Tamoxifen 20mg tablets

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Public Assessment Report Public Assessment Report (PAR)

30-11--0001

Active ingredient:
Tamoxifen citrate
Available from:
Mawdsley-Brooks & Company Ltd
ATC code:
L02BA01
INN (International Name):
Tamoxifen citrate
Dosage:
20mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 08030401

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’

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“

”

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























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





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





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

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





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









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

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

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





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









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

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



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

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

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



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





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

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

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









PACKAGE LEAFLET: INFORMATION FOR THE PATIENT















1

What Tamoxifen is and what it is

used for

2

What you need to know before

you take Tamoxifen





· 

· 

· 



· 



Tamoxifen 10mg and 20mg Tablets

(Tamoxifen Citrate)













3

How to take Tamoxifen

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













































































































































































































































































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4

Possible side effects

5

How to store Tamoxifen

6

Contents of the pack and

other information











XXXXXXXXXXX

Product name

Tamoxifen

Revision

Till-Ver.9.1

Strength & form

10 mg & 20 mg Tablets

Date updated

18/09/2018

Component type

Inks

Black

Typeface

SansSerif

Size

175 x 400 mm (43.75 x 50 mm folded)

Point size

Minimum 8 points (patient information)

Package leaflet

Pages

3 (including this one)

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Tamoxifen 20mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains: Tamoxifen Citrate 30.40mg (equivalent to 20mg tamoxifen)

Excipient with known effect: Each tablet contains 259.60mg of lactose

For full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Tablets

White, convex tablets with an approximate diameter of 9.5mm printed T20on

one side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Tamoxifen tablets are indicated for:

The treatment of breast cancer

The treatment of anovulatory infertility

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

Breast Cancer

Adults

The recommended daily dose of tamoxifen is normally 20mg. No additional

benefit, in terms of delayed recurrence or improved survival in patients, has

been demonstrated with higher doses. Substantive evidence supporting the use

of treatment with 30-40mg per day is not available, although these doses have

been used in some patients with advanced disease.

Elderly people

Similar dosing regimens of tamoxifen have been used in the elderly with

breast cancer and in some of these patients it has been used as sole therapy.

Anovulatory Infertility

Before commencing any course of treatment, whether initial or subsequent, the

possibility of pregnancy must be excluded. In women who are menstruating

regularly, but with anovular cycles, the initial course of treatment consists of

20mg given daily on the second, third, fourth and fifth days of the menstrual

cycle. If unsatisfactory basal temperature records 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 40mg and then 80mg daily.

In women who are not menstruating regularly, the initial course may begin on

any day. If no signs of ovulation are demostrable, then a subsequent course of

treatment may start 45 days later, with dosage increased as above. If a patient

responds with menstruation, then the next course of treatment is commenced

on the second day of the cycle.

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 20mg 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 has not yet been established (see sections 5.1 and 5.2).

Method of administration

For oral administration.

4.3

Contraindications

General contraindications (all indications)

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. Pre-menopausal patients must be carefully examined before

treatment for all indications to exclude the possibility of pregnancy (see

also section 4.6).

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 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.

Menstruation is suppressed in a proportion of pre-menopausal 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. 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.

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

prothrombic risk, patients should be screened for thrombophillic factors.

Patients who test positive should be counselled regarding their thromobotic

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 section 4.5)

The risk of VTE is further increased by severe obesity, increasing age and all

other 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 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 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.

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 20mg 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).

In the literature it has been shown that CYP2D6 poor metabolisers have a

lowered

plasma

level

endoxifen,

most

important

active

metabolites of tamoxifen (see section 5.2).

Concomitant

medications

that

inhibit

CYP2D6

lead

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).

Tamoxifen contains lactose. Patients with rare hereditary problems of

galactose intolerance, total lactase deficiency or glucose-galactose

malabsorption should not take this medicine.

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 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.

