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ELLESTE DUET 1MG

Active substance(s): ESTRADIOL HEMIHYDRATE / NORETHISTERONE ACETATE / ESTRADIOL HEMIHYDRATE / NORETHISTERONE ACETATE / ESTRADIOL HEMIHYDRATE / NORETHISTERONE ACETATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT
Elleste Duet 1 mg Tablets
1 mg + 1 mg/1 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
One white film-coated tablet contains 1 mg estradiol (as estradiol hemihydrate).
One green film-coated tablet contains 1 mg estradiol (as estradiol hemihydrate) and 1 mg
norethisterone acetate.
Excipient with known effect:
Estradiol tablet: 62.8 mg lactose monohydrate
Estradiol and norethisterone acetate tablet: 61.8 mg lactose monohydrate
For the full list of excipients, see Section 6.1

3.

PHARMACEUTICAL FORM
Film-coated tablet.
The estradiol only tablets are white, round biconvex tablets, marked with “01” on one
side.
The combination tablets are pale green, round biconvex tablets, marked with “P1” on
one side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications
Hormone Replacement Therapy (HRT) for oestrogen deficiency symptoms in postand peri-menopausal women (see also Section 4.4).
The experience of treating women older than 65 years is limited.

4.2

Posology and method of administration
Posology
This product is a continuous sequential HRT. One white tablet to be taken daily for the
first 16 days, followed by one pale green tablet for the next 12 days. A new cycle should
then begin without any break. Therapy may start at any time in patients with established

amenorrhoea or who are experiencing long intervals between spontaneous menses. In
patients who are menstruating, it is advised that therapy starts on the first day of
bleeding. Patients changing from another cyclical or continuous sequential preparation
should complete the cycle and may then change to Elleste Duet 1mg without a break in
therapy. Patients changing from a continuous combined preparation may start therapy at
any time if amenorrhoea is established, or otherwise start on the first day of bleeding.
Elleste Duet tablets are available in two strengths: Elleste Duet 1 mg (containing 1 mg
estradiol and 1 mg norethisterone acetate) and Elleste Duet 2 mg (containing 2 mg
estradiol and 1 mg norethisterone acetate).
For initiation and continuation of treatment of post- and peri-menopausal symptoms, the
lowest effective dose for the shortest duration (see also Section 4.4) should be used.
Elleste Duet 2 mg is additionally indicated for prevention of osteoporosis in
postmenopausal women at high risk of future fractures and who are intolerant of, or
contraindicated for, other medicinal products approved for the prevention of
osteoporosis.
Missed Tablet: If a tablet is missed it should be taken within 12 hours of when normally
taken; otherwise the tablet should be discarded, and the usual tablet should be taken the
following day. If a tablet is missed there is an increased likelihood of breakthrough
bleeding or spotting.
Elderly
There are no special dosage requirements for elderly patients.
Paediatric population
Not to be used in children.
Method of administration
For oral use.

4.3

Contraindications
Pregnancy;
Breast-feeding;
Known, past or suspected breast cancer;
Known or suspected oestrogen-dependent malignant tumours (e.g. endometrial
cancer);
Undiagnosed genital bleeding;
Untreated endometrial hyperplasia;
Previous idiopathic or current venous thromboembolism (deep venous thrombosis,
pulmonary embolism);
Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency,
see Section 4.4);
Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction);
Acute liver disease, or a history of liver disease as long as liver function tests have
failed to return to normal;
Known hypersensitivity to the active substances or to any of the excipients listed in
Section 6.1;
Porphyria.

4.4

Special warnings and precautions for use
For the treatment of postmenopausal symptoms, HRT should only be initiated for
symptoms that adversely affect quality of life. In all cases a careful appraisal of the
risks and benefits should be undertaken at least annually and HRT should only be
continued as long as the benefit outweighs the risk.
Evidence regarding the risks associated with HRT in the treatment of premature
menopause is limited. Due to the low level of absolute risk in younger women,
however, the balance of benefits and risks for these women may be more favourable
than in older women.
Medical Examination/Follow Up
Before initiating or reinstituting HRT, a complete personal and family medical history
should be taken. Physical (including pelvic and breast) examination should be guided
by this and by the Sections 4.3 Contraindications and 4.4 Special warnings and
precautions for use. During treatment, periodic check-ups are recommended of a
frequency and nature adapted to the individual woman. Women should be advised
what changes in their breasts should be reported to their doctor or nurse (see ‘Breast
cancer’ below).
Investigations, including appropriate imaging tools, e.g.
mammography, should be carried out in accordance with currently accepted screening
practices, modified to the clinical needs of the individual.
Conditions Which Need Supervision
If any of the following conditions are present, have occurred previously, and/or have
been aggravated during pregnancy or previous hormone treatment, the patient should be
closely supervised. It should be taken into account that these conditions may recur or be
aggravated during treatment with Elleste Duet 1 mg, in particular:
-

