Evidence Review for Prescribing Clinical Network
Treatment: Combined oral contraception: Zoely®▼ (nomegestrol 2.5mg/
estradiol 1.5mg)
Prepared by: Sumra Hussain
Topic Submitted by: Sumra Hussain
Date: 09/05/14
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Summary page
 How strong is the evidence for claimed efficacy?
Grade A = >1 RCT or meta-analysis
 Potential advantages in terms of: efficacy, compliance, pharmacokinetics,
drug interactions and adverse effects?
Zoely®1 is taken as a 24/4 regimen (24 active tablets followed by 4 inactive tablets).
The warnings of serious adverse events seen with other combined oral
contraceptives are considered applicable to Zoely®.
 Is there a clear place in therapy / treatment pathway?
The NICE evidence summary2 states that the manufacturer (MSD) of Zoely® has
suggested it is likely to be used as a second or third line option in women who have
found alternative combined hormonal contraceptives unsuitable.
 Is monitoring for efficacy/toxicity required? This is a black triangle drug that is
subject to additional monitoring.1
 Traffic light status – to be confirmed


Role of the specialist (if applicable)?
Role of GP (if applicable)? Initiate/continue prescribing.
1

National Guidance/information available
 NICE Evidence summary: new medicine - : Zoely® (nomegestrol/estradiol)2
 The faculty of Sexual & Reproductive Healthcare clinical guidance on
combined hormonal contraception.3
Recommendations:
Options for consideration:
1. Consider Zoely® as a second or third line option in women who have found
alternative combined hormonal contraceptives unsuitable
2. Consider Zoely® suitable for Black status, based on the fact that the Scottish
Medicines Consortium and other NHS organisations (see under precedent
setting) have not recommended it for routine prescribing.
2
VERSION CONTROL SHEET
Version
1.0
Date
Author
09/05/14 Sumra Hussain
Status
Draft
3
Comment
Circulated for comments
1. Purpose of the Review
To review the place of Zoely® (nomegestrol 2.5mg/ estradiol 1.5mg) in contraceptive
therapy.
This is a black triangle drug that is subject to additional monitoring.
2. Appropriateness
2.1 The patient:
Any woman requiring a combined oral contraceptive pill.
2.2 The problem:
The combined oral contraceptive pill is one of the most commonly used contraceptive
methods in the UK.2
2.3 The Intervention
How does it work:
The active tablets contain 2.5mg nomegestrol acetate, a highly selective progestogen
that is similar to human progesterone and has no oestrogenic, androgenic,
glucocorticoid or mineralocorticoid activity, and 1.5mg 17β-estradiol (as
hemihydrate), a synthetically produced oestrogen that is chemically identical to
human 17β-estradiol. Nomegestrol/estradiol is taken as a 24/4 regimen (24 active
tablets followed by 4 inactive tablets) unlike most other combined oral contraceptives,
which are taken as 21/7 regimens. It is 1 of 2 combined oral contraceptives that
contain synthetic estradiol; the other is dienogest/estradiol (Qlaira), which is taken as
a 26/2 regimen.2
Care setting:
Primary care and family planning clinics.
Frequency:
One tablet is taken daily for 28 consecutive days. Each pack starts with 24 white
active tablets, followed by 4 yellow inactive tablets. A subsequent pack is started
immediately with no break in taking a daily tablet and irrespective of the presence or
absence of withdrawal bleeding. Withdrawal bleeding usually starts on day 2-3 after
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taking the last active tablet and may not have finished before the next pack is
started.2
2.4 Alternative treatments:
Other combined oral contraceptives. User preference is an important factor in
contraceptive choice. A reduction in or absence of withdrawal bleeding may be
attractive to some women, but seen as a disadvantage to others. 2
Generally a preparation with the lowest oestrogen and progestogen content which
gives good cycle control and minimal side-effects in the individual woman is chosen.
Combined oral contraceptives containing a fixed amount of an oestrogen and a
progestogen in each active tablet are termed ‘monophasic’; those with varying
amounts of the two hormones are termed ‘phasic’.
Low strength preparations (containing ethinylestradiol 20 micrograms) are particularly
appropriate for women with risk factors for circulatory disease, provided a combined
oral contraceptive is otherwise suitable. It is recommended that the COC is not
continued beyond 50 years of age since more suitable alternatives exist.
Standard strength preparations (containing ethinylestradiol 30 or 35 micrograms or in
30-40 microgram phased preparations) are appropriate for standard use. Phased
preparations are generally reserved for women who either do not have withdrawal
bleeding or who have breakthrough bleeding with monophasic products. 4
3. Effectiveness
3.1 Expected benefits
Advantages of COC’s include:
 Reliable and reversible;
 Reduced dysmenorrhoea and menorrhagia;
 Reduced incidence of premenstrual tension;
 Less symptomatic fibroids and functional ovarian cysts;