4.5

Interaction with other medicinal products and other forms of interaction

When tamoxifen is used in combination with coumarin-type anticoagulants, a

significant increase in anticoagulant effect may occur. Where such co-

administration is initiated, careful monitoring of the patient is recommended.

When tamoxifen is used in combination with cytotoxic agents for the

treatment of breast cancer, there is an increased 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

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).

4.6

Pregnancy and lactation

Women of childbearing potential

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.

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 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.

Breast-feeding

It is not known if tamoxifen is excreted in human milk and 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 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 operating 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.

Frequency

Adverse Drug Reaction

Common

Uterine fibroids

Neoplasms benign,

malignant and unspecified

Uncommon

Endometrial cancer

(incl cysts and polyps)

Rare

Uterine Sarcoma (mostly malignant

mixed Mullerian tumours)

Tumour Flare

Common

Anaemia

Uncommon

Thrombocytopenia

Leukopenia

Blood and lymphatic system

disorders

Rare

Neutropenia

Agranulocytosis

Immune system disorders

Common

Hypersensitivity reactions

Very

common

Fluid retention

Metabolism and nutrition

disorders

Uncommon

Hypercalcaemia (in patients with

bony metastases)

Common

Ischaemic cerebrovascular events

Headache

Light headedness

Sensory disturbances (including

paraesthesia and dysgeusia)

Nervous system disorders

Rare

Optic neuritis

Common

Cataracts

Retinopathy

Uncommon

Visual disturbances

Eye disorders

Rare

Corneal changes Optic

neuropathy

Very

Common

Hot flushes

Vascular disorders

Common

Thromboembolic events (including

deep vein thrombosis,

microvascular thrombosis and

pulmonary embolism)

Respiratory, thoracic and

mediastinal disorders

Uncommon

Interstitial pneumonitis

Very

common

Nausea

Common

Vomiting

Diarrhoea

Constipation

Gastrointestinal disorders

Uncommon

Pancreatitis

Common

Changes in liver enzymes

Fatty liver

Uncommon

Cirrhosis of the liver

Hepatobiliary disorders

Rare

Hepatitis

Cholestasis

Hepatic failure

Hepatocellular injury

Hepatic necrosis

Very

common

Skin Rash

Common

Alopecia

Rare

Angioedema

Steven-Johnsons syndrome

Cutaneous vasculitis

Bullous pemphigoid

Erythema multiforme

Skin and subcutaneous tissue

disorders

Very rare

Cutaneous lupus erythematosus

Musculoskeletal and

connective tissue disorders

Common

Leg cramp

Myalgia

Very

common

Vaginal bleeding

Vaginal discharge

Common

Pruritus valvae

Endometrial changes (including

hyperplasia and polyps)

Reproductive system and

breast disorders

Rare

Endometriosis

Cystic ovarian swelling

Vaginal polyps

Congenital, familial and

genetic disorders

Very rare

Porphyria cutanea tarda

General disorders and

administration site conditions

Very

common

Fatigue

Investigations

Common

Elevated triglycerides

Injury, poisoning and

procedural complications

Very rare

Radiation Recall

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’.

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. gastro-intestinal 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 less than 20mg/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, 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. 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.

Public Assessment Report

UK PAR

Tamoxifen 20mg Tablets

(tamoxifen citrate)

UK Licence No: PL 16363/0135

Milpharm Limited

PL 16363/0135

UKPAR Milpharm Ltd, Tamoxifen 20mg Tablets

2

LAY SUMMARY

Tamoxifen 20mg Tablets

(tamoxifen citrate)

This is a summary of the Public Assessment Report (PAR) for Tamoxifen 20 mg Tablets

(PL 16363/0135). For ease of reading, Tamoxifen 20mg Tablets may be referred to as ‘Tamoxifen’ in

this lay summary. The lay summary explains how the application for Tamoxifen was assessed and its

authorisation recommended, as well as the conditions of use. It is not intended to provide practical

advice on how to use Tamoxifen.

For practical information about using Tamoxifen, patients should read the package leaflet or contact

their doctor or pharmacist.

