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 20 mg of tamoxifen (as citrate). For the full list of excipients, see 6.1.

3 PHARMACEUTICAL FORM

Tablets

Round, white to off-white tablets with a break-line and “20” imprinted on one side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Tamoxifen is indicated for:

- the treatment of breast cancer.

- the treatment of anovulatory infertility.

4.2 Posology and method of administration Posology Breast cancer

Adults:

The recommended daily dose for 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.

The 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.

Anovulatory infertility

The possibility of pregnancy must be excluded before the commencement of treatment. In women with regular menstruation but anovular cycles, initial course of treatment should commence with 20 mg daily administered on the 2nd, 3rd, 4th and 5 th days of the menstrual cycle. Should the initial course of treatment, as judged by basal temperature or pre-ovulatory cervical mucus, prove unsuccessful, further courses may be given during subsequent menstrual periods, increasing the dosage to 40 mg daily and then to 80 mg daily.

In women who are not menstruating regularly, the commencement of treatment may take place on any day. If no signs of ovulation are demonstrable, then a subsequent course of treatment may start 45 days with the dosage increased as above. If a patient responds with menstruation then the next course of treatment is started on the second day of the cycle.

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 section 5.1 and 5.2)

Method of administration

Tamoxifen tablets are for oral administration

4.3 Contraindications

Tamoxifen should not be used in the following:

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

- pregnancy, premenopausal patients must be carefully examined before treatment for breast cancer or infertility to exclude the possibility of pregnancy (see 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

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

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 (see section 4.8). 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 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.

A number of second primary tumours, occurring at sites other than the endometrium and the opposite breast, have been reported in clinical trials, following the treatment of breast cancer patients with tamoxifen. No causal link

has been established and the clinical significance of these observations remains unclear.

Venous thromboembolism

- A 2-3 fold increase in the risk for VTE has been demonstrated in healthy tamoxifen-treated women (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 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.

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

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 pharmacodynamics properties of tamoxifen, a causal relationship has not been established (see section 5.1).

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 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.

There is an increased risk of thromboembolic events occurring when used with cytotoxics.

4.5 Interaction with other medicinal products and other forms of interaction

Tamoxifen increases the dopaminergic effect of bromocriptine.

Aminoglutethimide reduces the plasma concentration of tamoxifen.

Concurrent use of oestrogens may interfere with tamoxifen’s therapeutic effect.

Tamoxifen may potentiate the anti-coagulant action of warfarin if these drugs are used concomitantly. Patients taking coumarin-type anti-coagulants will require close monitoring on the introduction or withdrawal of tamoxifen.

As tamoxifen is metabolised by cytochrome P450 3A4, care is required when coadministering with drugs, such as rifampicin, known to induce this enzyme, because tamoxifen levels may be reduced. The clinical relevance of this reduction is unknown.

Pharmacokinetic interaction with CYP2D6 inhibitors, showing a 65-75% reduction in plasma levels of one of the more active forms of the drug, i.e. endoxifen, has been reported in the literature. Reduced efficacy of tamoxifen has been reported with concomitant usage of some SSRI antidepressants (e.g. paroxetine) in some studies. As a reduced effect of tamoxifen cannot be excluded, co-administration with potent CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should whenever possible be avoided (see section 4.4 and 5.2).

4.6 Fertility, pregnancy and lactation

Pregnancy

Tamoxifen must not be administered 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 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. Premenopausal 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.

Table: 1- Adverse drug reactions (ADRs) seen with Tamoxifen

Frequency	System Organ class (SOC)	ADR
Very Common (> 1/10)	Metabolism and nutrition disorder	fluid retention
	Vascular disorder	hot flushes
	Gastrointestinal disorders	nausea
	Reproductive system and breast disorders	- vaginal bleeding - vaginal discharge
	Skin and subcutaneous tissue disorders	skin rash
	General disorders and administration site conditions	fatigue
Common (> 1/100 to <1/10)	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	uterine fibroids
	Blood and lymphatic system disorders	anaemia
	Immune system disorders	hypersensitivity reactions
	Nervous system disorders	- ischaemic cerebrovascular events - headache - light headedness - sensory disturbances (including

