ulipristal acetate : review of its use in emergency contraseption

7/26/2019 Ulipristal Acetate : Review of its Use in Emergency Contraseption

1/12

DRUG

EV LU TION

2 11

Ad* Data intofmotion

BV Ail

nghts lesefved

an d

amie D. Croxtall

a W olters Kluwer

Business

Auckland, New Zealand

ous sections of the manuscript reviewed by:

Brache.PROFAM ILIA,S mto Dot-ningo, Don-iinicdii Republic;S.T. Cam eron OKstetrics ntid Gyt-iaecology,

University of Edit-iburgh, Edii-iburgh, UK;M. Cremer Mi)unt Sitiai School of Medicitie, Beth Israel Hospital,

New York, NY, USA; S. Ferrero.Departn-ient of O bstetrics and Gynecology , Sati M artino H osp ital an d

Un iversity of Geno a, Ge noa, Italy;P.Fine Planned Parentho od Gulf Coast, Planned P arenthood of Housto n

Southeast Texas, Houston, TX, USA; K. Gcmzeii-Danieisson Division of Obstetrics and Gynecology,

Knrolinska Un iversity F4ospital, Stockho lm, Swe den .

Medical l iterature (including published an d unpublished data) on -ulipristal was identified by searching databases since 1996

uding MEDLINE and EM BASE and in-house AdisBase). bibliographies from pub lished iiterature. clinical trial registriesd ataba ses and

MEDLINE, EMBASE and AdisBase search terms were ulipristal or ulipristal acetate , and emergency con tracep tion .

21 April 20 11 .

Studies in females requesting emergency c ontracep tion who received ulipristal acetate. Inclusion of studies was based mainly

thods se ction of the trials. When available, large, well controlled trials with appropriate statistical m ethodology were preferred.

Ulipristal acetate, emergency contraception, pharmacodynamics. pharmacokinetics, progesterone receptor modulator,

Abstract 935

1. Introduction 936

2. Pha rmacodynamic Properfies 937

3. Pha rmacokine tic Properties 938

3.1 General Properties . 938

3.2 Drug Interactions 938

4. Clinical Efficacy 938

5. Tolerability 940

6.

Pha rmacoeco nom ic Considerations

94

7. Dosage an d Administration

94

8.

Place of Ulipristal Ac efa fe in Emergency Con traception

942


2/12


3/12

937

1.5mg tablet) is app rove d for use within

Ulipristal acetate (ellaOne; ella; formerly

n as CDB -2914) is the first o f a new class

1

) . '" ' It was developed specifically for em er-

y contrac eption and is approved for use up

120 ho urs after u npro tected intercourse. ' '--'-^'

con trac ep tion following un prote cted se.xual

2.

Pha rmacodyna mic Properties

Ulipristal acetate is an orally active, synthetie.

e rec ep tnr . '" where it has both antagi-inist

epto rs. l" ' Although ulipristal acetate has some

inity for the glucocorticoid recep tor in anitna ls.

nist activity is much reduced com pared

at of mifepristone, '"*' ind icatin g th at uli-

The principal effect of ulipristal acetate is to

which this occurs has not been fully cl

It may act by inhibiting or delaying the luteiniz-

ing hon-none (LH) surge, postponing I.H [teak if

LH surge has already con-imenced. or pcissibly by

directly inhibiting follicular rupture. ' '^-"' '

In a placebo-controlled study in women with

normal menstrual cycles, single doses of ulipristal

ace tate 10, 50 or 100 mg adm inistered at the m id-

follicular stage (lead follicle diatiieter of l4-16mti-i)

significantly suppressed lead follicle growth

(p=0.001), which led to a dos e-de pen den t delay

in foUiculogenesis (p


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938

McKeage Cr

3. Pharmacok inetic Properties

Phartnacokinctic dataon ulipri.stal acetateare

derived froni studies

in

women, which are reported

in the manufacturer's prescribing information.' '-' ' ' '

3.1 General Properties

Ulipristal acetate

is

rapidly absorb ed. M ean

peak plasma concentrations (C|,, . ,x)of the drug

176ng/mL) and the active major m etabolite, mo no-

dem ethylated-ulipristal acetate (69 ng/m L). were

reached (t,,,.,Jat 0.9 and 1.0 hours, respectively,

in

a

study

of

20 wom en u nder lasting cond itions

following administration of a single oral 30mg

d o s e . ' ' - " '

Corresponding values

for

the area under

the plasma concentration-timecut vefrom time zero

to intlnity (A U C ) were 556 and 246 ng h/niL .

