PROGESTERONE RECEPTOR MODULATORS
Ulipristal acetate 04-Oct-2018
l DRUG ACTION Ulipristal acetate is a progesterone receptor
modulator with a partial progesterone antagonist effect.
Pre-operative treatment of moderate to severe symptoms
of uterine fibroids (initiated by a specialist)
▶ Adult: 5 mg once daily for up to 3 months starting
during the first week of menstruation
Intermittent treatment of moderate to severe symptoms
of uterine fibroids if surgery not appropriate (initiated
▶ Adult: 5 mg once daily for up to 3 months starting
during the first week of menstruation, treatment
course may be repeated if necessary; re-treatment
should start no sooner than during the first week of the
second menstruation following completion of the
previous course; maximum 4 courses
▶ Females of childbearing potential: 30 mg for 1 dose, to be
taken as soon as possible after coitus, but no later than
MHRA/CHM ADVICE: ESMYA ® (ULIPRISTAL ACETATE) FOR
SYMPTOMS OF UTERINE FIBROIDS: RESTRICTIONS TO USE AND
REQUIREMENT TO CHECK LIVER FUNCTION BEFORE, DURING AND
Rare but serious cases of liver injury, including cases of
hepatic failure requiring liver transplantation, have been
reported worldwide in women treated with Esmya ® for
the symptoms of uterine fibroids. An EU review of the
available data concluded that Esmya ® may have
contributed to the onset of some of the cases of serious
liver injury and has now finalised with a number of
measures to minimise this risk. In particular, more than
one treatment course is now authorised only in women
who are not eligible for surgery, and liver function
monitoring is to be carried out in all women treated with
Esmya ®. See Monitoring requirements for further
cancer. vaginal bleeding not caused by uterine fibroids
l CAUTIONS Uncontrolled severe asthma
l INTERACTIONS → Appendix 1: ulipristal
mouth . fever. flatulence . hot flush . increased risk of
infection . insomnia . libido disorder. malaise . skin
reactions . vision disorders . vulvovaginal disorders
▶ Frequency not known Hepatic disorders
l CONCEPTION AND CONTRACEPTION When ulipristal is
given for uterine fibroids non-hormonal contraceptive
methods (barrier methods or intra-uterine device) should
be used both during treatment and for 12 days after
▶ When used for Emergency contraception Limited information
available—if pregnancy occurs, manufacturer advises
report to the ellaOne ® pregnancy registry.
▶ When used for Uterine fibroids Manufacturer advises avoid—
limited information available.
▶ When used for Emergency contraception Manufacturer advises
avoid for 1 week after administration—present in milk.
▶ When used for Uterine fibroids Manufacturer advises avoid—
▶ When used for Emergency contraception Manufacturer advises
avoid in severe impairment (no information available).
▶ When used for Uterine fibroids Manufacturer advises avoid
▶ When used for Uterine fibroids Manufacturer advises avoid in
severe impairment unless patient is closely monitored—no
▶ When used for Uterine fibroids Manufacturer advises perform
liver function tests before treatment initiation—do not
initiate if transaminases exceed 2 times the upper limit of
normal. During the first 2 treatment courses, monitor liver
function monthly; for further treatment courses, perform
liver function tests once before each new treatment course
and when clinically indicated. At the end of each
treatment course, perform liver function tests after
2–4 weeks. Discontinue treatment if serum transaminases
exceed 3 times the upper limit of normal and closely
monitor patient. Manufacturer advises periodic
monitoring of the endometrium following repeated
l PRESCRIBING AND DISPENSING INFORMATION The
manufacturer of Esmya ® has provided a Physician’s Guide
▶ When used for Emergency contraception When prescribing or
supplying hormonal emergency contraception,
manufacturer advises women should be told:
. if vomiting occurs within 3 hours of taking a dose, a
replacement dose should be taken;
. that their next period may be early or late;
. to seek medical attention promptly if any lower
abdominal pain occurs because this could signify an
The Faculty of Sexual and Reproductive Healthcare also
. that a barrier method of contraception needs to be
used—see Emergency contraception p. 794 for further
. that a pregnancy test should be performed if the next
menstrual period is delayed by more than 7 days, is
lighter than usual, or is associated with abdominal pain
that is not typical of the woman’s usual dysmenorrhoea;
. that a pregnancy test should be performed if hormonal
contraception is started soon after use of emergency
contraception even if they have bleeding; bleeding
associated with the contraceptive method may not
▶ When used for Uterine fibroids Before initiation of Esmya ®,
the MHRA advises that women are informed of the rare
risk of liver damage and the need for liver function testing.
