Ospemifene

1. R&D INSIGHT REPORT
Ospemifene: First Global Approval
Shelley Elkinson • Lily P. H. Yang
Published online: 20 April 2013
Ó Springer International Publishing Switzerland 2013
Abstract Ospemifene (OsphenaTM
) is an oral selective
estrogen receptor modulator (SERM), with tissue-specific
estrogenic agonist/antagonist effects. QuatRx Pharmaceu-
ticals conducted the global development of the agent before
licensing it to Shionogi for regulatory filing and commer-
cialization worldwide. Ospemifene is the first non-estrogen
treatment approved for moderate to severe dyspareunia in
women with menopause-related vulvar and vaginal atrophy.
The drug is approved in the USA, and application for EU
regulatory approval is underway. This article summarizes
the milestones in the development of ospemifene leading to
this first approval for moderate to severe dyspareunia, a
symptom of postmenopausal vulvar and vaginal atrophy.
1 Introduction
The decline in estrogen levels associated with menopause
is associated with several physiological changes that may
develop into disorders such as vulvar and vaginal atrophy
[1]. Symptoms related to this atrophy include vaginal
dryness, itching, irritation and dyspareunia [2]. These
symptoms, unlike vasomotor symptoms, typically worsen
over time [2] and have a substantial impact on sexual
function and health-related quality of life [1].
First-line treatment options include local non-pharma-
cological lubricants and moisturizers, and local or systemic
estrogen replacement therapy [2]. However, lubricants and
moisturizers provide symptomatic relief but they do not
treat the underlying atrophy, and are considered messy and
inconvenient by some women, especially for long-term use
[3]. Estrogen replacement therapy is the current standard of
care for vulvar and vaginal atrophy, and alleviates many of
the related symptoms [1]. However, exogenous estrogen use
is associated with a risk of adverse events such as endo-
metrial hyperplasia and venous thromboembolism [1, 2].
An alternative treatment option is the use of a
selective estrogen receptor modulator (SERM) [1, 3];
agents from this drug class are utilized or under evalu-
ation for various conditions associated with menopause
[4]. SERMs are structurally diverse [5] and do not have
any predictable class effects [6]. For example, tamoxifen
is used to prevent and treat breast cancer, but is asso-
ciated with an increased risk of endometrial hyperplasia
and malignancy; raloxifene is used to prevent and treat
postmenopausal osteoporosis and for the prevention of
breast cancer, but it (and tamoxifen) has no apparent
effect on the symptoms of vulvar and vaginal atrophy;
lasofoxifene appears to be beneficial in treating such
symptoms (and in reducing fracture risk and the inci-
dence of breast cancer) but is not approved for treating
vulvar and vaginal atrophy [1, 6].
Ospemifene (OsphenaTM
) is a third-generation oral
SERM, with a unique set of tissue-specific estrogenic
agonist/antagonist effects [5] (see Sect. 2.1). The drug
was approved by the US FDA in February 2013 for the
treatment of moderate to severe dyspareunia, a symptom
of vulvar and vaginal atrophy, due to menopause [7].
This profile has been extracted and modified from the Adis R&D
Insight drug pipeline database. Adis R&D Insight tracks drug
development worldwide through the entire development process,
from discovery, through pre-clinical and clinical studies to market
launch.
S. Elkinson (&)
Adis R&D Insight, 41 Centorian Drive, Private Bag 65901
Mairangi Bay, North Shore 0754 Auckland, New Zealand
e-mail: dru@adis.com
L. P. H. Yang
Adis, Auckland, New Zealand
Drugs (2013) 73:605–612
DOI 10.1007/s40265-013-0046-y

2. The approval was based on the results from nine clini-
cal trials conducted in almost 1,900 individuals [8]. The
key trials included two 12-week, placebo-controlled trials
that primarily evaluated efficacy [9, 10] and a 52-week,
placebo-controlled trial [11, 12] that primarily evaluated
tolerability. US launch is expected by the third quarter of
2013 [13].
