Tamoxifen 20 mg Tablets
*Company:
Gerard LaboratoriesStatus:
No Recent UpdateLegal Category:
Product subject to medical prescription which may be renewed (B)Active Ingredient(s):
*Additional information is available within the SPC or upon request to the company
Updated on 20 June 2022
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Updated on 20 June 2022
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Updated on 22 July 2021
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Updated on 22 July 2021
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Updated on 23 January 2019
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tamoxifen PIL.pdf
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Updated on 23 January 2019
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tamoxifen spc.pdf
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Updated on 28 November 2017
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Updated on 28 November 2017
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- Change to section 4.1 - Therapeutic indications
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- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.8 - Undesirable effects
- Change to section 6.3 - Shelf life
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4.1 Therapeutic indications
Tamoxifen is indicated i
4.2 Posology and method of administration
Posology
Breast cancer: Adults (including the elderly
In an uncontrolled trial in 28 girls aged 2–10 years with McCune Albright Syndrome (MAS), who received 20 mg tamoxifen 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).
4.8 Undesirable effects
Font has been changed in Table 1.
6.3 Shelf life
5
10. DATE OF REVISION OF THE TEXT
August
Updated on 24 November 2017
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PIL_9005_448.pdf
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Updated on 24 November 2017
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- Change to section 3 - overdose, missed or forgotten doses
- Change to section 4 - possible side effects
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Updated on 02 December 2016
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Updated on 24 May 2016
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Updated on 23 March 2016
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Updated on 26 February 2016
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- Change to section 4.2 - Posology and method of administration
- Change to section 4.3 - Contraindications
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.6 - Pregnancy and lactation
- Change to section 4.7 - Effects on ability to drive and use machines
- Change to section 4.8 - Undesirable effects
- Change to section 4.9 - Overdose
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- Change to section 8 - MA number
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4.2 Posology and method of administration
Posology
Breast cancer: Adults (including older peopleelderly): The dosage range is 20 to 40 mg daily, given either in divided doses twice daily or as a single dose once daily.
In early disease, it is currently recommended that treatment is given for not less than 5 years. The optimal duration of tamoxifen therapy remains to be determined.
Method of administration
For administration by the oral routeuse.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Tamoxifen should not be used in the following:
-
Tamoxifen must not be administered duringpregnancy. 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 (see also section 4.6).- hypersensitivity to the active substance, or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Paediatric population
In an uncontrolled trial in 28 girls aged 2–10 years with McCune Albright Syndrome (MAS), who received 20 mg tamoxifen 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 of endoxifen, one of the most important active metabolites of tamoxifen (see section 5.2).
Concomitant medications that inhibit CYP2D6 may lead to reduced concentrations of the active metabolite endoxifen. Therefore, potent inhibitors of CYP2D6 (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should whenever possible be avoided during tamoxifen treatment (see sections 4.5 and 5.2).
Paediatric population
In an uncontrolled trial in 28 girls aged 2–10 years with McCune Albright Syndrome (MAS), who received 20 mg tamoxifen 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).
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 (reference 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:
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 patients with VTE, tamoxifen should be stopped immediately and appropriate anti-thrombosis measures initiated. Tamoxifen should not be restarted 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.
4.5 Interaction with other medicinal products and other forms of interaction
When tamoxifen is used in combination with coumarin type anticoagulants, such as warfarin, a significant increase in anticoagulant effect may occur. Where such co-administration is initiated, careful monitoring of the patient is recommended.
When tamoxifen is used in combination with cytotoxic agents, there is increased risk of thromboembolic event occurring (see also section 4.8).
The use of tamoxifen in combination with anastrozole as adjuvant therapy has not shown improved efficacy compared with tamoxifen alone.
The known principal pathway for tamoxifen metabolism in humans is demethylation, catalysed by CYP3A4 enzymes. Pharmacokinetic interaction with the CYP3A4 inducing agent rifampicin, showing a reduction in tamoxifen plasma levels has been reported in the literature. The relevance of this finding is not known.
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.
