DTB | Bazedoxifene for HRT?
Bazedoxifene for HRT?
Duavive (Pfizer) is a modified-release formulation of conjugated oestrogens plus bazedoxifene acetate (a selective
oestrogen receptor modulator). It is licensed for treatment of oestrogen deficiency symptoms in postmenopausal women
with a uterus for whom treatment with progestogen-containing therapy is not appropriate.1,2 It was licensed by the
European Medicines Agency (EMA) in 2014 and launched in the UK in July 2016.1,3 Here, we review the evidence on
efficacy and safety of conjugated oestrogens/bazedoxifene and consider its place in the management of symptoms
associated with the menopause.
Background
During the menopause, many women experience a range of symptoms
associated with the loss of oestrogen production, including vasomotor
symptoms (hot flushes and sweats), low mood, symptoms of vulvovaginal
atrophy and loss of sexual desire.4,5 A National Institute of Health and Care
Excellence (NICE) guideline recommends offering women hormone
replacement therapy (HRT) for vasomotor symptoms after discussing with
them the short-term (up to 5 years) and longer-term benefits and risks.4
Although HRT reduces the risk of fragility fractures, the baseline risk of fragility
fractures for women around menopausal age in the UK is low. Other issues
associated with the use of HRT that need to be taken into consideration include:4
• venous thromboembolism (VTE)—there is a higher risk with oral compared
with transdermal HRT products;
• cardiovascular disease—HRT with oestrogen alone is associated with no,
or a reduced risk of coronary heart disease; HRT with oestrogen and
progestogen is associated with little or no increase in the risk of coronary
heart disease;
• stroke—HRT with oral oestrogen is associated with a small increase in the risk
of stroke; the baseline risk of stroke in women aged <60 years is very low;
• breast cancer—HRT with oestrogen alone is associated with little or no
change in the risk of breast cancer; HRT with oestrogen and progestogen
can be associated with an increase in the risk of breast cancer.
Oestrogens are associated with an increased risk of endometrial hyperplasia
and endometrial cancer in women with an intact uterus.6 The addition of a
progestogen (for at least 10 days per 28-day cycle) reduces the additional
risk of endometrial cancer; this additional risk is eliminated if a progestogen
is given continuously.7 However, this should be weighed against the
increased risk of breast cancer. Use of progestogen-containing HRT has been
associated with vaginal bleeding, breast pain or tenderness, and increase in
breast density. 5
Conjugated oestrogens/bazedoxifene
Duavive is a combination of 20mg bazedoxifene, a selective oestrogen
receptor modulator (SERM) and 450µg conjugated oestrogens. The summary
of product characteristics (SPC) describes the combination of a SERM with an
oestrogen as a tissue-selective oestrogen complex.1
SERMs have a range of agonistic and antagonistic effects on oestrogen
receptors in different tissues.6 This group of drugs includes raloxifene, which is
licensed in the UK for the treatment and prevention of osteoporosis in
postmenopausal women.8 Bazedoxifene has selective oestrogen-receptor
agonist activity in skeletal tissue and antagonist activity in breast and uterine
tissues. 5,9 It is licensed in several countries outside the UK for the prevention
or treatment of postmenopausal osteoporosis. 5 It is combined with conjugated
oestrogens to inhibit the adverse effects of oestrogen on the endometrium
and breast tissue without the adverse effects of progestogens.1,5
The combination of conjugated oestrogens and bazedoxifene as a modified
release tablet was licensed by the European Medicines Agency (EMA) in
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2014 for the treatment of oestrogen deficiency symptoms in
postmenopausal women with a uterus who have not had a menstrual
period for at least 12 months and for whom progestogen-containing
therapy is not appropriate. 5 The SPC states that for initiation and
continuation of treatment of postmenopausal symptoms, the lowest
effective dose for the shortest duration should be used.1 The licensed dose
is one tablet taken daily.