Leiomyoma (uterine fibroids) or endometriosis
Risk factors for thromboembolic disorders (see below)
Risk factors for oestrogen dependent tumours, e.g. 1st degree heredity for
breast cancer
Hypertension
Liver disorders (e.g. liver adenoma)
Diabetes mellitus with or without vascular involvement
Cholelithiasis
Migraine or (severe) headache
Systemic lupus erythematosus
A history of endometrial hyperplasia (see below)
Epilepsy
Asthma
Otosclerosis

Reasons for Immediate Withdrawal of Therapy
Therapy should be discontinued in case a contra-indication is discovered and in the
following situations:
-

Jaundice or deterioration in liver function
Significant increase in blood pressure
New onset of migraine-type headache

-

Pregnancy

Endometrial Hyperplasia and Carcinoma
In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is
increased when oestrogens are administered alone for prolonged periods. The reported
increase in endometrial cancer risk among oestrogen-only users varies from 2-to 12fold greater compared with non-users, depending on the duration of treatment and
oestrogen dose (see Section 4.8). After stopping treatment, risk may remain elevated
for at least 10 years.
The addition of a progestogen cyclically for at least 12 days per month/28 day cycle or
continuous combined oestrogen-progestogen therapy in non-hysterectomised women
prevents the excess risk associated with oestrogen-only HRT.
Break-through bleeding and spotting may occur during the first months of treatment. If
break-through bleeding or spotting appears after some time on therapy, or continues after
treatment has been discontinued, the reason should be investigated, which may include
endometrial biopsy to exclude endometrial malignancy.
Breast Cancer
The overall evidence suggests an increased risk of breast cancer in women taking
combined oestrogen-progestogen and possibly also oestrogen-only HRT, that is
dependent on the duration of taking HRT.
Combined oestrogen-progestogen therapy


The randomised placebo-controlled trial the (Women’s Health Initiative study
(WHI), and epidemiological studies are consistent in finding an increased risk of
breast cancer in women taking combined oestrogen-progestogen for HRT that
becomes apparent after about 3 years (see Section 4.8)

Oestrogen-only therapy


The WHI trial found no increase in the risk of breast cancer in hysterectomised
women using oestrogen-only HRT. Observational studies have mostly reported a
small increase in risk of having breast cancer diagnosed that is substantially lower
than that found in users of oestrogen-progestogen combinations (see Section 4.8).

The excess risk becomes apparent within a few years of use but returns to baseline
within a few (at most five) years after stopping treatment.
HRT, especially oestrogen-progestogen combined treatment, increases the density of
mammographic images which may adversely affect the radiological detection of
breast cancer.

Ovarian Cancer



Ovarian cancer is much rarer than breast cancer. Epidemiological evidence

from a large meta-analysis suggests a slightly increased risk in women
taking oestrogen-only or combined oestrogen-progestagen HRT, which
becomes apparent within 5 years of use and diminishes over time after
stopping.
Some other studies, including the WHI trial, suggest that the use of
combined HRTs may be associated with a similar, or slightly smaller risk
(see Section 4.8).
Venous Thromboembolism
HRT is associated with a 1.3-3 fold risk of developing venous thromboembolism
(VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such
an event is more likely in the first year of HRT than later (see Section 4.8).
Patients with known thrombophilic states have an increased risk of VTE and
HRT may add to this risk. HRT is therefore contraindicated in these patients (see
Section 4.3).
Generally recognised risk factors for VTE include, use of oestrogens, older age,
major surgery, prolonged immobilization, obesity (BMI>30 kg/m2),
pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer.
There is no consensus about the possible role of varicose veins in VTE.
As in all postoperative patients, prophylactic measures need to be considered to
prevent VTE following surgery. If prolonged immobilisation is to follow elective
surgery temporarily stopping HRT 4 to 6 weeks earlier is recommended.
Treatment should not be restarted until the woman is completely mobilised.
In women with no personal history of VTE but with a first degree relative with a
history of thrombosis at young age, screening may be offered after careful
counselling regarding its limitations (only a proportion of thrombophilic defects
are identified by screening). If a thrombophilic defect is identified which
segregates with thrombosis in family members or if the defect is ‘severe’ (e.g,
antithrombin, protein S, or protein C deficiencies or a combination of defects)
HRT is contraindicated.
Women already on anticoagulant treatment require careful consideration of the
benefit-risk of use of HRT.
If VTE develops after initiating therapy, the drug should be discontinued.
Patients should be told to contact their doctors immediately when they are aware
of a potential thromboembolic symptom (e.g., painful swelling of a leg, sudden
pain in the chest, dyspnoea).
Coronary Artery Disease (CAD)
There is no evidence from randomised controlled trials of protection against
myocardial infarction in women with or without existing CAD who received
combined oestrogen-progestogen or oestrogen-only HRT.