W hen ulipristal acetate was taken together with

a h igh-fat me al, mea n C^ .^ was redticed

by

=45%,

t,,,,,x wasdelayed from a median of 0.75 hou rs

to

3

hours ,

and

m e an A U C

was

increased

by

25%

compared with administration

in the

fast-

ing state. l ' -" ' Similar results were observed with

mono-demethylated-uhpris tal acetate. However,

the effect of concomitant food intake did not change

the efficacy

oi'

ulipristal ace tate

in

phase

III

Ulipristal acetate

is

highly boun d

to

plasma

proteins (>94%), including albtimin. alpha-1-acid-

glycoprotein

and

high-density lipoprotein. ' '- '-^1

After ingestion,

the

drug

is

extensively m etab o-

lized in the liver to mono-demethylated. di-

demethylated

and

hydro.xylated metabolites,

of

which only the mono-demethylated metaboliteis

phartnacologically active.

///

v tro

studies show

tliat metabolism

is

predom inant ly mediated

by

cytochrome P450 (CYP) 3A4 enzymes,and to a

lesser extent

by

CYP l A2

and

CYP2D6.1'-- '- ' '

Ulipristal acetate is primarily excietedvia the

taeces. After

a

single dose

of

ulipristal acetate

30 mg,

the

termin al elimina tion p lasm a half-life

is estimated at 32 hours for ulipristal acetate

and

27

hours

for

mono-demethylated-ulipristal

pharmacokinet ic parameters were observed

tween women

of

different ethnic gr ou ps

in

ical studies. ' '- '

The

dr ug 's effect

on the

hu

embryoisunkn ow n. Altliough repeated ulip

acetate doses

in

animal studies resulted

in

s

embryo-fetal loss,atdoseslowenough to m

tain gestation, there

was no

indication

of

teratogenic potential

in

these studies. ' '- '"*'

3.2 Drug Interactioris

Drug interaction studies with ulipristal ac

in humans have not been performed. Howeve

the drug is primarily m etabolized by CY P3A 4,

interactions

are

possible when co-adm inis

with agents that induceorinhibit CY P3A 4.1

Co-administration with CYP3A4 indticers

rifampicin. phenytoin)

or

agents that increase

tric pH e.g.proton pum p inhibi tors , an ta

is

not

recommended

as

plasma concentra

of ulipristal acetate may be reduced, leadin

a loss

of

efficacy. C o-ad min istration with p

CYP3A4 inhibi tors

e.g.

ketoco nazole, c

thromycin, ri tonavir) mayincrease exposu r

ulipristal a ceta te. ' ' - ' - ' I

It

is unk now n whether

potential increaseinexposure could beofcli

relevance.

As

a

result

of

its affinity

for the

progeste

receptor, ulipristal acetate may interfere wit

action

of

progesterone. Fo r example,

it

is po s

that thecontrace ptive action of combined

monal contracept ives and progesterone

contraceptives

may be

reduced.

It is

recom

ded that ulipristal acetate is not co-adminis

with other emergency contraception contai

levonorgestrel.

4 Clinical Efficacy

The efficacy oforal ulipristal aceta tehas

evaluated

in a

phase 11'-''

and

two phase Illl

multicentre clinical trials in wom en reque

emergency contraception following unprot

sexual intetcourse (table

I). Two

were ran


5/12

cetate: A Review

939

I. Efficacy of oral ulipristal acetate (UPA) in women requiring emergency contraception following unprotected sexual intercourse

i^" '' populations

al.i^"

Study design

r.

db .me.

n i

me .

o l

r,

sb ,me .

ni

Study drug (mg)

U P A 5 0 ' ' + P L a t t 2 b

LNG0.75 LNG

0.75 at 12 h

UPA 30

EE '

UPA 30

LNG 1.5

No.

of

valuable

pts

775

774

24

844

85 2

Period after

UPSI in primary

analysis (h)

Within 72

48-120

Within 72

Outcome

pregnancy rate

0.9''

1,7

2.1

5.5

1.8

2.6

95% CI

0

2 .

1 6

0.8. 2.6

1.4.3.1"

1.0.3.0

1 7. 3.9

OR UPAvsLNG

(95% CI)

0.50(0.18. 1.24)

0.68(0.35,1.31

Efficacy valuable populations included women aged 35 years, lost to follow-up, with unknown pregnancy status at follow-up or

whose pregnancy was not compatible with emergency contraception failure.'^-"i

Subsequent to this study, micronization of UPA allowed reduction of the dose from 50 to 30 mg when used in tablet form.

As the predefined upper limit of 97.5% CI (0.77') for the difference between treatments did not exceed

2 .

the noninferiority of UPA vs

LNG was demonstrated.

As the predefined upper limit of the 95' CI of the observed rate was lower than the EE rate, the observed rate with UPA was considered to

be significantly lower than the EE rate.

Expected pregnancy rate (using methodology of Trusse ll et al.l ^i) in the absence of emerge ncy contrac eption.

