Key points from the evidence

The content of this evidence summary was up-to-date in December 2016. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

In a randomised controlled trial (RCT; n=332), at week 12, conjugated oestrogens and bazedoxifene 0.45 mg/20 mg statistically significantly reduced the average daily number of moderate and severe hot flushes from baseline compared with placebo. In another RCT (n=664) in women with vulvar or vaginal atrophy, at week 12, there were statistically significant improvements compared with placebo in some but not all primary outcomes in the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group. Statistically significant improvements in certain elements of quality of life compared with placebo were seen in both RCTs. However, no active comparator was included, making it difficult to establish the effectiveness of conjugated oestrogens and bazedoxifene 0.45 mg/20 mg compared with existing treatments. Because of the small number of women exposed and short duration of exposure, the available safety data do not allow for assessment of whether the incidence of rare but important adverse events including cardiovascular or cerebrovascular events, venous thromboembolism or cancer (including breast or ovarian cancer) are increased in women taking conjugated oestrogens and bazedoxifene compared with placebo, or other treatments.

Regulatory status: conjugated oestrogens and bazedoxifene modified release tablets (Duavive, Merck Sharp and Dohme limited) were launched in the UK in July 2016. They are licensed for treatment of oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate.

Effectiveness

  • Conjugated oestrogens and bazedoxifene 0.45 mg/20 mg statistically significantly reduced the average daily number of moderate and severe hot flushes from a baseline of 10.3 to 2.8 at week 12. In the placebo group, hot flushes were reduced from 10.5 hot flushes at baseline to 5.4 at week 12. The difference between the groups was statistically significant (p<0.001) (1 RCT, n=332).

  • In women with vulvar or vaginal atrophy, at week 12, there was a statistically significantly greater increase in vaginal superficial cells, and decrease in parabasal cells from baseline in women in the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group compared with women in the placebo group. Decreases in vaginal pH and changes in the severity of the most bothersome vulvar or vaginal symptom were not statistically significantly different between the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group and the placebo group (1 RCT, n=664).

  • Statistically significant improvements in total score and some domains of the menopause-specific quality of life questionnaire (secondary endpoints) were seen in both trials in the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group compared with the placebo group.

Safety

  • In the 3 RCTs discussed in this evidence summary, common treatment-emergent adverse events in the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group included headache (13.3%−18.7%), pain (7.9%−11.4%), and back pain (9.6%−9.7%).

  • In an RCT (n=1,886), at 12 months there was 1 case (0.3%) of endometrial hyperplasia in the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group, 1 case (0.28%) in the placebo group and no cases in the conjugated oestrogens and medroxyprogesterone acetate group.

  • In an RCT (n=1,886), cumulative amenorrhoea rates were reported to be high and similar to placebo in the bazedoxifene and conjugated oestrogens group.

  • The European Public Assessment Report (EPAR) for conjugated oestrogens and bazedoxifene states that because the number of women exposed, lack of data in older women, and duration of treatment, the available safety data do not allow for assessment of whether the incidence of rare but important adverse events (such as cardiovascular or cerebrovascular events, venous thromboembolism or cancer) is increased in women taking conjugated oestrogens and bazedoxifene compared with placebo, or historical data for conjugated oestrogens and medroxyprogesterone.

Patient factors

  • Conjugated oestrogens and bazedoxifene 0.45 mg/20 mg are available as a modified release tablet which is taken once daily.

Resource implications

  • Conjugated oestrogens and bazedoxifene 0.45 mg/20 mg modified release tablets cost £15.00 for a pack of 28 tablets excluding VAT (MIMS, December 2016).

Introduction and current guidance

Menopause is a biological stage in a woman's life when she enters the end of her reproductive phase and is marked by the cessation of menstruation. A woman is defined as postmenopausal from 1 year after her last period. The changes associated with menopause and the perimenopause (the years leading up to the menopause) occur when ovarian function diminishes and ceases. This includes the cessation of both egg (oocyte) maturation and sex hormone (principally oestrogen and progesterone) secretion (NICE full guideline on menopause: diagnosis and management).

