WHAT DRUG | EMERGENCY CONTRACEPTION

CONTINUING PROFESSIONAL DEVELOPMENT

Ulipristal or levonorgestrel
as emergency contraception
BY DENISE HOPE, GARY GRANT & MICHELLE KING

Ulipristal acetate (ellaOne) has recently been approved for use in

Australia as a single 30 mg oral dose emergency contraceptive.1 It is
registered for use up to five days (120 hours) following unprotected
sexual intercourse or contraceptive failure.

This is an increased window of
treatment opportunity compared to
levonorgestrel, the only other dedicated
oral emergency contraceptive, which
is registered for use within three days
(72 hours) of intercourse. Despite more
than a decade of non-prescription
availability of levonorgestrel,
emergencycontraception is currently
underutilised in Australia2,3 and
elsewhere in theworld.4-6
Availability
The Therapeutic Goods Administration
(TGA) has approved ulipristal as a
Schedule 4 Prescription Only medicine
at this time as it is a new chemical
entity with no clinical or marketing
experience in Australia.7 Ulipristal has
been available on prescription in the
United States of America (USA) and
the United Kingdom (UK) since 2009.8,9
The UK recently switched ulipristal to
non-prescription availability, followinga
reclassification recommendation by the
European Medicines Agency (EMA) due
to its history of safety and efficacy.10
Despite the fact that ulipristal has a
higher drug cost than levonorgestrel,
American researchers have proposed a
similar shift to over-the-counter status
for ulipristal in the USA,11 arguing that its
improved efficacy over levonorgestrel
would ultimately provide cost savings
through reduction of unintended
pregnancies.12
Denise Hope, School of Pharmacy, Griffith University,
Queensland.
This article has been independently researched and peer reviewed.
Gary Grant, School of Pharmacy, Griffith University
and Menzies Health Institute Queensland, Griffith
University, Queensland.
Michelle King, School of Pharmacy, Griffith University
and Menzies Health Institute Queensland, Griffith
University, Queensland.
LEARNING OBJECTIVES
After reading this article, pharmacists should be
able to:
Describe the role and efficacy of ulipristal in
emergency contraception
Discuss the indications, dosage, precautions and
side effects of ulipristal
Discuss the place in therapy of ulipristal
compared to levonorgestrel for emergency
contraception.
Competencies addressed: 1.3, 4.2, 6.1, 6.2, 7.3.
Accreditation number: CAP151212F

Australian Pharmacist December 2015 I Pharmaceutical Society of Australia Ltd. 65