Ospemifene should be taken orally, once daily with
food, at the recommended dosage of 60 mg/day [8]. The
treatment duration should be the shortest possible, taking
into account treatment goals and risks to the individual
patient, with periodic re-evaluation [8]. The US prescribing
information includes a boxed warning regarding an
increased risk of endometrial cancer in non-hysterecto-
mized women without the addition of a progestin, and of
cardiovascular disorders [8]. Ospemifene is contraindicated
in women with undiagnosed abnormal genital bleeding,
known or suspected estrogen-dependent neoplasia, active
or a history of deep vein thrombosis, pulmonary embolism
or arterial thromboembolic disease (e.g. stroke or myo-
cardial infarction) [8].
Shionogi is preparing a marketing authorization appli-
cation (MAA) dossier for submission in the EU, according
to the company’s pipeline of February 2013 [14].
Although phase II clinical trials have evaluated the
effect of ospemifene on markers of bone turnover [15, 16]
and climacteric symptoms [17–19] in postmenopausal
women (see Sect. 2.1), there does not appear to be ongoing
investigations with the drug in osteoporosis or menopausal
syndrome. There are no ongoing trials with ospemifene in
any indication.
1.1 Company Agreements
QuatRx Pharmaceuticals conducted the global develop-
ment of the agent before licensing it to Shionogi for reg-
ulatory filing and commercialization worldwide. QuatRx
Pharmaceuticals acquired ospemifene as part of a merger
with Hormos Medical in May 2005. Under the terms of the
transaction, Hormos has become a wholly owned sub-
sidiary of QuatRx [20].
In March 2010, Shionogi entered into a worldwide
license agreement with QuatRx, to develop and market
ospemifene. Under the terms of the agreement, Shionogi
will have worldwide marketing rights to the product, while
QuatRx will receive an upfront payment of $US25 million
and will be eligible to receive over $US100 million in
development and regulatory milestones. QuatRx will also
be eligible to receive additional payments for the approval
Features and properties of ospemifene
Alternative names FC 1271a; FC-1271a; OphenaTM
; OsphenaTM
Class Small molecules; stilbenes
Mechanism of action Selective estrogen receptor modulation
Route of administration Oral
Pharmacodynamics Estrogenic effects on vaginal epithelium
Generally neutral effects on lipid or lipoprotein levels,
blood pressure, heart rate, electrocardiogram,
routine laboratory parameters or climacteric symptoms
Pharmacokinetics Highly ([99 %) bound to serum proteins
Metabolized primarily by cytochrome P450 (CYP) 3A4, CYP2C6 and CYP2C19
Adverse events (incidence 1–7.5 %) Hot flush, vaginal discharge, muscle spasms, hyperhidrosis, genital discharge
WHO ATC code G03X-C (selective estrogen receptor modulators), M05B (drugs affecting bone
structure and mineralization)
EphMRA ATC code G3J [SERMS (selective oestrogen receptor modulators)], G3X
(other sex hormones and similar products),
M5 (other drugs for disorders of the musculo-skeletal system),
M5B (bone calcium regulators)
Chemical Name 2- [p-[(Z)-4-Chloro-1,2-diphenyl-1-butenyl] phenoxy] ethanol
Cl
O
OH
Chemical structure of ospemifene
606 S. Elkinson, L. P. H. Yang

3. of ospemifene outside the USA, as well as sales milestones
and royalties on sales [21].
Previously, Hormos had been jointly evaluating osp-
emifene with Tess Diagnostics and Pharmaceuticals; it
appears that the collaboration has been concluded and that
Tess Diagnostics has ceased to exist. Before Hormos’
merger with QuatRx in May 2005, Tess Diagnostics and
Pharmaceuticals transferred all its rights to the patents for
ospemifene to Hormos Medical in exchange for royalties
and other payments payable by Hormos to Tess.
1.2 Patent Information
Ospemifene is covered by four patents owned by Hormos
Medical, Inc. (Finland) and QuatRx Pharmaceuticals Co.
(USA) [22]. The patents are WO-09607402 (issued in
1996), US-05750576 (issued in 1998), WO-00136360
(issued in 2001) and WO-03103649 (issued in 2003) [22].