Women should also be advised to seek urgent medical
attention if they develop any symptoms or signs of liver
injury (such as unusual tiredness, yellowing of the skin,
darkening of the urine, nausea and vomiting).
Manufacturer advises prescribers should explain the
requirement for treatment free intervals to women
receiving intermittent treatment.
▶ When used for Uterine fibroids Manufacturer advises a patient
▶ When used for Uterine fibroids Manufacturer advises if a dose
is more than 12 hours late, the missed dose should not be
taken and the next dose should be taken at the normal
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
Ulipristal acetate 30 mg EllaOne 30mg tablets | 1 tablet p £14.05
▶ Esmya (Gedeon Richter (UK) Ltd)
Ulipristal acetate 5 mg Esmya 5mg tablets | 28 tablet P £114.13 DT = £114.13
Other drugs used for Contraception, oral progestogenonly Norethisterone, p. 764
▶ Females of childbearing potential: 75 micrograms daily,
dose to be taken at same time each day, starting on day
1 of cycle then continuously, if administration delayed
for 12 hours or more it should be regarded as a ‘missed
l CONTRA-INDICATIONS Acute porphyrias p. 1058 . history
of breast cancer but can be used after 5 years if no evidence
of disease and non-hormonal contraceptive methods
unacceptable . severe arterial disease . undiagnosed
l CAUTIONS Active trophoblastic disease (until return to
normal of urine- and plasma-gonadotrophin
with positive (or unknown) antiphospholipid antibodies
▶ Other conditions The product literature advises caution in
patients with history of thromboembolism, hypertension,
diabetes mellitus and migraine; evidence for caution in
these conditions is unsatisfactory.
l INTERACTIONS → Appendix 1: desogestrel
▶ Common or very common Breast abnormalities . depressed
mood . headache . libido decreased . menstrual cycle
irregularities . mood altered . nausea . skin reactions . weight increased
▶ Rare or very rare Erythema nodosum
▶ Frequency not known Angioedema . embolism and
SIDE-EFFECTS, FURTHER INFORMATION The benefits of
using progestogen-only contraceptives (POCs), such as
desogestrel, should be weighed against the possible risks
There is a small increase in the risk of having breast
cancer diagnosed in women using a combined oral
contraceptive pill (COC); this relative risk may be due to an
earlier diagnosis, biological effects of the pill or a
combination of both. This increased risk is related to the
age of the woman using the COC rather than the duration
of use and disappears gradually within 10 years after
The risk of breast cancer in users of POCs is possibly of
similar magnitude as that associated with COCs, however
the evidence is less conclusive.
Available evidence does not support an association
between the use of a progestegen-only contraceptive pill
and breast cancer. Any increased risk is likely to be small
and reduces gradually during the 10 years after stopping;
there is no excess risk 10 years after stopping. The older
age at which the contraceptive is stopped appears to have
a greater influence on increased risk rather than the
l PREGNANCY Not known to be harmful.
l BREAST FEEDING Progestogen-only contraceptives do not
l HEPATIC IMPAIRMENT Caution in severe liver disease and
recurrent cholestatic jaundice. Avoid in liver tumour.
Surgery All progestogen-only contraceptives are suitable
for use as an alternative to combined hormonal
contraceptives before major elective surgery, before all
surgery to the legs, or before surgery which involves
prolonged immobilisation of a lower limb.
Starting routine One tablet daily, on a continuous basis,
starting on day 1 of cycle and taken at the same time each
day (if delayed by longer than 12 hours contraceptive
protection may be lost). Additional contraceptive
precautions are not required if desogestrel is started up to
and including day 5 of the menstrual cycle; if started after
this time, additional contraceptive precautions are
Changing from a combined oral contraceptive Start on the day
following completion of the combined oral contraceptive
course without a break (or in the case of ED tablets
After childbirth Oral progestogen-only contraceptives can
be started up to and including day 21 postpartum without
the need for additional contraceptive precautions. If
started more than 21 days postpartum, additional
contraceptive precautions are required for 2 days.
