Information about the sodium content of the tablets added to section 4.4:  This medicine contains less than 1 mmol (23 mg) sodium per tablet that is to say essentially ‘sodium-free’.

Information has been added about the sodium content of the tablets:  This medicine contains less than 1 mmol (23 mg) sodium per tablet that is to say essentially ‘sodium-free’.

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 60 mg toremifene (as citrate).

Excipients: 30 mg lactose per tablet.

For a full list of excipients, see section 6.1.

4.       Clinical particulars

4.1     Therapeutic indications

First line hormone treatment of hormone-dependent metastatic breast cancer in postmenopausal patients.

Fareston is not recommended for patients with estrogen receptor negative tumours.

4.2         Posology and method of administration

Posology

The recommended dose is 60 mg daily.

Renal impaiment
No dose adjustment is needed in patients with renal insufficiency.

Hepatic impairment
Toremifene should be used cautiously in patients with liver impairment (see section 5.2).

Pediatric use

There is no relevant indication for use of Fareston in children.

Method of administration

Toremifene is administered orally. Toremifene can be taken with or without food.

4.3     Contraindications

-        Pre-existing endometrial hyperplasia and severe hepatic failure are contra-indications in long-term use of toremifene.

-        Hypersensitivity to toremifene or to any of the excipients.

-        Both in preclinical investigations and in humans, changes in cardiac electrophysiology have been observed following exposure to toremifene, in the form of QT prolongation. For reasons of drug safety, toremifene is therefore contraindicated in patients with:

-     Congenital or documented acquired QT prolongation

-     Electrolyte disturbances, particularly in uncorrected hypokalaemia

-     Clinically relevant bradycardia

-     Clinically relevant heart failure with reduced left-ventricular ejection fraction

-     Previous history of symptomatic arrhythmias.

Toremifene should not be used concurrently with other drugs that prolong the QT interval (see also section 4.5).

4.4     Special warnings and precautions for use

Gynaecological examination should be performed before treatment administration, closely looking at

pre-existing endometrial abnormality. Afterwards gynaecological examination should be repeated at

least once a year. Patients with additional risk of endometrial cancer, e.g. patients suffering from

hypertension or diabetes, having high BMI (>30) or history of hormone replacement therapy should be

closely monitored (see also section 4.8).

Patients with a history of severe thromboembolic disease should generally not be treated with toremifene

(see also section 4.8).

Fareston has been shown to prolong the QTc interval on the electrocardiogram in some patients in a dose-related manner. The following information regarding QT-prolongation is of special importance (for contraindications see section 4.3).

A QT clinical study with a 5-arm parallel design (placebo, moxifloxacin 400 mg, toremifene 20 mg, 80 mg, and 300 mg) has been performed in 250 male patients to characterize the effects of toremifene on the QTc interval duration. The results of this study show a clear positive effect of toremifene in the 80 mg group with mean prolongations of 21 - 26 ms. Regarding the 20 mg group, this effect is significant as well, according to ICH guidelines, with upper confidence interval of 10 - 12 ms. These results strongly suggest an important dose-dependent effect. As women tend to have a longer baseline QTc interval compared with men, they may be more sensitive to QTc-prolonging medications. Elderly patients may also be more susceptible to drug-associated effects on the QT interval.

Fareston should be used with caution in patients with ongoing proarrhythmic conditions (especially elderly patients) such as acute myocardial ischaemia or QT prolongation as this may lead to an increased risk for ventricular arrhythmias (incl. Torsade de pointes) and cardiac arrest (see also section 4.3).

If signs or symptoms that may be associated with cardiac arrhythmia occur during treatment with Fareston, treatment should be stopped and an ECG should be performed.

If the QTc interval is > 500 ms, Fareston should not be used.

Patients with non-compensated cardiac insufficiency or severe angina pectoris should be closely monitored.

Hypercalcemia may occur at the beginning of toremifene treatment in patients with bone metastasis and

thus these patients should be closely monitored.

There are no systematic data available from patients with labile diabetes, from patients with severely

altered performance status or from patients with cardiac failure.

