Bilem

'Bilem' is indicated for:

1. The treatment of breast cancer.

2. The treatment of anovulatory infertility.

Posology

1. Breast cancer:

Adults: The recommended daily dose of Bilem 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.

Older people: Similar dosing regimens of Bilem have been used in older people with breast cancer and in some of these patients it has been used as sole therapy.

2. Anovulatory infertility:

Before commencing any course of treatment, whether initial or subsequent, the possibility of pregnancy must be excluded. In women who are menstruating regularly, but with anovular cycles, the initial course of treatment consists of 20 mg given daily on the second, third, fourth and fifth days of the menstrual cycle. If unsatisfactory basal temperature records or poor pre-ovulatory cervical mucus indicate that this initial course of treatment has been unsuccessful, further courses may be given during subsequent menstrual periods, increasing the dosage to 40mg and then 80mg daily.

In women who are not menstruating regularly, the initial course may begin on any day. If no signs of ovulation are demonstrable, then a subsequent course of treatment may start 45 days later, with dosage increased as above. If a patient responds with menstruation, then the next course of treatment is commenced on the second day of the cycle.

Paediatric population

The use of Bilem is not recommended in children. The safety and efficacy of Bilem in children has not yet been established.

Method of administration

For administration by the oral route.

Bilem should not be used in the following:

- pregnancy.).

-

- concurrent anastrozole therapy.

- treatment for infertility. Patients with a personal or family history of confirmed idiopathic venous thromboembolic events or a known genetic defect.

Menstruation is suppressed in a proportion of premenopausal women receiving Bilem 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 Bilem treatment.The underlying mechanism is unknown but may be related to the oestrogen-like effect of Bilem. Any patient receiving or having previously received Bilem who reports 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.

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 Bilem. No causal link has been established and the clinical significance of these observations remains unclear.

Venous thromboembolism (VTE)

- A two- to three-fold increase in the risk for VTE has been demonstrated in healthy Bilem-treated women.

- In patients with breast cancer, prescribers should obtain careful histories with respect to the patient's personal and family history of VTE.).

- 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 Bilem. In patients with breast cancer, this risk is also increased by concomitant chemotherapy. 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, Bilem 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, Bilem treatment should only be stopped if the risk of Bilem-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, Bilem should be stopped immediately and appropriate anti-thrombosis measures initiated. In patients being treated for infertility, Bilem should not be re-started unless there is a compelling alternative explanation for their thrombotic event. In patients receiving Bilem for breast cancer, the decision to re-start Bilem should be made with respect to the overall risk for the patient. In selected patients with breast cancer, the continued use of Bilem 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 Bilem may increase the risk of microvascular flap complications.

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. While this finding is in line with the pharmacodynamic properties of Bilem, a causal relationship has not been established.

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 Bilem.

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 Bilem treatment. Bilem contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Radiation recall has been reported very rarely in patients on Bilem who have received prior radiotherapy. The reaction is usually reversible upon temporary cessation of therapy and re-challenge may result in a milder reaction. Treatment with Bilem was continued in most cases.

Bilem is unlikely to impair the ability of patients to drive or operate machinery. However, fatigue has been reported with the use of Bilem and caution should be observed when driving or using machinery while such symptoms persist.

Tabulated list of adverse reactions

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.

Table 1 Adverse Drug Reactions (ADR) seen with Bilem

^a This adverse drug reaction was not reported in the Bilem arm (n= 3094) of the above study; however, it has been reported in other trials or from other sources. 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 e.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'.

Side effects can be classified as either due to the pharmacological action of the drug, e.g. hot flushes, vaginal bleeding, vaginal discharge, pruritus vulvae and tumour flare, or as more general side effects, e.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, cutaneous vasculitis and bullous pemphigoid) and commonly hypersensitivity reactions including angioedema have been reported.

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 Bilem therapy. Cataracts have been reported commonly in association with the administration of Bilem.

Cases of optic neuropathy and optic neuritis have been reported in patients receiving Bilem and, in a small number of cases, blindness has occurred.

Sensory disturbances (including paraesthesia and dysgeusia) have been reported commonly in patients receiving Bilem.

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 Bilem for breast cancer.

