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Ulipristal acetate (Esmya)

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London New Drugs Group

APC/DTC Briefing Document


May 2012

ULIPRISTAL ACETATE (ESMYA)


Contents
Summary
Background
Ulipristal
Clinical efficacy
PEARL I
PEARL II
Adverse events
Budget Impact model
References
Appendices

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3
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5
8
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Summary
The drug and the review
In April 2012 ulipristal acetate (Esmya), was launched in the UK for pre-operative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age.
Ulipristal, a selective progesterone receptor modulator, reduces fibroid volume by inhibiting cell proliferation and inducing apoptosis.
The aim of this review is to critically evaluate the main trials submitted for the marketing authorisation.
Background
Uterine fibroids are the most common benign, hormone-sensitive tumours occurring in 20-40% of women of reproductive age. They are nine times more common in Black women as in Caucasian women.
Clinical intervention is required in 20-50% of cases, and includes pharmacological therapies such as
NSAIDs, tranexamic acid and GnRH agonists, or, if medical management cannot control symptoms, surgery is warranted.
Literature
Two pivotal PIII studies (PEARL I and II) have been identified.
Efficacy studies
The two PEARL studies enrolled women aged 18-50 with a score on the pictorial blood-loss assessment
chart (PBAC) of >100 during days 1-8 of menstruation, an enlarged myomatous uterus and at least one
fibroid 3cm diameter, but none >10cm diameter.
Exclusion criteria included prior or current treatment with a GnRH agonist, tranexamic acid or mefenamic acid.

Produced for the


London New Drugs Group by:
Alexandra Denby,
Regional MI Manager
Medicines Information Service
Northwick Park Hospital
Middlesex
HA1 3UJ
Tel: 020 8869 3551
nwlh-tr.medinfo@nhs.net
Further copies of this document are
available from URL:
www.nelm.nhs.uk

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PEARL II
PEARL II assessed the efficacy and safety of ulipristal vs. leuprorelin acetate for treating symptomatic
fibroids prior to surgery. Patients were randomised to treatment with ulipristal 5mg (n=98) or 10mg
(n=104) daily plus a monthly intramuscular (IM) saline injection, or placebo tablets and a monthly
leuprorelin 3.75mg IM injection (n=101), for 3 months.
The primary endpoint, the proportion of patients with uterine bleeding at week 13 (PBAC <75) was
achieved in similar proportions of patients in each group (89-98%), indicating non-inferiority of ulipristal
to leuprorelin.

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PEARL I
The aim of PEARL I was to compare the efficacy and safety of ulipiristal 5mg (n=96), 10mg (n=98) or placebo (n=48), given daily for 3 months, on uterine bleeding and fibroid volume. After week 13, patients
could have surgery according to their clinical response.
There were two primary endpoints: Reduction in uterine bleeding (PBAC <75) was seen in 91% of the
5mg and 92% of the 10mg ulipristal groups, compared with 19% of the placebo group (p<0.001 for both
ulipristal groups vs. placebo). Statistically and clinically significant reductions in fibroid volume occurred
with ulipristal therapy (-21% with 5mg and -12% with 10mg), compared with placebo (-3%) (p=0.002 and
0.006 vs. placebo respectively).
There were a number of secondary endpoints. Excessive bleeding was controlled in >75% of patients
receiving ulipristal by day 8, compared with 6% receiving placebo. Approximately 50% treated with 5mg
and 70% treated with 10mg ulipristal became amenorrhoeic within the first 10 days. Greater reductions
in fibroid and uterine volume occurred with ulipristal compared with placebo treatment.

TO

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Ulipristal acetate (Esmya)

