Consumer medicine information

Fareston

Toremifene

BRAND INFORMATION

Brand name

Fareston

Active ingredient

Toremifene

Schedule

SUMMARY CMI

FARESTON^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using FARESTON?

FARESTON contains the active ingredient toremifene citrate. FARESTON is used to treat hormone-sensitive breast cancer in women who have had their menopause

For more information, see Section 1. Why am I using FARESTON? in the full CMI.

2. What should I know before I use FARESTON?

Do not use if you have ever had an allergic reaction to toremifene citrate, other anti-oestrogens (e.g. tamoxifen), or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use FARESTON? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with FARESTON and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use FARESTON?

The usual dose is one tablet once a day.
More instructions can be found in Section 4. How do I use FARESTON? in the full CMI.

5. What should I know while using FARESTON?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using FARESTON. Keep all of your doctor's appointments so that your progress can be checked. You will need to have regular gynaecological check-ups while you are taking FARESTON.
Driving or using machines	Be careful before you drive or use any machines or tools until you know how FARESTON affects you.
Looking after your medicine	Store FARESTON below 25°C.

For more information, see Section 5. What should I know while using FARESTON? in the full CMI.

6. Are there any side effects?

Less serious side effects include: sweating, itching, rash, nausea or vomiting, dizziness, depression, mood changes or shortness of breath, swelling of the hands, feet and/or ankles, pain, tiredness or hot flushes. Serious side effects include: a white vaginal discharge, heavy menstrual periods, blood clot in blood vessel, liver problems or high levels of calcium in your blood.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

FARESTON^®

Active ingredient(s): toremifene citrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using FARESTON. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using FARESTON.

Where to find information in this leaflet:

1. Why am I using FARESTON?
2. What should I know before I use FARESTON?
3. What if I am taking other medicines?
4. How do I use FARESTON?
5. What should I know while using FARESTON?
6. Are there any side effects?
7. Product details

1. Why am I using FARESTON?

FARESTON contains the active ingredient toremifene citrate. FARESTON belongs to the group of medicines known as anti-oestrogens. It helps to stop the tumour cells from growing and multiplying.

FARESTON is used to treat hormone-sensitive breast cancer in women who have had their menopause.

2. What should I know before I use FARESTON?

Warnings

Do not use FARESTON if:

you are allergic to toremifene citrate, other anti-oestrogens (e.g. tamoxifen), or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
you have endometrial hyperplasia (an overgrowth in the lining of the uterus)
you have severe liver failure
you are pregnant
you have a heart condition called QT prolongation, where the heart muscle takes longer to contract and then recover due to a disorder involving electrical impulses.
you have other heart conditions including bradycardia (slow heart rhythm), symptomatic arrhythmias (irregular heart rhythm) or heart failure.
you have electrolyte disturbances including uncorrected hypokalaemia (low blood potassium levels).

Check with your doctor if you:

have any other medical conditions, particularly:
- angina or a heart condition, including an irregular heart beat
- feel pain in your bones
- have had problems with blood clots in the past. In severe cases, FARESTON is not recommended.
- liver problems
- have any other medical conditions or health problems
are lactose intolerant. FARESTON tablets contain lactose.
take any medicines for any other condition.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

FARESTON is for use by women who have had their menopause and should not be used by pregnant or breastfeeding women.

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with FARESTON and affect how it works.

In particular, tell your doctor or pharmacist if you are taking any of the following:

medicines used to treat irregular heartbeat such as quinidine, hydroquinidine, disopyramide, amiodarone, sotalol, doretilide and ibutilide.
prochlorperazine, a medicine used to treat nausea and dizziness
medicines used to treat mental illness such as phenothiazides, pimozide, sertindole, haloperidol, sultopride, chlorpromazine.
certain antibiotics such as erythromycin and related medicines (including, clarithromycin, moxifloxacin and pentamidine, telithromycine, troleandomycin).
certain antimalarials, particularly halofantrine.
some antihistamines, such as terfenadine, astemizole and mizolastine
some diuretics, also called water or fluid tablets
phenytoin, carbamazepine and phenobarbitone, medicines used to treat epilepsy.
warfarin, a medicine used to stop blood clots, and related medicines
certain medicines used to treat fungal infections, such as ketoconazole, itraconazole, voriconazole and posaconazole.
medicines used to treat HIV infection such as ritonavir and nelfinavir
cisapride
bepridil
diphemanil.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect FARESTON.