Leucopenia has been observed following the administration of Bilem, sometimes in association with anaemia and/or thrombocytopenia. Neutropenia has been reported on rare occasions; this can sometimes be severe, and very rarely cases of agranulocytosis have been reported.

There is evidence of ischaemic cerebrovascular events and thromboembolic events, including deep vein thrombosis, microvascular thrombosis and pulmonary embolism, occurring commonly during Bilem therapy. When Bilem is used in combination with cytotoxic agents, there is an increased risk of thromboembolic events occurring.

Leg cramps and myalgia have been reported commonly in patients receiving Bilem.

Uncommonly, cases of interstitial pneumonitis have been reported.

Bilem has been associated with changes in liver enzyme levels and with a spectrum of more severe liver abnormalities which in some cases were fatal, including fatty liver, cholestasis and hepatitis, liver failure, cirrhosis, and, hepatocellular injury (including hepatic necrosis).

Commonly, elevation of serum triglyceride levels, in some cases with pancreatitis, may be associated with the use of Bilem.

Cystic ovarian swellings have rarely been observed in women receiving Bilem.

Vaginal polyps have rarely been observed in women receiving Bilem.

Cutaneous lupus erythematosus has been observed very-rarely in patients receiving Bilem.

Porphyria cutanea tarda has been observed very-rarely in patients receiving Bilem.

Fatigue has been reported very commonly in patients taking Bilem.

Radiation Recall has been observed very rarely in patients receiving Bilem.

Uncommonly incidences of endometrial cancer and rare instances of uterine sarcoma (mostly malignant mixed Mullerian tumours) has been reported in association with Bilem treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

On theoretical grounds an overdosage would be expected to cause enhancement of the pharmacological side-effects mentioned above. Observations in animals show that extreme overdosage (100 - 200 times recommended daily dose) may produce oestrogenic effects.

There have been reports in the literature that Bilem given at several times the standard dose may be associated with prolongation of the QT interval of the ECG.

There is no specific antidote to overdosage, and treatment must be symptomatic.

Pharmacotherapeutic group: Anti-estrogens. ATC code: L02BA01.

Bilem is a non-steroidal, triphenylethylene-based drug which displays a complex spectrum of oestrogen antagonist and oestrogen agonist-like pharmacological effects in different tissues. In breast cancer patients, at the tumour level, Bilem acts primarily as an antioestrogen, preventing oestrogen binding to the oestrogen receptor. In the clinical situation, it is recognised that Bilem leads to reductions in levels of blood total cholesterol and low density lipoproteins in postmenopausal women of the order of 10 - 20%. Bilem does not adversely affect bone mineral density.

An uncontrolled trial was undertaken in a heterogenous group of 28 girls aged 2 to 10 years with McCune Albright Syndrome (MAS), who received 20 mg 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 Bilem, a causal relationship has not been established. There are no long-term safety data in children. In particular, the long-term effects of Bilem on growth, puberty and general development have not been studied.

CYP2D6 polymorphism status may be associated with variability in clinical response to Bilem. 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.

CYP2D6 genotype

Available clinical data suggest that patients, who are homozygote for non-functional CYP2D6 alleles, may experience reduced effect of Bilem in the treatment of breast cancer. The available studies have mainly been performed in postmenopausal women

After oral administration, Bilem is absorbed rapidly with maximum serum concentrations attained within 4-7 hours. Steady state concentrations (about 300ng/ml) are achieved after four weeks treatment with 40mg daily. The drug is highly protein bound to serum albumin (>99%). 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. Excretion occurs primarily via the faeces and an elimination half-life of approximately seven days has been calculated for the drug itself, whereas that forN-desmethylBilem, the principal circulating metabolite, is 14 days.

In a clinical study where girls between 2 and 10 years with McCune Albright Syndrome (MAS) received 20mg Bilem 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.

Bilem is metabolised mainly via CYP3A4 to N-desmethyl-Bilem, 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.

Bilem was not mutagenic in a range of in vitro and in vivo mutagenicity tests. Bilem was genotoxic in some in-vitro and in-vivo genotoxicity tests in rodents. Gonadal tumours in mice and liver tumours in rats receiving Bilem have been reported in long term studies. The clinical relevance of these findings has not been established.

Bilem is a drug on which extensive clinical experience has been obtained.

Relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

Not applicable.

No special requirements for disposal.