Many women experience a range of symptoms during the menopause and perimenopause and these symptoms are often short lived and lessen or disappear over time. The most common include vasomotor symptoms (for example hot flushes and sweats), effects on mood (for example low mood) and urogenital symptoms (for example vaginal dryness) (NICE full guideline on menopause: diagnosis and management).

NICE recommends that an individualised approach at all stages of diagnosis, investigation and management of menopause is adopted, and that people should have the right to be involved in discussions and make informed decisions about their care. NICE recommends that menopausal women are given information about hormonal, non-hormonal and non-pharmaceutical treatments for menopausal symptoms (NICE guideline on menopause: diagnosis and monitoring).

Full text of introduction and current guidance.

Product overview

Bazedoxifene is a selective oestrogen receptor modulator. The addition of bazedoxifene, acting as an oestrogen receptor antagonist in the uterus, reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women (conjugated oestrogens and bazedoxifene summary of product characteristics).

Conjugated oestrogens and bazedoxifene modified release tablets (Duavive, Merck Sharp and Dohme limited) are licensed for treating oestrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate.

The experience of treating women older than 65 years is limited (conjugated oestrogens and bazedoxifene summary of product characteristics).

Conjugated oestrogens and bazedoxifene are available as a modified release tablet containing 0.45 mg of conjugated oestrogens and bazedoxifene acetate equivalent to 20 mg bazedoxifene. The recommended dose is 1 tablet taken once per day.

For the treatment of postmenopausal symptoms, conjugated oestrogens and bazedoxifene should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually, and treatment should only be continued as long as the benefit outweighs the risk (conjugated oestrogens and bazedoxifene summary of product characteristics).

Conjugated oestrogens and bazedoxifene 0.45 mg/20 mg modified release tablets cost £15.00 for a pack of 28 tablets excluding VAT (MIMS, December 2016).

Full text of product overview.

Evidence review

  • The effect of conjugated oestrogens and bazedoxifene on vasomotor symptoms was investigated in the SMART 2 trial (Pinkerton et al. 2009 and Utian et al. 2009). This was a 12-week, phase III, randomised, placebo-controlled, double-blind RCT in 332 postmenopausal women with an intact uterus (mean age of 53 years) who were experiencing moderate to severe hot flushes. It found that conjugated oestrogens and bazedoxifene 0.45 mg/20 mg reduced the average daily number of moderate and severe hot flushes by 7.5, from 10.3 at baseline to 2.8 at week 12. In the placebo group, moderate and severe hot flushes were reduced by 5.1, from 10.5 at baseline to 5.4 at week 12. The difference between the groups was statistically significant (p<0.001). The mean daily severity score of hot flushes (calculated by adding the number of mild, moderate and severe hot flushes multiplied by 1, 2 or 3 respectively, and dividing by the total number of hot flushes for that day) reduced from 2.30 at baseline in both groups, to 1.09 in the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group and to 2.04 in the placebo group. The difference between the groups was statistically significant (p<0.001). Other primary outcomes included change from baseline in average daily number of moderate and severe hot flushes and mean daily severity of hot flushes at week 4. The difference between the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg and the placebo group was statistically significant for both of these outcomes (p<0.001).

  • The effect of conjugated oestrogens and bazedoxifene on vulvar or vaginal atrophy was investigated in the SMART 3 trial (Kagan et al. 2010 and Bachman et al. 2010). This was a 12-week, phase III, randomised, placebo-controlled, double-blind RCT in 664 postmenopausal women with an intact uterus (mean age 56 years) who were experiencing vulvar or vaginal atrophy. At week 12, women in the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group had statistically significantly greater increases in vaginal superficial cells, and decreases in parabasal cells (surrogate markers suggesting an improvement in the condition) from baseline compared with women in the placebo group. However the decrease in vaginal pH and change in the severity of the most bothersome vulvar or vaginal symptom was not statistically significantly different between the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group and the placebo group.

