Ulipristal Acetate in Uterine Fibroids

8/16/2019 Ulipristal Acetate in Uterine Fibroids

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PROFILE

Drugs

2012: 72 (8) : 1075-1035

0012 0667/12/0008 1075/S55 55/0

Adis © 2012 Sprtnger International Publishing AG. Ali rights reserved.

liprist l

cetate

n Uterine Fibroids

mie

D Croxtall

Abstract

1075

1. Pharm acod ynam ic Protile 1077

2. Pha rm aco kinetic Pratile 1078

3. Therapeutic Efficacy

1079

4 . Tolerability 1081

5. Dosage an d Adm inistration

1083

6. Ulipristal A ce ta te ; Current Status in Uterine Leiomy om a 1084

Ulipristal acetate, a selective progesterone-receptor

in vitro

It also mod-

In two randomized, double-blind, multinational

trials of

13

weeks' duration in women aged

5

mg/day controlled ex-

5

mg/day was more ef-

Uterine bleeding was rapidly controlled by ulipristal

5 mg/day became amenorrhoeic within the first

cantly more rapidly for recipients

A significantly greater median reduction from base-

n total fibroid volume was observed for recipients

5 mg once daily than recipients of

g 13 weeks' treatment (coprimary

Ulipristal acetate was generally well tolerated in

Features and properties of ulipristal acetate (Esmya' )

Featured Indication

Pre operative treatment of moderate to severe symptoms of

uterine fibroids in adult women of reproductive age

Mechanism of action

Selective progesterone-receptor

modulator

Dosage and administration

Route of administration

Dose

Oral

Frequency of administration

5 m g

Once daily for up to 3

months

Pharmacoi inetlc profile oral administration of a single

mg dose) in the fasted state. All values are means, unless

stated otherwise

Peak plasma concentration (Cmax) 23.5 ng/mL

Median time to Cmax -1 h

Area under the plasma concentration- 61.3 ng • h/mL

time curve from time zero to infinity

Clearance

Terminal elimination half-life

=100

Uh

=3 8

h


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1076

Uterine fibroids (leiomyomas) are the most com-

mon form of benign gynaecological tumours and

occur in 20-40% of women of reproductive age.

They are mostly derived from myometrial smooth

muscle cells and connective tissue fibroblasts and

characteristically present as well encapsulated

fibrotic tissue within the wall of the ute ru s.' ' ' Al-

thou gh there is some evidence that they may arise

by somatic mutation,'^'^' fibroids are associated

with a low propensity for malignant transforma-

tion.'' ' '^' African-American women have a higher

risk of developing fibroids than Caucasian women,

which indicates there may be a genetic link.'^'^'

Many uterine fibroids go undiagnosed, and the

majority of women are asymptomatic.'^' However,

approximately 20-50% of women with fibroids

will require some kind of clinical intervention.'^'

In these wom en, the most comm on sy mptom s are

menorrhagia and iron-deficiency anaemia, which

may lead to chronic fatigue. ' Other sym ptoms,

such as pelvic pain and dysmenorrhoea and pres-

sure effects, which may lead to urinary problems,

also have a significant im pact on q uality of

life.'' -'

' '

In add ition, wom en with fibroids may experience a

higher risk of infertility, miscarriage, preterm deliv-

eries and complications in late pregnancy.' ^' '

Symptomatic fibroids are the leading reason

for hysterectomy, accounting for more than one-

third of all procedures performed, thus incurring

considerable healthcare costs. ' '^•'^' Hysterectomy

is the only procedure for permanent removal of

fibroids but is not appropriate for women who

wish to retain fertility.'' '*' The surgical removal

of fibroids without hysterectomy (myomectomy)

is an alternative option for women who wish to

become pregnant, but this procedure does not

prevent recurrence of the condition.' ' '*' Uterine

artery embolization is a less invasive alternative

but may compromise pregnancy due to the risk

of premature ovarian failure.' '^' All of these pro-

cedures are associated with considerable post-

operative morbidity. ' '^ '

There are several non-surgical treatments for

fibroids, both hormonal (contraceptives [either

oral or intrauterine devices], progestogens, danazol,

However, many of these treatments have q

tionable efficacy and are associated with adv

tolerability; consequently, the GnRH agonist

prolide acetate was, until recently, the only appro

pharmacological treatment for the condition.

Therefore, there still remains an unmet need

an effective treatment of fibroids that is

well tolerated in the longer term and that o

women the option of uterine preservation and

retention of fertility.

