Tamoxifen

Tamoxifen is a non-steroidal, triphenylethylene-based drug with a complex pattern of anti-oestrogenic and oestrogen-like effects that varies from tissue to tissue. In breast cancer tissue it acts mainly as an anti-oestrogen, preventing oestrogen from binding to the oestrogen receptor.

Mechanism of Action

• Receptor antagonism in the tumour: tamoxifen competes with oestrogen for the oestrogen receptor in breast cancer cells and so blocks oestrogen-driven growth.
• Tissue-selective effects: in other tissues tamoxifen behaves partly like an oestrogen, which may explain its effects on the endometrium. In postmenopausal women it lowers total cholesterol and low-density lipoprotein by about 10–20% and has been reported to maintain bone mineral density; in premenopausal women, decreases in bone mineral density have been described.
• Other tumour effects: laboratory studies describe lower levels of growth factors (TGF-α and insulin-like growth factor 1), a rise in sex hormone-binding globulin, which reduces free oestradiol, and induction of apoptosis in oestrogen receptor-positive cells.
• Adjuvant benefit: in women with oestrogen receptor-positive or unknown tumours, adjuvant tamoxifen significantly reduced recurrence and improved 10-year survival, with a significantly greater effect from 5 years of treatment than from 1 or 2 years. The benefit appears largely independent of age, menopausal status, tamoxifen dose and additional chemotherapy.
• Active metabolites: tamoxifen is converted into metabolites with a pharmacological profile similar to the parent drug, notably N-desmethyltamoxifen and endoxifen, and these contribute to the therapeutic effect.
• CYP2D6 variability: polymorphism of CYP2D6 may be linked with variable clinical response. Poor metabolisers may respond less, and clinical data suggest that women homozygous for non-functional CYP2D6 alleles may have a reduced tamoxifen effect. The consequences for poor metabolisers have not been fully worked out.

Pharmacokinetics

• Absorption: rapid after an oral dose, with peak serum concentrations after 4–7 hours. At 40 mg a day, steady-state concentrations of about 300 ng/mL are reached after 4 weeks. Tablets can be taken with or without food.
• Distribution: strongly bound to serum albumin (over 99%).
• Metabolism: by hydroxylation, demethylation and conjugation. The main pathway is demethylation by CYP3A4 to N-desmethyltamoxifen, which CYP2D6 converts to the active metabolite endoxifen. In patients who lack CYP2D6, endoxifen concentrations are about 75% lower than in patients with normal CYP2D6 activity, and potent CYP2D6 inhibitors lower circulating endoxifen to a similar degree.
• Elimination: mainly in the faeces. The elimination half-life is about 7 days for tamoxifen and about 14 days for the main circulating metabolite, N-desmethyltamoxifen.
• Special populations: in girls aged 2 to 10 years with McCune-Albright syndrome given 20 mg once daily for up to 12 months, clearance was lower (depending on age) and exposure (AUC) up to 50% higher than in adult women, highest in the youngest girls. Tamoxifen is not indicated in children.

• Breast cancer: treatment of hormone-dependent breast carcinoma and of its metastases.

• Pregnancy: tamoxifen must not be given during pregnancy. A small number of reports describe spontaneous abortions, birth defects and foetal deaths after tamoxifen use in women, although no causal relationship has been established.
• Hypersensitivity to tamoxifen or to any of the excipients.

Unless stated otherwise, frequencies were calculated from the adverse events reported in a large phase III study in 9,366 postmenopausal women with operable breast cancer treated for 5 years, without regard to the comparator group or to whether the investigator judged the event related to the study medicine.

Very common (≥1/10): fluid retention, hot flushes, nausea, rash, vaginal bleeding, vaginal discharge, fatigue.

Common (≥1/100 to <1/10): uterine fibroids, anaemia, hypersensitivity reactions, ischaemic cerebrovascular events (ischaemic stroke), headache, light-headedness, sensory disturbances (including paraesthesia and dysgeusia), cataracts, retinopathies, vomiting, diarrhoea, constipation, changes in liver enzymes, fatty liver, alopecia, leg cramps, myalgia, vulval itching, endometrial changes (including hyperplasia and polyps), raised serum triglycerides, thromboembolic reactions (including deep vein thrombosis, microvascular thrombosis and pulmonary embolism).