		paraesthesia and dysgeusia)
	Eye disorders	- cataracts - retinopathy
	Gastrointestinal disorders	- vomiting - diarrhea - constipation
	Hepatobiliary disorders	- changes in liver enzymes - fatty liver
	Skin and subcutaneous tissue disorders	alopecia
	Musculoskeletal and connective tissue disorders	- leg cramp - myalgia
	Reproductive system and breast disorders	- pruritus valvae - endometrial changes (including hyperplasia and polyps)
	Investigations	elevated triglycerides
	Multiple SOC terms	thromboembolic events (including deep vein thrombosis, microvascular thrombosis and pulmonary embolism)
Uncommon (> 1/1,000 to < 1/100)	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	endometrial cancer
	Blood and lymphatic system	- thrombocytopenia - leukopenia
	Metabolism and nutrition	hypercalcaemia (in patients with bony metastases)
	Eye disorders	visual disturbances
	Respiratory, thoracic and mediastinal disorders	interstitial pneumonitis
	Gastrointestinal disorders	pancreatitis
	Hepatobiliary disorders	cirrhosis of the liver
Rare (> 1/10,000 to < 1/1,000)	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	^- uterine sarcoma (mostly malignant mixed Mullerian tumours)^a - tumour flare^a
	Blood and lymphatic system disorders	- neutropenia^a - agranulocytosis^a
	Nervous system disorders	optic neuritis

	Eye disorders	- corneal changes - optic neuropathy^a
	Hepatobiliary disorders	- hepatitis - cholestasis^a - hepatic failure^a - hepatocellular injury^a - hepatic necrosis^a
	Skin and subcutaneous tissue disorders	- angioedema - Steven-Johnsons syndrome^a - cutaneous vasculitis^a - bullous pemphigoid^a - erythema multiforme^a
	Reproductive system and breast disorders	- endometriosis^a - cystic ovarian swelling^a - vaginal polyps
Very Rare (< 1/10,000)	Skin and subcutaneous tissue disorders	cutaneous lupus erythematosus^b
	Congenital, familial and genetic disorders	porphyria cutanea tarda^b
	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’.

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. If side effects do not respond to this measure, it may be necessary to stop the treatment.

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

Uncommonly, of 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.

Falls in platelet count, usually to 80,000 to 90,000 per cu mm but occasionally lower, have been reported in patients taking tamoxifen for breast cancer.

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 very 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, occurring commonly 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.

Cystic ovarian swellings have rarely been observed in women receiving 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.

Uncommonly incidences of endometrial cancer and rare instances of uterine sarcoma (mostly malignant mixed Mullerian tumours) has been reported in association with Tamoxifen 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 website: www.mhra.gov .uk/yellowcard.

4.9 Overdose

Overdose in humans has not been reported. On theoretical grounds, an overdose would be expected to cause an enhancement of the anti-oestrogenic effects as described above. In animals, extremely high doses (100-200 times the recommended daily dose) 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 of the ECG.

There is no special antidote to overdosage, and treatment should therefore be symptomatic.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-oestrogens ATC code: L02BA01.

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. 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.

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 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

Maximum plasma levels of tamoxifen occur at 4-7 hours after administration.

Steady- state levels of approximately 300 ng/ml are achieved after 4 weeks’ treatment with 40 mg daily. The drug is highly 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 Ndesmethyltamoxifen, the principal circulating metabolite, is 14 days.

In a clinical study where girls between 2 and 10 years with McCune Albright Syndrome (MAS) received 20mg 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.

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 n rodents. Gonadal tumours in mice and liver tumours in rates receiving tamoxifen have been reported in long term studies. The clinical relevance of these finding has not been established.

Tamoxifen is a drug on which extensive clinical experience has been obtained. There are no other preclinical data of relevance to the prescriber, which are additional to the information included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Calcium hydrogen phosphate Povidone K25

Sodium starch glycollate, Type A Magnesium stearate Microcrystalline cellulose Silica, colloidal anhydrous

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5 Nature and contents of container

Blister packs (PVC film 250 pm, dark green coloured / aluminium foil 20 pm) of 28, 30, 56, 60, 84, 90, 100, 250, 500 and 1000 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Chelonia Healthcare Limited 11 Boumpoulinas Street,

3^rd Floor, 1060 Nicosia Cyprus

8 MARKETING AUTHORISATION NUMBER(S)

PL 33414/0154

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/03/2012

10 DATE OF REVISION OF THE TEXT

04/10/2016