2 Scientific Summary
2.1 Pharmacodynamics
The mechanism of action of ospemifene is thought to be
mediated by estrogen receptors [22]. Ospemifene binds to
estrogen receptor-a and -b at relative binding affinities of
0.82 and 0.59 %, with respective half-maximal inhibitory
concentrations of 827 and 1,633 nmol/L [23].
As with all SERMs, ospemifene has its own set of tis-
sue-specific estrogenic or anti-estrogenic effects [24]. For
example, in animal models, ospemifene inhibited the
growth of breast cancer [23, 25–27], prevented bone loss
[23], lowered cholesterol levels [23], and had low estro-
genic activity at dosages that also prevented bone loss [23].
Data from animal studies did not suggest hepatic or uterine
genotoxicity with ospemifene [23, 28, 29], although
tamoxifen was associated with DNA adducts in the liver
[28]. In another animal study [30], ospemifene showed
similar modulatory effects as tamoxifen and raloxifene on
estrogen-regulated early response genes. Findings from
clinical trials in postmenopausal women are summarized
below.
2.1.1 Gynecological Effects
Ospemifene 25–200 mg/day (or raloxifene 60 mg/day
[19]) for 3 months generally had no [18] or little [17, 19,
31] effect on endometrial thickness; endometrial thickness
was increased from baseline at 52 weeks by a mean of
0.68 mm with ospemifene 30 mg/day and by 1.14 mm
with ospemifene 60 mg/day [31]. Endometrium-related
adverse events are reported in Sect. 2.4.
Ospemifene 25–200 mg/day for 3 months [9, 10, 17, 18]
or 52 weeks [32] had an estrogenic effect on vaginal epi-
thelium (as assessed by cell layers in the vaginal matura-
tion indices), which were a decrease in parabasal cells
(a co-primary endpoint [9, 10]) and an increase in inter-
mediate and superficial cells (a co-primary endpoint
[9, 10]); these changes were significantly (p 0.05)
greater than those with placebo for most of the ospemifene
dosage groups [9, 10, 17, 18, 32]. In contrast, raloxifene
60 mg/day for 3 months had no effect on the vaginal epi-
thelium [19].
After 3 months [9, 10] or 52 weeks [32], a significant
(p 0.001) reduction relative to placebo was seen with
ospemifene 30 or 60 mg/day in vaginal pH (a co-primary
endpoint [9, 10]).
No statistically significant changes relative to placebo in
mean uterine and ovarian volume were observed with
ospemifene 30–90 mg/day for 3 months [17].
2.1.2 Effect on Bone Markers
Ospemifene 30, 60 or 90 mg/day reduced various bio-
markers of bone turnover by a significantly greater extent
than with placebo (in a dose-dependent manner for some
endpoints) in a 3-month, phase II trial [15], and generally
to a statistically similar extent as raloxifene 60 mg/day in
another 3-month, phase II trial [16]. Findings from in vitro
studies indicate that, unlike tamoxifen, ospemifene and
raloxifene had no inhibitory effect on osteoclast formation
Key company agreements
Companies Type of
agreement
Key elements in agreement Date of
agreement
Agreement
status
Shionogi and QuatRx
Pharmaceuticals
License Worldwide license agreement to develop and market ospemifene 2 February
2010
Completed/
active
QuatRx Pharmaceuticals and
Hormos Medical
Merger QuatRx Pharmaceuticals merged with Hormos Medical; Hormos
Medical became a wholly owned subsidiary of QuatRx
16 May
2005
Completed/
active
Hormos Medical and Tess
Diagnostics and
Pharmaceuticals
Collaboration Collaborative agreement for development of ospemifene &1998 Terminated/
inactive
Ospemifene 607

4. and bone resorption [33], and unlike tamoxifen and
raloxifene, ospemifene protected osteoblast-derived cells
from etoposide-induced apoptosis [34].