WHAT DRUG | EMERGENCY CONTRACEPTION
CONTINUING PROFESSIONAL DEVELOPMENT

Dosing
Ulipristal is available as a single 30 mg
oral dose, to be administered as soon
as possible, and within 120 hours,
ofunprotected sexual intercourse or
contraceptive failure. Ulipristal may be
taken with or without food.13 Due to
pharmacokinetic data, if vomiting occurs
within 3 hours of ulipristal ingestion,
areplacement dose is recommended.13
In contrast, levonorgestrel is given as a
single 1.5 mg oral dose, available as either
a single 1.5mg tablet or two 750 mcg
tablets, within 72 hours of intercourse.
A replacement dose of levonorgestrel is
recommended if vomiting occurs within
2hours of administration.14
Mechanism of action
Ulipristal is an orally active synthetic
selective progesterone-receptor
modulator (SPRM) that acts via
Table 1. Comparison of levonorgestrel and ulipristal as emergency contraception
Approved use as EC
following unprotected intercourse
or contraceptive failure
Schedule
Dose
Repeat dose recommended
Pregnancy category
high affinity binding to the human
progesterone receptor.15 In addition
to use as an emergency contraceptive,
it is being developed for use in other
indications, including treatment
of uterine fibroids.16 When used
for emergency contraception the
main mechanism of action for both
levonorgestrel and ulipristal is inhibition
or delay of ovulation via suppression of
the luteinising hormone (LH) surge.13
The days prior to ovulation, in the late
follicular phase, are crucial for emergency
contraceptive efficacy.17 Atthis time
ulipristal has a direct inhibitory effect
on follicular rupture, allowing it to be
effective when administered shortly
before ovulation when the LH surge has
started to rise.17 Once LH has started to
rise levonorgestrel is no more effective
at delaying ovulation than placebo.13,17,18
Noemergency contraceptive is
Levonorgestrel Ulipristal
Up to 72 hours (3 days) Up to 120 hours (5 days)
Schedule 3 Schedule 4
1.5 mg single dose 30 mg single dose
If vomiting within 2 hours If vomiting within 3 hours
Category B3 Category D
effective in delaying follicular rupture if
administered on the day of the LH peak.17
Ulipristal may also induce endometrial
changes that interfere with embryo
implantation.19
Safety and efficacy
Trial data and subsequent analyses have
compared the safety and efficacy of
emergency contraceptives, including
danazol, mifepristone, the superseded
Yuzpe regimen (which used combined
oral contraceptives), levonorgestrel and
ulipristal.17,20,21 Ulipristal was identified
as the safest and most effective oral
emergency contraceptive currently
available.17,2124 Ulipristal is associated
with a lower pregnancy rate than
levonorgestrel.13,24 Ulipristal is reported
to prevent two thirds of pregnancies
within 72 hours of intercourse, compared
to approximately 50% of pregnancies
prevented with levonorgestrel.21
The efficacy of levonorgestrel decreases
with time in the 72 hours following
intercourse.14 In contrast, the efficacy of
ulipristal does not appear to be affected
by time during the 120 hours following
intercourse.23 Maintaining efficacy for
five days after unprotected intercourse
matches the survival time of sperm,
providing a medical advantage over
levonorgestrel.13

Pregnancy risk No reported risk Exclude pregnancy before Pregnancy

Breastfeeding Small amount transferred
into breastmilk, should not
be harmful to infant
Adverse effects Lower abdominal pain,
nausea and headache
Efficacy in overweight Efficacy may decrease
>70 kg or BMI >25 kg/m2
Metabolism CYP3A4
Drug interactions e.g. carbamazepine,
phenytoin and St Johns
wort
Drug interaction with regular Regular hormonal
contraception contraception can be
continued without
interaction
EC emergency contraception;
COC combined oral contraceptive;
POP progesterone only pill
administration
Transferred into breastmilk.
Breastfeeding not
recommended for 1 week
Lower abdominal pain,
nausea and headache
No reported loss of efficacy
CYP3A4
e.g. carbamazepine,
phenytoin and St Johns contraception with an actual intention
wort
May reduce efficacy of COC
or POP. Suggest barrier
methods until next period
Ulipristal is not recommended in
pregnancy and a pre-existing pregnancy
must be excluded before use.25
Cautionhas been expressed about the
safety and efficacy claims of ulipristal,
a pregnancy category D medicine.
Asulipristal is pharmacologically
related to mifepristone it has been
suggested that it might be sought by
women under the pretext of emergency
of terminating an early pregnancy, even
if multiple doses may be required.26 Itis
recognised that levonorgestrel taken
post-implantation is not associated
with any harm to early pregnancy;
thesame has not yet been demonstrated
forulipristal.26