  • Quality of life and treatment satisfaction were investigated as secondary outcomes in the SMART 2 and 3 trials. In both trials, women in the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group had statistically significantly greater improvements at week 12 in vasomotor function score and total score measured using the menopause-specific quality of life questionnaire (MENQOL; a self-administered questionnaire with scores from 1 to 8 for each of 4 domains: vasomotor, psychosocial, physical and sexual. Scores are averaged across the 4 domains with higher scores indicating more bothersome symptoms) compared with the placebo group. In the SMART 3 trial, statistically significant improvements in sexual function were also seen. There was no statistically significant difference between the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg and placebo groups for the physical or psychosocial function domains of the MENQOL for either trial. In both trials, women in the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group reported statistically significantly greater overall satisfaction with treatment on the menopause symptoms-treatment satisfaction questionnaire (MS-TSQ; an 8-item questionnaire which assesses women's satisfaction with treatment for symptoms associated with menopause) compared with women in the placebo group.

  • Sleep was measured as a secondary outcome in the SMART 2 trial. Women in the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group had statistically significantly greater improvements compared with the placebo group in time to fall asleep, sleep adequacy, sleep disturbance, and sleep problem indices I and II (a measure of overall sleep problems) but not for other domains on the medical outcomes study (MOS) sleep scale (a self-administered questionnaire with scores for 7 sleep domains and 2 measures of sleep quantity). The SMART 5 trial (Pinkerton et al. 2014a and Pinkerton et al. 2014b) was a 1-year, phase III, randomised, placebo and active-controlled, double-blind RCT (n=1,886) with safety (incidence of endometrial hyperplasia at 12 months) as a primary outcome. The trial included a sleep substudy which enrolled 459 women from the trial with bothersome hot flushes or night sweats, and certain sleep difficulties. The study found that after 3 months of treatment there was no statistically significant difference between the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group and the placebo group in the sleep disturbance subscale of the MOS sleep scale (primary outcome).

  • In the SMART 2 trial, the most common adverse events experienced by women in the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group were headache (15.7%), infection (7.9%), pain (7.9%) and arthralgia (7.9%). There was no statistically significant difference between the combined conjugated oestrogens and bazedoxifene groups and placebo group in the proportion of women who experienced any treatment-emergent adverse event (p=0.215).

  • In the SMART 3 trial, the most common adverse events experienced by women in the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group were headache (18.7%), pain (11.4%) and back pain (9.6%). There was no statistically significant difference between the combined conjugated oestrogens and bazedoxifene group and placebo group in the proportion of women who experienced any treatment-emergent adverse event (p=0.16). There was a statistically significantly higher incidence of vaginitis in the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group compared with placebo (1.8% compared with 1%, p<0.05).

  • In the SMART 5 trial, at 12 months there was 1 case (0.3%) of endometrial hyperplasia in the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group, 1 case (0.28%) in the placebo group and no cases in the conjugated oestrogens and medroxyprogesterone acetate group. Cumulative amenorrhoea rates were reported to be high and similar to placebo in the bazedoxifene and conjugated oestrogens group. In the conjugated oestrogens and medroxyprogesterone acetate group, cumulative amenorrhoea rates were statistically significantly lower compared with other groups at all time points (p<0.001). There was no difference between the treatment groups in the proportion of women who experienced any treatment-emergent adverse event. However more women in the conjugated oestrogens and medroxyprogesterone group (14.1%) discontinued treatment because of adverse events compared with the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg (7.6%) and placebo (7.0%) groups. The most common adverse events experienced by women in the conjugated oestrogens and bazedoxifene 0.45 mg/20 mg group were nasopharyngitis (18.0%), headache (13.3%), back pain (9.7%) and pain in extremity (8.1%).

  • Oestrogen therapy can increase the risk of endometrial hyperplasia and carcinoma, breast cancer, ovarian cancer, venous thromboembolism, and ischaemic stroke. For more information on this and cautions and contraindications see the summary of product characteristics for conjugated oestrogens and bazedoxifene modified release tablets.