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.
Tamoxifen was not mutagenic in a range of in vitro and in vivo mutagenicity tests. Investigations in different in vitro system and in vivo tests in rodents, have shown that tamoxifen has a genotoxic potential following hepatic activation.
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 ha
ved 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
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-feedinglactation. 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
useoperate 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
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.
Adverse drug reactions (ADRs) can be classified as either due to the pharmacological
(anti-oestrogenic) action of the drug e.g. hot flushes, vaginal bleeding, vaginal discharge and pruritus vulvae, or as more general ADRs e.g. nausea, fluid retention and skin rashes. When such side effects are severe, it may be possible to control them by simple reduction of dosage (within the recommended dose range) without loss of control of the disease.
When such side effects are severe, it may be possible to control them by simple reduction of dosage (within the recommended dose range) without loss of control of the disease
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Vaginal discharge
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hyperplasia and polyps)
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Vaginal polyps
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Congenital, familial and genetic disorders
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Porphyria cutanea tarda b |
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Injury, poisoning and procedural complications
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Radiation Recall
b |
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General disorders and administration site conditions
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Fatigue
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Investigations
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Elevated
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(including paraesthesia and dysgeusia)
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Eye disorders
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Cataracts Retinopathy
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Visual disturbance
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Corneal changes Optic neuropathy a |
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Vascular disorders
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Hot flushes
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Multiple SOC Terms
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Thromboembolic events (including deep vein thrombosis, microvascular thrombosis and pulmonary embolism)
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Respiratory thoracic and mediastinal disorders
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Interstitial pneumonitis
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Gastrointestinal disorders
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Nausea
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Vomiting Diarrhoea Constipation
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Pancreatitis j |
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Hepatobiliary disorders
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Changes in liver enzymes
Fatty liver i |
Cirrhosis of the liver
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Cholestasis a
Hepatitis
Hepatic failure a
Hepatocellular injury a
Hepatic necrosis a |
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Skin and subcutaneous tissue disorders
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Skin rash
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Alopecia
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Angioedema Stevens-Johnson syndrome a
Cutaneous vasculitis a
Bullous pemphigoid a
Erythema multiforme a |
Cutaneous lupus erythematosus b |
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Musculoskeletal and connective tissue disorders
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Leg cramp Myalgia
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Reproductive system and breast disorders
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Vaginal bleeding
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Pruritus vulvae Endometrial changes (including
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Endometriosisa Cystic ovarian swelling a |
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c
Uncommonly, patients with bony metastases have developed hypercalcaemia on initiation of therapy.
d
Cases of optic neuropathy and optic neuritis have been reported in patients receiving tamoxifen and, in a small number of cases, blindness has occurred.
e
Falls in platelet count, usually only to 80,000 – 90,000 per cu mm but occasionally lower, have been reported in patients taking tamoxifen, for breast cancer.
f
Leukopenia has been observed following the administration of tamoxifen sometimes in association with anaemia and/or thrombocytopenia.
g
Neutropenia has been reported on rare occasions; this can sometimes be severe.
h
When tamoxifen is used in combination with cytotoxic agents there is increased risk of thromboembolic events occurring.
i
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.
j
Elevation of serum triglyceride levels,
4.9 Overdose
Signs and symptoms
On theoretical grounds, overdosage would be expected to cause enhancement of the anti-oestrogenic side effects mentioned above. Observations in animals show that extreme overdosage (100-200 times recommended daily dose) may produce oestrogenic effects.
An overdose would theoretically enhance the anti-oestrogenic effects of tamoxifen. However, an oestrogenic effect has been seen in animals that have received between 100-200 times the recommended daily dose.
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.
Management
There is no specific antidote to overdosage and treatment must be symptomatic.
