FACULTY

OF SEXUAL
& REPRODUCTIVE
HEALTHCARE

Faculty of Sexual &

Reproductive Healthcare
New Product Review

Ulipristal Acetate (ellaOne)

Clinical Effectiveness Unit
October 2009

First published online in October 2009 at www.fsrh.org

FACULTY
OF SEXUAL
& REPRODUCTIVE
HEALTHCARE

Faculty of Sexual and Reproductive Healthcare

Clinical Effectiveness Unit
A unit funded by the FSRH and supported by NHS Greater Glasgow & Clyde
to provide guidance on evidence-based practice

New Product Review (October 2009)

Ulipristal Acetate (ellaOne)

PRODUCT SUMMARY
Ulipristal acetate (ellaOne) is a selective progesterone receptor modulator (SPRM) licensed for emergency
contraception (EC) up to 120 hours after unprotected sexual intercourse (UPSI) or contraceptive failure.
Mechanism of Action
Primary mechanism is inhibition or delay of ovulation

Alterations to the endometrium may also contribute to efficacy

Efficacy
Efficacy has been demonstrated up to 120 hours after UPSI

Two randomised controlled trials have shown that ulipristal is at least as effective as progestogen-only EC
(POEC)

Pooled data suggest superior efficacy of ulipristal over POEC for intake within 24, 72 and 120 hours

Safety
Side effect profile similar to POEC

No serious reactions reported

Interactions
Efficacy may be reduced by drugs that induce liver enzymes or increase gastric pH

Potential interaction with progestogen-containing products but clinical significance unknown

Cost

Net price: 16.95 per pack of ellaOne (1 x 30 mg tablet)

Background
Emergency contraception (EC) is an important means of preventing unwanted pregnancy. In recent years,
two methods of EC have been available in the UK: oral progestogen-only emergency contraception (POEC)
containing levonorgestrel 1.5 mg (Levonelle, Bayer Schering Pharma) and the copper-bearing intrauterine
device (IUD). Levonelle is licensed to be given up to 72 hours after UPSI, although there is some evidence
of reducing efficacy with use after 72120 hours.1,2 The IUD can be inserted within 120 hours (5 days) of
UPSI or up to 5 days after the expected date of ovulation.3 Despite the high efficacy of the IUD and the
option to retain the device for ongoing contraception,3 oral EC is more commonly used because it is less
invasive and more easily accessible.
Ulipristal (ellaOne, HRA Pharma) is an oral emergency contraceptive newly launched onto the UK market
and licensed for use throughout Europe. This review evaluates the available evidence and summarises the
manufacturers recommendations for use of ulipristal. Wherever possible we have accessed published
literature; however, recent clinical trial data are currently only available as conference abstracts.
The review is intended to inform health professionals and is not a guidance document. Existing Faculty of
Sexual and Reproductive Healthcare (FSRH) guidance on EC3 will be updated to incorporate
recommendations on ulipristal in due course.
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What is ulipristal?
ellaOne consists of one tablet containing 30 mg micronised ulipristal acetate (Figure 1). Ulipristal acetate
(also known as CDB-2914 and VA2914) is a synthetic steroid derived from 19-norprogesterone (Figure 2). It
is a selective progesterone receptor modulator (SPRM), a class of compounds that exert tissue-selective full
agonist, antagonist or partial agonist effects at the progesterone receptor.4 The Summary of Product
Characteristics (SPC) indicates that ulipristal has antagonistic and partial agonistic effects.5

Figure 1 ellaOne packaging (photograph reproduced

with the permission of HRA Pharma)

Ulipristal acetate

Mifepristone

Progesterone

Figure 2 Comparison of chemical structures of progesterone, ulipristal acetate and mifepristone (figure
reproduced with the permission of Pharmacorama)

The first SPRM, mifepristone, is licensed for use in medical abortion and is also an effective emergency
contraceptive. Although a Cochrane review concluded that mifepristone is more effective than POEC up to
120 hours after UPSI,6 it has not been developed for this indication in the UK and is not licensed as EC
anywhere in Europe.
Ulipristal has been described as a second-generation SPRM. In vivo, ulipristal has much weaker
antiglucocorticoid activity than mifepristone as a result of differences in their active metabolites.710

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What is the mechanism of action for ulipristal?

