TAMOXIFEN

Posology 1. Breast Cancer Adults The recommended daily dose of 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.

Elderly Similar dosing regimens of tamoxifen have been used in the elderly with breast cancer and in some of these patients it has been used as sole therapy. 2. Anovulatory infertility The possibility of pregnancy must be excluded before commencing any course of treatment whether initial or subsequent.

The initial course of treatment in women menstruating regularly but with anovular cycles, consists of 20 mg of tamoxifen given daily on the second, third, fourth and fifth days of the menstrual cycle. If unsatisfactory basal temperature or poor pre-ovulatory cervical mucus indicate that this initial course of treatment has been unsuccessful, further courses of treatment may be given during subsequent menstrual periods, increasing the dosage to 40 mg and then to 80 mg daily.

In women with irregular menstrual cycle, the initial course of treatment may begin on any day. If no signs of ovulation are demonstrable, then a subsequent course of treatment may begin 45 days later, with dosage increased to 40 mg and then 80 mg daily as above.

If a patient responds with menstruation, then the next course of treatment is commenced on the second day of the cycle. 3. Primary prevention of breast cancer Tamoxifen treatment for the primary prevention of breast cancer should only be initiated by a medical practitioner experienced in prescribing for this indication, and as part of a shared care pathway arrangement, with appropriate patient identification, management and follow up.

The recommended dose is 20 mg daily for 5 years for those women at moderate or high risk. There are insufficient data to support a higher dose or longer period of use. Before commencing treatment, an assessment of the potential benefits and risks is essential, including calculating a patient’s risk of developing breast cancer according to local guidelines and risk assessment tools.

Validated algorithms are available that calculate breast cancer risk based on features such as age, family history, genetic factors, reproductive factors and history of breast disease. The use of tamoxifen should be as part of a program including regular breast surveillance tailored to the individual woman, taking into account her risk of breast cancer.

Paediatric population The use of tamoxifen is not recommended in children. 2). Method of administration For oral use.

Tabulated list of adverse reactions The following definitions apply to the incidence of undesirable effects: Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

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.

The safety findings in the breast cancer prevention trials appeared consistent overall with the established safety profile of tamoxifen. Table 1 - Adverse Drug Reactions (ADR) by System Organ Class (SOC) and Frequency. SOC Frequency Adverse Drug Reaction Common Uterine fibroids Uncommon Endometrial cancer Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rare Uterine Sarcoma (mostly malignant mixed Mullerian tumours)a Tumour Flarea Common Anaemia Uncommon Thrombocytopenia Leukopenia Blood and lymphatic system disorders Rare Neutropenia Agranulocytosis Immune system disorders Common Hypersensitivity reactions Very common Fluid retentionMetabolism and nutrition disorders Uncommon Hypercalcaemia (in patients with bony metastases) Common Ischaemic cerebrovascular events Headache Light headedness Sensory disturbances (including paraesthesia and dysgeusia) Nervous system disorders Rare Optic neuritis Common Cataracts Retinopathy Uncommon Visual disturbances Eye disorders Rare Corneal changes Optic neuropathya Very Common Hot flushesVascular disorders Common Thromboembolic events (including deep vein thrombosis, microvascular thrombosis and pulmonary embolism) Respiratory, thoracic and mediastinal disorders Uncommon Interstitial pneumonitis Very common Nausea Common Vomiting Diarrhoea Constipation Gastrointestinal disorders Uncommon Pancreatitis Common Changes in liver enzymes Fatty liver Hepatobiliary disorders Uncommon Cirrhosis of the liver Rare Hepatitis Cholestasisa Hepatic failurea Hepatocellular injurya Hepatic necrosisa Very common Skin Rash Common Alopecia Rare Angioedema Steven-Johnsons syndromea Cutaneous vasculitisa Bullous pemphigoida Erythema multiformea Toxic epidermal necrolysisa Very rare Cutaneous lupus erythematosusb Skin and subcutaneous tissue disorders Not known Exacerbation of hereditary angioedema Common Leg cramp Myalgia Musculoskeletal and connective tissue disorders Not Known Decreased Bone Mineral Density (premenopausal women) Very common Vaginal bleeding Vaginal discharge Common Pruritus valvae Endometrial changes (including hyperplasia and polyps) Reproductive system and breast disorders Rare Endometriosisa Cystic ovarian swellinga Vaginal polyps Congenital, familial and genetic disorders Very rare Porphyria cutanea tardab General disorders and administration site conditions Very common Fatigue Common Elevated triglyceridesInvestigations Rare Electrocardiogram QT Prolonged Injury, poisoning and procedural complications Very rare Radiation Recallb Psychiatric Disorders Very common Depression a This adverse drug reaction was not reported in the tamoxifen arm (n=3094) of the above study; however, it has been reported in other trials or from other sources.

