Tamoxifen Citrate 20 mg

Tamoxifen Citrate 20 mg (Tamoxifen (as tamoxifen citrate)) · ATC L02BA01

Antiestrogen · selective estrogen receptor modulator

Each film-coated tablet contains Tamoxifen Citrate equivalent to Tamoxifen 20 mg.

For the full list of excipients, see section 6.1.

Tablet for oral administration.

Therapeutic indications

Management of estrogen-sensitive conditions and restoration of gonadotropin drive, as determined by a physician.

Posology and method of administration

Take orally as directed by a physician. Swallow whole with water. Do not exceed the prescribed dose.

Contraindications

Known hypersensitivity to the active substance. Pregnancy and breastfeeding. History of thromboembolic disease. Use under specialist supervision only.

Special warnings and precautions for use

Keep out of the reach and sight of children. Contains a substance prohibited in sport (WADA).

Interaction with other medicinal products

Potent CYP2D6 inhibitors — paroxetine, fluoxetine, bupropion, quinidine, cinacalcet

Substantially reduce the formation of endoxifen and may thereby diminish the clinical efficacy of tamoxifen; where an antidepressant is required, an agent with negligible CYP2D6 inhibition should be preferred.

Coumarin anticoagulants (warfarin)

Tamoxifen markedly potentiates the anticoagulant effect, with substantial rises in INR and reported haemorrhage; concomitant use is contraindicated in some indications and otherwise demands close INR monitoring.

CYP3A4 inducers — rifampicin, carbamazepine, phenytoin, St John's wort

Accelerate metabolism of tamoxifen and lower plasma concentrations of the parent drug, with potential loss of therapeutic effect.

Cytotoxic chemotherapy

Concurrent administration is associated with an increased incidence of thromboembolic events; the combination requires careful risk assessment.

Aromatase inhibitors (anastrozole, letrozole)

Tamoxifen lowers plasma concentrations of anastrozole and letrozole and combination has shown no efficacy advantage over tamoxifen alone; concurrent use is not recommended.

Oestrogens and oestrogen-containing preparations

Pharmacodynamic antagonism at the oestrogen receptor with potential loss of therapeutic effect; concurrent use is not recommended.

Use in special populations

Pregnancy and breastfeeding

Contraindicated in pregnancy. Tamoxifen has been associated with spontaneous abortion, congenital malformation and foetal death, and in-utero exposure raises theoretical concern by analogy with diethylstilbestrol. Effective non-hormonal contraception is required during treatment and for at least 9 months (commonly 2 months in some labelling; the longer interval is prudent) after discontinuation, as directed by the prescriber. Tamoxifen inhibits lactation and breastfeeding must be discontinued.

Paediatric population

Safety and efficacy have not been established in children; use in girls with McCune-Albright syndrome has been reported but is not an established indication, and effects on the growing skeleton, uterus and long-term reproductive function are not characterised.

Elderly

No dose adjustment is required on the basis of age. Baseline and background thromboembolic and cerebrovascular risk is higher, and any postmenopausal bleeding requires prompt gynaecological investigation given the endometrial risk.

Renal impairment

Elimination is predominantly hepatobiliary and no specific dose adjustment is established; caution and clinical monitoring are appropriate as data in significant renal impairment are limited.

Hepatic impairment

Clearance is reduced and exposure increased in hepatic impairment. Tamoxifen is itself hepatotoxic in rare cases; liver function should be assessed before and periodically during treatment, and treatment reconsidered where transaminases rise persistently or jaundice develops.

Patients with thromboembolic or endometrial risk

Personal or family history of venous thromboembolism, inherited thrombophilia, prolonged immobilisation and major surgery all raise risk and warrant reassessment of the benefit–risk balance. Any abnormal vaginal bleeding, pelvic pain or discharge should be investigated promptly.

Athletes

Tamoxifen is prohibited at all times, in and out of competition, under Section S4 (Hormone and Metabolic Modulators) of the WADA Prohibited List as an anti-oestrogenic substance. Its detection constitutes an anti-doping rule violation regardless of medical purpose unless a Therapeutic Use Exemption has been granted.