Ulipristals primary mechanism of action is thought to be inhibition or delay of ovulation. A single midfollicular dose has been shown to suppress growth of lead follicles.11Administration just before, or in some
cases just after, the luteinising hormone surge can inhibit follicular rupture.12
Endometrial changes may also play a role. Early luteal administration of ulipristal results in delayed
endometrial maturation and alterations in progesterone-dependent markers of implantation.13 A mid-luteal
dose has been shown to induce early endometrial bleeding in a dose-dependent manner.14 It has been
postulated that alterations to the endometrium may inhibit implantation by rendering the uterus less
receptive to the trophoblast. However, it is not known if ulipristal has a direct endometrial effect or if the
observed changes are a result of an ovarian effect.13

How should ulipristal be used?

One tablet should be taken orally as soon as possible, but no later than 120 hours after UPSI or contraceptive
failure.5 Ulipristal can be taken with or without food.5 If vomiting occurs within 3 hours, another tablet
should be taken.5 Ulipristal is not recommended to be used more than once per cycle as the safety and
efficacy of repeated exposure has not been assessed.5 If hormonal contraception is continued after
administering ulipristal, barrier contraception should be used until the next period or withdrawal bleed.5

How effective is ulipristal?

Individual studies suggest that ulipristal is as effective as levonorgestrel for EC. There have been no studies
comparing the efficacy of ulipristal to the IUD for the purpose of EC.
In a Phase II randomised double-blinded non-inferiority trial of women seeking EC within 72 hours of UPSI,
pregnancies occurred in 7/775 ulipristal users [0.9%, 95% confidence interval (CI) 0.21.6] and 13/774
levonorgestrel users (1.7%, 95% CI 0.82.6).15 Based on calculations of the risk of pregnancy on the
estimated cycle day of UPSI, the study suggested that 85% of anticipated pregnancies in the ulipristal group
had been avoided and 69% in the levonorgestrel group. The confidence intervals in this study were wide
and no significance differences were demonstrated. The authors concluded that ulipristal was at least as
effective as levonorgestrel. This trial used a 50 mg dose of non-micronised ulipristal, which is bioequivalent
to 30 mg micronised ulipristal.16
Newly presented abstract data suggests ulipristal is well tolerated and effective (pregnancy rate 2.1%, 95%
CI 1.43.1)) when administered to women between 48 and 120 hours following UPSI.17 A randomised trial
confirmed efficacy up to 120 hours with a trend towards greater efficacy in the ulipristal group versus
levonorgestrel.18
An unpublished meta-analysis of the two comparative studies suggests ulipristal is superior to levonorgestrel
when administered both within 120 and 24 hours of UPSI [odds ratio (OR) 0.55 (95% CI 0.320.93, p =
0.0253) and OR 0.35 (95% CI 0.110.93, p = 0.0346), respectively].16
The meta-analysis16 suggests that regardless of the type of EC drug used, the risk of pregnancy is significantly
increased with increasing body mass index (BMI) (8% per point increase in BMI). However, ulipristal acetate
appears to be more efficacious compared to levonorgestrel in women who are categorised as overweight or
obese (grade 1) (OR 3.1, 95% CI 0.110.74).

Are there any restrictions on use of ulipristal?

Ulipristal is contraindicated in pregnancy or suspected pregnancy, as well as in those with a hypersensitivity
to any of the excipients.5 In the absence of specific studies to monitor safety, ulipristal is not recommended
in those with severe hepatic impairment, nor is it recommended in women with severe asthma insufficiently
controlled by oral glucocorticoids.5 As it is not known whether ulipristal is excreted in breast milk,
breastfeeding women are advised not to breastfeed for 36 hours after treatment.5

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NEW PRODUCT REVIEW

Are there any side effects or safety issues?

The most commonly reported side effects are abdominal pain and menstrual disorders (irregular vaginal
bleeding, premenstrual syndrome, uterine cramps).5,15,17
Study data have shown that the post-treatment cycle length is on average 2.9 days longer than the expected
length.17 Some 7% of women reported a shortened cycle, and 19.2% reported an increase in cycle length
of more than 7 days.5
There have been no associated adverse outcomes in the small numbers of inadvertent pregnancies that have
occurred to date. The manufacturer has put a variety of measures in place to monitor outcomes of exposure
during pregnancy.5

Does ulipristal interact with other drugs?

Ulipristal is metabolised via cytochrome P450, in particular CYP3A4.5
Liver enzyme inducers
CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, ritonavir, St Johns wort) may reduce plasma
concentrations of ulipristal and may reduce efficacy.
Liver enzyme inhibitors
The effect of CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin) may increase exposure to
ulipristal, but the significance is uncertain.
Drugs that increase gastric pH
Use of ulipristal with antacids, proton pump inhibitors and H2 receptor antagonists, or any other drugs that
increase gastric pH, may reduce absorption of ulipristal and decrease efficacy.5
Other contraceptives
Ulipristal binds to progesterone receptors and so may reduce the efficacy of progestogen-containing
contraceptives.

