Tamoxifen Tablets Bp 20mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
TAMOXIFEN TABLETS BP 20mg
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Tamoxifen Citrate PhEur equivalent to 20mg tamoxifen.
3. PHARMACEUTICAL FORM
White film-coated tablets.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
1) Indicated for the treatment of breast carcinoma, particularly in oestrogen receptor positive patients.
2) For the treatment of anovulatory infertility.
4.2 Posology and method of administration
Posology
Breast carcinoma: 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 patients: Similar dosage regimens of tamoxifen have been used in elderly patients with breast cancer and in some of these pateints 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 with regular menstruation but anovular cycles, treatment should be initiated with 20mg daily given on the second, third, fourth and fifth days of the menstrual cycle. If treatment is unsuccessful (unsatisfactory basal temperature records or poor pre-ovulatory cervical mucus), further courses may be given during subsequent menstrual periods, increasing the dosage to 40mg and then 80mg daily.
In women with irregular menstruation, treatment may be initiated on any day. If no signs of ovulation are apparent, a subsequent course of treatment may be commenced 45 days later with dosage increased as above. If the patient responds with menstruation, the next course of treatment should start on the second day of the cycle.
Use in children: 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 administration.
4.3 Contraindications
• Hypersensitivity to tamoxifen or any of the ingredients in the product.
• Tamoxifen must not be administered during pregnancy. Pre-menopausal women must be carefully examined to exclude the possibility of pregnancy before commencement of treatment for breast carcinoma or infertility (see section 4.6)
• 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
Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose - galactose malabsorption should not take this medicine.
Menstruation is suppressed in a proportion of premenopausal women receiving tamoxifen for the treatment of breast cancer.
An increased incidence of endometrial changes including hyperplasia, polyps, cancer and uterine sarcoma (mostly malignant mixed Mullerian tumours), has been reported in association with tamoxifen treatment. The underlying mechanism is unknown but may be related to the oestrogen like effect of tamoxifen. Any patient receiving or having previously received tamoxifen who report abnormal gynaecological symptoms, especially vaginal bleeding, or who presents with menstrual irregularities, vaginal discharge and symptoms such as pelvic pain or pressure should be promptly investigated.
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 (cross-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: For patients being treated for infertility, tamoxifen should be stopped at least 6 weeks before surgery or long-term immobility (when possible) and re-started only when the patient is fully mobile. For patients with breast cancer, tamoxifen treatment should only be stopped if the risk of tamoxifen-induced thrombosis clearly outweighs the risks associated with interrupting treatment. All patients should receive appropriate thrombosis prophylactic measures and should include graduated compression stockings for the period of hospitalisation, early ambulation, if possible, and anticoagulant treatment.
• If any patient presents with VTE, tamoxifen should be stopped immediately and appropriate anti-thrombosis measures initiated. In patients being treated for infertility, tamoxifen should not be re ~ started unless there is a compelling alternative explanation for their thrombotic event. In patients receiving tamoxifen for breast cancer, the decision to re-start tamoxifen should be made with respect to the overall risk for the patient. In selected patients with breast cancer, the continued use of tamoxifen with prophylactic anticoagulation may be justified.
•All patients should be advised to contact their doctors immediately if they become aware of any symptoms of VTE.
Caution should be exercised in patients diagnosed with porphyria as tamoxifen is considered unsafe in these patients.
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 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
• Anticoagulants - 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.
• Cytochrome P450 3A4 inducers - 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.
• Cytotoxics - when tamoxifen is used in combination with cytotoxic agents for the treatment of breast cancer, there is 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.
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 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 toxicity 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, ethinyloestradiol, 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. 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.
Lactation
It is unknown whether tamoxifen is excreted in human breast milk. However tamoxifen is known to inhibit lactation.
A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with tamoxifen should be made taking into account the benefit of breast-feeding to the child and the benefit of tamoxifen therapy to the woman.
4.7 Effects on ability to drive and use machines
Tamoxifen causes light-headedness and visual disturbances this may affect the ability to drive or operate machinery .
4.8 Undesirable effects
Blood and lymphatic system disorders:
• leucopenia sometimes associated with anaemia and/or thrombocytopenia
• rarely neutropenia
• falls in platelet count, usually 80,000 to 90,000 per cu mm but occasionally lower
Immune system disorders:
• rarely hypersensitivity reactions including angioedema Metabolic and nutritional disorders:
• a small number of patients with bony metastases have developed hypercalcaemia
• rarely, elevation of serum triglyceride levels, in some cases with pancreatitis
Central and nervous system disorders:
• headache
• light-headedness
Eye disorders
• visual disturbance including corneal changes and retinoptathy
• Increased incidence of cataracts.
Vascular disorders:
• deep vein thrombosis and pulmonary embolism (see sections 4.3, 4.4 and 4.5).
• increased risk of thromboembolic events when used in combination with cytotoxic agents
Respiratory disorders:
very rarely interstitial pneumonitis
Gastro-intestinal disorders:
• nausea, gastro-intestinal intolerance
Hepato-bilary disorders:
• changes in liver enzyme levels
• rarely liver abnormalities including fatty liver
• cholestasis
• hepatitis.
Skin and subcutaneous system disorders:
• pruritis vulvae
• alopecia
• skin rashes (including isolated reports of erythema multiforme, Stevens -Johnson syndrome and bullous pemphigoid)
Reproductive system disorders:
• vaginal bleeding
• vaginal discharge
• uterine fibroids
• endometriosis and other endometrial changes including hyperplasia and polyps
• suppression of menstruation
• cystic ovarian swellings
• endometrial cancer and uterine sarcoma (mostly malignant mixed Mullerian tumours) (see section 4.4).