Diarrhoea and vomiting Vomiting and persistent, severe
diarrhoea can interfere with the absorption of oral
progestogen-only contraceptives. If vomiting occurs
within 2 hours of taking desogestrel, another pill should be
taken as soon as possible. If a replacement pill is not taken
within 12 hours of the normal time for taking desogestrel,
or in cases of persistent vomiting or very severe diarrhoea,
additional precautions should be used during illness and
Missed doses The following advice is recommended: ‘If
you forget a pill, take it as soon as you remember and carry
on with the next pill at the right time. If the pill was more
than 12 hours overdue you are not protected. Continue
normal pill-taking but you must also use another method,
such as the condom, for the next 2 days’.
The Faculty of Sexual and Reproductive Healthcare
recommends emergency contraception if one or more
tablets are missed or taken more than 12 hours late and
unprotected intercourse has occurred before 2 further
tablets have been correctly taken.
BNF 78 Contraception, oral progestogen-only 805
l NATIONAL FUNDING/ACCESS DECISIONS
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (September
2003) that Cerazette ® should be restricted for use in
women who cannot tolerate oestrogen-containing
contraceptives or in whom such preparations are contraindicated.
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
▶ Desogestrel (Non-proprietary)
Desogestrel 75 microgram Desogestrel 75microgram tablets | 84 tablet P £9.55 DT = £2.44
▶ Aizea (Besins Healthcare (UK) Ltd)
Desogestrel 75 microgram Aizea 75microgram tablets | 84 tablet P £5.21 DT = £2.44
▶ Cerazette (Merck Sharp & Dohme Ltd)
Desogestrel 75 microgram Cerazette 75microgram tablets | 84 tablet P £9.55 DT = £2.44
▶ Cerelle (Consilient Health Ltd)
Desogestrel 75 microgram Cerelle 75microgram tablets |
▶ Desomono (MedRx Licences Ltd)
Desogestrel 75 microgram Desomono 75microgram tablets | 84 tablet P £6.50 DT = £2.44
Desogestrel 75 microgram Desorex 75microgram tablets | 84 tablet P £2.99 DT = £2.44
▶ Feanolla (Lupin Healthcare (UK) Ltd)
Desogestrel 75 microgram Feanolla 75microgram tablets | 84 tablet P £3.49 DT = £2.44
Desogestrel 75 microgram Moonia 75microgram tablets |
84 tablet P s DT = £2.44 (Hospital only)
▶ Zelleta (Morningside Healthcare Ltd)
Desogestrel 75 microgram Zelleta 75microgram tablets | 84 tablet P £2.98 DT = £2.44
▶ Females of childbearing potential: 1.5 mg for 1 dose,
taken as soon as possible after coitus, preferably within
12 hours and no later than after 72 hours (may also be
used between 72–96 hours after coitus but efficacy
decreases with time), alternatively 3 mg for 1 dose,
taken as soon as possible after coitus, preferably within
12 hours and no later than after 72 hours (may also be
used between 72–96 hours after coitus but efficacy
decreases with time). Higher dose should be considered
for patients with body-weight over 70 kg or BMI over
▶ Females of childbearing potential: 30 micrograms daily
starting on day 1 of the cycle then continuously, dose is
to be taken at the same time each day, if
administration delayed for 3 hours or more it should be
JAYDESS ® 13.5MG INTRA-UTERINE DEVICE
▶ BY INTRA-UTERINE ADMINISTRATION
▶ Females of childbearing potential: Insert into uterine
cavity within 7 days of onset of menstruation, or any
time if replacement (additional precautions (e.g.