What is Tamoxifen and what is it used for?

Tamoxifen is a ‘generic’ medicine’. This means that Tamoxifen is similar to a ‘reference medicine’

called Nolvadex-D 20 mg tablets (PL 17901/0034; AstraZeneca UK Limited, UK), which was first

authorised in the UK in 1982.

This medicine is used to treat:

breast cancer

infertility in women caused by a failure to produce and release eggs (ovulate) properly

it can also reduce the risk of developing breast cancer occurring in those women who have an

increased likelihood of developing breast cancer (the patient’s risk). It is important that the patient’s

healthcare professional calculates the patient’s risk of developing breast cancer and discusses the

result with the patient before commencing treatment. There are a number of specific tools available

to calculate breast cancer risk, based on information such as the patient’s age, family history,

genetics, reproductive factors (e.g. age when periods started and stopped, had children or not, taken

or taking hormonal replacement therapy and/or oral contraceptive pill) and history of breast disease.

Although the tools can estimate the patient’s risk, it does not mean the patient will get breast cancer,

being at increased risk means the patient has a higher chance of developing breast cancer. If the

patient’s healthcare professional and patient are considering the patient using Tamoxifen for this

indication, it is important for the patient to understand the benefits as well as the side effects of taking

Tamoxifen as the patient does not currently have breast cancer and tamoxifen reduces, but does not

stop the risk of developing breast cancer.

The patient should ask their doctor if they are not sure why they have been prescribed these tablets.

How does Tamoxifen work?

The active substance, tamoxifen ( as tamoxifen citrate) belongs to a group of medicines known as ‘anti-

oestrogens’. Oestrogen is a natural substance in the body known as a ‘sex-hormone’. Tamoxifen works

by blocking the effects of oestrogen.

PL 16363/0135

UKPAR Milpharm Ltd, Tamoxifen 20mg Tablets

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How is Tamoxifen used?

The pharmaceutical form for this medicine is a tablet. The tablets should be swallowed with a glass of

water.

Tamoxifen can only be obtained with a prescription.

Tamoxifen should always be taken exactly as advised by the patient’s doctor or pharmacist. The patient

should check with their doctor or pharmacist if not sure. The patient’s doctor will advise him/her as to

how much medicine to take.

Please read section 3 of the package leaflet (PL) for detailed information on dosing recommendations,

the route of administration and the duration of treatment.

Use in children and adolescents

Children and adolescents should not take Tamoxifen.

What benefits of Tamoxifen has been shown in studies?

As Tamoxifen is a generic medicine, studies in patients have been limited to tests to determine that

Tamoxifen Tablets are bioequivalent to the reference medicine, Nolvadex-D 20 mg tablets (AstraZeneca

UK Limited, UK). Two medicines are bioequivalent when they produce the same levels of the active

substance in the body.

What are the possible side effects of Tamoxifen?

Because Tamoxifen is a generic medicine and is bioequivalent to the reference medicine Nolvadex-D 20

mg tablets (AstraZeneca UK Limited, UK), the possible side effects are taken as being the same as those

of the reference medicine.

For the full list of all side effects reported with Tamoxifen, see Section 4 of the package leaflet.

For the full list of restrictions, see the package leaflet.

Why is Tamoxifen approved?

It was concluded that, in accordance with EU requirements, Tamoxifen has been shown to have

comparable quality and to be bioequivalent to Nolvadex-D 20 mg tablets (AstraZeneca UK Limited,

UK). Therefore, the view was that, as for Nolvadex-D 20 mg tablets (AstraZeneca UK Limited, UK), the

benefits outweigh the identified risks.

What measures are being taken to ensure the safe and effective use of Tamoxifen?

A Risk Management Plan has been developed to ensure that Tamoxifen is used as safely as possible.

Based on this plan, safety information has been included in the Summary of Product Characteristics and

the package leaflet for Tamoxifen, including the appropriate precautions to be followed by healthcare

professionals and patients.