4. How do I use FARESTON?

How much to take

The usual dose is one tablet once a day.
Follow the instructions provided and use FARESTON until your doctor tells you to stop.

When to take FARESTON

FARESTON can be taken with or without food.
It is good practice to take FARESTON at about the same time each day.

How to take FARESTON

Swallow FARESTON tablets with a glass of water.

How long to take FARESTON

Take FARESTON for as long as your doctor tells you.

If you forget to use FARESTON

FARESTON should be used regularly at the same time each day.

If you miss your dose at the usual time, and it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking it as you would normally.

Do not take a double dose to make up for the dose you missed.

If you use too much FARESTON

If you think that you have used too much FARESTON, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using FARESTON?

Things you should do

Keep all of your doctor's appointments so that your progress can be checked.

You will need to have regular gynaecological check-ups while you are taking FARESTON.
FARESTON can cause problems with your blood and liver. Your doctor may organise blood tests to check for these problems.

Remind any doctor, dentist or pharmacist you visit that you are using FARESTON.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how FARESTON affects you.

FARESTON may cause dizziness or light-headedness in some people and may affect your ability to drive.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

Store FARESTON below 25°C.

Follow the instructions on the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects

What to do

Skin related:

sweating
itching, rash

Stomach and gut related:

nausea (feeling sick) or vomiting

Nerve related:

dizziness

Mental related:

depression
mood changes

Lung related:

shortness of breath

General related:

swelling of the hands, feet and/or ankles (oedema)
pain
tiredness
hot flushes

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Reproductive system related:

a white vaginal discharge
vaginal bleeding
heavy menstrual periods

Signs of blood clot in blood vessel:

weakness or paralysis on one side of the body or face, difficulty speaking or swallowing, headache, loss of balance or vision (signs of a stroke)
pain, swelling, redness and warmth in the leg (signs of a blood clot in the leg)
shortness of breath, chest pain and cough (signs of blockage of lung artery)

Signs of liver problems:

yellowing of the eyes and/or skin (jaundice)
nausea, vomiting, loss of appetite, itchy skin, pale coloured stools, dark coloured urine

Signs of high levels of calcium in your blood:

extreme thirst, frequent urination, stomach pain or upset, tiredness, muscle aches or bone pain.

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Some of side effects can only be found when your doctor does blood or other tests from time to time to check your progress.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What FARESTON contains

Active ingredient (main ingredient)	Each tablet contains toremifene citrate equivalent to 60 mg of toremifene
Other ingredients (inactive ingredients)	microcrystalline cellulose lactose monohydrate maize starch sodium starch glycollate povidone magnesium stearate colloidal anhydrous silica
Potential allergens	lactose

Do not take this medicine if you are allergic to any of these ingredients.

What FARESTON looks like

FARESTON tablets are white or almost white, flat, round, uncoated tablets marked with TO60 on one side of the tablet. It is available in blister packs of 30 tablets (AUST R 59743).

Who distributes FARESTON

Orion Pharma (Aus) Pty Limited
Level 24, Tower 3
300 Barangaroo Avenue, Sydney, NSW 2000, Australia
Telephone: 1800 861 913

This leaflet was prepared in November 2024.

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Fareston

Active ingredient

Toremifene

Schedule

1 Name of Medicine

Toremifene citrate.

2 Qualitative and Quantitative Composition

Each Fareston Tablet contains toremifene citrate equivalent to toremifene 60 mg.

Excipients with known effects.

Lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablet.
Fareston Tablets are white or almost white, round, flat, uncoated tablets with bevelled edges, embossed with "TO60" on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Fareston is indicated for first line treatment of hormone dependent metastatic breast cancer in postmenopausal patients. Fareston is not recommended for patients with oestrogen receptor negative tumours.

