Toremifene

Toremifene is a nonsteroidal triphenylethylene derivative. Like other members of this class it binds to oestrogen receptors and, depending on the duration of treatment, species, sex, target organ and endpoint, can produce oestrogenic, anti-oestrogenic or both effects. In rats and in humans its action is predominantly anti-oestrogenic, whereas in mice it is oestrogenic.

Mechanism of Action

• Receptor binding: binds specifically to oestrogen receptors in competition with oestradiol and inhibits oestrogen-induced stimulation of DNA synthesis and cell replication. In cytosols from human breast adenocarcinomas it competes with oestradiol for the receptor protein.
• Antitumour effect: in breast cancer this is mainly due to the anti-oestrogenic effect. Other mechanisms (changes in oncogene expression and growth factor secretion, induction of apoptosis, effects on cell-cycle kinetics) may also contribute, and in some experimental cancers or at high doses antitumour effects that do not depend on oestrogen have been seen.
• Lipids: in postmenopausal breast cancer patients, treatment is associated with modest reductions in total serum cholesterol and low-density lipoprotein (LDL).
• Main metabolite: N-demethyltoremifene has similar anti-oestrogenic activity but weaker antitumour activity than the parent compound.
• Cardiac electrophysiology: toremifene prolongs the QTc interval in a dose-related manner (see Special Instructions).

Pharmacokinetics

• Absorption: readily absorbed after oral dosing; peak serum concentrations are reached within about 3 hours (range 2–5). Food does not change the extent of absorption but may delay the peak by 1.5–2 hours, which is not clinically significant.
• Distribution: the serum concentration curve is biexponential, with a distribution half-life of about 4 hours (range 2–12) and an elimination half-life of about 5 days (range 2–10). Toremifene is more than 99.5% bound to serum proteins, mainly albumin. Kinetics are linear at daily oral doses of 11–680 mg, and the mean steady-state concentration at 60 mg daily is 0.9 µg/mL (range 0.6–1.3). Because elimination is slow, steady state is reached after 4 to 6 weeks.
• Metabolism: extensive, mainly by N-demethylation mediated by CYP3A. The main serum metabolite, N-demethyltoremifene, has a mean half-life of 11 days (range 4–20), reaches steady-state concentrations about twice those of the parent compound and is more than 99.9% protein-bound. Three minor metabolites are present at concentrations too low to matter.
• Elimination: mainly as metabolites in the faeces, with enterohepatic circulation expected; about 10% of the dose is excreted in the urine as metabolites.
• Special populations: in impaired renal function the kinetics were not significantly altered. Elimination of toremifene and its metabolites was decreased in impaired liver function and increased in patients with activated liver function (patients treated with antiepileptics). No information is available on polymorphic metabolism, and at 60 mg daily clinical antitumour efficacy shows no positive correlation with serum concentrations.

• Metastatic breast cancer: first-line hormone treatment of hormone-dependent metastatic breast cancer in postmenopausal patients.
• Toremifene is not recommended for patients with oestrogen receptor-negative tumours.

• Hypersensitivity to toremifene or to any of the excipients.
• Pre-existing endometrial hyperplasia and severe hepatic failure (contraindications in long-term use).
• Congenital or documented acquired QT prolongation.
• Electrolyte disturbances, particularly uncorrected hypokalaemia.
• Clinically relevant bradycardia.
• Clinically relevant heart failure with reduced left-ventricular ejection fraction.
• A previous history of symptomatic arrhythmias.
• Concurrent use with other medicines that prolong the QT interval (see Drug Interactions).

The most frequent side effects are hot flushes, sweating, uterine bleeding, leucorrhoea, fatigue, nausea, rash, itching, dizziness and depression. They are usually mild and mostly due to the hormonal action of toremifene.

Very common (≥1/10): hot flushes, sweating.

Common (≥1/100 to <1/10): depression, dizziness, nausea, vomiting, rash, itching, uterine bleeding, leucorrhoea, fatigue, oedema.

Uncommon (≥1/1,000 to <1/100): loss of appetite, insomnia, headache, thromboembolic events (deep vein thrombosis, thrombophlebitis, pulmonary embolism), dyspnoea, constipation, endometrial hypertrophy, weight increase.

Rare (≥1/10,000 to <1/1,000): vertigo, increased transaminases, endometrial polyps.

Very rare (<1/10,000): endometrial cancer, transient corneal opacity, jaundice, alopecia, endometrial hyperplasia.

Not known: thrombocytopenia, anaemia, leukopenia, hypertriglyceridaemia, hepatitis, hepatic steatosis.

Important serious effects are dose-related QT prolongation; endometrial changes (hypertrophy, hyperplasia, polyps and cancer) caused by the partial oestrogenic effect; liver injury; thromboembolic events; and hypercalcaemia at the start of treatment in patients with bone metastases.

Toremifene is metabolised mainly by CYP3A, and its most important interactions concern QT prolongation.

