Ospemifene

Ospemifene and its major metabolite, 4-hydroxyospemifene, inhibited organic cation transporter (OCT)1 in vitro at clinically relevant concentrations. Therefore, ospemifene may increase concentrations of medicinal products which are substrates of OCT1 (e.g. metformin, acyclovir, ganciclovir and oxaliplatin).

In vitro, ospemifene and 4-hydroxyospemifene inhibited glucuronidation mainly via UGT1A3 and UGT1A9 at clinically relevant concentrations. The pharmacokinetics of medicinal products that are mainly metabolised by UGT1A3 and UGT1A9 could be affected when administered concomitantly with ospemifene and co-administration should be made with caution.

Rifampicin, a strong CYP3A/CYP2C9 enzyme inducer, decreased the AUC of ospemifene by 58%. Therefore, co-administration of ospemifene with strong enzyme inducers like carbamazepine, phenytoin, St John’s wort and rifabutin would be expected to decrease the exposure of ospemifene, which may decrease the clinical effect.

Ospemifene has not been studied in patients with severe hepatic impairment, therefore it is not recommended for use in such patients.

The safety of using ospemifene concomitantly with oestrogens or other SERMS, such as tamoxifen, toremifene, bazedoxifene and raloxifene, has not been studied and its concurrent use is not recommended.

Caution is recommended when co-administering ospemifene with fluconazole. If necessary, because of impaired tolerance, ospemifene should be stopped as long as treatment with fluconazole lasts.

Fluconazole, a moderate CYP3A/moderate CYP2C9/strong CYP2C19 inhibitor, increased the AUC of ospemifene by 2.7-fold. These results suggest that co-administration of ospemifene with any medicinal product that inhibits both CYP3A4 and CYP2C9 activity (e.g. fluconazole) would be expected to increase the exposure of ospemifene in a similar way. Therefore, caution is recommended when co-administering ospemifene with fluconazole. In case of impaired tolerance of ospemifene, the latter should be stopped as long as treatment with fluconazole lasts.

Due to its lipophilic nature and absorption characteristics, an interaction between ospemifene and medicinal products like orlistat, cannot be ruled out. Therefore, caution is recommended when ospemifene is combined with orlistat. A clinical monitoring of a decrease in the efficacy of ospemifene should be made.

The risk of cerebrovascular events is possibly increased with other SERMs. The risk of cerebrovascular events associated with ospemifene cannot be excluded. This should be considered when prescribing ospemifene for postmenopausal women with a history of stroke or other significant stroke risk factors.

There are limited clinical trial data on the use of ospemifene in patients with other gynaecological conditions. It is recommended that any additional pathology be investigated and treated appropriately before starting ospemifene.

Ospemifene is only for use in postmenopausal women and should not be used in women of child-bearing potential. If pregnancy occurs during treatment with ospemifene, ospemifene should be withdrawn immediately.

There are no data on the use of ospemifene in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk in humans is unknown.

Ospemifene is not indicated during breast-feeding.

Fertility

Ospemifene is not indicated for fertile women.

Ospemifene has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most frequently reported adverse reactions are hot flushes (7.5%).

List of adverse reactions

Adverse reactions are listed below by MedDRA preferred term system organ class and by frequency. Frequencies are defined as 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 available data).

Adverse reactions:

^a Endometrial hypertrophy is a MedDRA dictionary term that represents sonographic endometrial thickness findings.
^b Hypersensitivity reactions including adverse reactions listed under skin and subcutaneous tissue disorders, swollen tongue, pharyngeal oedema and throat tightening were reported.
^c The frequency of headache reported in the table is that calculated from the Phase ⅔ clinical trials, where the frequency was comparable between 60 mg ospemifene (5.4%) and placebo (5.9%) groups.