There were a number of secondary endpoints. All three treatments reduced fibroid and uterine size, with greatest reductions
seen with leuprorelin therapy. Excessive bleeding was controlled more rapidly with ulipristal, with bleeding attenuated up to 2
weeks earlier than with leuprorelin. All three groups showed similar improvements in pain and quality of life. For those patients who did not undergo surgery, a more sustained effect on fibroid volume was seen up to six months after stopping treatment in those who had been treated with ulipristal.
Safety
The rate of adverse events did not differ significantly between ulipristal and placebo treatment.
Most common adverse events in the ulipristal treatment groups were headache, and pain/discomfort/tenderness in the
breasts, but these did not occur to a significantly greater extent than in the placebo group.
Moderate-to-severe hot flushes occurred in four times as many patients treated with leuprorelin than with ulipristal. No significant differences between the ulipristal and leuprorelin groups were seen in the proportion of patients reporting other adverse
events. Endometrial thicknesses were greater in patients treated with ulipristal than with leuprorelin, but no dysplasia or neoplasia were identified.
Ulipristal should not be given with CYP34 inducers or inhibitors, which will increase or decrease its blood levels. Ulipristal can
inhibit P-glycoprotein and should not be used with P-gp substrates such as dabigatran. Medicinal products containing progesterone should not be used during ulipristal treatment and for 12 days after stopping ulipristal: ulipristal has inhibitory effects on
the progesterone receptor and progesterones in e.g. hormonal contraceptives will compete with ulipristal for this receptor.
Critical evaluation
The PEARL studies showed that ulipristal is an effective treatment for controlling excessive bleeding and fibroid size in women
with uterine fibroids prior to surgery.
Both studies are limited by the short duration of treatment; more data are required to assess the long-term safety and efficacy
of ulipristal. The length of duration of PEARL II may be limited by the licensed duration of treatment of leuprorelin for this indication in the US, which is 3 months.
Neither study assessed treatment-related differences in surgical outcomes.
Potential benefits over existing technologies
Other current treatments prior to surgery to remove fibroids are GnRH agonists, which have side effects such as hot flushes and
reduced bone mineral density. Ulipristal has been shown to have a lower incidence of these side effects in the studies.
Ulipristal is an oral therapy; GnRH agonists are given by monthly intramuscular injections for 3-6 months.
Potential disadvantages over existing technologies
Ulipristal will initially be licensed for use up to 3 months based on available trial data. Leuprorelin and triptorelin can be used
for up to 6 months.
Health Economics
The total cost of treatment per person per treatment cycle, including administration, is estimated as 433.05 for ulipristal (3
months treatment) vs. 481.62 for leuprorelin (Prostap SR, 4 months) and 345.66 for goserelin (Zoladex, 3 months). Various
assumptions have been made, which are listed in the full budget impact, later in this document.
Issues for consideration
Ulipristal will be the first orally administered option for reducing excessive bleeding and uterine fibroid size prior to surgery,
compared with GnRH analogues which need to be given subcutaneously. This will give patients a choice which they may find
preferable.
Oral therapy will reduce the time and cost of doctors and nurses who currently administer the subcutaneous treatments.
There are only efficacy data for the use of ulipristal for up to 3 months. [Note that the GnRH agonist goserelin is only licensed
for 3 months and leuprorelin and triptorelin are licensed for up to 6 months of treatment for reducing uterine fibroids].
Reduction in fibroid volume was maintained for a longer period of time with ulipristal than with leuprorelin in patients who did
not undergo surgery.
There are no data on the use of ulipristal following a GnRH agonist, or followed by a GnRH agonist.
The PEARL studies did not assess surgical outcomes following ulipristal therapy.
This document reflects the views of the London New Drugs Group and may not reflect those of the reviewers.

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Ulipristal acetate (Esmya)

Background
In April 2012 ulipristal acetate (Esmya), was
launched in the UK for pre-operative treatment of
moderate to severe symptoms of uterine fibroids in
adult women of reproductive age. The duration of
treatment is limited to 3 months.1
Uterine fibroids (leiomyomas) are the most common
benign, hormone-sensitive tumours in women of
reproductive age, occurring in 20-40%.2;3 Fibroids
are at least nine times more common in black women than in Caucasian women, and Asian women have
the lowest incidence.2 Many are undiagnosed and
while most women with fibroids do not have symptoms, 20-50% require clinical intervention.4 The
most common symptoms are pelvic pain, pelvic pressure and menorrhagia, which can result in irondeficiency anaemia.2;4 Women may also experience
infertility, miscarriage, pre-term deliveries and complications in late pregnancy.4 Management is pharmacological or surgical.

tive procedure for the permanent removal of fibroids,


but for women who want to have children or retain
their uterus, a myomectomy (removal of fibroids) is
the alternative procedure.4;6 A concern with a myomectomy is that the fibroids may reappear and require further surgery.6 Uterine artery embolisation
(UAE) avoids major surgery and preserves the uterus.
In UAE, an embolic agent (such as polyvinyl alcohol) is
injected into the uterine arteries, flowing preferentially into the fibroid vessels, and ultimately limiting
the blood supply to the fibroids, causing them to
shrink.4;5
Ulipristal
Ulipristal is a selective progesterone receptor modulator which has a tissue-specific partial progesterone
antagonist effect, acting on progesterone receptors in
myometrial and endometrial tissue and depriving
uterine fibroids of growth stimulation due to progesterone.3;8 Ulipristal reduces fibroids through inhibition of cell proliferation and induction of apoptosis. 1