Although the underlying aetiology is po

understood, hormonal exposure, over expres

of growth factors, or genetic changes may pl

role in the pathogenesis of fibroid formatio

Fibroids usually develop during the reproduc

years and regress following the menopause,

plicating a growth-promoting role for estro

In vivo

models have shown that grow th horm

may also act synergistically w ith estrogens in fib

growth, and the incidence of fibroids is highe

wom en w ith acromegaly.'^ '^' ' Mo re rece

several lines of biochemical and clinical evid

have implicated a critical role for proge steron

the pa thogene sis of uterine fibroids.'^^ ^^'

Selective progesterone modulators (SPR

are a new class of progesterone-receptor lig

that exert tissue-selective agonist, antagonis

mixed agonist/antagonist activity in target cell

This class of compounds has numerous app

tions in female medicine, including emerg

contraception, long-term contraception, te

nation of pregnancy, premenstrual syndrom e

in assisted reproduction.'^''-' ' Many SPRMs

also been shown to inhibit endometrial cell p

feration and reduce endometriotic lesions in an

studies.'^''^^' This property has led to their ev

tion for the treatment of uterine fibroids, dysf

tional uterine bleeding and endometriosis.'^^'

Ulipristal acetate (Esmya™) is an SPRM

was initially approved as an emergency co

ceptive (reviewed by McKeage and Croxtall)

It has recently received approval for the t

ment of uterine fibroids'-'^' based on the effi

outcomes of two pivotal phase III trials, PE

I (PGL4001 [ulipristal acetate] Efficacy As


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1077

reviews its clinical efficacy and tolerab ility in

M edical literature on the use of ulipristal acetate

s since 1996 (including M E D LI N E and

clinical tdal registries/databases and websites

. Searches were last update d 17 April 2012.

1 Pharmacodynamic Profile

The pharmacodynamic properties of ulipristal

iew of features tha t are relevant to the manag e-

om the Electronic Medicines Compendium (EM C)

ary of product characteristics.'^ '1 R and om -

0 mg/day on hypothalamic-pituitary-ovarian axis

ion following 3 m on ths ' treatm ent (n = 46)t̂ l̂

12 weeks'

n = 41),P̂ l which are discussed briefly.

Ulipristal acetate is an orally active SP RM tha t

inity to the progesteron e receptor

coid receptor antago nist activity of ulipris-

ne.t''*' indicating th at it belongs to a new class of

In vitro ulipristal acetate inhibits the prolifera-

a cells by dow n-regulating

• Ulipristal acetate dow n-regulates the expression

of vascular endothelial growth factors (VEGFs),

adrenomedullin and their receptors and m odulates

the ratio of progesterone isoforms in leiomyoma

cells but not in normal myometrial cells.''*^' Simi-

larly, ulipristal acetate enhances the breakdown

of the extracellular matrix of leiomyoma cells by

increasing the expression of metalloproteinases

and decreasing the expression of inhibitors of

metalloproteinases and collagen, with no com-

parable effects observed in cultured myometrial

• Th e prin cipa l effect of ulipris tal acetate is to

inhibit or delay ovulation and induce amenor-

rhoea without down-regulating estradiol levels or

inducing endometrial hyperplasia.t^*' The mech-

anism by which this occurs is not fully clarified, but

it may act by inhibiting or delaying the luteinising

hormone (LH) surge, postponing LH peak if LH

surge has already started, or by directly inhibiting

follicular rupture.t'^''*^

• Ulipristal acetate inhibited ovulation and norm al

uterine bleeding in healthy women.'^^' Anovula-

tion rates were significantly (p


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Cro

•

Un like mifepristone, ulipristal acetate does

not appear to alter endometrial matrix or vascu-

lar morph ology. Following 12 weeks' treatm ent

with ulipristal acetate 2,5, 5 or

10

mg/day, endo-

metrial vessels, collagen network and messenger

RNA (mRNA) levels of VEGF-A were identical

to baseline during the luteal phase,'^^' In c ontra st,

mifepristone-induced amenorrhoea was associated

with increased microvessel density and glucocor-

ticoid receptor expression and decreased stromal

VEGF expression,' ' '^'

• How ever, treatmen t with SP RM s may result

in changes in the histological architecture of the

endometrium,''*^''*^' Biopsies obta ined from wo men

who had received 3 months' treatment with one

of four different progesterone-receptor modula-

tors (which included ulipristal acetate) revealed

evidence of glandular dilatation with each agent

that was histologically distinct from proliferative

or secretory endometrium,' ^' ^' Rather, the his-

tological changes were designated as progester-

one-receptor modulator-associated endometrial

changes (PAEC) that should not be confused

with endo me trial '^^'^'