4.2 Dose and Method of Administration

The recommended dose is one tablet (60 mg) daily.
No dose adjustment is needed in renal insufficiency. Fareston should be used cautiously in patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties, Characteristics in patients).
Toremifene is administered orally. Toremifene can be taken with or without food.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed, see Section 6.1 List of Excipients.
Pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Pre-existing endometrial hyperplasia and severe hepatic failure are contraindications for long-term use of toremifene.
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.

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.
Anemia, leukopenia and thrombocytopenia have been reported. Red blood cell, leukocyte or platelet counts 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 first months of treatment. The pattern of the liver damage was predominantly hepatocellular.
In clinical trials, Fareston has been shown to prolong the QT/QTc interval on the electrocardiogram in a dose-related manner. The following information regarding the effects of toremifene on QT/QTc-prolongation is of special importance (also see Section 4.3 Contraindications).
A thorough QT/QTc study was conducted in 250 healthy men to characterize the effects of toremifene on the QT/QTc interval duration. In a randomized, multiple-dose 5-arm parallel group study subjects (n = 50 per treatment group) received either placebo, moxifloxacin 400 mg or toremifene 20 mg, 80 mg, or 300 mg per day. The results of this study show that toremifene causes dose related increases in QT/QTc with a mean change from baseline in QTc of 6, 24 and 57 msec the 20 mg, 80 mg and 300 mg groups, respectively. As women tend to have a longer baseline QTc interval compared with men, they may be more sensitive to QT-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 (including Torsade de pointes) and cardiac arrest. 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 msec, Fareston should not be used.
Patients with non-compensated cardiac insufficiency or severe angina pectoris should be monitored closely.
Hypercalcaemia may rarely occur during the first week of treatment, especially in patients with bone metastases. They should be informed about the clinical symptoms of hypercalcaemia and closely monitored.
Patients with a history of severe thromboembolic disease should generally not be treated.
There are no clinical data available in patients with labile or poorly controlled diabetes, in patients with severely altered performance status or in patients with non-compensated cardiac insufficiency or serious angina pectoris.
Experience of the long-term use of toremifene is limited.
Patients who have known hypersensitivity to anti-oestrogens or ingredients in Fareston tablets should not take Fareston.
Fareston tablets contain lactose (30 mg/tablet). Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Use in the elderly.

See information above on QT interval.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No specific interaction studies have been performed.
An additive effect on QT interval prolongation between Fareston and the following drugs and other medicinal products that may prolong the QT 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 (also see Section 4.3 Contraindications):
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 antimicrobial agents (moxifloxacin, erythromycin IV, pentamidine, antimalarials particularly halofantrine);
Certain antihistamines (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 phenobarbitone, 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-oestrogens and warfarin-type anticoagulants leading to a seriously increased bleeding time. Therefore, the concomitant use of toremifene with such medicaments should be avoided.
Theoretically there is a metabolic interaction of toremifene with drugs known to inhibit the CYP3A4-6 enzyme system. Examples of such drugs are antifungal imidazoles (ketoconazole); other antifungal agents (itraconazole, voriconazole, posaconazole); protease inhibitors (ritonavir, nelfinavir), and similar macrolide antibiotics (clarithromycin, erythromycin, telithromycin, troleandomycin). Concomitant use of those drugs with toremifene should be carefully considered.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category D)
Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
Fareston must not be administered during pregnancy (see Section 4.3 Contraindications). Toremifene is recommended for postmenopausal patients. Owing to the lack of specific data in humans, toremifene should not be used during pregnancy. In animal reproduction studies toremifene has been shown to prevent implantation, to induce parturition failures and to reduce perinatal survival. In addition, treatment during organogenesis induced changes in ossification, rib abnormalities and oedematous foetuses.
Toremifene is recommended for postmenopausal patients. Owing to the lack of specific data in humans, toremifene should not be used during lactation. In preclinical studies in rats, decreased body weight gain of the offspring during lactation was observed.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Adverse drug reactions are usually mild. They are mostly due to the hormonal action of toremifene.
The frequency of adverse drug reactions reported in clinical trials or spontaneously is listed below and classified according to body system.

Very common (> 10%).

Vascular disorders.

Hot flushes.

Skin and appendages disorders.

Sweating.

Common (> 1%, < 10%).

Psychic disorders.

Depression.

Nervous system disorders.

Dizziness.

Gastrointestinal disorders.

Nausea, vomiting.