66 Australian Pharmacist December 2015 I Pharmaceutical Society of Australia Ltd.


Breastfeeding
Ulipristal is a lipophilic compound and
may be excreted in breastmilk.13 It is
therefore not recommended for use
by women who are breastfeeding.15
European guidelines recommend that
breastfeeding should be avoided for
one week after use of ulipristal, andthat
during that time, women should
express and discard breastmilk in order
to stimulate continued lactation.27
Incomparison, levonorgestrel is
accepted to be safe in breastfeeding.14
Adverse effects
Ulipristal and levonorgestrel may
both cause lower abdominal pain,
nausea and headache. Adverse effects
are usually self-limiting and of short
duration.13 Both drugs may alter bleeding
patterns following administration.13
Levonorgestrel is more likely to cause
menstrual return before the expected
date, whereas ulipristal is more likely
to cause menstrual return after the
expected date.24
Overweight patients
Concerns over the risk of emergency
contraception failure in overweight or
obese women is greater for levonorgestrel
than for ulipristal.28 Glasier et al
recommended that women with a body
mass index (BMI) >25 kg/m2 should be
offered an intrauterine device (IUD) or
ulipristal if presenting for emergency
contraception.28 Sexual Health and Family
Planning Australia reported in November
2013 that there was insufficient evidence
to deny emergency contraception to
women with higher BMIs, and that
currently available methods were
better than nothing.29 Currently the
TGA is reviewing information on the
effectiveness of levonorgestrel in women
weighing more than 70 kg and it is
anticipated that further information will
be disseminated to health professionals
once the review is complete.30 Ulipristal
was approved in Australia as an S4 in
June2015, providing health professionals
with a therapeutic alternative to consider
in overweight patients.
UNTIL NOW, THE AUSTRALIAN PHARMACIST PRESENTED WITH A
PATIENT SEEKING EMERGENCY CONTRACEPTION MORE THAN
72 HOURS SINCE UNPROTECTED INTERCOURSE HAD BEEN
SIGNIFICANTLY CHALLENGED.
Drug interactions
Ulipristal and levonorgestrel are both
metabolised by the cytochrome P450
(CYP) 3A4 enzyme. Coadministration
with CYP3A4 inducers, such as
carbamazepine, phenytoin, rifampicin
and St Johns wort, is not recommended
as they may reduce plasma
concentrations of either oral emergency
contraceptive.9,13 The clinical significance
of this potential drug interaction with
single dose emergency contraceptives
is currently unknown and requires
further investigation. Insertion of a
copper IUD may be a preferred method
of emergency contraception in women
taking enzyme-inducing drugs.31
The absorption of ulipristal is
pH-dependent and concomitant
administration of medicines that
increase gastric pH, such as antacids,
H2-receptor antagonists and proton
pump inhibitors, may reduce plasma
concentrations of ulipristal.9,13
As ulipristal binds to progesterone
receptors with high affinity, theoretical
concerns exist that it may interfere
with the action of ongoing hormonal
contraception commenced at the same
time as EC.13 Women using ulipristal
should be advised to use additional
barrier methods of contraception
(e.g.condoms) until the next menstrual
period starts. This contrasts with
levonorgestrel which is not known
to have adverse interactions with
hormonal contraception.26
Australian Pharmacist December 2015 I Pharmaceutical Society of Australia Ltd.
WHAT DRUG | EMERGENCY CONTRACEPTION
CONTINUING PROFESSIONAL DEVELOPMENT
Summary
Until now, the Australian pharmacist
presented with a patient seeking
emergency contraception more than
72 hours since unprotected intercourse
had been significantly challenged.
Levonorgestrel has been available as a
Schedule 3 Pharmacist Only medicine
since 2004, approved for use within
72hours of unprotected intercourse or
contraceptive failure. Even though it is
suspected that levonorgestrel may be