2 Pharmacokinetic Profiie

There are currently no fully published data re-

garding the pharmacokinetics of ulipristal acetate

in women with uterine fibroids. Therefore, this

section discusses briefly the limited pharmaco-

kinetic data in healthy female volunteers avail-

able from the EMC summary of product char-

acteristics focusing on, where possible, the ap-

proved dosage of ulipristal acetate

5

mg/day,'^^'

• Ulipristal acetate is rapidly abso rbed following

oral administration, A mean maximum plasma

concentration (Cn,ax) of 23 5 ng/m L w as achieved

in a median time of =1 hour (t^ax) following ad-

ministration of a single dose of ulipristal acetate

5mg, The corresponding mean area under the

plasma-concentration time curve from time zero

to infinity (AUC^) value was 61,3ng«h/mL,'^^l

• The major active me tabolite of ulipristal ace-

tate, mono-N -demethylated-ulipristal acetate, has a

• Coadministration of oral ulipristal ace

30 mg w ith a high-fat mea l resulted in a C

that was approximately 45% lower, a dela

tmax (from a median of 0.75 to 3 hours) and

A U C ^

tha t was 25% higher than with the

ed state.'^^l Similar results were observed

the active mon o-N-dem ethylated metabolite.

effect of food is not thought to be clinic

relevant,'^^'

• Ulipristal acetate is highly boun d (>98%

plasma proteins that include albumin, a-1-

glycoprotein, high-density liporotein cholest

and low-density lipoprotein cholesterol,'-'^'

• After inges tion, ulipris tal ace tate is extensi

metabolized in the liver by cytochrome P

(CYP) 3A4 to its active mono-N-demethyla

metabolite and subsequently to di-N-deme

lated metabolites that are inactive,'^^'

• The main route of elimination of ulipr

acetate is throug h the faeces, with


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A cetate: Adis Drug

Profile

1079

are no pharmac okinet ic da ta available

in

women with impaired renal

as a result of its

is

ed to alter the elimination of ulipristal acetate,

in increased exposure (section 5).'^^

3 Therapeutic Efficacy

The chnical efficacy of oral ulipristal acetate 5

was evaluated in two, fully pub-

shed, random ized, double-blind, pa rallel-group,

I)'^^' or active-

ro l led , doub le -dummy (PEA RL

phase III trials in wom en aged 18-50 years

and excessive uterine

Uterine bleeding was assessed using a self-

in which scores range from 0 to >500 ,

had a PBAC score >100 during

1

to 8 of

menst ruat ion,

a

myomatous uterus

in size to a uterus of


6/12

1080

ro

Table i Efficacy of oral uliprislal acetate in adult women with uterine fibroids. Results from the pre-planned 13-week analyses of the

domized,

double-blind, (double-dumm yl^'l), parallel-group, multinational, phase III PEARL trials in women aged 1 8-50 years with sympto

fibroids and excessive uterine bleeding.P^'^^ Efficacy analyses were evaluated using the modified intent-to-treat'^i or per-protocolP'i

ulation,

and missing values were imputed using the last observation during the preceding 28 days carried fonward

Treatment regimen

(mg/day)'^

No .

of

évaluable

pts

PBAC score


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Ad is Drug Profile

1081

In PE A R L I, a significantly greater median re-

5 mg once-daily

weeks' treatm ent in the PE A R L I trial

In P E A R L II, there was no significant differ-

I ) . ' '

However, by week 38 of the follow-

- 44 .8 %

in the ulipristal

5 mg/day group a nd

-16 .5%

in the leupro-

Ulipristal acetate also reduced uterine volume

bo th trials following 13 we eks' treatm ent. In

5 mg /day achieved at least a

% reduction in uterine volume than recipients

vs 6%; p


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1082

ro

acetate 3.75 mg on ce-m onthly grou p over the

same period in PEARL II . I"