NSAIDs are used to reduce menstrual blood loss and


dysmenorrhoea by antagonising prostaglandins
which cause the uterus to contract, leading to pain.5
Tranexamic acid and danazol reduce heavy bleeding.
Tranexamic acid inhibits fibrinolysis. Danazol creates
a high androgen and low oestrogen environment,
leading to fibroid shrinkage, but use is limited by
undesirable side effects such as acne, hirsutism and
weight gain.5 Oral contraceptive pills are used to
control menorrhagia and dysmenorrhoea but can
increase fibroid size because they are oestogendependent.5 GnRH agonists reduce hormonal stimulation of fibroids and can reduce fibroids to approximately 25-50% of their size within 3 months, but the
fibroids regrow to their former size within 3-6
months of stopping treatment. GnRH agonists also
cause amenorrhoea, menopausal symptoms and
bone loss.4 NICE guidance recommends that GnRH
agonists are used for 3-4 months prior to a hysterectomy or myomectomy when fibroids are causing an
enlarged or distorted uterus.6 Some GnRH agonists
are licensed for the reduction of uterine fibroids in
women with heavy bleeding, prior to surgery, but
can only be used for up to 3 months (goserelin) and
up to 6 months (triptorelin and leuprorelin).7

Treatment with ulipristal (Esmya) is 5mg daily started during the first week of a menstrual cycle, for up
to 3 months.1 There are no data for using ulipristal
for longer than 3 months, or for repeat courses.1 A
missed dose should be taken as soon as possible, unless the dose was missed by more than 12 hours, in
which case the missed dose should not be taken and
the usual dosing schedule resumed the next day.1
Most patients will complete their first menstruation
but will not menstruate again until after treatment is
stopped; menstrual cycles generally resume within 4
weeks.1

Surgery is indicated when the uterus is greatly enlarged, pressure symptoms are present, medical
management cannot control the symptoms and fertility is an issue.2 A hysterectomy is the only defini-

Interactions
Contraceptive methods containing progestagens
should not be used concomitantly; non-hormonal
methods of contraception are recommended.1

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Special populations
No dose adjustment is required in patients with mild
or moderate renal impairment or mild hepatic impairment.1 Due to the lack of data in patients with severe
renal impairment and moderate-severe hepatic impairment, ulipristal should not be used in these patients. The safety and efficacy of ulipristal has only
been established in women aged 18 years and over.
Ulipristal should not be used in patients with uterine,
cervical, ovarian or breast cancer, in those with genital bleeding of unknown cause or in those who are
pregnant/breast feeding.

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Ulipristal acetate (Esmya)

