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TAMOXIFEN TABLETS BP 40MG

Active substance(s): TAMOXIFEN CITRATE / TAMOXIFEN CITRATE / TAMOXIFEN CITRATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Tamoxifen Tablets BP 40 mg.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablets contains 60.80mg of Tamoxifen Citrate BP.

3

PHARMACEUTICAL FORM
White, normal convex tablets printed with the company logo on one face and
A390 on the other face.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
1. The treatment of breast cancer.
2. The treatment of anovulatory infertility.

4.2

Posology and method of administration
Breast Cancer
Adults :

The recommended daily dose of tamoxifen is normally 20 mg. No
additional benefit in terms of delayed recurrence or improved survival in
patients has been demonstrated with higher doses. Substantive evidence
supporting the use of treatment with 30-40 mg per day is not available
although these doses have been used in some patients with advanced
disease.

Elderly :

The same dosage regimes of tamoxifen have been used in elderly patients
with breast cancer and in some of these patients it has been used as sole
therapy.

Infertility
The possibility of pregnancy must be excluded before commencing any course
of treatment whether initial or subsequent.
The initial course of treatment in women menstruating regularly but with
anovular cycles, consists of 20 mg of tamoxifen daily on the second, third,
fourth and fifth days of the menstrual cycle. Should the initial course of
treatment, as judged by basal temperature and preovulatory cervical mucus,
prove unsuccessful, further courses of treatment may be given during
subsequent menstrual periods, increasing the dosage to 40 mg and then 80 mg
daily.
In women with irregular menstrual cycle, the initial course of treatment may
begin on any day. Should there be no sign of ovulation, then a subsequent
course of treatment may begin 45 days later with dosage increased to 40 mg
and then 80 mg daily. If a patient responds with menstruation then the next
course of treatment is commenced on the second day of the cycle.
Route of administration: oral.

4.3

Contraindications
Tamoxifen must not be given during pregnancy.
Premenopausal patients must be carefully examined before treatment for
breast cancer or infertility to exclude the possibility of pregnancy (see section
4.6).
Tamoxifen should not be given to patients who have experienced
hypersensitivity to the product or any of its ingredients.
Concurrent anastrozole therapy (see section 4.5).
Treatment for infertility: Patients with a personal or family history of
confirmed idiopathic venous thromboembolic events or a known genetic
defect.

4.4

Special warnings and precautions for use
Tamoxifen should not be used continuously in patients with existing
leucopenia or thrombocytopenia.
Complete blood counts including platelet counts should be carried out
periodically in patients receiving this drug.
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.
Abnormal vaginal bleeding including menstrual irregularities, vaginal
discharge and symptoms such as pelvic pain or pressure in patients who
are receiving or have previously received tamoxifen should be promptly
investigated.
Tamoxifen has been associated with changes in liver enzyme levels and
rarely with more severe abnormalities including fatty liver, cholestasis
and hepatitis.
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 (section 4.8).
• In patients with breast cancer, prescribers should obtain careful histories
with respect to the patient's personal and family history of VTE. If
suggestive of a prothrombotic risk, patients should be screened for
thrombophilic factors. Patients who test positive should be counselled
regarding their thrombotic risk. The decision to use tamoxifen in these
patients should be based on the overall risk to the patient. In selected
patients, the use of tamoxifen with prophylactic anticoagulation may be
justified (cross reference with section 4.5).
• The risk of VTE is further increased by severe obesity, increasing age
and all other risk factors for VTE. The risks and benefits should be
carefully considered for all patients before treatment with tamoxifen. In
patients with breast cancer, this risk is also increased by concomitant
chemotherapy. 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 antithrombosis 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 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.
In the literature it has been shown that CYP2D6 poor metabolisers have a
lowered plasma level of endoxifen, one of the most important active
metabolites of tamoxifen (see section 5.2).
Concomitant medications that inhibit CYPD2D6 may lead to reduced
concentrations of the active metabolite endoxifen. Therefore, potent
inhibitors of CYP2D6 (e.g. paroxetine, fluoxetine, quinidine, cinacalcet
or bupropion) should whenever possible be avoided during tamoxifen
treatment (see section 4.5 and 5.2).