Reproductive disorders.

Uterine bleeding, leucorrhoea.

Skin and subcutaneous tissue disorders.

Rash, itching.

General disorders.

Fatigue, oedema, pain.

Uncommon (> 0.1%, < 1%).

Skin and appendages disorders.

Skin discolouration.

Central and peripheral nervous system disorders.

Paresis, tremor, vertigo.

Vision disorders.

Reversible corneal verticillata (reversible corneal opacity).

Psychic disorders.

Insomnia.

Gastrointestinal disorders.

Constipation.

Respiratory system disorders.

Dyspnoea.

Reproductive disorders.

Vaginal bleeding, endometrial hypertrophy.

General disorders.

Anorexia, asthenia, back pain, chest pain, headache, weight increase, loss of appetite.

Vascular disorders.

Thromboembolic events.

Rare (> 0.01%, < 0.1%).

Skin and appendages disorders.

Alopecia, dermatitis.

Psychic disorders.

Emotional lability.

Central and peripheral nervous system disorders.

Stiffness.

Hepatic disorders.

Hepatic enzyme increase, jaundice.

Metabolic disorders.

Hypercalcaemia.

Reproductive system and breast disorders.

Endometrial polyps.

Very rare (< 1/10,000), not known (cannot be estimated from the available data).

Neoplasms benign, malignant and unspecified (including cysts and polyps).

Endometrial cancer.

Blood and lymphatic system disorders.

Thrombocytopenia, anaemia, and leukopenia.

Hepatobiliary disorders.

Hepatitis, hepatic steatosis.

Metabolism and nutrition disorders.

Hypertriglyceridemia.

Reproductive system and breast disorders.

Endometrial hyperplasia.
Thromboembolic events (include deep venous thrombosis, thrombophlebitis and pulmonary embolism) have been reported, although the causal relationship to toremifene treatment remains uncertain.
Treatment was discontinued due to adverse reactions in only about 3% of patients. Most of the cases were due to nausea, vomiting, vertigo, hypercalcaemia and vaginal bleeding. Development of hypercalcaemia in the beginning of the treatment is possible especially in patients with bone metastases.
Endometrial hypertrophy may develop during the treatment due to the hormonal (partial oestrogenic) 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 (also see Section 4.4 Special Warnings and Precautions for Use). It is unknown whether long-term toremifene use is associated with an increased risk of endometrial carcinoma.
Fareston increases the QTc interval in a dose related manner (see Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

No overdose cases are known. Vertigo, headache and dizziness were observed in healthy volunteer studies at a 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.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Toremifene is a non-steroidal triphenylethylene derivative. Like other members of this class, e.g. tamoxifen and clomifene, toremifene binds to oestrogen receptors and may exert oestrogenic, anti-oestrogenic or both activities, depending upon the duration of treatment, animal species, gender, target organ and variable selected. In general, however, non-steroidal triphenylethylene derivatives are predominantly anti-oestrogenic in rats and man and oestrogenic in mice.
In female rats the lowest dose of toremifene that exerts an intrinsic oestrogenic effect on the uterus is about 40 times higher than that of tamoxifen. In the same model the lowest anti-oestrogenically effective dose is 10 times higher than that of tamoxifen suggesting a lower oestrogenic to anti-oestrogenic ratio for toremifene than for tamoxifen. No data are available on this ratio in humans. In post-menopausal volunteers receiving oestrogen by oral or transdermal routes, toremifene was shown to exert an anti-oestrogenic effect on vaginal mucosa by reducing the cornification index. The latter effect was reproducibly found for toremifene doses ranging from 20 to 200 mg daily and could not be distinguished from that of 20 mg tamoxifen. Lower doses of toremifene did not oppose the oestrogenic stimulation of vaginal epithelium.
Toremifene binds specifically to oestrogen receptors, competitively with oestradiol, and inhibits oestrogen-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 oestrogen-dependent.
The anti-tumour effect of toremifene in breast cancer is mainly due to the anti-oestrogenic 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 antitumour effect.

Clinical trials.