Ulipristal acts as a selective progesterone receptor modulator and has inhibitory effects on the
progesterone receptor; hormonal contraceptives
are likely to compete with ulipristal for this receptor. Medicinal products containing progesterone should not be taken within 12 days of stopping ulipristal treatment.
Concomitant use with P-glycoprotein substrates
(e.g. dabigatran or digoxin) is not recommended
because ulipristal may inhibit P-gp and increase
plasma levels of medications that are P-gp substrates.1
Concomitant use with moderate/potent CYP3A4
inhibitors (e.g. erythromycin, ketoconazole, ritonavir) or inducers (e.g. rifampicin, carbamazepine, phenytoin) is not recommended because
these will increase or decrease ulipristal blood
levels.1
Clinical efficacy
There are two main randomised, parallel-group,
double-blind phase III, 13-week studies: PGL4001
(Ulipristal acetate) Efficacy Assessment in Reduction
of Symptoms due to Uterine Leiomyomata (PEARL I
and PEARL II). These studies have been classed as
class A data in the New England Journal of Medicine.
Inclusion criteria for women aged 18-50 were a
score on the pictorial blood-loss assessment chart
(PBAC, see Appendix 1) higher than 100 during days
1-8 of menstruation (range 0-500, higher score indicating more bleeding), a myomatous uterus with a
size equivalent to a uterus of 16 weeks gestation, at
least one fibroid 3cm diameter but none >10cm
diameter, and a body-mass index of 18-40.3;9 In
PEARL I, an additional inclusion criterion was fibroidrelated anaemia (Hb 10.2g/dL).3 Uterine bleeding
was assessed using the PBAC; menorrhagia was defined as a PBAC score of >100 during a menstrual
period, corresponding to a blood loss of 80mL.
Exclusion criteria included: history of uterine surgery
(except Caesarean section or cervical conisation),
endometrial ablation or uterine artery embolisation,
history of or current gynaecological cancer, current
endometrial hyperplasia, haemoglobinopathy, severe coagulation disorder, uterine polyp >2cm, previous or current treatment for fibroids with a GnRH
agonist, treatment with agents that affect CYP3A4 or
those taking progestins, aspirin, mefenamic acid,
anticoagulants, antifibrinolytic drugs or systemic
glucocorticoids.10;11
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PEARL I
The aim of PEARL I was to assess the efficacy of
ulipristal 5mg and 10mg daily on uterine bleeding and
fibroid volume in 242 women with symptomatic fibroids who were planning to undergo surgery.3 Patients were randomised to treatment with 5mg
(n=96), 10mg (n=98) or placebo (n=48) per day, stratified by haematocrit level ( or >28%) and race (black
or other). Treatment started during the first 4 days of
menstruation, and all patients received 80mg iron
supplementation. Patients could have surgery after
week 13 according to their clinical response, but no
further pharmacologic treatment of fibroids was given. At baseline, median PBAC scores ranges from 330
to 376. The median fibroid volume (cm3) was smaller
in the placebo group, (61.9, range 24.8 to 158.9) than
in the 5mg (100.7, range 40 to 205.3) and 10mg (96.7,
range 31.7 to 181.3) groups. Pain, as assessed by the
Visual Analogue Scale, was rated higher in the placebo group (49.5) than in the 5mg and 10mg groups
(39.0 for both). Efficacy analyses were carried out in
the intention-to-treat population (ITT). The efficacy
outcome for each dose group was considered to be
successful only if there were significant improvements
over placebo in both co-primary endpoints. The last
observation carried forward method was used for
missing values. The study would have 90% power to
show a significant between-group difference if 240
patients were randomised.
The co-primary endpoints were the percentage of
patients with a reduction in uterine bleeding at week
13, defined as a PBAC score (summed over the preceding 28 days) of <75, and the change in total fibroid
volume from screening to week 13. Menstrual bleeding was controlled in 91% of the 5mg group and 92%
of the 10mg group, compared with 19% of the placebo group (further results in Table 1). Clinically and
statistically significant reductions in uterine fibroid
size was seen in both ulipristal groups (-21% in the
5mg and -12% in the 10mg groups) compared with
the placebo group (-3%).
There were a number of secondary endpoints, details
of which are in table 1:
The median PBAC scores during weeks 9-12 were
significantly lower with ulipristal treatment compared with placebo treatment. Excessive bleeding
was controlled in >75% of patients receiving
ulipristal by day 8, compared with 6% receiving
placebo.

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Ulipristal acetate (Esmya)

Amenorrhoea (PBAC 28-day score 2 at weeks 9


and 13) was achieved in significantly more patients treated with ulipristal than with placebo.
Approximately 50% treated with 5mg and 70%
treated with 10mg became amenorrhoeic within
the first 10 days.
Significantly greater reductions in uterine and
fibroid volume (at least a 25% reduction) were
achieved with ulipristal treatment.
Changes in haemoglobin were significantly greater with ulipristal treatment.
Pain, as assessed by the Short-Form McGill Pain
Questionnaire, (range 0-45, higher scores indicating more pain), Visual Analogue Scale (0=none,
100=worst) and discomfort associated with fibroids (score 0-28, higher indicating more discomfort, see Appendix 2) were significantly improved with ulipristal treatment.
Approximately half the patients in each group had
fibroid surgery after completing the study. Menstruation occurred on average 30 days after stopping
ulipristal treatment.
In summary: the use of ulipristal was effective in
controlling excessive bleeding and reducing fibroid
size in women with severe bleeding and associated

Table 1: Results from PEARL I

anaemia at baseline. Bleeding was controlled within


8 days of starting treatment. Self-reported pain and
discomfort due to fibroids was also improved significantly with ulipristal therapy. The side effect profile
of ulipristal was similar to that of placebo. The study
is limited by the short duration of treatment: more
data are required to assess long-term benefits and
risks of ulipristal treatment. The study did not assess
treatment-related differences in surgical outcomes.
Only the 5mg strength is available and licensed for
use in the UK.

PEARL II
The aim of PEARL II was to assess the efficacy and side
effects of ulipristal versus leuprolide acetate
(leuprorelin) for treating symptomatic uterine fibroids
prior to surgery.9 Patients were randomised to 5mg
(n=98) or 10mg (n=104) ulipristal daily plus an intramuscular saline injection once a month, or placebo
tablets plus a 3.75mg leuprorelin acetate injection
once a month (n=101). Randomisation was stratified
to avoid imbalance with respect to race or ethnic
group. Treatment was started within 4 days after the
start of the menstrual period and continued until
week 13, when patients could have surgery. Approximately 10% of enrolled patients were black. The me-

3;10

Primary endpoints

Placebo (n=48)