2.1.3 Other Effects
Ospemifene 25–200 mg/day for 3 months had a neutral effect
onclimactericsymptoms, asthere werenosignificantchanges
from baseline in the Kupperman index [17], or in individual
symptoms, such as hot flush, sweating, paraesthesia, insom-
nia, depression, nervousness, melancholy, dizziness, weak-
ness, joint or muscle pain, headache, fatigue breast tenderness
or skin itch [17, 18]. The effect of ospemifene 30–90 mg/day
and raloxifene 60 mg/day for 3 months on climacteric
symptoms were generally similar [19].
Treatment with ospemifene (at various dosages of
25–200 mg/day) for 3 months [17–19] or 52 weeks [31]
was associated with a dosage-dependent decrease in serum
follicle stimulating hormone (FSH) levels [17–19] and a
dosage-dependent increase in serum sex-hormone-binding
globulin (SHBG) levels [18, 19]; there was an inconsistent
effect on serum luteinizing hormone levels after 3 months
[17–19], but a decrease was seen after 52 weeks [31].
Ospemifene had no effect on serum estradiol levels [17, 19,
31] or free testosterone levels [31], but decreased serum
insulin-like growth factor I levels [17, 19] and increased
total testosterone levels [31]. The decrease in serum FSH
levels was significantly greater with ospemifene 90 mg/day
than with raloxifene 60 mg/day, and the increase in serum
SHBG levels was significantly greater with ospemifene
30–90 mg/day than with raloxifene 60 mg/day [19].
Ospemifene 30–90 mg/day for 3 months [35] or
52 weeks [12, 31] generally had no effect on lipid or lipo-
protein levels relative to placebo. Total cholesterol levels
decreased significantly (p 0.05) more with raloxifene
60 mg/day than with ospemifene 30–90 mg/day, but
otherwise the lipid profiles were similar [19].
In general, ospemifene 30–90 mg/day for 3 months [35]
or 52 weeks [31] caused no major changes on endothelial
markers or coagulation parameters, with the exception of a
decrease in fibrinogen levels. Ospemifene had no effect on
fasting or fed glucose levels, or baseline insulin levels [35].
Compared with placebo, ospemifene 30–90 mg/day for
3 months [35] or ospemifene 60 mg/day for 52 weeks [12]
had no effect on ambulatory blood pressure [35] or elec-
trocardiogram assessments [12].
Ospemifene 30–90 mg/day [17, 19] or raloxifene
60 mg/day [19] for 3 months did not appear to affect
health-related quality of life, as assessed by the Work
Ability Index scores for depression, anxiety or activity (i.e.
self-confidence).
Data from pre-clinical studies in various breast cancer
models showed that ospemifene had anti-estrogenic effects,
with dose-dependent inhibitions in tumour cell growth such
as those seen with tamoxifen [22, 36]. No serious breast-
related adverse events have been reported with the use of
ospemifene in clinical trials (Sect. 2.4).
2.2 Pharmacokinetics
In fasting postmenopausal women who received a single
oral dose of ospemifene 60 mg, mean maximum serum
concentration (Cmax) of 533 ng/mL was reached in a
median time (tmax) of &2 h; mean area under the plasma
concentration-time curve from time zero to infinity (AUC)
was 4,165 ngÁh/mL [8]. Single-dose drug administration
with a high fat and calorie meal was associated with a
2.3-fold increase in Cmax and a 1.7-fold increase in AUC,
with no effect on tmax or elimination half-life (t1/2); it is
recommended that ospemifene be taken with food [8].
Steady state was reached in 9 days, and drug accumulation
(in terms of AUC) was &2 [8]. The absolute bioavail-
ability of ospemifene is not known [8]. The pharmacoki-
netics of repeated ospemifene administration have also
been studied in postmenopausal women, albeit at dosages
of 25, 50, 100 and 200 mg/day [37].
Ospemifene is highly ([99 %) bound to serum proteins,
and the apparent volume of distribution is 448 L [8].