Fareston tablets contain lactose (30 mg/tablet). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5     Interaction with other medicinal products and other forms of interaction

An additive effect on QT interval prolongation between Fareston and the following drugs and other medicinal products that may prolong the QTc interval cannot be excluded. This might lead to an increased risk of ventricular arrhythmias, including Torsade de pointes. Therefore co-administration of Fareston with any of the following medicinal products is contraindicated (see also section 4.3):

-           antiarrhythmics class IA (e.g. quinidine, hydroquinidine, disopyramide) or

-           antiarrhythmics class III (e.g. amiodarone, sotalol, dofetilide, ibutilide),

-           neuroleptics (e.g. phenothiazines, pimozide, sertindole, haloperidol, sultopride),

-        certain antimicrobials agents (moxifloxacin, erythromycin IV, pentamidine, antimalarials particularly halofantrine),

-           certain antihistaminics (terfenadine, astemizole, mizolastine),

-        others (cisapride, vincamine IV, bepridil, diphemanil).

Drugs which decrease renal calcium excretion, e.g. thiazide diuretics, may increase the risk of

hypercalcaemia.

Enzyme inducers, like phenobarbital, phenytoin and carbamazepine, may increase the rate of toremifene

metabolism thus lowering the steady-state concentration in serum. In such cases doubling of the daily

dose may be necessary.

There is a known interaction between anti-estrogens and warfarin-type anticoagulants leading to a

seriously increased bleeding time. Therefore, the concomitant use of toremifene with such drugs should

be avoided.

Theoretically the metabolism of toremifene is inhibited by drugs known to inhibit the CYP 3A enzyme

system which is reported to be responsible for its main metabolic pathways. Examples of such drugs are

ketoconazole and similar antimycotics, erythromycin and troleandomycin. Concomitant use of those

drugs with toremifene should be carefully considered.

4.6     Pregnancy and lactation

Toremifene is recommended for postmenopausal patients.

There are no adequate data from the use of Fareston in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Fareston should not be used during pregnancy.

In rats, decreased body weight gain of the offspring during lactation was observed.

Fareston should not be used during lactation.

4.7     Effects on ability to drive and use machines

Toremifene has no influence on the ability to drive and use machines.

4.8         Undesirable effects

The most frequent adverse reactions are hot flushes, sweating, uterine bleeding, leukorrhea, fatigue,

nausea, rash, itching, dizziness and depression. The reactions are usually mild and mostly due to the

hormonal action of toremifene.

The frequencies of the adverse reactions are classified as follows:

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).

Thromboembolic events include deep venous thrombosis, thrombophlebitis and pulmonary embolism (see also section 4.4).

Toremifene treatment has been associated with changes in liver enzyme levels (increases of transaminases) and in very rare occasions with more severe liver function abnormalities (jaundice).

A few cases of hypercalcaemia have been reported in patients with bone metastases at the beginning of toremifene treatment.

Endometrial hypertrophy may develop during the treatment due to the partial estrogenic effect of toremifene. There is a risk of increased endometrial changes including hyperplasia, polyps and cancer. This may be due to the underlying mechanism/estrogenic stimulation (see also section 4.4).

Fareston increases the QT interval in a dose-related manner (see also section 4.4).

4.9     Overdose

Vertigo, headache and dizziness were observed in healthy volunteer studies at daily dose of 680 mg. The dose-related QTc interval prolongation potential of Fareston should also be taken into account in cases of overdose. There is no specific antidote and the treatment is symptomatic.

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Anti-estrogens, ATC code: L02BA02

Toremifene is a nonsteroidal triphenylethylene derivative. As other members of this class, e.g. tamoxifen and clomifene, toremifene binds to estrogen receptors and may produce estrogenic, anti-estrogenic or both effects, depending upon the duration of treatment, animal species, gender, target organ and variable selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly anti-estrogenic in rats and man and estrogenic in mice.

In post-menopausal breast cancer patients, toremifene treatment is associated with modest reductions in both total serum cholesterol and low density lipoprotein (LDL).

Toremifene binds specifically to estrogen receptors, competitively with oestradiol, and inhibits estrogen-induced stimulation of DNA synthesis and cell replication. In some experimental cancers and/or using high-dose, toremifene displays anti-tumour effects which are not estrogen-dependent.

The anti-tumour effect of toremifene in breast cancer is mainly due to the anti-estrogenic effect, although other mechanisms (changes in oncogene expression, growth factor secretion, induction of apoptosis and influence on cell cycle kinetics) may also be involved in the anti-tumour effect.

5.2     Pharmacokinetic properties

Absorption

Toremifene is readily absorbed after oral administration. Peak concentrations in serum are obtained within 3 (range 2 - 5) hours. Food intake has no effect on the extent of absorption but may delay the peak concentrations by 1.5 - 2 hours. The changes due to food intake are not clinically significant.