Uncommon (≥1/1,000 to <1/100): endometrial cancer, thrombocytopenia, leucopenia, hypercalcaemia (in patients with bone metastases), visual disturbances, interstitial pneumonitis, pancreatitis, hepatic cirrhosis (in some cases fatal).

Rare (≥1/10,000 to <1/1,000): uterine sarcoma (mainly malignant mixed Müllerian tumours), tumour-related symptoms, neutropenia, agranulocytosis, optic neuritis and optic neuropathy (in a small number of cases with loss of vision), corneal changes, hepatitis, cholestasis, hepatic failure, hepatocellular damage, hepatic necrosis (in some cases fatal), angioedema, Stevens-Johnson syndrome, cutaneous vasculitis, bullous pemphigoid, erythema multiforme, toxic epidermal necrolysis, endometriosis, ovarian cystic swelling, vaginal polyps.

Very rare (<1/10,000): cutaneous lupus erythematosus, porphyria cutanea tarda.

Not known: exacerbation of hereditary angioedema, decreased bone mineral density (premenopausal women), QT prolongation.

How some categories were set: several of the rare reactions were not seen among the 3,094 tamoxifen-treated women of the main study but were reported in other studies or sources, so they are classed as rare using the upper limit of the 95% confidence interval. Cutaneous lupus erythematosus and porphyria cutanea tarda were not seen in other relevant studies and are classed as very rare on the same basis (13,357 patients).

Reactions that need prompt attention include venous thromboembolism and ischaemic stroke, abnormal vaginal bleeding (possible endometrial cancer or uterine sarcoma), severe liver reactions, severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), loss of vision, and QT prolongation.

• Coumarin-type anticoagulants: tamoxifen can markedly increase the anticoagulant effect. Monitor the patient closely.
• Cytotoxic agents: the combination increases the risk of thromboembolic adverse effects.
• Aromatase inhibitors: adjuvant tamoxifen combined with an aromatase inhibitor has not shown greater efficacy than tamoxifen alone.
• Potent CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine, cinacalcet, bupropion): published studies show that they lower plasma endoxifen by 65–75%, and some studies report reduced tamoxifen efficacy with concomitant SSRI antidepressants such as paroxetine. A reduced effect cannot be excluded, so avoid the combination whenever possible.
• CYP3A4 inducers: rifampicin lowers tamoxifen plasma levels; its relevance in clinical practice is unknown. St John’s wort also induces CYP3A4 and may lower tamoxifen concentrations, so use it with caution.
• QT-prolonging medicines: at the recommended dose tamoxifen can prolong the QTc interval, and other medicines that prolong the QT interval may add to this effect. Take care with such combinations and monitor the ECG and electrolytes.
• Food: tamoxifen can be taken with or without food.

Tamoxifen tablets are taken by mouth. Treatment is prescribed by a doctor experienced in treating breast cancer.

Recommended Dose

• 20 to 40 mg a day, given as 10 mg or 20 mg twice daily, or as 20 mg once daily.
• Duration: treatment for at least 5 years is recommended. The optimal duration of tamoxifen therapy has still to be determined.

Special Populations

• Elderly: the dose range is the same for adults over 65 years.
• Children and adolescents: tamoxifen is not indicated, because safety and efficacy have not been established.

Gynaecological Effects and Endometrial Cancer

Menstruation is suppressed in some premenopausal women taking tamoxifen. A higher incidence of endometrial cancer and uterine sarcoma (mainly malignant mixed Müllerian tumours) has been reported with tamoxifen. The mechanism is unknown but may be related to its oestrogen-like effect. Any woman who is taking or has previously taken tamoxifen and reports abnormal gynaecological symptoms, especially vaginal bleeding, should be examined immediately.

Thromboembolism

Before treatment starts, the doctor should assess the patient’s family history and risk factors for thrombosis. In patients at increased prothrombotic risk, prophylactic anticoagulant treatment should be considered; it is always justified during surgery and prolonged immobility. If venous thromboembolism occurs, tamoxifen must be stopped immediately and anticoagulant treatment started. Restarting tamoxifen is decided after weighing benefit and risk, and anticoagulant measures must be put in place if it is restarted. Combination with cytotoxic agents increases the risk of thromboembolic effects.