In vitro studies have shown that ospemifene is primarily
metabolized by cytochrome P450 (CYP) 3A4, CYP2C9
and CYP2C19 [8], the drug’s major metabolite is 4-hy-
droxyospemifene [8, 38]. Ospemifene has an apparent total
body clearance of 9.16 L/h. Recovery of an orally admin-
istered dose of ospemifene was &75 % in the faeces and
7 % in the urine; 0.2 % of the dose was excreted as
unchanged drug in the urine [8].
Age (in the range of 40–80 years), race or renal
impairment had no clinically relevant effects on ospemif-
ene pharmacokinetics [8]. While no clinically significant
pharmacokinetic changes for ospemifene were observed in
women with mild to moderate hepatic impairment (Child-
Pugh Class A to B), thus not requiring dosage adjustments,
ospemifene is not recommended for use in women with
severe hepatic impairment (Child-Pugh Class C) because
of a lack of data [8].
2.2.1 Drug Interactions
Ospemifene is metabolized by CYP3A4, CYP2C9 and
CYP2C19; drugs that induce or inhibit these enzymes
affect the pharmacokinetics of ospemifene and may
increase the risk of adverse events or reduce the clinical
efficacy of ospemifene [8]. Some examples are fluconazole
(moderate inhibitor of CYP3A and CYP2C19, strong
inhibitor of CYP2C9), rifampin (strong inducer of CYP3A,
moderate inducer of CYP2C9 and CYP2C19) and
608 S. Elkinson, L. P. H. Yang

5. ketoconazole (strong CYP3A4 inhibitor). Multiple admin-
istration of ospemifene did not affect the pharmacokinetics
of a single dose of warfarin 10 mg [8].
2.3 Therapeutic Trials
The clinical efficacy of ospemifene was evaluated in two
12-week, randomized, double-blind, placebo-controlled,
multicentre trials in postmenopausal women (aged
40–80 years) with vulvar and vaginal atrophy, regardless
of uterine intactness [9, 10]. These trials stratified patients
according to their most bothersome symptom (MBS),
either dyspareunia or vaginal dryness. Patients were ran-
domized to receive ospemifene 30 mg/day (n = 268),
ospemifene 60 mg/day (n = 282) or placebo (n = 276) in
one trial [9], or ospemifene 60 mg/day (n = 303) or pla-
cebo (n = 302) in the other trial [10]. Patients also
received a non-hormonal lubricant for use as needed [9,
10]. One trial [10] included a 40-week extension phase in
women with dyspareunia as their MBS [39], during which
patients continued their randomized treatment.
2.3.1 Dyspareunia
In postmenopausal women with moderate to severe dyspa-
reunia as their MBS, ospemifene 60 mg/day for 12 weeks
significantly improved dyspareunia (co-primary endpoint)
compared with placebo [9, 10]. The decrease in dyspareunia
symptom score in the ospemifene 60 mg/day and placebo
groups was 1.19 versus 0.89 (p = 0.023) in one trial [9] and
was 1.5 versus 1.2 (p = 0.0001) in the other trial [10]. Dys-
pareunia severity was assessed using a 4-point Likert scale
(ranging from 0 = none to 3 = severe).
At 12 weeks, the proportion of patients reporting no
vaginal pain during sexual activity was 38.0 % with osp-
emifene 60 mg/day versus 25.1 % with placebo, and that
for mild vaginal pain was 28.1 versus 19.2 % [10]. At
12 weeks, 52.8 % of ospemifene 60 mg/day recipients
reported an improvement of 2–3 levels in vaginal pain
severity (out of four possible levels) compared with 38.8 %
of placebo recipients [10].
In the trial that also evaluated ospemifene 30 mg/day
[9], there was no significant difference between this
dosage group and placebo in the improvement in dyspa-
reunia (a reduction from baseline at 12 weeks of 1.02 vs.
0.89).
2.3.2 Other Clinical Endpoints
In patients with vaginal dryness as their MBS, vaginal
dryness (co-primary endpoint) was significantly (p = 0.01
[22] and p 0.001 [9]) improved with ospemifene
60 mg/day for 12 weeks compared with placebo. Osp-
emifene 30 mg/day also significantly (p = 0.04) improved
vaginal dryness compared with placebo [9].