4.5

Interaction with other medicinal products and other forms of interaction
Concurrent use with oestrogens may interfere with tamoxifen's therapeutic
effect.
When tamoxifen is used in combination with coumarin-type anticoagulants,
significant increase in anticoagulant effect may occur. When such coadministration 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 increased risk of thromboembolic events
occurring (see 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 section 4.4 and 5.2).

4.6

Fertility, Pregnancy and lactation
Tamoxifen tablets must not be given during pregnancy. Pre-menopausal
patients must be carefully examined before treatment for breast cancer or
infertility to exclude the possibility of 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.
Women should be advised not to become pregnant whilst taking Tamoxifen
and should use barrier or other non-hormonal contraceptive methods if
sexually active. 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.
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
None reported.

4.8

Undesirable effects
Occasional adverse effects reported and attributed to the anti-oestrogenic
action of tamoxifen include hot flushes, vaginal bleeding including menstrual
irregularities, vaginal discharge, pruritus vulvae and alopecia
When side effects are severe, it may be possible to control them by a simple
reduction of dosage (to not less than 20 mg/day) without loss of control of
the disease. If side effects do not respond to this measure, it may be
necessary to stop the treatment.

Skin rashes (including isolated reports of erythema multiforme, Stevens
Johnson syndrome and bullous pemphigoid) and rare hypersensitivity
reactions including angioedema have been reported.
Less frequently reported adverse reactions include gastro-intestinal
intolerance, tumour flare, headache, light headedness and fluid retention.
Suppression of menstruation has been reported in a proportion of
premenopausal women receiving tamoxifen for the treatment of breast cancer.
The administration of 40 mg of tamoxifen, twice daily for short periods, has
occasionally caused reversible cystic ovarian swellings. Transient falls in
platelet count, usually to 80,000-90,000 per cu mm but occasionally lower,
have been reported in patients taking tamoxifen for breast cancer. No
haemorrhagic tendency has been reported and the platelet counts have
recovered even though treatment with the drug has continued.
A small number of patients with bony metastases have developed
hypercalcaemia on initiation of therapy.
A small number of cases of visual disturbances including infrequent
reports of corneal changes, cataracts and retinopathy have been
described, mainly in patients treated with exceptionally high doses of
tamoxifen for long periods of time.
Cases of optic neuropathy and optic neuritis have been reported in patients
receiving tamoxifen and, in a small number of cases, blindness has occurred.
Uterine fibroids, endometriosis and other endometrial changes including
hyperplasia and polyps have been reported in association with tamoxifen
treatment.
An increased incidence of endometrial cancer and uterine sarcoma (mostly
malignant mixed Mullerian tumours) has been reported in association with
Tamoxifen treatment.
Cystic ovarian swellings have occasionally been observed in premenopausal
women receiving tamoxifen.
Leucopenia has been observed following the administration of Tamoxifen,
sometimes in association with anaemia and/or thrombocytopenia.
Neutropenia has been reported on rare occasions; this can sometimes be
severe.
There is evidence of an increased incidence of ischaemic cerebrovascular
events and thromboembolic events, including deep vein thrombosis and
pulmonary embolism, during tamoxifen therapy (see sections 4.3, 4.4 and
4.5). When Tamoxifen is used in combination with cytotoxic agents, there is
an increased risk of thromboembolic events occurring.
Leg cramps have been reported commonly in patients receiving Tamoxifen.
Very rarely, cases of interstitial pneumonitis have been reported.
Tamoxifen has been associated with changes in liver enzyme levels and on
rare occasions with a spectrum of more severe liver abnormalities including
fatty liver, cholestasis and hepatitis.
Rarely, elevation of serum triglyceride levels, in some cases with pancreatitis,