Less benign breast disease;
Reduced risk of ovarian and endometrial cancer;
Reduced risk of pelvic inflammatory disease.4
3.3 Side-effects/complications
The most frequently reported adverse events have been acne, irregular withdrawal
bleeding and weight gain.2
5
The warnings of serious adverse events seen with other combined oral
contraceptives (such as venous thromboembolism, other circulatory disorders, breast
cancer and cervical cancer) are considered applicable to Zoely®.1
3.4 Review of evidence
The evidence summary is based on 2 randomised, open-label multicentre trials of
similar size and design, which were conducted in parallel in different countries.
Mansour et al. (2011)5 was conducted in Europe, Asia and Australia. Westhoff et al.
(2012)6 was conducted in the United States, Canada, Brazil, Chile and Mexico. Both
studies were funded by Merck Sharp & Dohme.
The studies included health, sexually active women aged 18-50 with a body mass
index (BMI) between 17 and 35 kg/m2 who needed contraception and did not plan to
use condoms.
Participants were randomly allocated in a 3:1 ratio to either nomegestrol/estradiol
(Zoely®) or drospirenone/ethynylestradiol (Yasmin®) for 13 consecutive 28-day
cycles.
The primary outcome in both studies was contraceptive efficacy in women aged 1835, assessed by recording in-treatment pregnancies between the first and the last
day of taking the trial drug plus an extension window. Contraceptive efficacy was
expressed as the Pearl Index, which is defined as the number of pregnancies for
every 100 years of contraceptive exposure.
Secondary outcomes included:
 Contraceptive efficacy in the overall age group (18-50 years).
 The number of days of bleeding or spotting per 91-day reference period.
 Incidence and duration of unscheduled bleeding or spotting.
 Incidence of absence of withdrawal bleeding.
 Safety and tolerability.

The two trials found:
 nomegestrol/estradiol (Zoely®) and drospirenone/ethinylestradiol (Yasmin®),
had a similar contraceptive efficacy.
 The mean number of days on which women experienced bleeding or spotting
was lower in women taking Zoely® than in women taking Yasmin®. The
number of bleeding or spotting days decreased over the course of the study
(13 cycles) in women taking (Zoely®), but not in women taking Yasmin®.
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


Unscheduled bleeding or spotting decreased over time in the Zoely® group.
However, in some cycles, particularly early cycles, unscheduled bleeding or
spotting was statistically significantly more common with Zoely® than with
Yasmin®.
Withdrawal bleeds, in women who experienced them, were shorter and lighter
in the group taking Zoely®.
About 50% of women taking Zoely® had adverse events that were considered
to be related to the contraceptive, compared with 37% of women taking
Yasmin®. The most frequently reported adverse events (occurring in 5% or
more women) were acne, irregular withdrawal bleeding and weight gain in
both studies. Adverse events led to about 18% of women stopping Zoely® and
10% of women stopping Yasmin®. In both studies, the body weight of women
taking Zoely® increased by 1 kg on average over 13 cycles. In comparison,
women taking Yasmin® gained 0.35kg in Mansour et al. (2011) and 0.2kg in