In terms of lubricant use at 12 weeks, the proportion was
31 % of ospemifene 30 mg/day, 22 % of ospemifene
60 mg/day and 29 % of placebo recipients (compared with
33–36 % across all groups at baseline) in one trial [9], and
was 35.1 % of ospemifene 60 mg/day and 39.3 % of pla-
cebo recipients (compared with 41.7 and 43.1 % at base-
line) in the other trial [10].
In the 9-month extension study [31, 39], therapy with
ospemifene (for a total of 52 weeks) was associated with
improvements in the severity scores for vaginal character-
istics, as determined by visual examination. These charac-
teristics included petechiae, pallor, friability, and vaginal
mucosal dryness and redness [31], some of which reached
statistical significance relative to placebo [39].
2.4 Adverse Events
Ospemifene treatment for up to 52 weeks was generally
well tolerated in clinical trials in postmenopausal women
Key clinical trials of ospemifene in postmenopausal vulvar and vaginal atrophy
Drugs Study phase Study status Study location Trial identifiers Company
Ospemifene vs. placebo III Completed Multinational NCT00566982 Hormos Medical, QuatRx
Pharmaceuticals and Shionogi
Ospemifene vs. placebo III Completed USA NCT00276094 Hormos Medical, QuatRx
Pharmaceuticals and Shionogi
Ospemifene vs. placebo III Completed USA NCT00729469 Hormos Medical, QuatRx
Pharmaceuticals and Shionogi
Ospemifene vs. placebo III Completed Multinational NCT01585558 QuatRx Pharmaceuticals and Shionogi
Ospemifene vs. placebo III Completed Multinational NCT01586364 QuatRx Pharmaceuticals and Shionogi
Ospemifene vs. placebo II Completed Multinational NCT00630539 Hormos Medical, QuatRx
Pharmaceuticals and Shionogi
Ospemifene 609

6. [9–11, 31]. The majority of the reported adverse events
were of mild or moderate severity [10, 11, 31].
2.4.1 In 12-Week Trials
In one trial [9], the proportion of women who experienced
an adverse event was 64.5 % in the ospemifene 30 mg/day
group, 59.4 % in the ospemifene 60 mg/day group and
52.2 % in the placebo group (n = 282, 276 and 268,
respectively); discontinuation because of adverse events
occurred in 5.3, 4.7 and 4.9 % of patients in the corre-
sponding groups, with serious adverse events reported in
1.8, 0.0 and 1.5 %. In the other 12-week trial [10], treat-
ment-emergent adverse events (TEAEs) were reported in
61.4 % of ospemifene 60 mg/day and 51.0 % of placebo
recipients (n = 303 and 302), treatment-related adverse
events (TRAEs) in 26.1 and 14.6 %, discontinuation
because of adverse events in 4.6 and 3.3 %, discontinuation
because of TRAEs in 3.3 and 1.3 %, and serious adverse
events in 1.3 and 1.3 % (none of these was considered to be
treatment related).
The most commonly reported adverse events (i.e. with
an incidence C5 % in any study group) were hot flush
(9.6 % with ospemifene 30 mg/day, 8.3 % with ospemif-
ene 60 mg/day and 3.4 % with placebo), urinary tract
infection (4.6, 7.2 and 2.2 %) and headache (6.0, 2.5 and
5.2 %) in one trial [9], and were hot flush (6.6 % with
ospemifene 60 mg/day and 4.3 % with placebo) and uri-
nary tract infection (5.6 and 3.6 %) in the other trial [10].
No endometrial hyperplasia or carcinoma, polyps or cancer
were observed in any patient in either of the trials [9, 10].
Vaginal spotting was reported in one each of the osp-
emifene 30 mg/day, 60 mg/day and placebo groups [9],
and vaginal bleeding in two placebo recipients [10]; one
placebo recipient experienced a cerebrovascular event
(ischaemic stroke) [10].