somewhat effective for up to 120hours,
its anticipated efficacy would be low.25
The preferred option has been to refer
a patient for immediate insertion
of a copper IUD, although there are
significant patient barriers to accessing
IUDs.32 Now, referring a patient to
a prescriber for a ulipristal acetate
prescription offers a viable alternative.
References
1. Therapeutic Goods Administration. Public
Summary: EllaOne ulipristal acetate 30 mg tablet
blister pack. 2015. At: https://www.ebs.tga.gov.au/
servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.
nsf&docid=219535&agid=(PrintDetailsPublic)&actionid=1.
Accessed 3 June 2015.
2. Calabretto H. Emergency contraception knowledge
and attitudes in a group of Australian university students.
Australian and New Zealand Journal of Public Health.
2009;33(3):2349.
3. Trussell J, Calabretto H. Cost savings from use of emergency
contraceptive pills in Australia. Australian and New Zealand
Journal of Obstetrics and Gynaecology. 2005;45(4):30811.
4. Dalby J, Hayon R, Paddock E, Schrager S. Emergency
contraception: an underutilized resource. Journal of Family
Practice. 2012;61(7):3927.
5. Rodriguez MI, Curtis KM, Gaffield ML, Jackson E, Kapp N.
Advance supply of emergency contraception: a systematic
review. Contraception. 2013;87(5):590601.
6. Rafie S, McIntosh J, Gardner DK, et al. Over-the-counter
access to emergency contraception without age restriction:
an opinion of the Womens Health Practice and Research
Network of the American College of Clinical Pharmacy.
Pharmacotherapy:The Journal of Human Pharmacology &
Drug Therapy. 2013;33(5):54957.
7. Therapeutic Goods Administration. Reasons for the
medicines scheduling delegates final decisions, May 2015
(Medicines). 2015. At: https://www.tga.gov.au/book/
export/html/621318, 3 Jun 2015.
8. Cameron S, Glasier A. The need to take a new look at
emergency contraception. Journal of Family Planning &
Reproductive Health Care. 2010;36(1):34.
67
WHAT DRUG | EMERGENCY CONTRACEPTION
CONTINUING PROFESSIONAL DEVELOPMENT
9. The Pharmaceutical Journal. New emergency hormonal
contraceptive effective for up to five days after sex.
2009;283:375.
10. The Pharmaceutical Journal. ellaOne emergency
contraception available for sale through UK pharmacies.
2015;294 (No 7860 online).
11. Bayer LL, Edelman AB, Caughey AB, Rodriguez MI. Response
to letter to the editor. Contraception. 2013;87(4):504-505.
12. Bayer LL, Edelman AB, Caughey AB, Rodriguez MI. The price
of emergency contraception in the United States: what is
the cost-effectiveness of ulipristal acetate versus single-
dose levonorgestrel? Contraception. 2013;87(3):38590.
13. Gemzell-Danielsson K, Meng C-X. Emergency
contraception: potential role of ulipristal acetate.
International Journal of Womens Health. 2010;2:53.
14. Pharmaceutical Society of Australia. Guidance for the
provision of Pharmacist Only medicine levonorgestrel 2011;
http://www.psa.org.au/supporting-practice/professional-
practice-standards/pharmacist-only-medicines-s3-protocols.
15. Richardson AR, Maltz FN. Ulipristal acetate: review of
the efficacy and safety of a newly approved agent
for emergency contraception. Clinical therapeutics.
2012;34(1):2436.
16. Biglia N, Carinelli S, Maiorana A, DAlonzo M, Monte
GL, Marci R. Ulipristal acetate: a novel pharmacological
approach for the treatment of uterine fibroids. Drug design,
development and therapy. 2014;8:285.
17. Brache V, Cochon L, Deniaud M, Croxatto HB. Ulipristal
acetate prevents ovulation more effectively than
levonorgestrel: analysis of pooled data from three
randomized trials of emergency contraception regimens.
Contraception. 2013;88(5):6118.
QUESTIONS
1. How many hours after unprotected
intercourse is ulipristal acetate
effective?
a) 24.
b) 48.
c) 72.
d) 96.
e) 120.
2. What is the approved dose of
ulipristal acetate for emergency
contraception?
a) 750 mcg every 12 hours for two doses.
b) 1.5 mg as a single dose.
c) 3 mg as a single dose.
d) 15 mg every 12 hours for two doses.