Known side effects are continuously monitored. Furthermore, new safety signals reported by patients

and healthcare professionals will be monitored and reviewed continuously as well.

Other information about Tamoxifen

A Marketing Authorisation was granted in the UK to Milpharm Limited on 29 August 2007.

PL 16363/0135

UKPAR Milpharm Ltd, Tamoxifen 20mg Tablets

4

A variation to add the indication ‘primary prevention of breast cancer in women at moderate or high risk’

was granted on 19 July 2018.

The full PAR for Tamoxifen follows this summary.

For more information about treatment with Tamoxifen, read the package leaflet, or contact your doctor

or pharmacist.

This summary was last updated in August 2018.

PL 16363/0135

UKPAR Milpharm Ltd, Tamoxifen 20mg Tablets

5

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 6

Quality aspects

Page 7

Non-clinical aspects

Page 9

Clinical aspects

Page 9

User consultation

Page 12

Overall conclusion, benefit/risk assessment and

recommendation

Page 13

Steps taken after authorisation - Summary

Page 15

Annex 1

Page 16

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Scientific discussion

I

INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the UK granted a Marketing

Authorisation for the medicinal product Tamoxifen 20mg Tablets (PL 16363/0135) on 29 August 2007.

Tamoxifen 20mg Tablets were shown to correspond to the current EU definition of a generic medicinal

product because it complies with the criteria of having the same qualitative and quantitative composition

in terms of active substance and the same dosage form to the reference product (Nolvadex-D 20mg

Tablets, PL 17901/0034, Astra-Zeneca Ltd).

Tamoxifen is a prescription only medicine.

II

QUALITY ASPECTS

II.1

Introduction

The submitted documentation concerning the proposed product is of sufficient quality and meets the

current EU regulatory requirements.

The quality overall summary has been written by an appropriately qualified person and is a suitable

summary of the pharmaceutical aspects of the dossier.

The product is a white to off-white, round, biconvex, tablets with scoring and ‘20’ embossed on one

side.

Each tablet contains 20 mg of tamoxifen (as citrate). Other ingredients consist of the pharmaceutical

excipients calcium hydrogen phosphate, microcrystalline cellulose, sodium starch glycollate (Type A),

Povidone K25, magnesium stearate and colloidal anhydrous silica. Appropriate justification for the

inclusion of each excipient has been provided.

II.2

Drug Substance

Tamoxifen Citrate is 2-[4-[(Z)-1,2-diphenylbut-1-enyl] phenoxy]-N,N-dimethylethanamine dihydrogen

2-hydroxypropane-1,2,3-tricarboxylate.

NO, C

MW = 563.6

CAS No: 54965-24-1

Tamoxifen citrate is white or almost white powder. It is slightly soluble in water and acetone but soluble

in methanol.

A current certificate of suitability was provided for the source of the drug substance. The certificate of

suitability indicates that:

An appropriate specification has been provided.

Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the

relevant specifications.

Tamoxifen is stored in appropriate packaging. The specifications and typical analytical test reports are provided

and are satisfactory.

PL 16363/0135

UKPAR Milpharm Ltd, Tamoxifen 20mg Tablets

7

Batch analysis data are provided and comply with the proposed specification.

Satisfactory certificates of analysis have been provided for working standards used by the active substance

manufacturer and finished product manufacturer during validation studies.

Appropriate stability data have been generated and support a shelf-life of 5 years.

II.3

Medicinal Product

Composition of Drug Product

Tamoxifen

Calcium hydrogen phosphate

Microcrystalline cellulose

Sodium starch glycollate (Type A)

Povidone K25

Magnesium stearate

Colloidal anhydrous silica

All excipients comply with their respective European Pharmacopoeia monographs and satisfactory

certificates of analysis have been provided. There are no excipients of animal or human origin, the

magnesium stearate used is of plant origin. There were no novel excipients used and no overages.

Dissolution and impurity profiles

Dissolution and impurity profiles for both strengths of drug product were found to be similar to those for the

reference products.