  • The RCTs discussed in this evidence summary were all double-blind trials, enrolling between 332 and 1,886 women. The SMART 2 trial found that at week 12, conjugated oestrogens and bazedoxifene 0.45 mg/20 mg statistically significantly reduced the average daily number of moderate and severe hot flushes from baseline compared with placebo. However no active control group was included in this study. This makes it difficult to determine how conjugated oestrogens and bazedoxifene compare to established treatments for vasomotor symptoms such as conjugated oestrogens and progestogen. The SMART 3 trial investigated the effect of conjugated oestrogens and bazedoxifene 0.45 mg/20 mg on vulvar or vaginal atrophy. First-line recommended treatment for urogenital atrophy is vaginal (rather than oral) oestrogen. In the SMART 5 trial, 4 women who had an endometrial thickness of at least 4 mm did not have an endometrial biopsy and 8 did not have a biopsy or transvaginal ultrasound carried out meaning endometrial hyperplasia could not be determined. The European Medicines Agency (EMA) highlight that even a very low number of additional cases of hyperplasia would change the outcome of the study (EPAR for conjugated oestrogens and bazedoxifene). The EPAR for conjugated oestrogens and bazedoxifene states that because the number of women exposed, lack of data in older women, and duration of treatment, the available safety data do not allow for assessment of whether the incidence of rare but important adverse events such as cardiovascular or cerebrovascular events, venous thromboembolism or cancer (including breast or ovarian cancer) is increased in women taking conjugated oestrogens and bazedoxifene compared with placebo, or historical data for conjugated oestrogens and medroxyprogesterone.

Full text of evidence review.

Context

The NICE guideline on menopause: diagnosis and monitoring recommends that women should be offered HRT for vasomotor symptoms of the menopause after discussing with them the short-term (up to 5 years) and longer-term benefits and risks. For women with a uterus, the choice of preparation should be an oestrogen and progestogen.

For women with an intact uterus, unscheduled vaginal bleeding is a common adverse effect of HRT within the first 3 months of treatment. The NICE guideline on menopause recommends that bleeding should be reported at the 3-month review appointment, or promptly if it occurs after the first 3 months. The NICE clinical knowledge summary on menopause recommends that unexplained bleeding should always be investigated before changing treatment, to exclude serious gynaecological pathology, such as endometrial cancer. If serious gynaecological pathology has been excluded, altering the progestogen part of the regimen may improve bleeding problems.

Progestogen-related adverse effects other than bleeding can also occur. The NICE clinical knowledge summary on menopause recommends that women who experience progestogen-related adverse effects other than bleeding should be encouraged to persist with treatment for 3 months as adverse effects may resolve. For persistent or troublesome symptoms altering the progestogen part of the regimen can also be tried. Changing to continuous combined therapy or tibolone often reduces non-bleeding progestogenic adverse effects with established use. However, this option is only suitable for postmenopausal women.

Conjugated oestrogens and bazedoxifene 0.45 mg/20 mg modified release tablets may offer an alternative treatment option for women with an intact uterus for whom treatment with a progestin-containing treatment is not suitable.

Full text of context.

Estimated impact for the NHS

Conjugated oestrogens and bazedoxifene 0.45 mg/20 mg modified release tablets have been shown in an RCT to reduce the average daily number of moderate and severe hot flushes in the short term. However comparisons were against placebo and so it is not possible to determine from the available evidence the effectiveness of conjugated oestrogens and bazedoxifene compared with other treatments for vasomotor symptoms such as progestogen-based HRT. Although in another RCT conjugated oestrogens and bazedoxifene 0.45 mg/20 mg had some beneficial effects on vulvar or vaginal atrophy compared with the placebo, first-line recommended treatment for urogenital atrophy is vaginal (rather than oral) oestrogen.

The limited number of women exposed, lack of data in older women, and limited duration of treatment, means that the available safety data do not allow for assessment of whether the incidence of rare but important adverse events such as cardiovascular or cerebrovascular events, venous thromboembolism or cancer (including breast or ovarian cancer) is increased in women taking conjugated oestrogens and bazedoxifene compared with placebo, or historical data for conjugated oestrogens and medroxyprogesterone.

Conjugated oestrogens and bazedoxifene modified release tablets may present an alternative treatment option for oestrogen deficiency symptoms in postmenopausal women for whom treatment with a progestin-containing therapy is not suitable. However, local decision makers will need to take safety (in particular the limited data on rare adverse events), efficacy, patient factors and cost into account when considering the likely place in therapy of conjugated oestrogens and bazedoxifene modified release tablets.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.