barrier methods) advised for at least 7 days before), or
any time if reasonably certain woman is not pregnant
and there is no risk of conception (additional
precautions (e.g. barrier methods) necessary for next
7 days), or immediately following termination of
pregnancy below 24 weeks’ gestation; postpartum
insertions should be delayed until at least 4 weeks after
delivery; effective for 3 years
KYLEENA ® 19.5MG INTRA-UTERINE DEVICE
▶ BY INTRA-UTERINE ADMINISTRATION
▶ Females of childbearing potential: Insert into uterine
cavity within 7 days of onset of menstruation, or any
time if replacement (additional precautions (e.g.
barrier methods) advised for at least 7 days before), or
any time if reasonably certain woman is not pregnant
and there is no risk of conception (additional
precautions (e.g. barrier methods) necessary for next
7 days), or immediately following termination of
pregnancy below 24 weeks’ gestation; postpartum
insertions should be delayed until at least 4 weeks after
delivery; effective for 5 years
LEVOSERT ® 20MICROGRAMS/24HOURS INTRA-UTERINE
▶ BY INTRA-UTERINE ADMINISTRATION
▶ Females of childbearing potential: Insert into uterine
cavity within 7 days of onset of menstruation, or any
time if replacement (additional precautions (e.g.
barrier methods) advised for at least 7 days before), or
any time if reasonably certain woman is not pregnant
and there is no risk of conception (additional
precautions (e.g. barrier methods) necessary for next
7 days), or immediately following termination of
pregnancy below 24 weeks’ gestation; postpartum
insertions should be delayed until at least 4 weeks after
delivery; effective for 4 years
MIRENA ® 20MICROGRAMS/24HOURS INTRA-UTERINE DEVICE
▶ BY INTRA-UTERINE ADMINISTRATION
▶ Females of childbearing potential: Insert into uterine
cavity within 7 days of onset of menstruation, or any
time if replacement (additional precautions (e.g.
barrier methods) advised for at least 7 days before), or
any time if reasonably certain woman is not pregnant
and there is no risk of conception (additional
precautions (e.g. barrier methods) necessary for next
7 days), or immediately following termination of
pregnancy below 24 weeks’ gestation; postpartum
insertions should be delayed until at least 4 weeks after
delivery; effective for 5 years
Prevention of endometrial hyperplasia during oestrogen
▶ BY INTRA-UTERINE ADMINISTRATION
▶ Females of childbearing potential: Insert during last days
of menstruation or withdrawal bleeding or at any time
if amenorrhoeic; effective for 4 years
DOSE ADJUSTMENTS DUE TO INTERACTIONS
▶ When used orally as an emergency contraceptive, the
effectiveness of levonorgestrel is reduced in women
taking enzyme-inducing drugs (and for up to 4 weeks
after stopping); a copper intra-uterine device should
preferably be used instead. If the copper intra-uterine
device is undesirable or inappropriate, the dose of
levonorgestrel should be increased to a total of 3 mg
taken as a single dose; pregnancy should be excluded
following use, and medical advice sought if pregnancy
▶ There is no need to increase the dose for emergency
contraception if the patient is taking antibacterials that
▶ With the progestogen-only intra-uterine device,
levonorgestrel is released close to the site of the main
contraceptive action (on cervical mucus and
endometrium) and therefore progestogenic side-effects
contraceptive effect of the progestogen-only intrauterine system and additional contraceptive
▶ With intra-uterine use The Faculty of Sexual and
Reproductive Healthcare (FSRH) advises levonorgestrel is
used as detailed below, although these situations are
. Insertion at any time if reasonably certain the woman is
not pregnant or at risk of pregnancy;
. Additional precautions (e.g. barrier methods) for at least
7 days before replacement even if immediate
. Insertion immediately following termination of
pregnancy below 24 weeks’ gestation;
. Postpartum insertions 4 weeks after delivery.
▶ With oral use The FSRH advises levonorgestrel is used as
detailed below, although these situations are considered
. Higher dose option for emergency contraception in
patients with body-weight over 70 kg or BMI over
. Use for emergency contraception between 72–96 hours
▶ With intra-uterine use or oral use in children Consult product
literature for licensing status of individual preparations.