Manufacture

A description and flow-chart of the manufacturing method has been provided.

In-process controls are appropriate considering the nature of the product and the method of manufacture.

Process validation has been carried out on batches of the drug product. The results are satisfactory.

Finished product specification

The finished product specification is satisfactory. Acceptance limits have been justified with respect to

conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described

and have been adequately validated, as appropriate. Batch data have been provided and comply with the release

specification. Certificates of analysis have been provided for any working standards used.

Container Closure System

The tablets are in a blister pack of aluminium foil and Polyvinylchloride film which is declared to meet

EEC requirements.

Stability

Satisfactory stability data for the finished product has been provided for normal and accelerated

conditions and support a shelf-life of 4 years with the special storage instructions ‘Do not store above

C. Store in the original package.’

Conclusion

The grant of a Marketing Authorisation is recommended, from a quality point view.

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III

NON-CLINICAL ASPECTS

No non-clinical data were provided for this application and none were required.

The grant of a Marketing Authorisation is recommended, from a non-clinical point view.

IV.

CLINICAL ASPECTS

CLINICAL PHARMACOLOGY

Tamoxifen is a non-steroidal, triphenylethylene-based drug, which displays a complex spectrum of

estrogen antagonist and estrogen agonist-like pharmacological effects in different tissues. In breast

cancer patients, at the tumour level, tamoxifen acts primarily as an antiestrogen, preventing estrogen

binding to the estrogen receptor.

After oral administration, tamoxifen is absorbed rapidly with maximum serum concentrations attained

within 4 - 7 hours. Steady state concentrations (about 300 mg/ml) are achieved after four 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 N-desmethyltamoxifen, the principal circulating

metabolite, is 14 days.

PHARMACOKINETICS - BIOEQUIVALENCE STUDY

Study TAM-BIO-EFE-91

This is a study investigating the pharmacokinetics, distribution and the relative bio-availability of

tamoxifen in healthy volunteers. The study was an open label, fixed dose study with 5 different study

groups.

Study Groups I and II were given either 20mg of Nolvadex or Tamoxifen 20mg Tablets.

There were 18 patients in each group which were studied in the fasting state.

Results

Tamoxifen 20mg

There were no statistical differences between the treatment groups. Thus the 2 groups can be considered

identical based on demographic criteria for age, weight, height and body surface area.

The statistical calculations for the bio-availability of tamoxifen and N-desmethyltamoxifen from the

reference Nolvadex 20 mg and the applicant tamoxifen are shown in Tables 1 and 2, below:

PL 16363/0135

UKPAR Milpharm Ltd, Tamoxifen 20mg Tablets

9

Table 1:

Mean Pharmacokinetic Parameters of Tamoxifen after a Single Oral Dose of 20mg Tamoxifen (Nolvadex

or Tamoxifen 20)

Pharmacokinetic

Nolvadex

®

20

Parameter

mean

CV(%)

(ng/ml)

31.0

28.4

18.8

56.9

5.28

0.83

15.7

3.00

6.00

(ng·h/ml)

2070

26.1

1230

3310

0.-oo

(ng·h/ml)

2250

25.3

1320

3510

21.4

63.3

180

Pharmacokinetic

Tamoxifen 20

Parameter

mean

CV(%)

(ng/ml)

30.7

20.5

20.6

43.7

5.31

1.30

24.5

2.50

8.00

(ng·h/ml)

2030

23.2

1040

3120

0.-oo

(ng·h/ml)

2240

25.0

1140

3830

23.9

69.7

PL 16363/0135

UKPAR Milpharm Ltd, Tamoxifen 20mg Tablets

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Table 2

Statistical Results of Testing Treatment with Tamoxifen 20 against Treatment with Nolvadex

20 Using Mean

Square Error Term From 2 Treatment ANOVA

R e s u l t s f o r T a m o x i f e n

Parameter

Diff

Stat

Power

90% Sym Cl 90% Shortest

Cl

(ng/ml)

n.s.d.