Assessing outcomes
EMA guidance on clinical trials of medicinal products for hormone replacement
therapy of oestrogen deficiency symptoms in postmenopausal women
recommends that the proposed primary outcome for efficacy is the frequency
of moderate to severe hot flushes.10 Enrolled subjects should have a defined
minimum number of hot flushes per day at baseline to justify a need for
treatment (at least five moderate to severe hot flushes). Other scales for
assessing menopausal symptoms, if fully validated, can be used as secondary
outcomes (see Box). A 3-month duration of treatment is generally recommended
for evaluation of efficacy.10
Box: Assessing outcomes in menopause trials3,11-13
Menopause-specific Quality of Life questionnaire (MENQOL):
self-administered 29-item scale (range 1–8 in each of four domains
[vasomotor, psychosocial, physical and sexual]); higher scores represent
more troublesome symptoms. Estimated clinically important difference
for the domains ranges from 0.5–1.2.
Menopause Symptoms—Treatment Satisfaction Questionnaire
(MS-TSQ): eight-item questionnaire on a five-point scale.
Medical Outcomes Study (MOS) sleep scale: 12-item self-administered
questionnaire, including assessment of sleep disturbance, sleep
adequacy, somnolence and quantity of sleep.
Arizona Sexual Experiences (ASEX) scale: five-item questionnaire on a
six-point scale (1=hyperfunction, 6=hypofunction)
Clinical efficacy
The majority of evidence for the safety and efficacy of conjugated oestrogens/
bazedoxifene in the treatment of menopausal symptoms comes from a series
of five trials known by the acronym SMART (Selective estrogens, Management
And Response to Therapy). The EMA assessment report for Duavive included
four efficacy and safety studies (a 2-year study [SMART-1], two 12-week efficacy
studies [SMART-2 and 3] and a 12-month safety study [SMART-5]). 3,5 A fifth trial,
SMART-4, used a tablet formulation that was not bioequivalent to the marketed
product and is not reported here.
Most of the trials included conjugated oestrogens/bazedoxifene 450µg/20mg
and 625µg/20mg. The higher strength was removed from the licence
application, along with an indication for osteoporosis in menopausal women. 3
Except where specified, we report results for the conjugated oestrogens/
bazedoxifene 450µg/20mg dose licensed in the UK.
▶

We are not aware of any published studies of direct comparisons with other
combination HRT preparations, although some trials used an active control.
In a randomised placebo-controlled double-blind study in 332 postmenopausal
women aged 40–65 years (mean 53 years) with moderate to severe hot flushes
(SMART-2), the number and severity of hot flushes at 4 and 12 weeks (primary
outcome) was significantly reduced in the conjugated oestrogens/bazedoxifene
group (p<0.001).14 The average number of moderate and severe hot flushes
daily at 12 weeks was reduced by 7.5 (from 10.3 to 2.8) in the conjugated
oestrogens/bazedoxifene group (133 women) and by 5.1 (from 10.5 to 5.4) in
the placebo group (66 women), a difference between the two groups of 2.4
hot flushes (p<0.001). Quality of life and effects on sleep (secondary outcomes)
were reported separately.12 There were statistically significant improvements
in sleep parameters (time to fall asleep, sleep adequacy, sleep disturbance
and sleep problems as assessed by the MOS index) compared with placebo
(p<0.001) and regression analysis showed a significant relationship between
sleep disturbance and reduction in hot flushes (p<0.05). Small but statistically
significant improvements were reported for total MENQOL score compared with
placebo (change from baseline at 12 weeks –1.6 vs. –1.0, p<0.001) and MS-TSQ
(percentage reporting overall satisfaction 73.5% vs. 44.4%, p<0.001).12
A randomised double-blind placebo and active-comparator (bazedoxifene
alone) controlled study in 664 postmenopausal women aged 40–65 years
(mean 56 years) with vulvar or vaginal atrophy (SMART-3) investigated the
effects on vulvovaginal symptoms.15 There was a statistically significant
increase in vaginal superficial cells and a decrease in parabasal cells
(co-primary outcomes) at 12 weeks in the conjugated oestrogens/
bazedoxifene group compared with placebo (p<0.01 and p<0.001, respectively)
and with bazedoxifene 20mg alone (both p<0.001). The authors concluded
that these changes in surrogate markers suggested an improvement in the
condition and were associated with patient-reported improvements in
symptoms. However, decreases in vaginal pH and the severity of vulvar or
vaginal symptoms (co-primary outcomes) were not significantly different
between conjugated oestrogens/bazedoxifene and placebo groups. The
difference in total ASEX score (secondary outcome) with conjugated
oestrogens/bazedoxifene compared with placebo was not statistically
significant (–1.87 vs. –1.34).13 Statistically significant improvements with
conjugated oestrogens/bazedoxifene compared with placebo and
bazedoxifene alone were reported for change in total MENQOL score (–1.09 vs.