Westhoff et al. (2012). The results are consistent with a cochrane review that
concluded that combined hormonal contraceptives do not have a large effect
on weight.
Venous thromboembolism was not reported by any women taking Zoely®.
However, according to the summary of product characteristics, venous
thromboembolic events have been reported during post-marketing use.
4. Summary of Key Points for Consideration
4.1 National guidance:
A Faculty of Sexual & Reproductive Healthcare statement7 on the use of
nomegestrol/estradiol (Zoely®) notes that COC’s that have extended regimens or
that contain hormones similar to endogenous hormones may appeal to some women.
Current evidence suggests that nomegestrol/estradiol (Zoely®) is acceptable and
safe. However, until more data are available the indications and contraindications
must be assumed to be the same as for other COC’s.
The faculty of Sexual & Reproductive Healthcare clinical guidance on combined
hormonal contraception (2011)8 advises that healthcare professionals prescribing
combined hormonal contraceptives should be guided by the women’s personal
preference, risk of venous thromboembolism, any contraindications, possible noncontraceptive benefits and experience with other contraceptive formulations.
The Scottish Medicines Consortium9 does not recommend Zoely® for use within NHS
Scotland on the basis that no submission was received from the manufacturer.
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4.2 Potential advantages/disadvantages
A reduction in or absence of withdrawal bleeding may be attractive to some women,
but seen as a disadvantage to others.2
4.5 Budgetary Impact
4.5.1 Cost:
Preparation
Cost per 3 months
Zoely
£16.501
Yasmin
£14.701
Qlaira
£25.181
Lucette
£9.352
1costs
(excluding VAT) taken from MIMS, November 2013
2 costs
(excluding VAT) taken from drugtariff.co.uk (February 2014)
4.5.2 Precedent setting:
NICE evidence summary
The manufacturer (Merck Sharp & Dohme) of nomegestrol/estradiol (Zoely®) and the
specialists involved in the production of the summary have suggested that
nomegestrol/estradiol is likely to be used as a second – or third – line option in a
small subgroup of women who have found alternative combined hormonal
contraceptives unsuitable.2
Scottish Medicines Consortium (SMC) 9
In the absence of a submission from the holder of the marketing authorisation Zoely®
is not recommended for routine use within NHS Scotland.
South Kent Coast CCG10
East Kent prescribing group (EKPG) recommend that Zoely® is not routinely
prescribed in primary care in East Kent as it was not felt to be cost effective.
Lincolnshire NHS11
Zoely® has been designated RED-RED and has not been approved for inclusion in
the joint formulary.
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Leicestershire Medicines strategy Group12
Zoely® has been assigned Black status because of lack of evidence of clinical
effectiveness, cost prioritization or concerns over safety.
5. Conclusions and Recommendations
The evidence available for Zoely® is based upon 2 randomised controlled trials that
do have their limitations.
The evidence suggests that Zoely® has a similar contraceptive efficacy to Yasmin®.
Options for consideration:
3. Consider Zoely® as a second or third line option in women who have found
alternative combined hormonal contraceptives unsuitable
4. Consider Zoely® suitable for Black status, based on the fact that the Scottish
Medicines Consortium and other NHS organisations (see under precedent
setting) have not recommended it for routine prescribing.
Consultant Comments for Zoely® for PCN June 2014
Dr Tina Peers
Dear Sumra,
My comments re Zoely are as follows:
1. I see it as a second or third line option for women who desire and are suitable for
CHC if they have irregular or heavy bleeding-in the absence of any pathology, on
other CHC.
The nomogestrel is helpful as it seems to give a more predictable and short, lighter
bleed.
2. Women who prefer to use a natural oestrogen preparation may prefer Zoely.
3. The regimen of 24/4 is much more contraceptively affective than a 21/7 regimen which we no longer recommend in Contraception and Reproductive Health-(have not
done for the last 10 years.) This is because the true failure rate of the pill is 9%Trussell 2010.For women who prefer a monthly bleed this regimen is preferable.
4. To say that it is not cost-effective is quite frankly inaccurate. The NHS spent
£135.5 million in 2012 on Terminations in England and Wales. We need to be able
toy offer as many options to women as possible. Obviously we recommend LARC
usage over SARC usage-especially intrauterine contraception (especially the
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intrauterine systems, the Mirena and Jaydess). However some women prefer the
option of a pill, and preventing as many unplanned pregnancies as possible is our
aim. The unintended pregnancy rate in the UK is still approximately 44%-48%. This is
a safe and effective pill and therefore should be available.
5. As a 30 mcg pill it is much safer and preferable to any 35 mcg preparations, which
we do not recommend, except for Dianette for short term use in severe acne.
I hope that this is helpful.
Best wishes,
Tina
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Appendix 1: Evidence search
Search terms used:
Resource
Used in
this
review?
National Library for Health (NHL)
http://www.library.nhs.uk/Default.aspx
A gateway site with access to other resources such as Reviews
(Bandolier, Cochrane, CRD etc), Guidelines (e.g. NICE), Clinical
Knowledge Summaries (CKS) and Journals including AMED, British
Nursing Index, CINAHL, E-books, EMBASE, HMIC, MEDLINE, My
Journals, PsycINFO, PubMed, Databases from Dialog.
National Institute of Health and Clinical Excellence (NICE)
http://www.nice.org.uk/