• In the PE A R L I trial,'^*' the incidence of ad-

verse events in recipients of ulipristal acetate

5 mg/da y w as similar to tha t in patients receiving

placebo. There was no significant difference be-

tween the treatment arms in the frequency of any

adverse event with an incidence > 3% (figure l).'^^

The most com mon adverse events were head ache

and breast pain, tenderness or discomfort; the

incidence of hot flush was


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Hot flush

Headache

Procedural pain

Abdominal pain

Nausea

Fatigue

Anaemia

Nasopharyngitis

Acne

Breast pain

Influenza

insomnia

Pharyngitis

n Ulipnsfal acetate 10 mg/day

D Ulipristal acetate 5 mg/day

H Leuprolide acetate

^ ^

_e

10

20 30 40 50

Percentage of patients

60 70

2. Comparative tolerability of oral ulipristal acetate in aduit women aged 18-50 years with uterine fibroids. The most frequently reported

of

>5

in any treatment arm) adv erse events from the random ized, doubie-blind, double-dumm y, m ultinational, phase III PEARL II

Adverse events that occurred after

the

first dose

of the

study dnjg

and up to

week

17 are

included. Patients received

13

weeks

5 n = 97) or 10 mg/day n = 103) or intramuscular leuprolide acetate 3.75 mg once monthly (n = 101

,

e=zer

vs

leuprolide ac etate.

a

6-month treatment-free follow-

the changes had mostly disappeared in

t

[3637]

5 Dosage nd Administration

For adult women with uterine fibroids, the rec-

of oral ulipristal a cetate is one

mg tablet once daily, w hich may be taken with

dur-

g the first week of the menstrual cycle and the

not exceed 3 months.

a patient misses a dose, treatment should re-

as

quickly

as

possible.

If the

dose

was mis-

d

by

more than

12

hours,

the

patient should

the

missed dose

and

resume

the

normal

dos-

those with uterine, cervical, ovarian

or

breas

cancer.

The

concomitant use

of

progestogen-only

pills, a

progestogen-releasing intrauterine device

or combined oral contraceptive pills with ulipristal

acetate

is not

recommended

and a

non-hormona

method

of

contraception should

be

used instead.'^^

Unless closely monitored, ulipristal acetate

is

not recommended for use inipalients with severe

renal impairment or in those with moderate or

severe hepatic impairment, '^^' Its use in patients

with severe asthma that is insufficiently controlled

by oral gluco corticoids is also not recommended.^^

Like other SPRMs, ulipristal acetate may af-

fect the histology of the endometrium.'^^' These

changes are termed P AE C (discussed in section 1

and are distinct from en dom etrial hyperp lasia

Approximately 10-15

of

recipients

of

uhprista

acetate may experience end om etrial thickening

(>16mm) during treatment, '^^' The thickening


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1084

Cr

end of treatment and the return of menses, as per

usual clinical practice, appropriate investigation

is recommended.'3^1

Patients should be informed that ulipristal

acetate treatment should lead to a marked re-

duction in menstrual blood loss within the first

10 days.'^^' Ho we ver, if excessive ute rine bleeding

persists, the patient should notify their physician.

M enses norm ally retu rn w ithin 4 weeks of the end

of the treatment course.'3^1

Local prescribing information should be con-

sulted for more details regarding contraindica-

tions,

precautions and warnings.

6 Uiipristai A ce ta te : Current Status in

Uterine Leiomyoma

Ulipristal acetate 5 mg/day is approved in the

EU for the pre-operative treatment of moderate

to severe symptoms of uterine fibroids in adult

women of reproductive age. The longer-term

tolerability of ulipristal acetate has not been es-

tablished and for this reason it is not approved for

treatmen t periods of more than 3 m onths' duration.

Two well designed trials have shown that, fol-

lowing 13 weeks' treatment, oral ulipristal acetate

5 mg/day controlled excessive uterine bleeding in

>90% of women with uterine fibroids. Ulipristal

acetate 5 mg/da y was mo re effective than placebo

and was shown to be noninferior to intramus-

cular leuprolide a cetate 3.75 mg once m onthly in

controlling uterine bleeding. Treatment with uli-

pristal acetate reduced uterine fibroid volume and,

for patients who did not undergo surgery, the vol-

ume reduction was maintained for at least 6 mon ths

after discontinuing treatment. Over a 13-week treat-

ment period, ulipristal acetate was generally well

tolerated in women w ith uterine fibroids.

Disciosure

This manuscript was reviewed by T.

Al-Shawaf

Fertility

Centre, St. Bartholomew's Ho spital, Londo n, U K;

L .

Balunondes

Human Reproduction Unit , Department of Obstetrics and

Gynaecology, University of Campinas, Campinas, Brazil;

on this article. Changes resulting from comments received

made by the author on the basis of xientific and editorial m

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