Tamoxifen 20 Mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Tamoxifen 20 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 20 mg tamoxifen (as citrate).
For the full list of excipients, see 6.1.
3 PHARMACEUTICAL FORM
Tablets
Round, white to off-white tablets with a break-line and “20” imprinted on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Tamoxifen 20 mg Tablets are indicated for:
The treatment of breast cancer.
The treatment of anovulatory infertility.
4.2 Posology and method of administration
Tamoxifen 20 mg Tablets are for oral administration.
Breast cancer
Adults:
The recommended daily dose for tamoxifen is normally 20 mg. No additional benefit, in terms of delayed recurrence or improved survival in patients, has been demonstrated with higher doses. Substantive evidence supporting the use of treatment with 30-40 mg per day is not available, although these doses have been used in some patients with advanced disease.
The elderly:
The adult dosage range has been used in elderly patients with breast cancer.
Anovulatory infertility
The possibility of pregnancy must be excluded before the commencement of treatment. In women with regular menstruation but anovular cycles, treatment should commence with 20 mg daily administered on the 2nd, 3rd, 4th and 5th days of the menstrual cycle. Should the initial course of treatment, as judged by basal temperature or pre-ovulatory cervical mucus, prove unsuccessful, further courses may be given during subsequent menstrual periods, increasing the dosage to 40 mg daily and then to 80 mg daily.
In women who are not menstruating regularly, the commencement of treatment may take place on any day. If this initial course is not successful then a further course may be initiated after an interval of 45 days with the dosage increased as above. If a patient responds with menstruation then the next course of treatment is started on the second day of the cycle.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients. Pregnancy and breast feeding (see Section 4.6).
4.4 Special warnings and precautions for use
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).
Tamoxifen may be given to pre-menopausal women only after thorough examination has excluded the possibility of pregnancy.
An increased incidence of endometrial changes, including hyperplasia, polyps and cancer, has been reported in association with tamoxifen (see Undesirable Effects).
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.
Occasional cystic ovarian swellings may occur in premenopausal women. Hypercalcaemia can occasionally occur if bony metastases are present. There is an increased risk of thromboembolic events occurring when used with cytotoxics.
Tamoxifen is unsafe for use in acute porphyrias.
4.5 Interaction with other medicinal products and other forms of interaction
Tamoxifen increases the dopaminergic effect of bromocriptine.
Aminoglutethimide reduces the plasma concentration of tamoxifen.
Concurrent use of oestrogens may interfere with tamoxifen’s therapeutic effect.
Tamoxifen may potentiate the anti-coagulant action of warfarin if these drugs are used concomitantly. Patients taking coumarin-type anti-coagulants will require close monitoring on the introduction or withdrawal of tamoxifen.
As tamoxifen is metabolised by cytochrome P450 3A4, care is required when coadministering with drugs, such as rifampicin, known to induce this enzyme, because tamoxifen levels may be reduced. The clinical relevance of this reduction is unknown.
Pharmacokinetic interaction with CYP2D6 inhibitors, showing a 65-75% reduction in plasma levels of one of the more active forms of the drug, i.e. endoxifen, has been reported in the literature. Reduced efficacy of tamoxifen has been reported with concomitant usage of some SSRI antidepressants (e.g. paroxetine) in some studies. As a reduced effect of tamoxifen cannot be excluded, co-administration with potent CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should whenever possible be avoided (see section 4.4 and 5.2).
4.6 Fertility, pregnancy and lactation
Tamoxifen must not be administered during pregnancy. There have been a small number of reports of spontaneous abortions, birth defects and foetal deaths after women have taken tamoxifen, although no causal relationship has been established.
Reproductive toxicology studies in rats, rabbits and monkeys have shown no teratogenic potential.
In rodent models of foetal reproductive tract development, tamoxifen was associated with changes similar to those caused by oestradiol, ethynyloestradiol, clomiphene and diethylstilboestrol (DES). Although the clinical relevance of these changes is unknown, some of them, especially vaginal adenosis, are similar to those seen in young women who were exposed to DES in-utero and who have a 1 in 1000 risk of developing clear-cell carcinoma of the vagina or cervix. Only a small number of pregnant women have been exposed to tamoxifen. Such exposure has not been reported to cause subsequent vaginal adenosis or clear-cell carcinoma of the vagina or cervix in young women exposed in utero to tamoxifen.