2.4.2 In 52-Week Trials
In a 40-week extension study (of a 12-week trial [9]) in
women with an intact uterus [31], TEAEs were reported in
61.3 % of ospemifene 30 mg/day (n = 62), 63.8 % of
ospemifene 60 mg/day (n = 69) and 44.9 % of placebo
(n = 49) recipients, with serious TEAEs in 3.2, 7.2 and
2.0 %, severe adverse events in 9.7, 10.1 and 4.1 %, and
TEAEs leading to discontinuation in 4.8, 5.8 and 2.0 %.
The most common (incidence C5 % in any group) TEAEs
were nasopharyngitis, sinusitis, urinary tract infection,
vaginal candidiasis or vulvar and vaginal mycotic infec-
tions, hypercholesterolaemia, pharyngolaryngeal pain and
hot flush. The incidence of hot flush considered to be at
least possibly related to study drug was 3.2 % with osp-
emifene 30 mg/day, 7.2 % with ospemifene 60 mg/day and
2.0 % with placebo [31].
No endometrial hyperplasia or carcinoma, discontinua-
tion because of any endometrial or cervical pathology,
clinically significant breast-related or gynaecological
adverse changes, TEAEs of pelvic organ prolapse, or
venous thromboembolism were reported in ospemifene
recipients [31]. At baseline and at 52 weeks, [95 % of
endometrial tissue samples were classified as atrophic or
inactive (or had insufficient tissue for diagnosis); one
ospemifene 30 mg/day recipient had atypical epithelial
proliferation and one ospemifene 60 mg/day recipient had
disordered proliferation. Vaginal bleeding/spotting was
reported in one ospemifene 30 mg/day and one ospemifene
60 mg/day recipient; both were self-limiting and lasted
1–3 days [31].
In a 52-week trial, TEAEs were reported in 84.6 % of
ospemifene 60 mg/day and in 75.8 % of placebo recipients
(n = 363 vs. 63); most of these were mild or moderate in
severity, and the most common TEAE was hot flush (12.6
vs. 6.5 %) [11]. Serious adverse events were reported in
4.9 % of ospemifene and 6.5 % of placebo recipients [11].
One ospemifene recipient developed deep vein thrombosis
that subsequently resolved [11]. There were no reports of
pulmonary embolus, retinal vein thrombosis, myocardial
infarction, or breast or endometrial cancer [11]. Five osp-
emifene recipients (1.4 vs. 0 % with placebo) experienced
vaginal bleeding or spotting; one of these patients had an
active proliferative endometrium [40]. In total, three study
participants had active endometrial proliferation (one of
whom had simple hyperplasia without atypia) that subse-
quently resolved [12]. One recipient (study medication
group not specified) who had hypercholesterolemia devel-
oped non-fatal thrombotic stroke [12].
2.4.3 Pooled Data
According to pooled data from 1,242 ospemifene
60 mg/day and 958 placebo recipients [8], the most com-
mon adverse events were hot flush (7.5 vs. 2.6 %), vaginal
discharge (3.8 vs. 0.3 %), muscle spasms (3.2 vs. 0.9 %),
hyperhidrosis (1.6 vs. 0.6 %) and genital discharge (1.3 vs.
0.1 %). In ospemifene 60 mg/day and placebo recipients,
the incidence rates for were 0.72 versus 1.04 per thousand
women for thromboembolic stroke, 1.45 versus 0 for
haemorrhagic stroke, 1.45 versus 1.04 per thousand women
for deep vein thrombosis, 86.1 versus 13.3 per thousand
women for any type of proliferative (i.e. weak, active or
disordered) endometrium, 5.9 versus 1.8 per thousand
women for uterine polyps, and 60.1 versus 21.2 per
610 S. Elkinson, L. P. H. Yang

7. thousand women for endometrial thickening of C5 mm.
Myocardial infarction was reported in a recipient of osp-
emifene 60 mg/day [8].
3 Current Status
Ospemifene received its first global approval in the USA
on 26 February 2013 [7] for moderate to severe dyspa-
reunia, a symptom of menopause-related vulvar and vagi-
nal atrophy [8].
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