Is ulipristal cost effective?

There are currently no published cost effectiveness data. Comparative prices are shown in Table 1 for
information. Levonelle One-Step can be bought over the counter, whereas ellaOne will be available only
on prescription, at least initially. In time it may become possible for nurses and pharmacists to provide
ellaOne by patient group direction (PGD) as currently practised for the supply of Levonelle 1500.19
Table 1 Cost of emergency contraceptives available in the UK*
Method

Cost

ellaOne
Levonelle One-Step
Levonelle 1500
Intrauterine devices

16.95
13.83
5.11
8.0026.64

*Based on British National Formulary (Vol. 57)20 and personal

communication with HRA Pharma.

What does ulipristal add to the range of EC currently available?

The introduction of ulipristal to the UK market marks an important development in EC. It will be the first oral
emergency contraceptive to be licensed for use between 72 and 120 hours of UPSI. Its place in UK
contraceptive practice will become clearer as new data are published and clinical experience increases. If
ulipristal proves to be as well tolerated and effective as existing evidence suggests, the advantages are likely
to justify its cost, particularly when compared to the costs of unwanted pregnancy.

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NEW PRODUCT REVIEW

References
1

von Hertzen H, Piaggio G, Ding J, Chen J, Song Si, Bartfai G, et al. Low dose mifepristone and two regimens of levonorgestrel for emergency
contraception: a WHO multicentre randomised trial. Lancet 2002; 360: 18031810.

Ngai SW, Fan S, Li S, Cheng L, Ding J, Jing X, et al. A randomized trial to compare 24h versus 12h double dose regimen of levonorgestrel for
emergency contraception. Hum Reprod 2004; 20: 307311.

Faculty of Family Planning and Reproductive Health Care Clinical Effectiveness Unit. Emergency contraception. J Fam Plann Reprod Health
Care 2006; 32: 121128. http://www.ffprhc.org.uk/admin/uploads/449_EmergencyContraceptionCEUguidance.pdf [Accessed 28 September
2009].

Chabbert-Buffet N, Meduri G, Bouchard P, Spitz IM. Selective progesterone receptor modulators and progesterone antagonists: mechanisms
of action and clinical applications. Hum Reprod Update 2005; 11: 293307.

HRA Pharm. ellaOne: Summary of Product Characteristics (SPC). 2009. http://ww.emc.medicines.org.uk [Accessed 28 September 2009].

Cheng L, Gulmezoglu AM, Van Look PFA. Interventions for emergency contraception. Cochrane Database Syst Rev 2008; 2: CD001324.

Reel JR, Hild-Petito S, Blye RP. Antiovulatory and postcoital antifertility activity of the antiprogestin CDB-2914 when administered as single,
multiple or continuous doses to rats. Contraception 1998; 58: 129136.

Hild SA, Reel JR, Hoffman LH, Blye RP. CDB-2914: anti-progestational/anti-glucorticoid profile and post-coital anti-fertility activity in rats and
rabbits. Hum Reprod 2000; 15: 822829.

Attardi BJ, Burgenson J, Hild SA, Reel JR, Blye RP. CDB-4124 and its putative monodemethylated metabolite, CDB-4453, are potent
antiprogestins with reduced antiglucocorticoid activity: in vitro comparison to mifepristone and CDB-2914. Mol Cell Endocrinol 2002; 188:
111123.

10

Attardi BJ, Burgenson J, Hild SA, Reel JR. In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor
binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124 and mifepristone. J Steroid Biochem 2004; 88: 277288.

11

Stratton P, Hartog B, Hajizadeh N, Merina M, Lee YJ, Nieman LK. A single mid-follicular dose of CDB-2914, a new antiprogestin, inhibits
folliculogenesis and endometrial differentiation in normally cycling women. Hum Reprod 2000; 15: 10921099.

12

Croxatto HB, Brache V, Cochon L, Jesam C, Salvatierra AM, Levy D, et al. The effects of immediate pre-ovulatory administration of 30 mg
ulipristal acetate on follicular rupture. Abstract presented at the 8th Congress of the European Society of Gynecology, Rome, Italy, 10-13
September 2009.