• Medicines that prolong the QT interval (contraindicated): an additive effect on QT prolongation cannot be excluded, with an increased risk of ventricular arrhythmias including torsade de pointes. Co-administration is contraindicated with class IA antiarrhythmics (quinidine, hydroquinidine, disopyramide), class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide), neuroleptics (phenothiazines, pimozide, sertindole, haloperidol, sultopride), certain antimicrobials (moxifloxacin, intravenous erythromycin, pentamidine, antimalarials particularly halofantrine), certain antihistamines (terfenadine, astemizole, mizolastine) and others (cisapride, intravenous vincamine, bepridil, diphemanil).
• Thiazide diuretics: medicines that decrease renal calcium excretion, such as thiazide diuretics, may increase the risk of hypercalcaemia.
• Enzyme inducers (phenobarbital, phenytoin, carbamazepine): can speed up toremifene metabolism and lower its steady-state serum concentration. Doubling of the daily dose may be necessary.
• Warfarin-type anticoagulants: anti-oestrogens interact with warfarin-type anticoagulants, seriously increasing bleeding time. Concomitant use should be avoided.
• CYP3A inhibitors: metabolism may in theory be inhibited by antifungal imidazoles (ketoconazole), other antifungals (itraconazole, voriconazole, posaconazole), protease inhibitors (ritonavir, nelfinavir) and macrolides (clarithromycin, erythromycin, telithromycin). Concomitant use should be carefully considered.
• Grapefruit: avoid grapefruit products, which inhibit CYP3A4 and may raise toremifene levels. Toremifene can be taken with or without food.

Toremifene is given by mouth and can be taken with or without food.

Recommended Dose

• 60 mg once daily.

Special Populations

• Renal impairment: no dose adjustment is needed.
• Hepatic impairment: use cautiously (see Pharmacokinetics).
• Children and adolescents: there is no relevant use of toremifene in the paediatric population.

QT Prolongation and Cardiac Safety

• Toremifene has been shown to prolong the QTc interval on the electrocardiogram in some patients in a dose-related manner. For the cardiac conditions in which it is contraindicated, see Contraindications. It must not be used together with other medicines that prolong the QT interval.
• In a five-arm parallel QT study (placebo, moxifloxacin 400 mg, and toremifene 20 mg, 80 mg and 300 mg) in 250 male patients, the 80 mg group showed mean QTc prolongations of 21–26 ms. The effect in the 20 mg group was also significant by ICH guidelines, with an upper confidence limit of 10–12 ms, which strongly suggests a dose-dependent effect.
• Women tend to have a longer baseline QTc interval than men and may be more sensitive to QT-prolonging medicines. Elderly patients may also be more susceptible.
• Use with caution in patients with ongoing proarrhythmic conditions (especially elderly patients), such as acute myocardial ischaemia or QT prolongation, because of an increased risk of ventricular arrhythmias (including torsade de pointes) and cardiac arrest.
• If signs or symptoms that may be associated with cardiac arrhythmia occur during treatment, treatment should be stopped and an ECG performed. If the QTc interval is above 500 ms, toremifene should not be used.
• Patients with non-compensated cardiac insufficiency or severe angina pectoris should be closely monitored. No systematic data are available from patients with cardiac failure.

Endometrial Effects

• A gynaecological examination should be performed before treatment, looking closely for pre-existing endometrial abnormality, and repeated at least once a year.
• Patients with additional risk of endometrial cancer, for example those with hypertension or diabetes, a body mass index above 30 or a history of hormone replacement therapy, should be closely monitored.

Blood Counts and Liver Function

• Anaemia, leukopenia and thrombocytopenia have been reported. Red blood cell, leukocyte and platelet counts should be monitored.
• Liver injury has been reported, including liver enzyme elevation above 10 times the upper limit of normal, hepatitis and jaundice. Most cases occurred during the first months of treatment, and the pattern of damage was predominantly hepatocellular.

Thromboembolic Disease

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

Hypercalcaemia

Hypercalcaemia may occur at the beginning of treatment in patients with bone metastasis, so these patients should be closely monitored.

Limited Data

No systematic data are available from patients with labile diabetes or from patients with a severely altered performance status.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no adequate data from the use of toremifene in pregnant women. Animal studies have shown reproductive toxicity, and the potential risk for humans is unknown. It should not be used during pregnancy.
• Breastfeeding: in rats, offspring gained less body weight during lactation. It should not be used during lactation.
• Fertility: toremifene is recommended for postmenopausal patients.

Excipients

The tablets contain lactose (28.5 mg per tablet, as monohydrate). Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. Each tablet contains less than 1 mmol (23 mg) sodium, that is to say it is essentially ‘sodium-free’.

Effect on Driving

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

Fareston tablets do not require any special storage conditions. They are supplied in green PVC and aluminium foil blister packs in a cardboard box, in packs of 30 or 100 tablets; not all pack sizes may be marketed.

3 years.

Prescription only (Rx): a medicinal product subject to medical prescription. Toremifene is a daily tablet taken at home, so it is supplied to the patient or to the treating clinic on prescription.