Leaflet FARESTON 60mg tablets

Fareston 60 mg tablets

Each tablet contains 60 mg toremifene (as citrate).

One tablet contains 28.5 mg of lactose (as monohydrate). For the full list of excipients, seesection 6.1.

Tablet.

White, round, flat, bevelled edge tablet with TO 60 on one side.

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

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

The recommended dose is 60 mg daily.

No dose adjustment is needed in patients with renal insufficiency.

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

There is no relevant use of Fareston in the paediatric population.

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

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

- hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- both in preclinical investigations and in humans, changes in cardiac electrophysiology havebeen observed following exposure to toremifene, in the form of QT prolongation. For reasonsof 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 alsosection 4.5).

Gynaecological examination should be performed before treatment administration, closely looking atpre-existing endometrial abnormality. Afterwards gynaecological examination should be repeated atleast once a year. Patients with additional risk of endometrial cancer, e.g. patients suffering fromhypertension or diabetes, having high BMI (> 30) or history of hormone replacement therapy shouldbe closely monitored (see also section 4.8).

Anemia, leukopenia and thrombocytopenia have been reported. Red blood cell, leukocyte or plateletcounts should be monitored when using Fareston.

Cases of liver injury, including elevation of liver enzymes (> 10 times upper limit of normal),hepatitis and jaundice have been reported with toremifene. Most of them occurred during the firstmonths of treatment. The pattern of the liver damage was predominantly hepatocellular.

Patients with a history of severe thromboembolic disease should generally not be treated withtoremifene (see also section 4.8).

Fareston has been shown to prolong the QTc interval on the electrocardiogram in some patients in adose-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 toremifeneon the QTc interval duration. The results of this study show a clear positive effect of toremifene in the80 mg group with mean prolongations of 21-26 ms. Regarding the 20 mg group, this effect issignificant as well, according to ICH guidelines, with upper confidence interval of 10-12 ms. Theseresults 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. Elderlypatients 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 (especiallyelderly patients) such as acute myocardial ischaemia or QT prolongation as this may lead to anincreased risk for ventricular arrhythmias (incl. Torsade de pointes) and cardiac arrest (see alsosection 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 closelymonitored.

Hypercalcemia may occur at the beginning of toremifene treatment in patients with bone metastasisand thus these patients should be closely monitored.

There are no systematic data available from patients with labile diabetes, from patients with severelyaltered performance status or from patients with cardiac failure.

Fareston tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, totallactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol (23 mg) sodium per dosage unit, that is to sayessentially ‘sodium-free’.

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

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

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

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

- certain antimicrobials agents (moxifloxacin, erythromycin IV, pentamidine, antimalarialsparticularly 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 ofhypercalcaemia.

Enzyme inducers, like phenobarbital, phenytoin and carbamazepine, may increase the rate oftoremifene metabolism thus lowering the steady-state concentration in serum. In such cases doublingof the daily dose may be necessary.

There is a known interaction between anti-estrogens and warfarin-type anticoagulants leading to aseriously increased bleeding time. Therefore, the concomitant use of toremifene with such drugsshould be avoided.

Theoretically the metabolism of toremifene is inhibited by drugs known to inhibit the CYP3A enzymesystem which is reported to be responsible for its main metabolic pathways. Examples of such drugsare antifungal imidazoles (ketoconazole); other antifungal agents (itraconazole, voriconazole,posaconazole); protease inhibitors (ritonavir, nelfinavir), macrolides (clarithromycin, erythromycin,telithromycine). Concomitant use of those drugs with toremifene should be carefully considered.

There are no adequate data from the use of Fareston in pregnant women. Studies in animals haveshown 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.

Toremifene is recommended for postmenopausal patients.

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

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 thehormonal 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).