As the prede fined upper limit of the

95%

CI for the OR of pregnancy occurring w ith UPA vs LNG did not exceed 1.6. the noninferiority of UPA

vs LNG was demonstrated.

double-blind: EE=estimated expected: LNG=levono rgestre l: me =-multicentre: ni=noninteriority: ol=open-label: OR=odds ratio;

placebo: r= randomized: sb=single-blind.

Women with regular menstrual cycles aged

72' - ' '

or 120'--''--'*'

single do se o f 30 mg , e.Kcept in the pha se II

which ulipristal ac etate 50 mg capsules

from 50 to 30 mg whe n used in tablet

estrel w as adm inistered as a single 1.5 mg dose

120 hours of unprotected intercourse, ' '^'*' Across

all trials, the mean age of wome n w as 24-25 y ears,

60-70% were Caucasian, and about half had not

been pregnant previously. '-'--'--' '1 Reasons for re-

questing emergency contraception included a fiiiled

condom or no contracept ive methods used. The

final efficacy valuable'-'--' ' and modified intent-

to-treat'- *' pop ul ati on s (defined in table I) ex-

cluded those aged >35 years, as recommended by

the US FDA because of reduced fertility in this

group.

Results from noninferiority trials demonstra-

ted tha t ulipristal a ce tate 30 mg w as no less ef-

fective than levonorgestrel 1.5mg when taken

within 72 hour s of unprotec ted sexual intercourse

with regard to the pregnancy rate in efficacy

valuable populations (table

I),'-'--^'

Similar results


6/12

94 0

M c K e a g e C r

In the open-label study.'-"*' the pregnancy rate

m patients receiving ulipristal acetate within

48-120 hours ol unprotected sexual intercourse

vva.s significantly lower th an tha t of the expecled

pregnancy rate in the absence of emergency con-

tracep tion (table I). Ov erall, ulipristal acetate re-

duced the pregnaticy rate by 62..^%. In addition,

as the uppe r limit of the 95% CI of the o bserved

rate in patients receiving ulipristal acetate was

lower than the clinical irrelevance threshold of

4% ,

the protocol definition of study success was

met. The clinical irrelevance threshold was de-

tettnined by halving the estimated expected pteg-

nancy rate of 8% (as determined from results of

previous sttidies) in the absence of contraception.

Also in this study, ulipristal acetate detnon-

strated sustained efficacy when administered at

any tii-ne throughout the 48- to 120-hour period

after unp rotec ted intercourse. '-'*' Ob served p reg-

nancy rates for 2- 3, 3-4 and 4-5 da ys were 2.3% ,

2.1% and 1.3%, respectively.

Pregnancy rates with uliprista aeetate (1.8% vs

5.5%) and Ievonorgestrel (2.6% vs 5.4%) were both

significantly (p=0.001 for both) lower than expec-

ted rates in the phase III noninferiority study.'-' ' In

this same study, although the pt-egnancy rate was

not significantly different between uliptistal acetate

or Ievonorgestrel treatment groups when either

agent was taken within 120 hours of ttnprotected

ititercourse (odds ratio 0.57; 95% CI 0.29.

1.09).

a

treatment difference became evident fo v the latest

I-)eriod.'-'' When either agent was takct-i withiti

5

4.5

_ 4

3.5

I 3

& 2.5

I 2

i 1.5

1

0.5

0

Ulipristal acetate

Levonorgestrel

0-24 h

0-72

h

0-120

h

72-120 houts of unprotected intercourse, there

significantly fewer pregnancies (0 vs 3; p

0

with ulipristal acetate than with levonorgestrel

In

i

p o s t h o c t-i-ieta-analysis of data lVom

two studies'-'---^' (see table I for design and re

of individual trials) [n =.3445], the pregnancy

was significantly (p


7/12

cetate: A Review

94t

le II. Modelled cost-effectiveness study of ulipristal acetate (UPA) compared with levonorgestrel (LNG) in wom en requesting emergency

UK I ^1

The study was conducted from the perspective of the

Cost () Probabiiity of

pregnancy after

UPSI (0-1 20 h) :;]

16,95 1,28

5,37 2,20

Cost of unintended

pregnancy ()

12,13

20,85

Includes drug acquisition cost and cost of gnerai practitioner visits,

=

incremen tal cost-effectiveness ratio.