Ulipristal 5mg (n=95)

Ulipristal 10mg (n=94)

PBAC <75
Median % change in total fibroid volume
(range)
Secondary endpoints

9/48 (19%)

86/94 (91%), p<0.001

86/93 (92%), p<0.001

3.0 (-19.7 to 23)

-21.2 (-41.2 to -1.1), p=0.002

-12.3 (-39.1 to 4.3), p=0.006

Median PBAC score, wk 9-12 (range)


Median change from baseline in PBAC, to
wk 9-12
Amenorrhoea, PBAC 2, weeks 9-12

336 (115 to 543)

0 (0 to 5)

0 (0 to 0)

-59 (-216 to 58)

-329 (-571 to -205), p<0.001

-326 (-527 to -226), p<0.001

3/48 (6%)

69/94 (73%), p<0.001

76/93 (82%), p<0.001

25% total reduction in fibroid vol, wk 13

8/45 (18%)

35/85 (41%), p=0.01

33/80 (41%), p=0.01

25% reduction in uterine volume, wk 13

3/47 (6%)

30/88 (34%), p<0.001

24/85 (28%), p=0.006

+3.101.68

+4.251.90, p<0.001

+4.20 1.83, p<0.001

-2.5

-5.0, p=0.10

-2.0, p=0.04

-16.5

-30, p=0.09

-27, p=0.08

-6.0 (-9 to -2)

-9.0 (-13 to -6), p=0.001

-11.0 (-14 to -5), p<0.001

Changes from baseline to week 13


Haemoglobin, g/dL
Pain assessment: SF McGill
Visual analogue scale

10

Discomfort questionnaire
P values: ulipristal vs. placebo

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Ulipristal acetate (Esmya)

dian total volume (cm3) of the three largest fibroids


at baseline was greatest in the 5mg group (79.6,
range 30.3 to 151.0) and smallest in the 10mg group
(47.6, range 24.1 to 110.6). Efficacy analyses were
carried out in the modified ITT and per-protocol populations. The sample size (95 per group) was based
on the requirement to show non-inferiority of
ulipristal to leuprorelin with a power of 90% and a
pre-specified non-inferiority margin of -20%. The
per-protocol population (mITT excluding patients
with major protocol deviations and <80% compliance) was the primary interest for the non-inferiority
analysis. The last observation carried forward method was used for missing values.
The primary endpoint was the proportion of patients
with uterine bleeding at week 13 defined as a PBAC
score <75 for the preceding 4 weeks. In the perprotocol population, similar proportions of patients
in each group reached the primary endpoint, indicating non-inferiority for both doses of ulipristal in controlling bleeding (see table 2, page 7, for further results). [The lower limit of the confidence interval was
more than the prespecified non-inferiority margin of
-20%.] A subsequent superiority analysis showed
that ulipristal 10mg was superior to leuprorelin
(p=0.03).
There were a number of secondary endpoints (see
table 2). All three treatments reduced the volume of
the three largest fibroids and uterine volume, with
the greatest reductions seen with leuprorelin treatment. Median PBAC scores at week 13 were 0 in all
three groups. Excessive bleeding was controlled
more rapidly with ulipristal than with leuprorelin
(p<0.001, both doses vs. leuprorelin). Amenorrhoea
was induced more quickly in ulipristal-treated patients, with bleeding attenuated up to 2 weeks earlier than with leuprorelin treatment (p<0.001). All
three groups showed similar improvements in pain,
quality of life and haemoglobin levels. Approximately half the patients had surgery and for those who
did not have surgery, bleeding, pain and quality of
life improvements were sustained during follow-up
(up to week 38) without treatment.11 Menstruation
returned on average 31-34 days and 43 days after
end of treatment with ulipristal and leuprorelin respectively.

treatment, but volume reduction was maintained for


6 months in those who had been treated with
ulipristal (see figure 1, page 811). The investigators
suggest that this is due to apoptosis of the leiomyoma
cells.
In summary: The efficacy of ulipristal to reduce
bleeding associated with fibroids was non-inferior to
that of leuprorelin. All three treatments groups responded well to treatment, with the majority of patients achieving PBAC scores <75% at 13 weeks. Reduction in fibroid volume was maintained for a longer
time after stopping ulipristal than after stopping
leuprorelin; this was based on exploratory analysis of
patients who did not undergo surgery (approximately
half). The incidence of hot flushes was significantly
higher with leuprorelin treatment, and there may be a
higher incidence of bone resorption with leuprorelin,
compared with ulipristal. The study has limitations
which are the same to those of PEARL I. Surgical outcomes were not assessed, though the numbers and
types of surgery were similar in the three groups.
Treatment was given for only 13 weeks, so long-term
efficacy and safety data are lacking. The duration of
the study is likely to be based on the licensed duration of treatment of leuprorelin: in the US, leuprorelin can be used for up to 3 months to treat excessive bleeding caused by uterine fibroids, prior to surgery.12 In the UK, leuprorelin can be used for up to 6
months.7

Exploratory analysis of the women who did not undergo surgery showed that fibroids began to enlarge
approximately 1 month after stopping leuprorelin

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Ulipristal acetate (Esmya)

Table 2: Results from PEARL II

9;11

Endpoints at week 13

Ulipristal 5mg (n=93)

Ulipristal 10mg (n=95)

Leuprorelin (n=93)

PBAC <75

84/93 (90%)

93/95 (98%)

82/92 (89%)

Difference vs. leuprorelin %, 95% CI

1.2 (-9.3 to 11.8)

8.8 (0.4 to 18.3)

Median % change in total fibroid volume (range)

-36 (-58 to -11)

-42 (-69 to -14)

-53 (-69 to -36)

Difference vs. leuprorelin %, 95% CI

1.23 (0.99 to 1.52)

1.12 (0.91 to 1.38)

Amenorrhoea, PBAC 2

70/93 (75%)

85/95 (89%)

74/92 (80%)

Median time to amenorrhoea

7 days, p<0.001

5 days, p<0.001

21 days

Uterine volume, % change from baseline, median

-20 (-40 to -3)

-22 (-45 to 0)

-47 (-57 to -35)

Haemoglobin, g/dL

12.81.4

12.91.2

12.71.6

SF McGill, score, median (range)

2.0 (0 to 4)

1 (0 to 3)

0 (0 to 4)

SF McGill change from baseline, median

-5 (-11 to -2)

-6 (-14 to -1)

-5.5 (-14.5 to 2)

Uterine fibroid symptom and QoL questionnaire

76.423.2

81.522.1

73.223.0

Serum oestradiol, picogram/mL (median)

64, p<0.001

60.5, p<0.001

25, p<0.001

Moderate to severe hot flushes

11/97 (11%), p<0.001

10/103 (10%), p<0.001

40/101 (40%)

Headache

25/97 (25.8%)

19/103 (18.4%)

29/101 (28/7%)

Mean endometrial thickness

9.4mm, p<0.001

10.7mm, p<0.001

5.1mm

Non-physiological endometrial changes

58%

59%

12%

Endpoints at week 38
11
Patients who did not have surgery

Ulipristal 5mg (n=43)

Ulipristal 10mg (n=45)

Leuprorelin (n=43)

PBAC, median

236 (143 to 387)

141 (103 to 311)

239 (103 to 458)

-73 (-242 to 65)

-96 (-155 to -6)

-115 (-161 to 19)

29.1 (9.5 to 55.4)

17.7 (7 to 47.6)

32.7 (17 to 65.3)

-44.8% (-75.1 to -12)

-54.8% (-75 to 1.8)

-16.5% (-41.1 to 19.3)

Uterine volume, % change from baseline, median

-21.8% (-37.7 to -5.6)

-14.9 (-24.6 to 4.7)

-11.1 (-22.9 to -1.0)

SF McGill score, median

2 (0 to 6)

2.0 (0.0 to 6.0)

1.0 (0.0 to 5.0)

SF McGill change from baseline, median

-3.0 (-9 to -1)

-4.0 (-10 to -1)

-2.0 (-8 to 1)

VAS score, median

8.0 (0 to 34)

9.0 (0 to 24)

3.0 (0 to 32)

VAS change from baseline, median

-20 (-43 to -1)

-27 (-46 to -8)

-23 (-43 to 0)

UFS QoL, mean

38.724.7

25.918.6

54.724.9

UFS QoL, change from baseline, mean

-25.423.6

-20.720.1

-0.8 25.8

Adverse events

PBAC, median change from baseline


Total volume of 3 largest fibroids, median
% change from baseline, median

A lower limit of the CI of more than -20% indicates non-inferiority.


A lower limit of the CI of more than zero indicates superiority.
P values: ulipristal vs. leuprorelin
UFS-QoL: uterine fibroid symptom and quality of life questionnaire, symptom score 0-100, higher score indicating increased severity

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Page 8

Ulipristal acetate (Esmya)

Adverse events
In PEARL I, the rate of adverse events did not differ
significantly between the three groups.3 The most
common adverse events in the ulipristal group were
headache (4-10%) and pain, discomfort or tenderness in the breasts (2-6%), but these events did not
occur to a significantly greater extent than in the
placebo group. Less than 3% of patients experienced hot flushes. There was no significant difference between the treatments in mean endometrial
thickness. Two serious adverse events: one event of
a fibroid protruding through the cervix (placebo
group) and one event of uterine haemorrhage (10mg
group). Three serious adverse events occurred within 1 month of follow up: one case of breast cancer
(placebo group) and one event each of ovarian
haemorrhage and uterine haemorrhage (5mg
group). One case of menometrorrhagia (excessive,
prolonged uterine bleeding at irregular, frequent
intervals, placebo group) and one of uterine haemorrhage (10mg group) occurred during follow-up to 6
months. Oestradiol levels after ulipristal treatment
were consistent with midfollicular-phase levels for a
premenopausal woman (60-150picogram/mL).

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In PEARL II, moderate to severe hot flushes occurred


in four times as many patients treated with leuprorelin than ulipristal. No significant differences between the ulipristal and leuprorelin groups were seen
in the proportion of patients reporting other side effects, or discontinuing treatment because of adverse
effects. Endometrial thicknesses were greater in patients treated with ulipristal but biopsy examinations
gave no reason for concern; there was no dysplasia or
neoplasia identified. Non-physiological endometrial
changes occurred in five times as many patients treated with ulipristal than with leuprorelin, but after 6
months of treatment-free follow-up in women who
did not have surgery, the changes were low and similar in all three study groups (6-7%). Median levels of
one of the four markers of bone turnover monitored
during the study (CTX) were significantly lower at the
end of treatment in the ulipristal groups than in the
leuprorelin group (158 to 175 vs. 258 mcg/mmol,
p<0.00111), which may indicate a higher rate of bone
resorption in patients receiving leuprorelin.

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Page 9

Ulipristal acetate (Esmya)

Health economics / budget impact model


PreGlem UK have provided the follow budget impact model.13 An interactive model is available from them; local
data can be inputted into this model.
Produced by the London New Drugs Group. Correspondence to Alexandra Denby, Regional MI Manager, London
Budget Impact Model

13

Cost per treatment cycle

Leuprorelin (Prostap SR)

Service provision costs


Specialist diagnosis (20 mins)
Initial of treatment
Follow-on administration (GP
consultation)
Total cost of treatment
administration
Follow-up by specialist (20 mins)
Total service provision costs
Drug cost
Total drug cost
Total cost
Cost to Acute Trust (2 x specialist
consults plus drug costs)
Cost to Primary Care (GP consults plus
drug costs)

Goserelin (Zoladex)

Ulipristal (Esmya)

45.33

45.33

45.33

0.00
90.00

0.00
60.00

0
0

135.33

105.33

45.33

45.33
180.66
75.24 per injection
4 injections given
300.96
481.62

45.33
150.66
14
65.00 per injection
3 injections given
195
345.66

45.33
90.66
114.13 per month
3 months treatment
343.39
433.05

45.33 x 2 + 75.24 =
165.90
30 x 3 + 75.24 x 3
315.72

45.33 x 2 + 65 =
155.66
30 x 2 + 65 x 2
190

45.33 x 2 + 114.13 =
204.79
228.26

Budget impact considering patient


25 patients
25 patients
25 patients
numbers
Total cost
12,040.50
8,641.50
10,826.25
Assumptions made in model:
First initiation of GnRH agonist is made by the consultant as part of the diagnosis. Subsequent administrations are made
in primary care.
No GP consultation for ulipristal prescription.
4 months treatment with Prostap SR is compared with 3 months of Zoladex and of ulipristal, based on customer insight to
the average number of months of GnRH agonist treatment used.
All default consultation/administration costs are based on actual costs estimated by the Personal Social Services Research
Unit, not on National Tariff Prices which would be the commissioning cost. Tariff prices are likely to be higher.
GPs will receive a fee for administering GnRH agonist.

Table 3: Basic NHS costs


Treatment
Ulipristal
(Esmya)

Dose

Cost

5mg orally daily for a maximum of 3 months.

Goserelin (Zoladex)

3.6mg by SC injection every 28 days for a maximum of 3 months, in women


7
who have anaemia due to uterine fibroids, prior to surgery.

65.00 per 3.6mg


14
injection

Leuprorelin acetate
(Prostap SR DCS)

3.75mg by SC or IM injection every month for 3-4 months (max 6 months),


7
to reduce size of uterine fibroids and associated bleeding prior to surgery.

75.24 per 3.75mg


14
injection

Triptorelin
(Decapeptyl SR)

3mg by IM injection every 4 weeks for at least 3 months, max 6 months, to


7
reduce size of uterine fibroids.

69.00 per 3mg injection

Cost of
hysterectomy

Without major cc: 2,599 x MFF


With major cc: 3,684 x MFF

PRODUCED

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DOCUMENT NOT TO BE USED FOR COMMERCIAL AND MARKETING PURPOSES.

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Page 10

Ulipristal acetate (Esmya)

Produced by the London New Drugs Group. Correspondence to Alexandra Denby, Regional MI Manager, London Medicines Information Centre, Northwick
Park Hospital, Watford Road, Harrow, Middlesex.
HA1 3UJ. e-mail: alexandra.denby@nhs.net. This
document reflects the views of the LNDG and may
not reflect those of the reviewers. The LNDG would
like to thank Dr Alvan Priddy, Consultant Gynaecologist, NWLH NHS Trust for his comments on this
review. PregLem UK has commented on this review.
Embase: ULIPRISTAL/ AND UTERUS MYOMA
Medline: ulipristal.af and LEIOMYOMA/

Reference List
(1) Summary of Product Characteristics. Esmya
5 mg Tablets (ulipristal acetate). Date of
first authorisation: 23 February 2012.
Preglem UK http://www.medicines.org.uk

(8) Summary of opinion (initial authorisation).


Esmya, ulipristal acetate.
EMA/679632/2011. Committee for Medicinal
Products for Human Use (CHMP).
www.ema.europa.eu
(9) Donnez J, Tomaszewski J, Vzquez F et al.
Ulipristal acetate versus leuprolide acetate
for uterine fibroids. (PEARL II). N Engl J Med
2012; 366(5):421-432.
(10) Donnez J, Tatarchuk TF, Bouchard P et al.
Supplementary appendix: Ulipristal acetate
versus placebo for fibroid treatment before
surgery. (PEARL I). N Engl J Med 2012; 366
(5). http://www.nejm.org/
(11) Donnez J, Tomaszewski J, Vzquez F et al.
Supplementary appendix: Ulipristal acetate
versus leuprolide acetate for uterine fibroids.
(PEARL II). N Engl J Med 2012; 366(5). http://
www.nejm.org/

(2) Fibroids. Document ID: 1236, version 25.


Last checked 04/01/12. Willacy, H.
www.patient.co.uk

(12) Lupron Depot 3.75mg (leuprolide acetate for


depot suspension). Rev 1/2012. Abbott Laboratories http://www.lupron.com/
prescribing-information.cfm

(3) Donnez J, Tatarchuk TF, Bouchard P et al.


Ulipristal acetate versus placebo for fibroid
treatment before surgery. (PEARL I). N Engl
J Med 2012; 366(5):409-420.

(13) Esmya Budget Impact Model. April 2012. PG


-ADV 12/0018. Preglem UK

(4) McCarthy-Keith DM, Armstrong AY. Innovations in uterine fibroid therapy. Therapy
2011; 8(2):189-200.

(14) Department of Health, Welsh Government.


National Health Service England and Wales.
Drug Tariff April 2012. TSO, London.,
2012.http://www.ppa.org.uk/edt/
April_2012/mindex.htm

(5) Duhan N. Current and emerging treatments


for uterine myoma - an update. International Journal of Women's Health 2011; 3:231241.
(6) Clinical Guideline 44. Heavy menstrual
bleeding. National Collaborating Centre for
Women's and Children's Health http://
www.nice.org.uk
(7) British National Formulary 63rd edition.
March 2012. Ryan, RSM. editor. British
Medical Association and Royal Pharmaceutical Society of Great Britain. http://
www.bnf.org/bnf/

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Page 11

Ulipristal acetate (Esmya)

Appendix 1: PBAC score3


The pictorial blood-loss assessment chart (PBAC) is a validated method used to assess menstrual blood loss. 3
Monthly scores ranged from 0 to >500, with higher scores indicating more bleeding.
Patients record the number of tampons or sanitary pads they use and the extent of soiling with blood.
Menorrhagia was defined as a PBAC score of >100 during one menstrual period, corresponding to a blood loss of
>80mL.
A PBAC score of 400 corresponds to a blood loss of approximately 300mL, or the use of approximately 80 tampons
or pad.
Appendix 2: Measurement of Discomfort due to Uterine Fibroids Questionnaire 10
Seven symptoms evaluated: bleeding, abdominal pressure, urination frequency, daily activity, fatigue, mood, sexual activity.
Minimum score 0, maximum worst score 28.
This was developed by the study sponsor using questions from other validated questionnaires, because there was
no disease specific quality of life questionnaire validated in the languages in the participating countries.

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London New Drugs Group APC/DTC Briefing