0.916

8.40

89.4 to 09.1

n.s.d.

0.979

6.90

92.4 to 108.8

(ng·h/ml)

n.s.d.

0.919

9.70

88.1 to 107.7

0.-oo

(ng·h/ml)

n.s.d.

0.906

8.50

89.2 to 109.2

n.s.d.

0.928

17.2

100.2 to 119.4

R e s u l t s f o r N-D e s m e t h y l t a m o x i f e n

Parameter

Diff

Stat

Power

90% Sym Cl 90% Shortest

Cl

(ng/ml)

12.7

n.s.d.

0.433

26.9

69.0 to 105.7

19.5

n.s.d.

0.236

40.0

54.0 to 107.1

(ng·h/ml)

n.s.d.

0.865

16.0

97.0 to 118.5

0.-oo

(ng·h/ml)

n.s.d.

0.719

16.1

93.2 to 119.1

n.s.d.

0.480

21.8

91.3 to 125.7

Diff:

Observed difference between means as % of reference mean

Stat:

P value statistic

n.s.d.:

no significant difference

90% Sym Cl:

90% confidence interval based on 2 one-sided t-tests (α=0.05)

expressed as % of reference mean + 100%

90% Shortest Cl:

90% confidence interval based on 2 one-sided t-tests (α=0.05)

expressed as % of reference mean + 100%

PL 16363/0135

UKPAR Milpharm Ltd, Tamoxifen 20mg Tablets

11

N-desmethytamoxifen

The Pharmacokinetic parameters for N desmethyltamoxifen with the 20mg dose of tamoxifen is shown in

Table 3, below:

Table 3:

Mean Pharmacokinetic Parameters of N-Desmethyltamoxifen after a Single Oral Dose of 20mg Tamoxifen

(Nolvadex

20 or Tamoxifen 20)

Pharmacokinetic

Nolvadex

®

20

Parameter

mean

CV(%)

(ng/ml)

13.3

63.9

5.82

44.4

68.18

50.76

74.4

3.00

192.67

(ng·h/ml)

3330

1000

30.0

2040

5620

0.-oo

(ng·h/ml)

4970

1480

29.8

2770

8110

35.3

Pharmacokinetic

Tamoxifen 20

Parameter

mean

CV(%)

(ng/ml)

11.6

15.5

9.10

16.2

54.90

39.30

71.6

6.00

143.65

(ng·h/ml)

3590

21.7

2830

5640

0.-oo

(ng·h/ml)

5270

1730

32.8

3490

9080

45.9

Study Conclusions

Bio-equivalence of 20mg Tamoxifen

The results demonstrate that Nolvadex 20 mg and the applicant’s Tamoxifen 20mg Tablet formulation

are bio-equivalent for tamoxifen. Bio-equivalence for the metabolite N-desmethytamoxifen is also

suggested by the results of this study.

EFFICACY

Efficacy is reviewed in the Clinical Expert Report. The reference product is established and the

application depends upon the ability to show bioequivalence with the reference product.

PL 16363/0135

UKPAR Milpharm Ltd, Tamoxifen 20mg Tablets

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SAFETY

Safety is reviewed in the Clinical Expert Report. The reference product is established and the application

depends upon the ability to show bioequivalence with the reference product.

EXPERT REPORT

The expert report is written by a medically qualified pharmaceutical consultant and is satisfactory.

SUMMARY OF PRODUCT CHARACTERISTICS (SmPC)

This is satisfactory.

PATIENT INFORMATION LEAFLET (PIL)

This is satisfactory.

CONCLUSION

The applicant has demonstrated bioequivalence for Tamoxifen 20mg Tablets. A Marketing Authorisation may

be granted for this product, from a clinical point of view.

V.

USER CONSULTATION

A package leaflet has been evaluated via a user consultation study in accordance with the requirements

of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing

the pack leaflet was English.