Three prospective, randomised, controlled clinical studies (North American 5/044, Eastern European 5/050 and Nordic 5/049) were conducted to evaluate the efficacy of Fareston for the treatment of breast cancer in postmenopausal women. The patients were randomised to parallel groups receiving Fareston 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high dose toremifene arms of 200 and 240 mg daily, respectively. The studies included postmenopausal patients with tumour oestrogen receptor (ER) positive or ER unknown metastatic or locally advanced breast cancer. The patients had at least one measurable or evaluable lesion. The primary efficacy variables were response rate (RR), and time to progression (TTP). Survival (S) was also determined.
The studies showed similar response rates and two of the studies showed similar times to progression. The Nordic study showed a longer time to progression with tamoxifen in the tumour ER unknown group of patients. Survival in the three studies was similar between Fareston and tamoxifen. See Table 1.

Toremifene 200 mg daily in the North American study and 240 mg daily in the Eastern European study produced, respectively, 22.6% and 28.3% response rates, 5.7 and 6.1 month median times to progression, and 30.1 and 26.0 month median survival times.

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 an intravenous formulation. Toremifene binds extensively (> 99.5%) to serum proteins, mainly to albumin. Toremifene obeys linear serum kinetics at oral daily doses between 10 and 680 mg. The mean concentration of toremifene at steady state is 0.9 (range 0.6-1.3) microgram/mL at the recommended dose of 60 mg daily.

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 double those of the parent compound. It has similar anti-oestrogenic, albeit weaker antitumour activity than the parent compound. It is bound to plasma proteins even more extensively than toremifene, the protein bound fraction being > 99.9%. There is no significant potential for competition between toremifene and N-demethyltoremifene in protein binding. 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 concentration during toremifene treatment are too low to have any major biological importance.

Elimination.

Toremifene is eliminated mainly as metabolites in the faeces. Enterohepatic circulation of toremifene, but not its biologically active metabolites, 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 concentration have no positive correlation at the standard recommended daily dose of 60 mg.
No information is available concerning polymorphic metabolism. The 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 CYP3A4-6.
Renal insufficiency has no influence on toremifene kinetics.
Severe hepatic failure decreases the elimination rate of toremifene. The severity of hepatic failure when measured by liver enzymes does not, however, correlate with the elimination kinetics of toremifene.

5.3 Preclinical Safety Data

Genotoxicity.

Toremifene was not genotoxic in a range of in vitro and in vivo mutagenicity, clastogenicity and DNA effect studies.

Carcinogenicity.

Toremifene was not genotoxic in a range of in vitro and in vivo mutagenicity, clastogenicity and DNA effect studies. Toremifene has not been found to be carcinogenic in rats. In mice, oestrogens induce ovarian and testicular tumours as well as hyperostosis and osteosarcomas. Toremifene has a species specific oestrogen-like effect in mice and causes similar tumours. These findings are postulated to be of little relevance for the safety in humans, where toremifene acts mainly as an anti-oestrogen.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, lactose monohydrate, maize starch, sodium starch glycollate, povidone, magnesium stearate and colloidal anhydrous silica.

6.2 Incompatibilities

Incompatibilities were either not assessed or identified as part of the registration of this medicine.

6.3 Shelf Life

3 years.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Blister (PVC/Al) pack containing 30 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Toremifene citrate is a white or almost white crystalline powder. It is (Z)-4-Chloro-1,2-diphenyl-1-{4-[2-(N,N-dimethylamino) ethoxy] phenyl}-1-butene citrate.
The molecular formula is C₃₂H₃₆ClNO₈. MW: 598.1.

CAS number.

Toremifene citrate [89778-27-8].

7 Medicine Schedule (Poisons Standard)

S4: Prescription Only Medicine.

Summary Table of Changes

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BRAND INFORMATION
SUMMARY CMI
1. Why am I using FARESTON?
2. What should I know before I use FARESTON?
3. What if I am taking other medicines?
4. How do I use FARESTON?
5. What should I know while using FARESTON?
6. Are there any side effects?
FULL CMI
1. Why am I using FARESTON?
2. What should I know before I use FARESTON?
3. What if I am taking other medicines?
4. How do I use FARESTON?
5. What should I know while using FARESTON?
6. Are there any side effects?
7. Product details

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Fareston

Toremifene

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BRAND INFORMATION

Fareston 60 mg Tablets