13

Stratton P, Levens ED, Hartog B, Piquion J, Wei Q, Merino M, et al. Endometrial effects of a single early luteal dose of the selective progesterone
receptor modulator CDB-2914. Fertil Steril 2009; 5 February (Epub ahead of print).

14

Passaro MD, Piquion J, Mullen N, Sutehrland D, Zhai S, Figg WD, et al. Luteal phase dose-response relationship of the antiprogestin CDB2914 in normally cycling women. Hum Reprod 2003; 18: 18201827.

15

Creinin MD, Schlaff WD, Archer DF, Wan L, Frezieres R, Thomas MR, et al. Progesterone receptor modulator for emergency contraception: a
randomized controlled trial. Obstet Gynecol 2006; 108: 10891097.

16

Ulmann A, Scherrer B, Mathe H, Gainer E, HRA Pharm. Meta-analysis demonstrating superiority of the selective progesterone receptor
modulator ulipristal acetate versus levonorgestrel for emergency contraception. Abstract and Poster Presentation presented at the 8th Congress
of the European Society of Gynecology, Rome, Italy, 1013 September 2009.

17

Fine P, Ginde S, Morfesisi J., Mathe H, Gainer. A multicentre trial of ulipristal acetate for late-intake emergency contraception. Abstract
presented at the 8th Congress of the European Society of Gynecology, Rome, Italy, 1013 September 2009.

18

Cameron S, Glasier A, Fine P, Mathe H, Gainer E. Ulipristal aceate compared to levonorgestrel for emergency contraception within five days
of unprotected intercourse: a randomised controlled trial. Abstract presented at the 8th Congress of the European Society of Gynecology,
Rome, Italy, 1013 September 2009.

19

Mansour D. EllaOne: a second-generation emergency contraceptive? J Fam Plann Reprod Health Care 2009; 35: 217218.

20

British National Formulary, Vol. 57. March 2009.

The FSRH Clinical Effectiveness Unit (CEU) has prepared the information given in this New Product Review. It is based on a
structured search and review of published evidence available at the date of preparation. This New Product Review has been
prepared as a service to FSRH members but is not a formal Faculty guidance document. It is not intended to be construed or to
serve as a standard of medical care. Such standards are determined on the basis of all clinical data available and are subject to
change as scientific knowledge advances. Members are welcome to reproduce this document by photocopying or other means,
in order to share the information with colleagues.
The CEU welcomes feedback on published documents, and will review all comments received and amend any significant errors.
The CEU is, however, unable to respond individually to all feedback.
Tel: +44 (0)141 232 8459

FSRH 2009

Fax: +44 (0)141 232 8448

E-mail: ceu.members@ggc.scot.nhs.uk

FACULTY
OF SEXUAL
& REPRODUCTIVE
HEALTHCARE

Faculty of Sexual and Reproductive Healthcare

of the Royal College of Obstetricians and
Gynaecologists

The Faculty
The Faculty of Family Planning and Reproductive Health Care (of the Royal College of Obstetricians
and Gynaecologists) was established on 26 March 1993. In 2007 the organisation changed its name
to the Faculty of Sexual and Reproductive Healthcare as this was more relevant to the current functions
of the specialty. The Faculty grants diplomas, certificates, fellowships and equivalent recognition of
specialist knowledge and skills in sexual and reproductive health care. As a body it promotes
conferences and lectures, provides a clinical advisory service and publishes the Journal of Family
Planning and Reproductive Health Care.

The Journal
The Journal of Family Planning and Reproductive Health Care publishes high-quality, peer reviewed
research and information relevant to clinical care, service delivery, training and education in the field of
contraception and reproductive/sexual health.
Visit the Faculty website at www.fsrh.org for further information about membership or Associate
membership and for details of how to subscribe to the Journal (subscriptions to this quarterly journal
include free online access).

The CEU
The Clinical Effectiveness Unit (CEU) provides a clinical enquiry service for Faculty members.
A standard process for developing evidence-based responses is used to respond to enquiries. The
CEU also publishes guidance documents, key statements and new product reviews.

Extra copies of this new product review may be available. For further information contact:
Sarah Monger, Commercial Manager, Keyways Publishing Ltd, part of the OLM Group.
Tel: +44 (0) 1243 816689. Fax: +44 (0) 1243 576456.
E-mail: sarah.monger@keywayspublishing.com
Published by the Faculty of Sexual and Reproductive Healthcare
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First published online in October 2009 at www.fsrh.org
Copyright Faculty of Sexual and Reproductive Healthcare 2009