–0.67 and -0.37, respectively, both p≤0.001) and MS-TSQ (overall satisfaction
62.6% vs. 47.4%; p<0.05 and 62.6% vs. 40.4%, p<0.001, respectively).
While the fourth study (SMART-5) was primarily concerned with safety,
the effect on bone density was evaluated in a subgroup of 590
postmenopausal women aged 40–65 years without history of
osteoporosis.9 At 12 months, bone mineral density increased slightly from
baseline in the conjugated oestrogens/bazedoxifene group compared
with the placebo group in whom bone density decreased (adjusted mean
change from baseline 0.24% [±0.29] vs. -1.28% [±0.28], p<0.01). Effects on
sleep and quality of life were evaluated in a subgroup of 459 women
reporting sleep disturbances related to vasomotor symptoms.16 Beneficial
responses on sleep, assessed by MOS sleep score, were reported with
conjugated oestrogens/bazedoxifene at 12 months compared with
placebo (mean adjusted change from baseline: time to fall asleep –16.2
mins vs. –8.6; sleep disturbance score –17.4 vs. –12.0, both p<0.05). There
was also an improvement in quality of life assessed using the total
MENQOL score (mean adjusted change –1.4 vs. placebo –0.9, p<0.001).
Unwanted effects
The commonest unwanted events in clinical trials included headache
(13.3–18.7%), pain (7.9–11.4%) and back pain (9.6–9.7%). 3,17 Other adverse
effects categorised as common (≥1/100 to <1/10) included vulvovaginal
candidiasis, constipation, nausea, diarrhoea, muscle spasms and increased
blood triglyceride concentrations.1 Venous thromboembolic events were rare
(≥1/10,000 to <1/1,000).
A randomised double-blind dose-ranging study (SMART-1) evaluated six
combinations of conjugated oestrogens 450µg or 625µg plus bazedoxifene
10mg, 20mg or 40mg compared with active (raloxifene) and placebo
controls in 3,397 postmenopausal women (40–75 years, mean 56.5 years)
over 2 years.18 The primary outcome was the incidence of endometrial
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DTB | Bazedoxifene for HRT?
hyperplasia. However, the EMA reported concerns over certain aspects of
the study (including missing source data and the handling of biopsy
specimens and reports from pathologists), and the results on endometrial
safety were not taken into account in the evaluation for the European
licensing application. 5
A randomised, double-blind placebo- and active-controlled 1-year safety
study in 1,886 women (SMART-5) reported endometrial hyperplasia in
one of 335 women receiving conjugated oestrogens/bazedoxifene
450µg/20mg, one of 354 women in the placebo group (both 0.3%), and
none in the conjugated oestrogens/medroxyprogesterone group (n=149) at
12 months.9 The EMA noted that four women who had an endometrial
thickness of at least 4mm did not have an endometrial biopsy and a further
eight did not have either a biopsy or transvaginal ultrasound carried out.
The amount of missing data was not considered unusual for a study of this
size, but some members of the EMA’s Committee for Medicinal Products for
Human Use (CHMP) pointed out that even a very low number of additional
cases of hyperplasia would change the outcome of the study from success
to failure. 5
Changes in breast density were assessed by mammography in a subset of 507
women from SMART-1 after 24 months19 and in a subset of 940 women from
SMART-5 after 1 year.20 Treatment with conjugated oestrogens/bazedoxifene
was not associated with increases in breast density.