The results show that the package leaflet meets the criteria for readability as set out in the Guideline on

the readability of the label and package leaflet of medicinal products for human use.

VI.

OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT

Quality

The quality characteristics of Tamoxifen 20mg Tablets are well defined and controlled. The

specifications and batch analytical results indicate consistency from batch to batch. There are no

outstanding quality issues that would have a negative impact on the benefit/risk balance.

Non-Clinical

No new non-clinical data were submitted and none are required for this type of application.

Efficacy

Bioequivalence has been demonstrated between the applicant’s Tamoxifen 20mg Tablets and the

reference product Nolvadex 20 mg. No new or unexpected safety concerns arose from this application.

The SmPC, PIL and labelling are satisfactory and consistent with that for Nolvadex 20mg Tablets.

Risk/Benefit Analysis

The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been

identified. The bioequivalence study supports the claim that the applicant’s product and the innovator

product are interchangeable. Extensive clinical experience with tamoxifen is considered to have

demonstrated the therapeutic value of the compound. The risk benefit is, therefore, considered to be

positive.

PL 16363/0135

UKPAR Milpharm Ltd, Tamoxifen 20mg Tablets

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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and labelling

The SmPC, PIL and labelling are satisfactory and, where appropriate, in line with current guidance.

In accordance with Directive 2010/84/EU, the current version of the SmPC and PIL is available on the

MHRA website. The current labelling is presented below:

PL 16363/0135

UKPAR Milpharm Ltd, Tamoxifen 20mg Tablets

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PL 16363/0135

UKPAR Milpharm Ltd, Tamoxifen 20mg Tablets

15

Tamoxifen 20 mg Tablets

(tamoxifen citrate)

PL 16363/0135

STEPS TAKEN AFTER AUTHORISATION – SUMMARY

The following table lists a non-safety update to the Marketing Authorisation for Tamoxifen 20mg

Tablets (PL 16363/0135) that have been approved by the MHRA since the Marketing Authorisation was

approved. The table includes an update that has been added as an annex to this PAR. This is not a

complete list of the post-authorisation changes that have been made to this Marketing Authorisation.

Date submitted

Application

type

Scope

Outcome

15/06/2018

Type IB

To update sections 4.1, 4.2,

4.3, 4.4. 4.5, 4.8 and 5.1 of

the SmPC in line with the

reference product for

Tamoxifen 20mg Tablets.

Consequently, impacting

the PIL.

To introduce a new Risk

Management Plan (RMP)

Approved on 19 July

2018

PL 16363/0135

UKPAR Milpharm Ltd, Tamoxifen 20mg Tablets

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Annex 1

Our Reference:

PL 16363/0135, Application 0022

Product:

Tamoxifen 20mg Tablets

Marketing Authorisation Holder:

Milpharm Limited

Active Ingredient(s):

Tamoxifen citrate

Type of Procedure:

National

Submission Type:

Variation

Submission Category:

Type IB

Submission Complexity:

Standard

EU Procedure Number (if applicable):

Reason:

To update sections 4.1, 4.2, 4.3, 4.4. 4.5, 4.8 and 5.1 of the SmPC in line with the reference product

for Tamoxifen 20mg Tablets. Consequently, impacting the PIL.

To introduce a new Risk Management Plan (RMP).

Supporting Evidence

Revised SmPC fragments

Updated PIL

New RMP

Evaluation

The proposed changes to the SmPC and PIL are satisfactory.

An acceptable Risk Management Plan (RMP) has been submitted. Routine pharmacovigilance and

routine risk minimisation activities are proposed for all safety concerns.

Conclusion

The proposed changes to the SmPC and PIL are considered acceptable and there are no objections to

approval.

In accordance with Directive 2010/84/EU, the current version of the SmPC and PIL is available on the

MHRA website

The proposed changes to the RMP are acceptable. There are no differences from the reference product in

terms of proposed uses, posology, strength or pharmaceutical form / formulation that would have any

implications for safety.

Decision –

Approved on 19 July 2018

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