Severe Skin Reactions

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which can be life-threatening or fatal, have been reported. When tamoxifen is prescribed, patients should be told about the signs and symptoms and monitored closely for skin reactions. If signs or symptoms suggest such a reaction, tamoxifen must be stopped immediately and an alternative treatment considered as appropriate. A patient who has developed a serious reaction such as Stevens-Johnson syndrome or toxic epidermal necrolysis with tamoxifen must never be given it again.

CYP2D6 Activity and Interacting Medicines

Poor CYP2D6 metabolisers have low plasma levels of endoxifen, one of tamoxifen’s most important active metabolites. Potent CYP2D6 inhibitors (for example paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) can lower endoxifen in the same way and should be avoided during tamoxifen treatment whenever possible.

QT Prolongation

Tamoxifen at the recommended dose can prolong the QTc interval, especially in patients with underlying risks of QT prolongation, including cardiac comorbidities or treatment with other medicines known to prolong the QT interval. ECG and electrolyte monitoring is recommended in these patients.

Bone Health in Premenopausal Women

Studies in premenopausal women treated with tamoxifen have described decreases in bone mineral density. Premenopausal women taking tamoxifen should be advised on measures to maintain bone health, in line with local clinical guidelines.

Other Precautions

• Second primary tumours: clinical studies reported a number of second primary tumours at sites other than the endometrium and the opposite breast after tamoxifen in breast cancer patients. No causal relationship has been established and the clinical significance is unclear.
• Breast reconstruction: tamoxifen may increase the risk of microvascular flap complications in delayed microsurgical breast reconstruction.
• Bone metastases: a small number of patients with bone metastases developed hypercalcaemia when treatment started.
• Hereditary angioedema: tamoxifen may induce or worsen angioedema symptoms.
• Doping tests: tamoxifen may produce a positive result in anti-doping tests, and athletes should be told so.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: tamoxifen must not be used in pregnancy. Premenopausal patients should be examined carefully before treatment to exclude pregnancy, and women should be told of the potential risks to the foetus. Reproductive toxicology studies in rats, rabbits and monkeys showed no teratogenic potential. In rodent models of foetal reproductive-tract development, tamoxifen produced changes similar to those caused by oestradiol, ethinylestradiol, clomifene and diethylstilbestrol (DES). Their clinical relevance is unknown, but some, especially vaginal adenosis, resemble those seen in young women exposed to DES in utero, who have a risk of about 1 in 1,000 of developing clear-cell carcinoma of the vagina or cervix. Only a small number of pregnant women have been exposed to tamoxifen, and no vaginal adenosis or clear-cell carcinoma has been reported in young women exposed in utero.
• Contraception: because of the genotoxic potential of tamoxifen, women of childbearing potential must use effective contraception during treatment and for 7 months after completing it; barrier methods or other non-hormonal methods are advised. Men are advised to use effective contraception and not to father a child during treatment and for 4 months after completing it.
• Breastfeeding: limited data suggest that tamoxifen and its metabolites pass into breast milk and build up over time, so breastfeeding is not recommended. The decision to stop breastfeeding or to stop tamoxifen should take into account the importance of the medicine for the mother.

Lactose, Sunset Yellow and Sodium

Each tablet contains 85.3 mg lactose. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it. The tablets also contain sunset yellow S (E110), which may cause allergic reactions and can provoke asthma, especially in patients allergic to acetylsalicylic acid. Each tablet contains less than 23 mg (1 mmol) sodium, so it is essentially ‘sodium-free’.

Girls With McCune-Albright Syndrome

In an uncontrolled trial in 28 girls aged 2 to 10 years with McCune-Albright syndrome given 20 mg once daily for up to 12 months, mean uterine volume rose after 6 months and had doubled by the end of the one-year study. This agrees with the pharmacodynamic properties of tamoxifen, but no causal relationship has been established.

Effect on Driving

Tamoxifen has a small influence on the ability to drive and use machines. Fatigue has been reported, so patients should take care while it lasts.

Tamoxifen 20 mg tablets (as in the Spanish SmPC) do not need refrigeration and have no temperature limit. Keep them in the original package to protect them from light, out of the sight and reach of children. They are supplied in PVC/aluminium blisters in cartons of 30 or 60 tablets; not all pack sizes may be marketed.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), started by a doctor experienced in treating breast cancer. Tamoxifen tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription.