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Ulipristal acetate (Esmya®)

May 2012 London New Drugs Group APC/DTC Briefing

THIS IS AN NHS DOCUMENT NOT TO BE USED FOR COMMERCIAL AND MARKETING PURPOSES.PRODUCED TO INFORM LOCAL DECISION-MAKING USING THE BEST AVAILABLE EVIDENCE AT THE TIME OF PUBLICATION.

May 2012

ULIPRISTAL ACETATE (ESMYA®)

Summary

The drug and the review

In April 2012 ulipristal acetate (Esmya®), was launched in the UK for pre-operative treatment of mod-

erate to severe symptoms of uterine fibroids in adult women of reproductive age.

Ulipristal, a selective progesterone receptor modulator, reduces fibroid volume by inhibiting cell prolif-

eration 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 wom-

en 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, sur-

gery 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 mefenam-

ic acid.

PEARL I

The aim of PEARL I was to compare the efficacy and safety of ulipiristal 5mg (n=96), 10mg (n=98) or pla-

cebo (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.

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.

Contents

Summary 1

Background 3

Ulipristal 3

Clinical efficacy 4

PEARL I 4PEARL II 5

Adverse events 8

Budget Impact model 9

References 10

Appendices 11

THIS IS AN NHS DOCUMENT NOT TO BE USED FOR COMMERCIAL AND MARKETING PURPOSES.PRODUCED TO INFORM LOCAL DECISION-MAKING USING THE BEST AVAILABLE EVIDENCE AT THE TIME OF

PUBLICATION.

London New Drugs Group

APC/DTC Briefing Document

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

[email protected]

Further copies of this document are

available from URL:

www.nelm.nhs.uk






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 pa-

tients who did not undergo surgery, a more sustained effect on fibroid volume was seen up to six months after stopping treat-

ment 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 signifi-

cant 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 neo-

plasia 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 proges-

terone 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 indi-

cation 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.






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 wom-

en than in Caucasian women, and Asian women have

the lowest incidence.2 Many are undiagnosed and

while most women with fibroids do not have symp-

toms, 20-50% require clinical intervention.4 The

most common symptoms are pelvic pain, pelvic pres-

sure and menorrhagia, which can result in iron-

deficiency anaemia.2;4

Women may also experience

infertility, miscarriage, pre-term deliveries and com-

plications in late pregnancy.4 Management is phar-

macological or surgical.

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 byundesirable 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 oestogen-

dependent.5 GnRH agonists reduce hormonal stimu-

lation of fibroids and can reduce fibroids to approxi-

mately 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 hysterec-tomy 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

Surgery is indicated when the uterus is greatly en-

larged, pressure symptoms are present, medical

management cannot control the symptoms and fer-

tility is an issue.2 A hysterectomy is the only defini-

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 myo-

mectomy is that the fibroids may reappear and re-

quire 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 preferen-

tially 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 modula-

tor 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 proges-

terone.3;8

Ulipristal reduces fibroids through inhibi-

tion of cell proliferation and induction of apoptosis.1

Treatment with ulipristal (Esmya® ) is 5mg daily start-

ed 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, un-

less the dose was missed by more than 12 hours, in

which case the missed dose should not be taken andthe 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

Special populations

No dose adjustment is required in patients with mild

or moderate renal impairment or mild hepatic impair-

ment.1 Due to the lack of data in patients with severe

renal impairment and moderate-severe hepatic im-

pairment, ulipristal should not be used in these pa-tients. 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 geni-

tal bleeding of unknown cause or in those who are

pregnant/breast feeding.

Interactions

Contraceptive methods containing progestagens

should not be used concomitantly; non-hormonal

methods of contraception are recommended.1






Ulipristal acts as a selective progesterone recep-

tor modulator and has inhibitory effects on the

progesterone receptor; hormonal contraceptives

are likely to compete with ulipristal for this re-

ceptor. Medicinal products containing progester-

one should not be taken within 12 days of stop-

ping 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 sub-

strates.1

Concomitant use with moderate/potent CYP3A4

inhibitors (e.g. erythromycin, ketoconazole, ri-

tonavir) or inducers (e.g. rifampicin, carbamaze-

pine, 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 indi-

cating 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 fibroid-

related anaemia (Hb ≤10.2g/dL).3 Uterine bleeding

was assessed using the PBAC; menorrhagia was de-

fined 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, se-

vere coagulation disorder, uterine polyp >2cm, pre-

vious 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

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 fi-

broids who were planning to undergo surgery.3 Pa-

tients were randomised to treatment with 5mg

(n=96), 10mg (n=98) or placebo (n=48) per day, strati-

fied 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 giv-

en. 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 place-

bo 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 240patients 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 pre-

ceding 28 days) of <75, and the change in total fibroid

volume from screening to week 13. Menstrual bleed-

ing was controlled in 91% of the 5mg group and 92%

of the 10mg group, compared with 19% of the place-

bo group (further results in Table 1). Clinically and

statistically significant reductions in uterine fibroid

size was seen in both ulipristal groups (-21% in the5mg 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 com-

pared with placebo treatment. Excessive bleeding

was controlled in >75% of patients receiving

ulipristal by day 8, compared with 6% receiving

placebo.






Amenorrhoea (PBAC 28-day score ≤2 at weeks 9

and 13) was achieved in significantly more pa-

tients 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 great-

er with ulipristal treatment.

Pain, as assessed by the Short-Form McGill Pain

Questionnaire, (range 0-45, higher scores indicat-

ing more pain), Visual Analogue Scale (0=none,

100=worst) and discomfort associated with fi-

broids (score 0-28, higher indicating more dis-

comfort, see Appendix 2) were significantly im-

proved with ulipristal treatment.

Approximately half the patients in each group had

fibroid surgery after completing the study. Menstru-

ation 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

anaemia at baseline. Bleeding was controlled within

8 days of starting treatment. Self-reported pain and

discomfort due to fibroids was also improved signifi-

cantly 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 intra-

muscular 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. Approxi-

mately 10% of enrolled patients were black. The me-

Table 1: Results from PEARL I3;10

Primary endpoints Placebo (n=48) Ulipristal 5mg (n=95) Ulipristal 10mg (n=94)

PBAC <75 9/48 (19%) 86/94 (91%), p<0.001 86/93 (92%), p<0.001

Median % change in total fibroid volume

(range)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

Secondary endpoints

Median PBAC score, wk 9-12 (range) 336 (115 to 543) 0 (0 to 5) 0 (0 to 0)

Median change from baseline in PBAC, to

wk 9-12-59 (-216 to 58) -329 (-571 to -205), p<0.001 -326 (-527 to -226), p<0.001

Amenorrhoea, PBAC ≤2, weeks 9-12 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

Changes from baseline to week 13

Haemoglobin, g/dL +3.10±1.68 +4.25±1.90, p<0.001 +4.20 ±1.83, p<0.001

Pain assessment: SF McGill -2.5 -5.0, p=0.10 -2.0, p=0.04

Visual analogue scale10

-16.5 -30, p=0.09 -27, p=0.08

Discomfort questionnaire -6.0 (-9 to -2) -9.0 (-13 to -6), p=0.001 -11.0 (-14 to -5), p<0.001

P values: ulipristal vs. placebo






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 pop-

ulations. 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% compli-

ance) was the primary interest for the non-inferiority

analysis. The last observation carried forward meth-

od 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 per-

protocol population, similar proportions of patients

in each group reached the primary endpoint, indicat-

ing non-inferiority for both doses of ulipristal in con-

trolling bleeding (see table 2, page 7, for further re-

sults). [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 (seetable 2). All three treatments reduced the volume of

the three largest fibroids and uterine volume, with

the greatest reductions seen with leuprorelin treat-

ment. 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 pa-

tients, with bleeding attenuated up to 2 weeks earli-

er than with leuprorelin treatment (p<0.001). All

three groups showed similar improvements in pain,

quality of life and haemoglobin levels. Approximate-ly 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 re-

spectively.

Exploratory analysis of the women who did not un-

dergo surgery showed that fibroids began to enlarge

approximately 1 month after stopping leuprorelin

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 re-

sponded well to treatment, with the majority of pa-

tients achieving PBAC scores <75% at 13 weeks. Re-

duction 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 out-

comes 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 dura-

tion of treatment of leuprorelin: in the US, leupro-

relin can be used for up to 3 months to treat exces-

sive bleeding caused by uterine fibroids, prior to sur-

gery.12 In the UK, leuprorelin can be used for up to 6months.

7






Table 2: Results from PEARL II9;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 12.8±1.4 12.9±1.2 12.7±1.6

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 76.4±23.2 81.5±22.1 73.2±23.0

Serum oestradiol, picogram/mL (median) 64, p<0.001 60.5, p<0.001 25, p<0.001

Adverse events

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

Patients who did not have surgery11

Ulipristal 5mg (n=43) Ulipristal 10mg (n=45) Leuprorelin (n=43)

PBAC, median236 (143 to 387) 141 (103 to 311) 239 (103 to 458)

PBAC, median change from baseline -73 (-242 to 65) -96 (-155 to -6) -115 (-161 to 19)

Total volume of 3 largest fibroids, median 29.1 (9.5 to 55.4) 17.7 (7 to 47.6) 32.7 (17 to 65.3)

% change from baseline, median -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 38.7±24.7 25.9±18.6 54.7±24.9

UFS – QoL, change from baseline, mean -25.4±23.6 -20.7±20.1 -0.8 ±25.8

† 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






Adverse events

In PEARL I, the rate of adverse events did not differsignificantly between the three groups.

3 The most

common adverse events in the ulipristal group were

headache (4-10%) and pain, discomfort or tender-

ness 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 experi-

enced hot flushes. There was no significant differ-

ence 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 with-in 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 haemor-

rhage (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).

In PEARL II, moderate to severe hot flushes occurred

in four times as many patients treated with leupro-

relin than ulipristal. No significant differences be-tween the ulipristal and leuprorelin groups were seen

in the proportion of patients reporting other side ef-

fects, or discontinuing treatment because of adverse

effects. Endometrial thicknesses were greater in pa-

tients 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 treat-

ed 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 simi-

lar in all three study groups (6-7%). Median levels ofone 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.






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 Model13

Cost per treatment cycle Leuprorelin (Prostap SR) Goserelin (Zoladex) Ulipristal (Esmya® )

Service provision costs

Specialist diagnosis (20 mins) £45.33 £45.33 £45.33

Initial of treatment

Follow-on administration (GP

consultation)

£0.00

£90.00

£0.00

£60.00

0

0

Total cost of treatment

administration£135.33 £105.33 £45.33

Follow-up by specialist (20 mins) £45.33 £45.33 £45.33

Total service provision costs £180.66 £150.66 £90.66

Drug cost£75.24 per injection

4 injections given

£65.00 per injection14

3 injections given

£114.13 per month

3 months treatment

Total drug cost £300.96 £195 £343.39

Total cost £481.62 £345.66 £433.05

Cost to Acute Trust (2 x specialist

consults plus drug costs)

£45.33 x 2 + £75.24 =

£165.90

£45.33 x 2 + £65 =

£155.66

£45.33 x 2 + £114.13 =

£204.79

Cost to Primary Care (GP consults plus

drug costs)

£30 x 3 + £75.24 x 3

£315.72

£30 x 2 + £65 x 2

£190£228.26

Budget impact considering patient

numbers25 patients 25 patients 25 patients

Total cost £12,040.50 £8,641.50 £10,826.25Assumptions 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 Dose Cost

Ulipristal

(Esmya® )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

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

£65.00 per 3.6mg

injection14

Leuprorelin acetate

(Prostap SR DCS)

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

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

£75.24 per 3.75mg

injection14

Triptorelin

(Decapeptyl SR)

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

reduce size of uterine fibroids.7

£69.00 per 3mg injection7

Cost of

hysterectomy

Without major cc: £2,599 x MFF

With major cc: £3,684 x MFF






Produced by the London New Drugs Group. Corre-

spondence to Alexandra Denby, Regional MI Manag-

er, London Medicines Information Centre, NorthwickPark Hospital, Watford Road, Harrow, Middlesex.

HA1 3UJ. e-mail: [email protected]. 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 Gynaecol-

ogist, 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

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

Last checked 04/01/12. Willacy, H.

www.patient.co.uk

(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.

(4) McCarthy-Keith DM, Armstrong AY. Innova-

tions in uterine fibroid therapy. Therapy

2011; 8(2):189-200.

(5) Duhan N. Current and emerging treatments

for uterine myoma - an update. Internation-

al Journal of Women's Health 2011; 3:231-

241.

(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 Pharmaceu-

tical Society of Great Britain. http://

www.bnf.org/bnf/

(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, Vázquez 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, Vázquez 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/

(12) Lupron Depot 3.75mg (leuprolide acetate for

depot suspension). Rev 1/2012. Abbott La-

boratories http://www.lupron.com/

prescribing-information.cfm

(13) Esmya Budget Impact Model. April 2012. PG-ADV 12/0018. Preglem UK

(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

mailto:[email protected]


http://www.medicines.org.uk/


http://www.patient.co.uk/


http://www.nice.org.uk/



http://www.bnf.org/bnf/



http://www.ema.europa.eu/


http://www.nejm.org/





http://www.lupron.com/prescribing-information.cfm



http://www.ppa.org.uk/edt/April_2012/mindex.htm























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 Questionnaire10

Seven symptoms evaluated: bleeding, abdominal pressure, urination frequency, daily activity, fatigue, mood, sexu-

al 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.

Ulipristal_May12b

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