Women should be advised not to become pregnant whilst taking tamoxifen and should use barrier or other non-hormonal contraceptive methods if sexually active. Premenopausal patients must be carefully examined before treatment to exclude pregnancy. Women should be informed of the potential risks to the foetus, should they become pregnant whilst taking tamoxifen or within two months of cessation of therapy.
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
There is no evidence that tamoxifen results in impairment of these activites.
4.8 Undesirable effects
Side effects can occasionally be controlled by reducing the dosage (to not less then 20 mg/day) without loss of therapeutic effect. If side-effects persist, it may be necessary to discontinue treatment.
The following side-effects have been reported: hot flushes, rashes, dry skin, pruritus vulvae, vaginal discharge or bleeding, uterine fibroids, dizziness, confusion, headache, light-headedness, depression, muscle cramps, fatigue, fluid retention, alopecia, and gastrointestinal disturbances including nausea, vomiting and anorexia.
On rare occasions Stevens-Johnson syndrome, erythema multiforme, bullous pemphigoid and hypersensitivity reactions including angioedema have been reported.
Occasional tumour flare and pain have been reported. In some patients with bony metastases, hypercalcaemia has been observed at the start of treatment.
The incidence of thromboembolic events may increase. These include deep vein thrombosis and pulmonary embolism.
Elevation of serum triglyceride levels have been reported and pancreatitis has occurred. Leucopenia has been reported sometimes in association with anaemia and/or thrombocytopenia. Neutropenia has also been reported on rare occasions. Decreased platelet counts - usually to 80,000-90,000 per mm3 but occasionally lower
- have been reported in patients taking tamoxifen for breast cancer.
Rarely blurred vision, loss of visual acuity, retinopathy, corneal opacities and cataracts have been reported.
Menstruation is suppressed in a number of pre-menopausal women receiving tamoxifen. Cystic ovarian swellings have occasionally been observed.
Endometrial hyperplasia, endometriosis, endometrial polyps, an increased incidence of endometrial carcinoma and uterine sarcoma (mostly malignant mixed Mullerian tumours) have been reported in association with tamoxifen treatment. Abnormal vaginal bleeding including menstrual irregularities, vaginal discharge, and symptoms such as pelvic pain or pressure in patients receiving (or who have previously received) tamoxifen should be promptly investigated.
Tamoxifen has been associated with changes in liver enzyme levels and rarely with more severe liver abnormalities including fatty liver, cholestasis, and hepatitis.
Very rarely, cases of interstitial pneumonitis have been reported.
4.9 Overdose
Overdose in humans has not been reported. On theoretical grounds, an overdose would be expected to cause an enhancement of the anti-oestrogenic effects as described above. In animals, extremely high doses (over 100 times the recommended daily dose) have caused oestrogenic effects. There is no special antidote to overdosage and treatment should therefore be symptomatic.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Tamoxifen is a non-steroidal anti-oestrogen, ATC code: L02B A. It binds to oestrogen receptors preventing the stimulating effects of oestrogen on nucleic acid synthesis. The metabolites of tamoxifen are also anti-oestogens.
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)
5.2 Pharmacokinetic properties
Maximum plasma levels of tamoxifen occur at 4-7 hours after administration. Steady-state levels of approximately 300 mg/l are achieved after 4 weeks’ treatment with 20 mg daily. The elimination half-life is about 7 days but may be up to 14 days for the principal metabolite.
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
In animals, extremely high doses (over 100 times the recommended daily dose) have caused oestrogenic effects.
There are no other preclinical data of relevance to the prescribes which are additional to the information included in other sections of the SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Calcium hydrogen phosphate Povidone K25
Sodium starch glycollate, Type A Magnesium stearate Microcrystalline cellulose Silica, colloidal anhydrous
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
4 years
6.4 Special precautions for storage
Do not store above 25°C. Store in the original package.
6.5 Nature and contents of container
Blister packs (PVC film 250 pm, dark green coloured / aluminium foil 20 pm) of 28, 30, 56, 60, 84, 90, 100, 250, 500 and 1000 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
MARKETING AUTHORISATION HOLDER
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Chatfield Pharmaceuticals Limited Trading as Chatfield Laboratories Kramer Mews London SW5 9JL
MARKETING AUTHORISATION NUMBER(S)
PL 02142/0050
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
14/03/2012
DATE OF REVISION OF THE TEXT
21/01/2014