Treatment of overdose must be symptomatic as there is no antidote.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Mannitol (E421)
Maize
Sstarch
Croscarmellose
Ssodium
Magnesium Stearate
7. MARKETING AUTHORISATION HOLDER
Generics (UK) Limited
Station Close
Potters Bar
Hertfordshire
EN6 1TL
U
nited KingdomK
8. MARKETING AUTHORISATION NUMBERS
PA
0405/001/001
PA
0405/001/002
Updated on 26 February 2016
Reasons for updating
- Change to warnings or special precautions for use
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Updated on 23 February 2015
Reasons for updating
- Change to section 1 - Name of medicinal product
- Change to section 2 - Qualitative and quantitative composition
- Change to section 4.2 - Posology and method of administration
- Change to section 4.3 - Contraindications
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.6 - Pregnancy and lactation
- Change to section 4.7 - Effects on ability to drive and use machines
- Change to section 4.8 - Undesirable effects
- Change to Section 4.8 – Undesirable effects - how to report a side effect
- Change to section 4.9 - Overdose
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 5.2 - Pharmacokinetic properties
- Change to section 6.4 - Special precautions for storage
- Change to section 6.6 - Special precautions for disposal and other handling
- Change to section 10 - Date of revision of the text
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name amended (BP removed)
section 4.2
In early disease, it is currently recommended that treatment is given for not less than 5 years. The optimal duration of tamoxifen therapy remains to be determined.
Paediatric population
The use of tamoxifen is not recommended in children, as safety and efficacy have not been established (see sections 5.1 and 5.2)
Method of administration
For oral use.
section 4.3
Tamoxifen must not be administered during pregnancy. There have been a small number of spontaneous abortions, birth defects and foetal deaths after women have taken tamoxifen, although no causal relationship has been established (see also section 4.6).
section 4.4
A small number of cases of endometrial hyperplasia, endometrial polyps and a n increased incidence of endometrial cancer and uterine sarcoma (mostly malignant mixed Mullerian tumours) have been reported in association with tamoxifen treatment. The underlying mechanism is unknown, but may be related to the oestrogen-like effects of tamoxifen.
Any patients receiving or having previously received tamoxifen who report abnormal gynaecological symptoms, especially vaginal bleeding including menstrual irregularities, post-menopausal bleeding and vaginal discharge, should be promptly investigated.
The known principal pathway for tamoxifen metabolism in humans is demethylation, catalysed by CYP3A4 enzymes. Pharmacokinetic interaction with the CYP3A4 inducing agent rifampicin, showing a reduction in tamoxifen plasma levels has been reported in the literature. The relevance of this finding is not known.
section 4.6
Pregnancy
Breast-feeding
section 4.8
table 4.8
section 5.1
Mechanism of action
Paediatric populationAn uncontrolled trial was undertaken in a heterogeneous group of 28 girls aged 2 to 10 years with McCune Albright Syndrome (MAS), who received 20 mg tamoxifen 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) 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.
section 5.2
headers added
section 6.4
Blisters:
Store in the original package.
Updated on 19 February 2015
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Updated on 04 February 2014
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Updated on 28 August 2012
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endrometrial correced to endometrial
trigyceride corrected to triglyceride
Updated on 16 February 2011
Reasons for updating
- Change to side-effects
- Change due to user-testing of patient information
Updated on 27 January 2011
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 5.2 - Pharmacokinetic properties
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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).
section 4.5: added
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).
section 5.1:added
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 non-functional 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)
section 5.2:added
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.
Updated on 26 January 2011
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- Change to warnings or special precautions for use
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Updated on 29 April 2010
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- Change to section 3 - Pharmaceutical form
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Section 10 Date of Revision of text updated
Updated on 20 November 2009
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Updated on 11 February 2008
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- Change to section 9 - Date of renewal of authorisation
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Section 9: Date of last renewal corrected from 14th March 2001 to 14th March 2006
Updated on 07 March 2007
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- Correction of spelling/typing errors
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Updated on 15 January 2007
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Updated on 11 December 2006
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- Change to section 3 - Pharmaceutical form
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Updated on 17 October 2006
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- Change to side-effects
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Updated on 09 October 2006
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- Change to section 2 - Qualitative and quantitative composition
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Updated on 23 August 2006
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Updated on 22 September 2004
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