Undesirable effects

Vascular

Hot flushes, venous thromboembolism including deep vein thrombosis and pulmonary embolism, superficial thrombophlebitis, cerebrovascular events; risk is increased perioperatively and with immobility

Reproductive system and breast

Vaginal discharge, vaginal bleeding, vulvovaginal dryness or pruritus, menstrual irregularity or amenorrhoea, ovarian cysts, endometrial hyperplasia, polyps, and an increased incidence of endometrial carcinoma and uterine sarcoma

Eye

Cataract, corneal changes, retinopathy, optic neuritis and visual impairment; ophthalmological assessment is warranted where visual symptoms arise

Hepatobiliary

Raised transaminases, fatty liver and steatohepatitis, cholestasis, hepatitis and, very rarely, hepatic necrosis

Blood and lymphatic system

Thrombocytopenia, leucopenia, neutropenia, anaemia; a transient tumour flare with hypercalcaemia may occur early in treatment of metastatic disease

Musculoskeletal and connective tissue

Leg cramps, arthralgia, myalgia; in premenopausal women oestrogen suppression may reduce bone mineral density, whereas bone density is generally preserved after the menopause

Nervous system and psychiatric

Headache, dizziness, light-headedness, sensory disturbance, taste alteration, fatigue, mood disturbance and depressed mood

Skin and subcutaneous tissue

Rash, alopecia or hair thinning, hypersensitivity reactions including angioedema; bullous pemphigoid, erythema multiforme and Stevens–Johnson syndrome have been reported very rarely

Overdose

Experience of gross overdose is limited. In animal studies very high doses produced oestrogenic effects, convulsions and neurotoxicity, and in humans doses substantially above the therapeutic range have been associated with acute neurotoxicity — tremor, hyperreflexia, unsteady gait and dizziness — and with QT interval prolongation on the electrocardiogram. There is no specific antidote; management is symptomatic and supportive with cardiac rhythm and electrolyte monitoring where a large ingestion is suspected.

Pharmacodynamic properties

Tamoxifen citrate is a non-steroidal triphenylethylene selective oestrogen receptor modulator (ATC L02BA01) whose activity is tissue-dependent. In breast tissue it and its active metabolites bind the oestrogen receptor with high affinity and act as antagonists, recruiting co-repressor complexes, displacing oestradiol and arresting oestrogen-dependent cells in the G0/G1 phase of the cell cycle. In bone, hepatic tissue and the endometrium it behaves as a partial agonist, which accounts for its preservation of bone mineral density in postmenopausal women, its effects on lipids and coagulation factors, and its association with endometrial proliferation. Much of the antioestrogenic activity resides not in tamoxifen itself but in its metabolites 4-hydroxytamoxifen and, principally, endoxifen (4-hydroxy-N-desmethyltamoxifen), which possess some 30 to 100 times the receptor affinity of the parent compound.

Pharmacokinetic properties

Tamoxifen is well absorbed after oral administration, with peak plasma concentrations at approximately 4 to 7 hours, and is more than 99% bound to plasma albumin. It undergoes extensive hepatic biotransformation: CYP3A4/5 mediates N-demethylation to N-desmethyltamoxifen, the dominant circulating metabolite, while CYP2D6 catalyses the 4-hydroxylation step that generates endoxifen — making CYP2D6 activity, whether determined by genotype or by inhibitor co-medication, the principal determinant of active metabolite exposure. Elimination is chiefly biliary and faecal following glucuronide and sulphate conjugation, with minimal urinary excretion of unchanged drug. The terminal half-life of tamoxifen is approximately 5 to 7 days and that of N-desmethyltamoxifen approximately 14 days, so steady state is reached only after several weeks of continuous dosing.

List of excipients

Tablet core: lactose monohydrate, maize starch, croscarmellose sodium, povidone K30, colloidal anhydrous silica, magnesium stearate. Film-coat: hypromellose 5 cP, macrogol 400, titanium dioxide (E171). Coating is applied under controlled inlet-air humidity to a target weight gain of approximately 3 %.

Excipient warnings

Contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Incompatibilities

Not applicable to this dosage form.

Shelf life

36 months from the date of manufacture in the unopened container.

After first opening

No special in-use storage requirements. Tablets should remain in the intact blister until immediately before administration; a tablet removed from its blister must not be returned to it.

Storage

Store below 25 °C in a dry place. Keep tablets in the outer carton until use.

Container

50 film-coated tablets in PVC/PVdC–aluminium push-through blisters (10 tablets per blister, 5 blisters per carton), in a tamper-evident, GS1-serialised outer carton with the patient leaflet. Blister materials are qualified to ISO 15378. Not all pack sizes may be marketed.

Disposal

No special requirements for handling. Any unused medicinal product or waste material, including partially used blisters and the outer carton, should be disposed of in accordance with local requirements; do not dispose of via wastewater or household waste.

Pack

50 Tablets

GTIN

05012345678925

Serial

8741 6529 4307 25

LOT

TX2711L

MFG

01 / 2028

EXP

01 / 2031

Every carton carries a GS1 DataMatrix and a verification code; a pack can be checked at ergopharm.net/verify.

Ergopharm Advanced Research Centre, Tandalja, Vadodara, Gujarat 390012, India. For Export Only.

Report a suspected adverse reaction or quality defect to pv@ergopharm.net.