g. 3094). This is calculated as 3/3094 which equates to a frequency category of ‘rare’. b The event was not observed in other major clinical studies. The frequency has been calculated using the upper limit of the 95% confidence interval for the point estimate (based on 3/X, where X represents the total sample size of 13,357 patients in the major clinical studies).

This is calculated as 3/13,357 which equates to a frequency category of ‘very rare’. g. g. gastrointestinal intolerance, headache, light-headedness and occasionally, fluid retention and alopecia. When side effects are severe, it may be possible to control them by a simple reduction of dosage (to not less than 20 mg/day) without loss of control of the disease.

If side effects do not respond to this measure, it may be necessary to stop the treatment. Skin rashes (including rare reports of erythema multiforme, Stevens Johnson syndrome, toxic epidermal necorlysis, cutaneous vasculitis, and bullous pemphigoid) and commonly hypersensitivity reactions including angioedema have been reported.

Cases of exacerbation of angioedema have been reported in patients with hereditary angioedema receiving tamoxifen. Uncommonly, patients with bony metastases have developed hypercalcaemia on initiation of therapy. Cases of visual disturbances including rare reports of corneal changes, and common reports of retinopathy have been described, in patients receiving tamoxifen therapy.

Cataracts have been reported commonly in association with the administration of tamoxifen. Cases of optic neuropathy and optic neuritis have been reported in patients receiving tamoxifen and, in a small number of cases, blindness has occurred.

Sensory disturbances (including paraesthesia and dysgeusia) have been reported commonly in patients receiving tamoxifen. Uterine fibroids, endometriosis and other endometrial changes including hyperplasia and polyps have been reported.

Falls in platelet count, usually to 80,000 to 90,000 per cu mm but occasionally lower, have been reported in patients taking tamoxifen for breast cancer. Leucopenia has been observed following the administration of […]

Tamoxifen must not be given during pregnancy. 6). Tamoxifen should not be given to patients who have experienced hypersensitivity to the product or any of its ingredients. 5).

Treatment for infertility:

Patients with a personal or family history of confirmed idiopathic venous thromboembolic events or a known genetic defect. 4 Special warnings and precautions for use The warnings and precautions for use are different depending on the indication being treated.

The specific warnings and precautions for the primary prevention of breast cancer can be found at the end of the section. Suppression of menstruation Menstruation is suppressed in a proportion of premenopausal women receiving tamoxifen for the treatment of breast cancer.

Endometrial changes 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.

There are several factors that influence the risk of developing endometrial cancer, with the majority of risk factors affecting oestrogen levels. Therefore, tamoxifen treatment may increase the incidence of endometrial cancer. In addition, other risk factors include obesity, nulliparity, diabetes mellitus, polycystic ovary syndrome and oestrogen-only Hormone replacement therapy (HRT).

There is also the general risk for endometrial cancer with increasing age. Any patient receiving or having previously received tamoxifen who report abnormal gynaecological symptoms, especially non- menstrual vaginal bleeding, or who presents with menstrual irregularities, vaginal discharge and symptoms such as pelvic pain or pressure should be promptly investigated.

Secondary tumours In patients with hereditary angioedema, tamoxifen may induce or exacerbate symptoms of angioedema. 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. 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.

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. 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 longterm 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.

In delayed microsurgical breast reconstruction tamoxifen may increase the risk of microvascular flap complications. Paediatric population In an uncontrolled trial in 28 girls aged 2–10 years with McCune Albright Syndrome (MAS), who received 20 mg 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.

1). Tamoxifen tablets at the recommended dose, may prolong the QTc interval on the electrocardiogram (ECG). ECG and electrolyte monitoring are recommended in patients with underlying risks of QT prolongation and cardiac comorbidities such as: • Long QT syndrome • Clinically significant or uncontrolled heart disease, such as congestive heart failure, recent myocardial infarction, and cardiac conduction and repolarisation abnormalities • Concomitant use of QT prolonging medicines • Electrolyte abnormalities ECG should be assessed before initiating treatment […]