Distribution

The serum concentration curve can be described by a biexponential equation. The half-life of the first (distribution) phase is 4 (range 2 - 12) hours, and of the second (elimination) phase 5 (range 2 - 10 ) days. The basal disposition parameters (CL and V) could not be estimated due to the lack of intravenous study. Toremifene binds extensively ( > 99.5 %) to serum  proteins, mainly to albumin. Toremifene obeys linear serum kinetics at oral daily doses between 11 and 680 mg. The mean concentration of toremifene at steady-state is 0.9 (range 0.6 - 1.3) g/ml at the recommended dose of 60 mg per day.

Metabolism

Toremifene is extensively metabolised. In human serum the main metabolite is N-demethyltoremifene with mean half-life of 11 (range 4 - 20) days. Its steady-state concentrations are about twice compared to those of the parent compound. It has similar anti-estrogenic, albeit weaker anti-tumour activity than the parent compound.

It is bound to plasma proteins even more extensively than toremifene, the protein bound fraction being > 99.9 %. Three minor metabolites have been detected in human serum: (deaminohydroxy)toremifene, 4-hydroxytoremifene, and N,N-didemethyltoremifene. Although they have theoretically interesting hormonal effects, their concentrations during toremifene treatment are too low to have any major biological importance.

Elimination

Toremifene is eliminated mainly as metabolites to the faeces. Enterohepatic circulation can be expected. About 10 % of the administered dose is eliminated via urine as metabolites. Owing to the slow elimination, steady-state concentrations in serum are reached in 4 to 6 weeks.

Characteristics in patients

Clinical anti-tumour efficacy and serum concentrations have no positive correlation at the recommended daily dose of 60 mg.

No information is available concerning polymorphic metabolism. Enzyme complex, known to be responsible for the metabolism of toremifene in humans, is cytochrome P450-dependent hepatic mixed function oxidase. The main metabolic pathway, N-demethylation, is mediated mainly by CYP 3A.

Pharmacokinetics of toremifene were investigated in an open study with four parallel groups of ten subjects: normal subjects, patients with impaired (mean AST 57 U/L - mean ALT 76 U/L - mean gamma GT 329 U/L) or activated liver function (mean AST 25 U/L - mean ALT 30 U/L - mean gamma GT 91 U/L - patients treated with antiepileptics) and patients with impaired renal function (creatinine: 176 mol/L). In this study the kinetics of toremifene in patients with impaired renal function were not significantly altered as compared to normal subjects. The elimination of toremifene and its metabolites was significantly increased in patients with activated liver function and decreased in patients with impaired liver function.

5.3     Preclinical safety data

The acute toxicity of toremifene is low with LD-50 in rats and mice of more than 2000 mg/kg. In repeated toxicity studies the cause of death in rats is gastric dilatation. In the acute and chronic toxicity studies most of the findings are related to the hormonal effects of toremifene. The other findings are not toxicologically significant. Toremifene has not shown any genotoxicity and has not been found to be carcinogenic in rats. In mice, estrogens induce ovarian and testicular tumours as well as hyperostosis and osteosarcomas. Toremifene has a species-specific estrogen-like effect in mice and causes similar tumours. These findings are postulated to be of little relevance for the safety in man, where toremifene acts mainly as an anti-estrogen.

Non clinical in vitro and in vivo studies have evidenced the potential of toremifene and its metabolite to prolong cardiac repolarisation and this can be attributed to the blockade of hERG channels.

In vivo, high plasma concentrations in monkeys caused a 24 % prolongation in QTc, which is in line with QTc findings in humans.

It is also to be noted that the C_max observed in the monkeys (1800 ng/ml) is two-fold compared to the mean C_max observed in humans at a daily dose of 60 mg.

Action potential studies in isolated rabbit heart have shown that toremifene induce cardiac electrophysiological changes which start to develop at concentrations approximately 10 fold compared to the calculated  free therapeutic plasma concentration in human.

6.6     Special precautions for disposal

No special requirements.

7.       MARKETING AUTHORISATION HOLDER

Orion Corporation
Orionintie 1

FIN-02200 Espoo

Finland

8.       MARKETING AUTHORISATION NUMBERS

EU/1/96/004/001

EU/1/96/004/002

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14 February 1996 / 2 February 2006

10.     DATE OF REVISION OF THE TEXT

{MM/YYYY}

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/