MHRA/CHM ADVICE (JUNE 2015) INTRA-UTERINE
CONTRACEPTION: UTERINE PERFORATION—UPDATED
Uterine perforation most often occurs during insertion,
but might not be detected until sometime later. The risk
of uterine perforation is increased when the device is
inserted up to 36 weeks postpartum or in patients who
are breastfeeding. Before inserting an intra-uterine
contraceptive device, inform patients that perforation
occurs in approximately 1 in every 1000 insertions and
. severe pelvic pain after insertion (worse than period
. pain or increased bleeding after insertion which
continues for more than a few weeks;
Patients should be informed on how to check their
threads and to arrange a check-up if threads cannot be
felt, especially if they also have significant pain. Partial
perforation may occur even if the threads can be seen;
consider this if there is severe pain following insertion
▶ With intra-uterine use active trophoblastic disease (until
return to normal of urine- and plasma-gonadotrophin
concentration . acute cervicitis . acute malignancies
affecting the blood (use with caution in remission). acute
vaginitis . distorted uterine cavity . history of breast cancer
but can be considered for a woman in long-term remission
who has menorrhagia and requires effective contraception
. increased risk factors for pelvic infections . infected
abortion during the previous three months . not suitable
▶ With oral use Acute porphyrias p. 1058
▶ When used for contraception with oral use for contraception
history of breast cancer but can be used after 5 years if no
evidence of disease and non-hormonal contraceptive
methods unacceptable . severe arterial disease . undiagnosed vaginal bleeding
GENERAL CAUTIONS Risk factors for ectopic pregnancy
(including previous ectopic pregnancy, tubal surgery or
▶ With intra-uterine use disease-induced immunosuppression
infection—avoid if marked immunosuppression) . endometriosis . epilepsy (risk of seizure at time of
insertion). fertility problems . history of pelvic
inflammatory disease . increased risk of expulsion if
inserted before uterine involution . jaundice (consider
removal). marked increase of blood pressure (consider
removal). migraine (consider removal). nulliparity . severe
arterial disease (consider removal). severe cervical
stenosis . severe headache (consider removal). severe
primary dysmenorrhoea . severely scarred uterus
(including after endometrial resection). young age
▶ When used for contraception with oral use for contraception
active trophoblastic disease (until return to normal of
urine- and plasma-gonadotrophin concentration)—seek
syndromes . past ectopic pregnancy . sex-steroid
dependent cancer. systemic lupus erythematosus with
positive (or unknown) antiphospholipid antibodies
▶ When used for emergency contraception with oral use for
emergency contraception active trophoblastic disease
▶ With intra-uterine use The Faculty of Sexual and
Reproductive Healthcare advises intercourse should be
avoided or another method of contraception used for at
least 7 days before removal of intra-uterine device—
emergency contraception may need to be considered if
recent intercourse has occurred and the intra-uterine
▶ Risk of infection with intra-uterine devices
The main excess risk of infection occurs in the first 20 days
after insertion and is believed to be related to existing
carriage of a sexually transmitted infection. Women are
considered to be at a higher risk of sexually transmitted
. they are under 25 years old or
. they are over 25 years old and
. have had more than one partner in the past year or
. their regular partner has other partners.
In these women, pre-insertion screening (for chlamydia
and, depending on sexual history and local prevalence of
disease, Neisseria gonorrhoeae) should be performed. If
prophylactic antibacterial cover should be given. The
woman should be advised to attend as an emergency if she
experiences sustained pain during the next 20 days.
▶ Use as a contraceptive in co-morbidities
▶ With oral use The product literature advises caution in
patients with history of thromboembolism, hypertension,
diabetes mellitus and migraine; evidence for caution in
these conditions is unsatisfactory.