may be associated with the use of Tamoxifen.
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
Overdosage in humans has not been reported. Theoretically an overdosage
would be expected to cause enhancement of the anti-oestrogenic side effects
as described above. Observations in animals show that extreme overdosage
(100 - 200 times recommended daily dose) may produce oestrogenic effects.
No specific treatment for overdosage is known and treatment must be
symptomatic.
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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Tamoxifen citrate is the trans-isomer of a triphenylethylene derivative. The
chemical name is Z-2[4-(1,2-dipheny 1-1-buteny 1)phenoxy]-N, N-dimethylethanamine 2-hydroxy-1 ,2,3-propane-tricarboxylate (1:1).
It is a nonsteroidal agent which has demonstrated potent antioestrogenic
properties in animal test systems. In mice, however, tamoxifen citrate behaves
as an oestrogen. Its antioestrogenic effects may be related to its ability to
compete with oestrogen for binding sites in target tissues such as breast and
uterus.
Tamoxifen citrate inhibits the induction of rat mammary carcinoma induced
by dimethylbenzanthracene (DMBA), and causes the regression of already
established DMBA-induced tumours.
In this rat model, it appears to exert its antitumour effects by binding to
oestrogen receptors. In cytosols derived from human endometrium and human
breast and uterine adenocarcinomas, tamoxifen citrate competes with estradiol
for estrogen receptor protein.
The dosage for the treatment of breast cancer is 20 to 40 mg given either

in divided doses twice daily or as a single dose once daily.
Tamoxifen may induce ovulation in anovulatory women, stimulating release
of gonadotropin-releasing hormone from the hypothalamus, which in turn
stimulates release of pituitary gonadotrophins.
The usual dose is 10 mg twice daily on days 2, 3, 4 and 5 of the menstrual
cycle, increased if necessary in subsequent cycles, to 40 mg twice daily;
alternatively single daily doses of 20 to 80 mg be employed on the same
days.
Tamoxifen has a low order of acute toxicity when given orally or
intravenously to mice, rats, rabbits, and marmoset monkeys. The acute oral
LD 50 was greater than 1 g/kg in all species tested.
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
Tamoxifen is metabolised mainly in the liver and the peak plasma
concentrations after a single dose occur 4 to 7 hours after ingestion.
Elimination is accomplished with an initial half-life of 7-14 hours, but with a
long secondary half-life or more than 7 days. The majority of the compound is
metabolised to conjugates and hydroxylated derivatives, which are likewise
eliminated very slowly. It is excreted slowly in the faeces with only small
amounts appearing in the urine.
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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose BP
Microcrystalline Cellulose BP
Povidone BP
Carmellose Sodium BP
Magnesium Stearate BP
Potable Water HSE

6.2

Incompatibilities
None reported.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
Protect from heat, light and moisture.
Keep out of the reach of children.

6.5

Nature and contents of container
1. The product is packed in blister packaging (10 tablets/strip) in 20 MU
hard temper aluminium foil and white opaque 200MU PVC laminated
with 60 G/M2 PVC (35MU) in pack sizes of 28, 30, 42, 50, 56, 60, 84,
90, 100, 112 and 250 tablets. It is subsequently packed in printed box
board cartons.
2.

The product is also blister packed (10 tablets per strip) in aluminium foil
with the dull side laminated to the plain 25MU nylon and the bright side

lacquer laminated to 60MU UPVC in pack sizes of 28, 30, 42, 50, 56, 60,
84, 90, 100, 112 and 250 tablets. It is subsequently packed in printed box
board cartons.

6.6

Special precautions for disposal
None.

7

MARKETING AUTHORISATION HOLDER
Crescent Pharma Ltd
Units 3 and 4, Quidhampton Business Units
Polhampton Lane
Overton
Hampshire
RG25 3ED
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 20416/0226

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
10/03/2009

10

DATE OF REVISION OF THE TEXT
12/04/2016

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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