,

ATC Code: L02BA01

Mechanism of action

Tamoxifen citrate is an oestrogen antagonist which is believed to compete with oestrogen for binding sites in target organs. It does not have androgenic properties.

It is used as an alternative to androgens and oestrogens in the management of breast cancer in doses equivalent to 10 and 20mg of Tamoxifen twice daily by mouth.

Tamoxifen is a non-steroidal, triphenylethylene-based drug which displays a complex spectrum of oestrogen antagonist and oestrogen agonist-like pharmacological effects in different tissues. In breast cancer patients, at the tumour level, tamoxifen acts primarily as an antioestrogen, preventing oestrogen binding to the oestrogen receptor. However, clinical studies have shown some benefit in oestrogen receptor negative tumours which may indicate other mechanisms of action. In the clinical situation, it is recognised that tamoxifen leads to reductions in levels of blood total cholesterol and low density lipoproteins in postmenopausal women of the order of 10-20%. Tamoxifen does not adversely affect bone mineral density.

Paediatric population

An uncontrolled trial was undertaken in a heterogenous group of 28 girls aged 2 to 10 years with McCune Albright Syndrome (MAS), who received 20 mg once a day for up to 12 months duration. Among the patients who reported vaginal bleeding during the pre-study period, 62% (13 out of 21 patients) reported no bleeding for a 6-month period and 33% (7 out of 21 patients) reported no vaginal bleeding for the duration of the trial. Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. While this finding is in line with the pharmacodynamic properties of tamoxifen, a causal relationship has not been established (see section 4.4). There are no long-term safety data in children. In particular, the long-term effects of tamoxifen on growth, puberty and general development have not been studied.

CYP2D6 polymorphism

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

Absorption

After oral administration, tamoxifen is absorbed rapidly with peak plasma concentrations of Tamoxifen occurring 4 to 7 hours after an oral dose. Steady state concentrations (about300 ng/ml) are achieved after four weeks treatment with 40 mg daily.

Distribution

Tamoxifen is highly protein bound to serum albumin (>99%). Biotransformation and elimination

Plasma clearance is reported to be biphasic and the terminal half-life may be longer than 7 days for tamoxifen itself, whereas that for N-desmethyltamoxifen, the principal circulating metabolite, is 14 days.

It is extensively metabolised by hydroxylation, demethylation and conjugation, the major serum metabolite being N-desmethyltamoxifen, and is excreted slowly in the faeces, mainly as conjugates. Small amounts are excreted in the urine. Tamoxifen appears to undergo enterohepatic circulation.

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.

CYP2D6 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

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.

Relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol Maize Starch Croscarmellose sodium Magnesium Stearate

6.2 Incompatibilities

None known

6.3 Shelf life

60 months for polypropylene pots and blisters; 48 months for HDPE.

6.4 Special precautions for storage

Do not store above 25°C.

Pots: Keep the pot tightly closed in order to protect from light and moisture.

Blisters: Store in the original package in order to protect from light and moisture.

6.5 Nature and contents of container

Polypropylene tablet container with white polyethylene caps and polyethylene ullage filler; and PVC/Aluminium Blister Pack; and High density polyethylene (HDPE) containers with polyethylene snap closures in packs of 5, 7, 10, 14, 20, 21, 25, 28, 30, 50, 56, 60, 100 and 250 tablets.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Generics [UK] Ltd t/a Mylan

Station Close

Potters Bar

Herts

EN6 1TL

8 MARKETING AUTHORISATION NUMBER(S)

PL 04569/0070

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of MA grant : 31/8/89 Date of last renewal : 24/01/2006

10 DATE OF REVISION OF THE TEXT

20/07/2016