BNF 78 Contraception, oral progestogen-only 807
MIRENA ® 20MICROGRAMS/24HOURS INTRA-UTERINE
DEVICE Advanced uterine atrophy
l INTERACTIONS → Appendix 1: levonorgestrel
▶ With oral use Breast tenderness . diarrhoea . dizziness . fatigue . haemorrhage . vomiting
▶ With intra-uterine use Alopecia . endometritis . oedema . uterine rupture
▶ With oral use Face oedema . pelvic pain
▶ With oral use Cerebrovascular insufficiency . depressed
mood . diabetes mellitus . embolism and thrombosis . neoplasms . sexual dysfunction . weight changes
SIDE-EFFECTS, FURTHER INFORMATION
Breast cancer There is a small increase in the risk of
having breast cancer diagnosed in women using, or who
have recently used, a progestogen-only contraceptive pill;
this relative risk may be due to an earlier diagnosis. The
most important risk factor appears to be the age at which
the contraceptive is stopped rather than the duration of
use; the risk disappears gradually during the 10 years after
stopping and there is no excess risk by 10 years. A possible
small increase in the risk of breast cancer should be
With intra-uterine use There is no evidence of an
association between the levonorgestrel intra-uterine
system and breast cancer. The levonorgestrel intra-uterine
system should be avoided in patients with a history of
breast cancer; any consideration of it’s use should be by a
specialist in contraception and in consultation with the
Patients should be informed about the device that has
been inserted and when it should be removed or replaced
(including refering them to a patient information leaflet
and other sources of information).
Patients may experience irregular, prolonged or
infrequent menstrual bleeding in the 3–6 months
following insertion; bleeding pattern improves with time
but persists in some patients.
Progestogenic side-effects resolve with time (after the
▶ With oral use Not known to be harmful.
▶ With intra-uterine use If an intra-uterine device fails and the
woman wishes to continue to full-term the device should
be removed in the first trimester if possible. Avoid; if
pregnancy occurs remove intra-uterine system.
l BREAST FEEDING Progestogen-only contraceptives do not
▶ With intra-uterine use or oral use for Contraception in
adults Manufacturer advises avoid in liver tumour.
▶ With oral use for Contraception or Emergency
contraception Manufacturer advises avoid in severe
▶ With intra-uterine use Manufacturer advises avoid in severe
impairment—no information available; avoid in acute
▶ With intra-uterine use Gynaecological examination before
insertion, 4–6 weeks after insertion, then annually.
l DIRECTIONS FOR ADMINISTRATION
▶ With intra-uterine use The doctor or nurse administering (or
removing) the system should be fully trained in the technique
and should provide full counselling reinforced by the patient
l PRESCRIBING AND DISPENSING INFORMATION
and insertion technique—the MHRA recommends to
prescribe and dispense by brand name to avoid inadvertent
Diarrhoea and vomiting with use as an oral contraceptive
Vomiting and persistent, severe diarrhoea can interfere
with the absorption of oral progestogen-only
contraceptives. If vomiting occurs within 2 hours of taking
an oral progestogen-only contraceptive, another pill
should be taken as soon as possible. If a replacement pill is
not taken within 3 hours of the normal time for taking the
progestogen-only pill, or in cases of persistent vomiting or
very severe diarrhoea, additional precautions should be
used during illness and for 2 days after recovery.
▶ With oral use for Contraception One tablet daily, on a
continuous basis, starting on day 1 of cycle and taken at
the same time each day (if delayed by longer than 3 hours
contraceptive protection may be lost). Additional
contraceptive precautions are not required if
levonorgestrel is started up to and including day 5 of the
menstrual cycle; if started after this time, additional
contraceptive precautions are required for 2 days.
Changing from a combined oral contraceptive Start on the day
following completion of the combined oral contraceptive
course without a break (or in the case of ED tablets
After childbirth Oral progestogen-only contraceptives can
be started up to and including day 21 postpartum without
the need for additional contraceptive precautions. If
started more than 21 days postpartum, additional
contraceptive precautions are required for 2 days.
▶ With oral use for Emergency contraception When prescribing or
supplying hormonal emergency contraception,
manufacturer advises women should be told:
. if vomiting occurs within 3 hours, a replacement dose
. that their next period may be early or late;
. to seek medical attention promptly if any lower
abdominal pain occurs because this could signify an
The Faculty of Sexual and Reproductive Healthcare also
. that a barrier method of contraception needs to be
used—see Emergency contraception p. 794 for further
. that a pregnancy test should be performed if the next
menstrual period is delayed by more than 7 days, is
lighter than usual, or is associated with abdominal pain
that is not typical of the woman’s usual dysmenorrhoea;
. that a pregnancy test should be performed if hormonal
contraception is started soon after use of emergency
contraception even if they have bleeding; bleeding
associated with the contraceptive method may not
▶ With intra-uterine use Counsel women on the signs,
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