e) 30 mg as a single dose.
DECEMBER 2015
Australian Pharmacist Continuing Professional
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68 Australian Pharmacist December 2015 I Pharmaceutical Society of Australia Ltd.
18. Gemzell-Danielsson K, Berger C, Lalitkumar PGL. Emergency
contraception mechanisms of action. Contraception.
2013;87(3):300308.
19. Mozzanega B, Cosmi E, Nardelli GB. Ulipristal acetate in
emergency contraception: mechanism of action. Trends in
pharmacological sciences. 2013.
20. Webb A, Russell J, Elstein M. Comparison of Yuzpe
regimen, danazol, and mifepristone (RU486) in oral
postcoital contraception. BMJ: British Medical Journal.
1992;305(6859):927.
21. Glasier AF, Cameron ST, Fine PM, et al. Ulipristal acetate
versus levonorgestrel for emergency contraception: a
randomised non-inferiority trial and meta-analysis. The
Lancet. 2010;375(9714):55562.
22. Fine PM. Ulipristal acetate: a new emergency contraceptive
that is safe and more effective than levonorgestrel.
Womens health. 2011;7(1):917.
23. Martinez AM, Thomas MA. Ulipristal acetate as an
emergency contraceptive agent. Expert Opinion on
Pharmacotherapy. 2012;13(13):193742.
24. Cheng L, Che Y, Gulmezoglu AM. Interventions for
emergency contraception. Cochrane Database of
Systematic Reviews. 2012;8:CD001324.
25. Gemzell-Danielsson K, Rabe T, Cheng L. Emergency
contraception. Gynecological Endocrinology. 2013;29
Suppl 1:114.
26. Pittrof R, Rubenstein P, Sauer U. LNG may still be the best
oral EC option. Journal of Family Planning & Reproductive
Health Care. 2010;36(2):105-106; author reply 106.
3. What percentage of pregnancies
is prevented by ulipristal acetate if
used within 72 hours of unprotected
intercourse?
a) 10%.
b) 33%.
c) 50%.
d) 67%.
e) 100%.
4. Which one of the following
statements is INCORRECT regarding
ulipristal acetate as an emergency
contraceptive?
a) It may be taken with or without food.
b) It is an orally active synthetic selective
progesterone-receptor modulator.
c) It is not recommended in pregnancy or
breastfeeding.
d) It is more likely to cause menstrual
return before the expected date.
e) It is the recommended oral emergency
contraceptive in obese patients.
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27. Faculty of Sexual and Reproductive Healthcare. Ulipristal
acetate (ellaOne) and Breastfeeding Women. 2013; http://
www.fsrh.org/pdfs/CEUstatementUPAandBreastfeeding.
pdf. Accessed 3 Jun 2015.
28. Glasier A, Cameron ST, Blithe D, et al. Can we identify
women at risk of pregnancy despite using emergency
contraception? Data from randomized trials of ulipristal
acetate and levonorgestrel. Contraception. 2011;84(4):3637.
29. Sexual Health and Family Planning Australia. Statement on
Emergency Contraception (29 November 2013) 2013; http://
www.fpnsw.org.au/shfpa_ec.pdf. Accessed 3 Jun 2015.
30. Therapeutic Goods Administration. Levonorgestrel 1.5 mg
and 0.75 mg, oral emergency contraceptive. Monitoring
Communication 28 Feb 2014 2014; https://www.tga.gov.
au/monitoring-communication/levonorgestrel-15-mg-
and-075-mg-oral-emergency-contraceptive. Accessed 3
Jun 2015.
31. Australian Medicines Handbook, 2015. Adelaide, South
Australia: Australian Medicines Handbook; 2015.
32. International Consortium of Emergency Contraception. The
Intrauterine Device (IUD) for Emergency Contraception.
2012; http://www.cecinfo.org/custom-content/
uploads/2014/01/ICEC_IUD-FactSheet_Sep-2012.pdf.
Accessed 6 Mar 2014.
75
UP TO
CPD CREDITS
GROUP2
5. Which one of the following
statements is INCORRECT regarding
ulipristal acetate as an emergency
contraceptive?
a) It is a substrate for the cytochrome
P450(CYP) 3A4 enzyme.
b) Its plasma concentration may be
reduced by rifampicin.
c) Its absorption is unaffected by
gastricpH.
d) It may interfere with ongoing hormonal
contraception.
e) Its adverse effects are usually
selflimiting and of short duration.
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