Drug

administration

costs" ()

52,95

41,37

Total costs ()

65,08

62,22

ICER(e)

311,00

Following treatment with ulipristal acetate,

pared with 3.3% before enrolmen t (based on

s 3 months). '-'*' In 100 wom en mo nitore d

6. Ptiarmacoeconomic Considerations

A mod elled, cost-effectiveness study in the UK,

par ed the use of ulipristal ace tate 30 mg ver-

1 5nig in women requesting

eption within 120 hou rs of

4) , ' - ' -^ '

the probability of pregnancy when the drug is

taken w ithin 120 ho urs of unp rotec ted sexual

intercourse was considered to be lower with uli-

pristal acetate, the difference in total costs be-

tween the two agents was only 2.86 in favour of

levonorgestrel (table II). As a result, the incre-

mental cost-effectiveness ratio (ICER) [i.e, the

cost of preventing one additional unintended

pregnancy] with ulipristal acetate versus levo-

norgestrel was 311. which was less than the es-

timated cost of an unintended pregnancy (948).

In a sensitivity analysis that compared direct

costs associated with the two drugs when taken

within 72 hours of unprotected sexual inter-

course, the ICER associated with ulipristal ace-

tate was 500.'^ '

As with all rnodelled analyses, this cost-utility

study is a simplified simulation of reality and,

therefore, subject to some limitations. For example,

pregnancy rates were derived from a single meta-

analysis of two ra ndom ized, h ead-to-head clinical

trials,

which demonstrated significantly lower

pregnancy rates with ulipristal acetate than with

levonorgestrel (section 4 ); howeve r, both individual

trials were noninferiority studies and were not

powered to show superiority.

7. Dosage an d Administration

A single tablet of ulipristal ac etate 30 mg h as

recently been approved for emergency contra-

ception w ithin 120 ho urs ol' unp rotec ted sexual

intercourse or contraceptive failure in several


8/12


9/12

l Acetate: A Review

943

emergency co ntraception (5-6%).'^-^-'''

In secondary efficacy analyses, ulipristal acetate

meta-analysis of two clinical studies

4). ' - ' Data from the two studies, which

confirm wh ether ulipristal aceta te is mo re ef-

Ulipristal acetate was generally well tolerated

effects associate d with ulipristal ac eta te

headache, nausea and abdom inal pain, with

As with many new drugs, ulipristal acetate is

to-pay thresholds when administered vviihui

120 hours of unprotected intercourse and was

lower than the estimated cost of an unintended

pregnancy (section 6). In a sensitivity analysis, the

ICER for ulipristal acetate versus levonorgestrel

was higher when administered within 0-72 hours

after unprotected intercourse, consistentw ith the

improv ed efficacy that wou ld be expected with

levonorgestrel in this period compared with later

(72-120 hours). Whether the use of ulipristal ace-

tate will prove to be cost effective in other geo-

graphical regions remains to be seen.

Levonorgestrel is approved for use within

72 hours of unprotected sexual intercourse, ' '" '

and its efficacy has been shown to wane over

time.'**' In order to optimize efficacy, educatio-

nal programmes have focused on the importance

of accessing emergency contraception as soon

as possible after unprotected sexual intercourse.

The time-dependent efficacy was also a factor

in making levonorgestrel easily available over-

the-counter in many countries for women aged

>17 years. ' '" ' Data from clinical sttidies suggest

that about 10-12% of women requiring emer-

gency contraception present >72 hours after un-

protected intercourse. Whether more women

would present in this period if they knew that

emergency contraception remained an option is

unknown.

The search for effective and well tolerated

emergency contraceptive measures is ongoing.

Two potential alternatives include the cyclo-

oxygenase-2-inhibitor meloxicam, which works

by inhibiting prostaglandin synthesis, thereby

suppressing ovulation and follicular rupture, and

the anti-progestin gestrinone, which appears to

inhibit implantation.' ' ' ' Ongoing clinical trials

should help determine whether these agents will

have a place in emergency contraception in the

future.

In conclusion, ulipristal acetate is the first of

new class of selective progesterone receptor mod-

ulators, and it provides effective, sustained and

well tolerated emergency contraception when taken


10/12

9

McKeage f Cr

intercourse and was more effective when taken

between 72 and 120 hours. Results of a meta-

analysis suggest that ulipristal acetate may be

more effective than levonorgestrel from day

1

and

throughout the entire 5 day period following

unprotected sexual intercourse. Unlike levonor-

gestrel, ulipristal acetate is able to prevent folli-

cular rupture, potentially preventing pregnancy,

when given in the advanced follicular stage of the

menstrual cycle and. thus, provides a longer treat-

ment window than levonorgestrel.

isclosure

The preparation of this review was not supporled by any

external funcling. During the peer review process, the manu-

lacturer of the agent under review was offered an opportunity

to comment on this article. Changes resulting from comments

received were made on the basis of scientific and editorial

merit.

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Cor respondence : Knte McKeage Adis , a Wolters Kluwer

Business, 41 Centoriai-i Drive, Private Bag

659(11,

M.iirangi

Bay, North Shore 0754, Auck land, New Zealand.

E-mail: [email protected]


12/12

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