Cautions
Conjugated oestrogens/bazedoxifene should not be prescribed for women
with undiagnosed genital bleeding, untreated endometrial hyperplasia,
known thrombophilic disorders (e.g. protein C, protein S or antithrombin
deficiency) or with a current or past history of breast or endometrial cancer,
venous or arterial thromboembolic disorders or liver disease.1
The drug should be used with caution in women with uterine fibroids,
endometriosis, hypertension, liver disorders, diabetes mellitus, cholelithiasis,
migraine, epilepsy, asthma or otosclerosis, and in those with a history of
endometrial hyperplasia or with risk factors for thromboembolic disorders
(e.g. SLE, obesity, cancer) or oestrogen-dependent tumours.1
People with a personal or family history of hypertriglyceridaemia should be
monitored during treatment and all patients should have triglyceride levels
monitored once a year.21
Other potential risks identified by the EMA that need further
investigation include use in people with cardiovascular risk factors or a
history of cardiovascular disease, and use in people with a history
of malignancies. 21
Limitations of the evidence
There is limited evidence in women aged over 65 years and a lack of direct
comparisons with established HRT options. Overall, the effects on the
incidence of cardiovascular or cerebrovascular events, VTE or cancer (including
breast and ovarian cancer) compared with placebo or with conjugated
oestrogens/progestogen remains unclear. 5,17
The evidence relating to the efficacy and safety of conjugated oestrogens/
bazedoxifene comes almost entirely from a single series of trials and the
reproducibility of these results must be determined before firm conclusions
can be reached as to its place in therapy.17
The EMA noted that, although the efficacy of conjugated oestrogens/
bazedoxifene in reducing vasomotor symptoms was lower than that of
conjugated oestrogens/progestogen combinations, the difference could not
be quantified. 5
Conjugated oestrogens/bazedoxifene has been shown to have an effect on
surrogate markers of vulvovaginal atrophy.4 However, the clinical significance
of such findings is not clear. Usual first-line treatment for urogenital atrophy is
with vaginal rather than oral oestrogens.
Patient-orientated outcomes such as fracture prevention are currently lacking.17
Three members of the EMA’s CHMP did not agree with the CHMP’s opinion
recommending the granting of marketing authorisation for Duavive. 5
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DTB | Bazedoxifene for HRT?

Costs What guidelines say

Drug Cost for In the absence of a submission from the company, neither the Scottish
84 days Medicines Consortium nor the All Wales Medicines Strategy Group has
approved conjugated oestrogens/bazedoxifene for use within NHS Scotland
Conjugated oestrogens 450µg/bazedoxifene 20mg (Duavive) £45.00 or NHS Wales.22,23
Conjugated oestrogens 300µg/medroxyprogesterone £6.52 NICE has published an evidence summary on the use of conjugated
1.5mg (Premique low dose) oestrogens/bazedoxifene. 3
Conjugated oestrogens 625µg/medroxyprogesterone £10.61 The Revised Global Consensus Statement on Menopausal Hormone
5mg (Premique) Therapy lists the combination of conjugated oestrogens plus bazedoxifene
as an effective treatment for vasomotor symptoms and in the prevention
Conjugated oestrogens 625µg/norgestrel 150µg (Prempak-C) £6.25 of bone loss. 24
Conjugated oestrogens 1.25mg/norgestrel 150µg (Prempak-C) £7.40
Costs based on prices in Chemist and Druggist and the Drug Tariff.

Conclusion
For women with an intact uterus, hormone replacement therapy (HRT) with a combination of oestrogen and progestogen is an established treatment
option for menopausal symptoms. The progestogen component, included to protect against oestrogen-related endometrial hyperplasia, may be associated
with vaginal bleeding and breast disease.
Duavive is a combination of conjugated oestrogens with bazedoxifene, a selective oestrogen receptor modulator that acts as an oestrogen antagonist in
endometrial tissue. It is licensed as an alternative to conventional HRT for women with a uterus who are unable to tolerate progestogens. Clinical trials
have shown that conjugated oestrogens/bazedoxifene produced a modest reduction in the number of moderate and severe hot flushes, and
improvements in measures of quality of life and sleep in younger postmenopausal women for periods of up to two years. However, the majority of the
evidence comes from a single series of clinical studies with no direct comparisons with conventional HRT.
The combination of oestrogen with a selective oestrogen receptor modulator holds the possibility of HRT without the concerns of breast cancer. There
remains some uncertainty relating to endometrial safety during long-term treatment. We believe that independent confirmation of efficacy and safety,
direct comparisons with conventional HRT, and more experience in older women and for longer periods will be needed before it can be recommended as
an alternative to standard HRT products.

[R=randomised controlled trial; M=meta-analysis]
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DOI: 10.1136/dtb.2017.4.0466

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