4.1. Therapeutic indications

Senshio is indicated for the treatment of moderate to severe symptomatic vulvar and vaginal atrophy (VVA) in post-menopausal women.

4.2. Posology and method of administration

Posology

The recommended dose is one 60 mg tablet once daily with food taken at the same time each day.

If a dose is missed it should be taken with food as soon as the patient remembers. A double dose should not be taken in the same day.

Elderly

No dose adjustment is necessary in patients above the age of 65 years (see section 5.2).

Renal impairment

No dose adjustment is necessary for patients with mild, moderate or severe renal impairment (see section 5.2).

Hepatic impairment

No dose adjustment is necessary for patients with mild to moderate hepatic impairment. Ospemifene has not been studied in patients with severe hepatic impairment, therefore Senshio is not recommended for use in such patients (see section 5.2).

Paediatric population

There is no relevant use of ospemifene in the paediatric population for the indication of the treatment of moderate to severe symptomatic VVA in post-menopausal women.

Method of administration

Oral use.

One tablet should be swallowed whole once daily with food and should be taken at the same time each day.

4.3. Contraindications

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

- Active or past history of venous thromboembolic events (VTEs), including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis.

- Unexplained vaginal bleeding.

- Patients with suspected breast cancer or patients undergoing active treatment (including adjuvant therapy) for breast cancer (see section 4.4).

- Suspected or active sex-hormone dependent malignancy (e.g. endometrial cancer).

- Patients with signs or symptoms of endometrial hyperplasia; safety in this patient group has not been studied.

4.4. Special warnings and precautions for use

For the treatment of vulvar and vaginal atrophy, ospemifene should only be initiated for symptoms that adversely affect quality of life e.g. dyspareunia and vaginal dryness. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually taking into consideration other menopausal symptoms, effects on uterine and breast tissues, thromboembolic and cerebrovascular risks. Ospemifene should only be continued as long as the benefit outweighs the risk.

Endometrial findings

In clinical studies, a mean increase of 0.8 mm in endometrial thickness after 12 months (as assessed by protocol-specified ultrasonography) was observed and there was no increase in vaginal bleeding or spotting in the ospemifene-treated group compared to the placebo-treated group. If bleeding or spotting occurs on therapy, or continues after treatment has been discontinued, this should always be investigated, which may include an endometrial biopsy to exclude endometrial malignancy. The incidence of endometrial hyperplasia was 0.3% (1 case out of 317 biopsies) after 1 year of treatment with an upper 95% confidence limit of 1.74% (see section 5.1). In post-menopausal women who received ospemifene treatment up to 1 year, benign endometrial polyps were reported in 0.4% compared to 0.2% in women who received placebo treatment.

Venous thromboembolic events (VTEs)

The risk of VTE (deep vein thrombosis and pulmonary embolism) is increased with other selective oestrogen receptor modulators (SERMs). The risk of VTE associated with ospemifene cannot be excluded. Generally recognised risk factors for VTE include advanced age, a family history, severe obesity (BMI>30 kg/m2) and systemic lupus erythematosus (SLE). The risk of VTE is temporarily increased with prolonged immobilisation, major trauma or major surgery. Ospemifene should be discontinued at least 4 to 6 weeks prior to and during prolonged immobilisation (e.g., post-surgical recovery, prolonged bed rest). Treatment should be resumed only after the patient is mobilised.

If VTE develops after initiating therapy, the treatment should be discontinued. Patients should be advised to contact their doctors immediately when they experience a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

Cerebro-vascular events

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 post-menopausal women with a history of stroke or other significant stroke risk factors.

Pre-existing gynaecological pathology other than signs of vaginal atrophy

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.

Breast cancer

Ospemifene has not been formally studied in women with a prior history of breast cancer. No data are available on its concomitant use with medicinal products used in the treatment of early or advanced breast cancer. Therefore ospemifene should be used for the treatment of VVA only after the treatment of breast cancer, including adjuvant therapy, has been completed.

Hot flushes

Ospemifene may increase the incidence of hot flushes and is not effective in reducing hot flushes associated with oestrogen deficiency. In some asymptomatic patients, hot flushes may occur upon beginning therapy. About 1% of subjects discontinued in the phase 2/3 clinical programme due to hot flushes.

Co-administration with fluconazole

Caution is recommended when co-administering ospemifene with fluconazole (see section 4.5). If necessary, because of impaired tolerance, ospemifene should be stopped as long as treatment with fluconazole lasts.

Lactose content

Senshio contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium content

Senshio contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on ospemifene

Fluconazole, a moderate CYP3A / moderate CYP2C9 / strong CYP2C19 inhibitor, increased the area under the curve (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.

Ketoconazole, a strong CYP3A4 inhibitor and moderate P-glycoprotein inhibitor, increased the AUC of ospemifene by 1.4-fold. This increase is not considered to be clinically significant given the inherent pharmacokinetic variability of ospemifene. There is therefore no reason to expect that strong CYP3A4 inhibitors would cause a clinically meaningful change in ospemifene exposure. Co-administration of ospemifene with strong/moderate CYP3A4 inhibitors should be avoided in patients who are known or suspected to be CYP2C9 poor metabolizers based on genotyping or previous history/experience with other CYP2C9 substrates.

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.

Inhibition of UGT1A3, UGT2B7, UGT1A1, or UGT1A8 may potentially affect the glucuronidation of ospemifene and/or 4-hydroxyospemifene.

In healthy subjects, the absorption of ospemifene is not affected by co-administration of oral omeprazole, a medicinal product that increases gastric pH.

Effects of ospemifene on other medicinal products

Interaction studies were performed with probe substrates for CYP2C9 (warfarin), CYP3A4 (midazolam), CYP2C19, and CYP3A4 (omeprazole) and CYP2B6 (bupropion). Ospemifene did not cause a clinically meaningful change in the exposure to the substrates, indicating that ospemifene does not affect those enzyme activities in vivo to a clinically significant extent.

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.

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.

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.

4.6. Fertility, pregnancy and lactation

Pregnancy

Senshio is only for use in post-menopausal 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 from the use of ospemifene in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk in humans is unknown.

Breast-feeding

Senshio should not be used during breast-feeding.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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

Tabulated list of adverse reactions

Averse 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).

Table 1 Adverse reactions

MedDRA system organ class

Common

Uncommon

Infections and infestations

Vulvovaginal candidiasis / mycotic infections

-

Immune system disorders

-

Drug hypersensitivityb,

Hypersensitivityb,

Swollen tongue

Nervous system disorders

Headachec

Vascular disorders

Hot flushd

-

Skin and subcutaneous tissue disorders

Rash (includes rash erythematous, rash generalised)

Pruritus

Urticaria

Musculoskeletal and connective tissue disorders

Muscle spasms

-

Reproductive system and breast disorders

Vaginal discharge, Genital discharge, Vaginal haemorrhage

Endometrial hypertrophya (sonographic endometrial thickness)

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 2/3 clinical trials, where the frequency was comparable between 60 mg ospemifene (5.4%) and placebo (5.9%) groups.

d Hot flushes including hyperhidrosis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme, website: https://yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Ospemifene has been administered to subjects in single doses for up to 800 mg day and repeat doses up to 240 mg/day for 7 days and up to 200 mg/day for 12 weeks. There is no specific antidote for ospemifene. In the event of overdose, general supportive measures should be initiated based on the patient's signs and symptoms.