General disorders and administration site conditions:
• hot flushes
• fluid retention
• tumour flare
• pain from metastases and tumour pain.
4.9 Overdose
Features
Nausea and possibly vomiting, dizziness, tremor, hyperreflexia, ataxia, convulsions and prolonged QT interval. Observations in animals indicate that extreme overdosage (100-200x recommended dose) may produce oestrogenic effects.
Management
There is no specific antidote and treatment should be symptomatic.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC Code L02B A01
Tamoxifen citrate is a non-steroidal anti-oestrogen.
In man tamoxifen acts primarily as an anti-oestrogen, inhibiting the effects of endogenous oestrogen, probably by binding with oestrogen receptors.
However, clinicl results have shown some benefit in oestrogen receptor negative tumours which may indicate other mechanisms of action. In the clinical situation, it is recongnised that tamoxifen leads to reductions of 10 -20% in levels of blood total cholesterol and low density lipoproteins in postmenonpausal women. Bone mineral density is not affected.
An uncontrolled trial was undertaken in a heterogenous group of 28 girls aged 2 to 10 years with McCune Albright Syndrome (MAS), who received 20mg once a day for up to 12 months duration. Among the patients who reported vaginal bleeding during the pre-study period, 62% (13 out of 21 patients) reported no bleeding for a 6 month period and 33% (7 out of 21 patients) reported no vaginal bleeding for the duration of the trial. Mean uterine volume increased after 6 months of treatment and doubled at the end of the one year study. While this finding is in line with the pharmacodynamic properties of tamoxifen, a causal relationship has not been established (see section 4.4). There are no long-tem safety data in children. In particular, the long-term effects of tamoxifen on growth, puberty and general development have not been studied.
CYP2D6 polymorphism status may be associated with variability in clinical response to tamoxifen. The poor metaboliser status may be associated with reduced response. The consequences of the findings for the treatment of CYP2D6 poor metabolisers have not been fully elucidated (see sections 4.4, 4.5 and 5.2).
CYP2D6 genotype
Available clinical data suggest that patients, who are homozygote for nonfunctional CYP2D6 alleles, may experience reduced effect of tamoxifen in the treatment of breast cancer.
The available studies have mainly been performed in postmenopausal women (see sections 4.4 and 5.2).
5.2 Pharmacokinetic properties
Absorption - after oral administration, tamoxifen is rapidly absorbed with peak plasma concentration obtained within 4-7 hours. Steady state concentrations (about 300ng/ml) are achieved after four weeks of treatment with 40mg daily.
Distribution - it is extensively protein bound to serum albumin > 99%. Metabolism - 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. An elimination half-life of approximately seven days has been calculated for the drug itself and 14 days for the principle circulating metabolite N-desmethyltamoxifen.
Elimination - tamoxifen is excreted slowly in the faeces, mainly as conjugates. Small amounts are excreted in the urine.
In a clinical study where girls between 2 and 10 years with McCune Albright Syndrome (MAS) received 20mg tamoxifen once a day for up to 12 months duration, there was an age-dependent decrease in clearance and an increase in exposure (AUC), (with values up to 50% higher in the youngest patients) compared with adults.
Tamoxifen is metabolised mainly via CYP3A4 to N-desmethyl-tamoxifen, which is further metabolised by CYP2D6 to another active metabolite endoxifen. In patients who lack the enzyme CYP2D6 endoxifen concentrations are approximately 75% lower than in patients with normal CYP2D6 activity. Administration of strong CYP2D6 inhibitors reduces endoxifen circulating levels to a similar extent.
5.3. Preclinical Safety Data
Tamoxifen was not mutagenic in a range of in vitro and in vivo mutagenicity tests. Tamoxifen was genotoxic in some in vitro and in vivo genotoxicity tests 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.
6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
Also contains:
Lactose
Maize starch
Magnesium stearate
Pregelatinised maize starch
Propylene glycol
Titanium dioxide (E171)
Methylhydroxypropylcellulose (E464)
6.2. Incompatibilities
None known.
6.3. Shelf life
Twenty four months (polypropylene containers, polyethylene containers and amber glass bottles).
Thirty six months (blister packs).
6.4. Special precautions for storage
Store below 25°C in a dry place. Protect from light.
6.5. Nature and contents of container
The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers; in case any supply difficulties should arise, the alternative is amber glass bottles with screw caps.
The product may also be supplied in blister packs and cartons:
a) Carton: Printed carton manufactured from white folding box board.
b) Blister pack: (i) 250pm white rigid PVC. (ii) Surface printed 20pm hard temper aluminium foil with 5-6g/M2 PVC and PVdC compatible heat seal lacquer on the reverse side.
Not all pack sizes may be marketed.
Pack sizes: 28s, 30s, 56s, 60s, 84s, 90s, 100s, 112s, 120s, 168s, 180s, 250s, 500s, 1000s
Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.
Maximum size of bulk packs: 50,000
6.6. Instruction for use, handling and disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Actavis UK Limited (Trading style: Actavis)
Whiddon Valley BARNSTAPLE N Devon EX32 8NS
8. MARKETING AUTHORISATION NUMBER
PL 00142/0272
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
17.4.89 / 21.03.06
10 DATE OF REVISION OF THE TEXT
07/12/2010