System organ Very Common Uncommon Rare Very rare Not knownclass common

Neoplasms Endometrialbeningn, cancermalignant andunspecified(including cystsand polyps)

Blood and Thrombo-lymphatic cytopenia,system anaemia anddisorders leukopenia

Metabolism Loss of Hyper-and nutrition appetite triglyceridaemiadisorders

Psychiatric Depression Insomniadisorders

Nervous Dizziness Headachesystemdisorders

Eye disorders Transientcornealopacity

Ear and Vertigolabyrinthdisorders

Vascular Hot Thrombo-disorders flushes embolicevents

Respiratory, Dyspnoeathoracic andmediastinaldisorders

Gastrointestinal Nausea, Constipationdisorders vomiting

Hepatobiliary Increase of Jaundice Hepatitis,disorders transaminases hepaticsteatosis

Skin and Sweating Rash, Alopeciasubcutaneous itchingtissue disorders

Reproductive Uterine Endometrial Endometrial Endometrialsystem and bleeding, hypertrophy polyps hyperplasiabreast disorders leukorrhea

General Fatigue, Weightdisorders and oedema increaseadministrationsite conditions

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 oftransaminases) 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 beginningof toremifene treatment.

Endometrial hypertrophy may develop during the treatment due to the partial estrogenic effect oftoremifene. 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).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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 incases of overdose. There is no specific antidote and the treatment is symptomatic.

Pharmacotherapeutic group: Endocrine therapy, 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, targetorgan and variable selected. In general, however, nonsteroidal triphenylethylene derivatives arepredominantly anti-estrogenic in rats and man and estrogenic in mice.

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

Toremifene binds specifically to estrogen receptors, competitively with oestradiol, and inhibitsestrogen-induced stimulation of DNA synthesis and cell replication. In some experimental cancersand/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 ofapoptosis and influence on cell cycle kinetics) may also be involved in the anti-tumour effect.

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

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 ofintravenous 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 meanconcentration of toremifene at steady-state is 0.9 (range 0.6-1.3) µg/ml at the recommended dose of60 mg per day.

Toremifene is extensively metabolised. In human serum the main metabolite is N-demethyltoremifenewith mean half-life of 11 (range 4-20) days. Its steady-state concentrations are about twice comparedto those of the parent compound. It has similar anti-estrogenic, albeit weaker anti-tumour activity thanthe 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 interestinghormonal effects, their concentrations during toremifene treatment are too low to have any majorbiological importance.

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

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

No information is available concerning polymorphic metabolism. Enzyme complex, known to beresponsible for the metabolism of toremifene in humans, is cytochrome P450-dependent hepaticmixed function oxidase. The main metabolic pathway, N-demethylation, is mediated mainly by

CYP3A.

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

The acute toxicity of toremifene is low with LD-50 in rats and mice of more than 2 000 mg/kg. Inrepeated toxicity studies the cause of death in rats is gastric dilatation. In the acute and chronictoxicity studies most of the findings are related to the hormonal effects of toremifene. The otherfindings are not toxicologically significant. Toremifene has not shown any genotoxicity and has notbeen found to be carcinogenic in rats. In mice, estrogens induce ovarian and testicular tumours as wellas hyperostosis and osteosarcomas. Toremifene has a species-specific estrogen-like effect in mice andcauses 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 metaboliteto 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 linewith QTc findings in humans.

It is also to be noted that the Cmax observed in the monkeys (1 800 ng/ml) is two-fold compared to themean Cmax observed in humans at a daily dose of 60 mg.

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

Maize starch

Lactose monohydrate

Povidone

Sodium starch glycolate

Magnesium stearate

Cellulose, microcrystalline

Silica, colloidal anhydrous.

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Green PVC foil and aluminium foil blister in a cardboard box.

Package sizes: 30 and 100 tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Orion Corporation

Orionintie 1

FI-02200 Espoo

Finland

EU/1/96/004/001

EU/1/96/004/002

Date of first authorisation: 14 February 1996

Date of latest renewal: 2 February 2006

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.