NICE produces national guidance in three areas of health:
1. Public health - guidance on the promotion of good health and
the prevention of ill health
2. Health technologies - guidance on the use of new and
existing medicines, treatments and procedures within the
NHS
3. Clinical practice - guidance on the appropriate treatment and
care of people with specific diseases and conditions within
the NHS.
Bandolier
http://www.medicine.ox.ac.uk/bandolier/index.html
 (through
NHL)
Bandolier is a website about the use of evidence in health,
healthcare, and medicine. Information comes from systematic
reviews, meta-analyses, randomised trials, and from high quality
observational studies.
Centre for Reviews and Dissemination
http://www.york.ac.uk/inst/crd/
CRD undertakes high quality systematic reviews that evaluate the
effects of health and social care interventions and the delivery and
organisation of health care. Databases maintained by CRD include
Database of Abstracts of Reviews of Effects (DARE), NHS
Economic Evaluation Database (NHS EED), Health Technology
Assessment (HTA) Database
Scottish Intercollegiate Guidelines Network (SIGN)
http://www.sign.ac.uk/
Scottish equivalent of NICE
Medical Services Advisory Committee (Australia)
http://www.msac.gov.au/internet/msac/publishing.nsf/Content/home1
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
The principal role of the Medical Services Advisory Committee
(MSAC) is to advise the Australian Minister for Health and Ageing
on evidence relating to the safety, effectiveness and costeffectiveness of new medical technologies and procedures.
Canadian Agency for Drugs and Technologies in Health (CADTH)
http://www.cadth.ca/index.php/en/home
The Canadian Agency for Drugs and Technologies in Health
(CADTH) is a national body that provides Canada’s federal,
provincial and territorial health care decision makers with credible,
impartial advice and evidence-based information about the
effectiveness and efficiency of drugs and other health technologies.
Appendix 2: Grading of evidence
 Ia:
systematic review or meta-analysis of randomised controlled trials
 Ib: at least one randomised controlled trial
 IIa: at least one well-designed controlled study without randomisation
 IIb: at least one well-designed quasi-experimental study, such as a cohort
study
 III: well-designed non-experimental descriptive studies, such as comparative
studies, correlation studies, case–control studies and case series
 IV: expert committee reports, opinions and/or clinical experience of respected
authorities
Appendix 3: References
1. Summary of Product Characteristics (SPC): Zoely® 2.5 mg/1.5 mg film-coated
tablets
http://www.medicines.org.uk/emc/medicine/27581/SPC/
2. NICE evidence summary: new medicine
Combined oral contraception: nomegestrol/estradiol (Zoely)
http://publications.nice.org.uk/combined-oral-contraceptionnomegestrolestradiol-zoely-esnm28
3. The Faculty of Sexual & Reproductive Healthcare clinical guidance on
hormonal contraception (2011)
http://www.fsrh.org/pages/Clinical_Guidance_2.asp
4. British National Formulary. 66th edition. P520-527
5. Mansour et al. (2011) Efficacy and tolerability of a monophasic combined oral
contraceptive containing nomegestrol acetate and 17β-oestradiol in a 24/4
regimen, in comparison to an oral contraceptive containing ethinylestradiol
and drospirenone in a 21/7 regimen
http://informahealthcare.com/doi/abs/10.3109/13625187.2011.614029
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6. Westhoff et al. (2012) Efficacy, Safety, and Tolerability of a Monophasic Oral
Contraceptive Containing Nomegestrol Acetate and 17β-Estradiol: A
Randomized Controlled Trial.
http://journals.lww.com/greenjournal/Fulltext/2012/05000/Efficacy,_Safety,_an
d_Tolerability_of_a_Monophasic.16.aspx
7. A faculty of Sexual & Reproductive Healthcare statement on the use of
nomegestrol/estradiol
http://www.fsrh.org/pages/Clinical_Guidance_6.asp
8. Faculty of Sexual Reproductive Healthcare clinical guidance on combined
hormonal contraception (2011)
http://www.fsrh.org/pages/Clinical_Guidance_2.asp
9. Scottish Medicines Consortium (2013)
http://www.scottishmedicines.org.uk/SMC_Advice/Advice/898_13_nomegestro
l_acetate_estradiol_Zoely_Non_Submission/nomegestrol_acetate_estradiol_Z
oely
10. South Kent Coast CCG prescribing recommendations
http://www.southkentcoastccg.nhs.uk/about-us/prescribingrecommendations/?assetdet7876608=367736&categoryesctl7876619=9940
11. Lincolnshire NHS. PACE bulletin Volume 8; Number 7 April 2014.
From www.lincolnshire.nhs.uk
12. Leicestershire Medicines strategy Group
http://www.lmsg.nhs.uk/prescribing/leitraffic.asp
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