Toremifene Other names: Toremifene citrate

Theoretically the metabolism of toremifene is inhibited by drugs known to inhibit the CYP3A enzyme system which is reported to be responsible for its main metabolic pathways. Examples of such drugs are 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 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.

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

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

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.

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.

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

There are no adequate data from the use of toremifene in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.

Toremifene should not be used during pregnancy.

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

Toremifene should not be used during lactation.

Fertility

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 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).

Neoplasms beningn, malignant and unspecified (including cysts and polyps)

Very rare: endometrial cancer

Blood and lymphatic system disorders

Not known: thrombocytopenia, anaemia and leukopenia

Metabolism and nutrition disorders

Uncommon: loss of appetite

Psychiatric disorders

Common: depression

Uncommon: insomnia

Nervous system disorders

Common: dizziness

Uncommon: headache

Eye disorders

Very rare: transient corneal opacity

Ear and labyrinth disorders

Rare: vertigo

Vascular disorders

Very common: hot flushes

Uncommon: thromboembolic events

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnoea

Gastrointestinal disorders

Common: nausea, vomiting

Uncommon: constipation

Hepatobiliary disorders

Rare: increase of transaminases

Very rare: jaundice

Not known: hepatitis, hepatic steatosis

Skin and subcutaneous tissue disorders

Very common: sweating

Common: rash, itching

Very rare: alopecia

Reproductive system and breast disorders

Common: uterine bleeding leukorrhea

Uncommon: endometrial hypertrophy

Rare: endometrial polyps

Very rare: endometrial hyperplasia

General disorders and administration site conditions

Common: fatigue, oedema

Uncommon: weight increase

Thromboembolic events include deep venous thrombosis, thrombophlebitis and pulmonary embolism.

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. Toremifene increases the QT interval in a dose-related manner.