Combined oestrogen-progestogen therapy
The relative risk of CAD during use of combined oestrogen-progestogen HRT is
slightly increased. As the baseline absolute risk of CAD is strongly dependent on
age, the number of extra cases of CAD due to oestrogen-progestogen use is very low
in healthy women close to menopause, but will rise with more advanced age.
Oestrogen-only
Randomised controlled data found no increased risk of CAD in hysterectomised
women using oestrogen-only therapy.
Ischaemic Stroke
Combined oestrogen-progestogen and oestrogen-only therapy are associated with an
up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change
with age or time since menopause. However, as the baseline risk of stroke is
strongly age-dependent, the overall risk of stroke in women who use HRT will
increase with age (see Section 4.8).
Hypothyroidism
Patients who require thyroid hormone replacement therapy should have their
thyroid function monitored regularly while on HRT to ensure that thyroid
hormone levels remain in an acceptable range.
Angioedema
Oestrogens may induce or exacerbate symptoms of angioedema, in particular in
women with hereditary angioedema.
Other Conditions
Oestrogens may cause fluid retention, and therefore patients with cardiac or renal
dysfunction should be carefully observed.
Women with pre-existing hypertriglyceridaemia should be followed closely during
oestrogen replacement or hormone replacement therapy, since rare cases of large
increases of plasma triglycerides leading to pancreatitis have been reported with
oestrogen therapy in this condition.
Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating
total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by
column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin
uptake is decreased, reflecting the elevated TBG. Free T4 and free T3
concentrations are unaltered. Other binding proteins may be elevated in serum, i.e.
corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to
increased circulating corticosteroids and sex steroids, respectively. Free or
biological active hormone concentrations are unchanged. Other plasma proteins
may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin,
ceruloplasmin).
HRT does not improve cognitive function. There is some evidence of increased
risk of probable dementia in women who start using continuous combined or
oestrogen-only HRT after the age of 65.

Patients with rare hereditary disorders of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction
The metabolism of oestrogens and progestogens.may be increased by concomitant use
of substances known to induce drug-metabolising enzymes, specifically cytochrome
P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin,
carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit
inducing properties when used concomitantly with steroid hormones. Herbal
preparations containing St John's Wort (Hypericum Perforatum) may induce the
metabolism of oestrogens and progestogens.
Clinically, an increased metabolism of oestrogens and progestogens may lead to
decreased effect and changes in the uterine bleeding profile.
The requirement for oral anti-diabetics or insulin can change as a result of the effect
on glucose tolerance.
Some laboratory tests can be influenced by oestrogens, such as tests for thyroid
function (see Section 4.4) or glucose tolerance.

4.6

Fertility, pregnancy and lactation
Pregnancy:
Elleste Duet 1 mg is not indicated during pregnancy. If pregnancy occurs during
medication with Elleste Duet 1 mg treatment should be withdrawn immediately.
Data on a limited number of exposed pregnancies indicate adverse effects of
norethisterone on the foetus. At doses higher than normally used in OC and HRT
formulations masculinisation of female foetuses was observed.
The results of most epidemiological studies to date relevant to inadvertant foetal
exposure to combinations of oestrogens + progestogens indicate no teratogenic or
foetotoxic effect.
Lactation:
Elleste Duet 1 mg is not indicated during lactation.

4.7

Effects on ability to drive and use machines
Elleste Duet 1 mg Tablets have no or negligible influence on the ability to drive and use
machines.

4.8

Undesirable effects

The most commonly reported adverse experiences are breast tension and pain,
dysmenorrhoea, irregular bleeding, and headache.
Within each frequency grouping, adverse drug reactions are presented in the order of
decreasing seriousness. Very common (≥ 1/10); Common (≥ 1/100 to < 1/10);
Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000); Very rare
(<1/10,000); not known (cannot be estimated from the available data).
System organ
class (MedDRA
SOC level)

Very common
(≥1/10)

Headache*.

Depression*,
nervousness*,
affect lability,
libido disorder
Dizziness*,
insomnia*

Nausea,
abdominal
distension*,
diarrhoea*,
dyspepsia*,
abdominal pain

Gastrointestinal
disorders

Hepatobiliary
disorders
Skin and
subcutaneous
tissue disorders
Musculoskeletal
and connective
tissue disorders
Reproductive
system and
breast
disorders

General
disorders and
administration
site conditions

Uncommon
(≥1/1,000 to
<1/100)

Rare
(≥1/10,000 to
<1/1,000)

Very rare
(<1/10,000)

Breast pain*,
breast
tenderness,
dysmenorrhoea*,
menstrual
disorder*

Acne*, rash,
pruritus*, dry
skin
Back pain*,
pain in
extremity*
Breast
enlargement*,
menorrhagia*,
genital
discharge *,
irregular
vaginal
bleeding,
uterine spasms,
vaginal
infection,
endometrial
hyperplasia
Pain, asthenia,
oedema
peripheral*,
weight
increased*

Migraine,
vertigo
Hypertension,
varicose veins

Paraesthesia
Embolism
venous***,
thrombophlebitis

Vomiting

Gallbladder
disorder,
cholelithiasis
Skin
discoloration

Jaundice
cholestatic
Hirsutism

Muscle spasms

Myasthenia

Breast cancer

Uterine
leiomyoma,
fallopian tube
cysts,
endocervical
polyps

Transaminases
increased
(*) Adverse reactions associated with oestrogen and progestogen have been found to be relatively less
frequent with the lowest dosage strength.
(**) Reported in post-marketing experience.

Investigations

not
known**
(cannot be
estimated
from the
available
data)

Hypersensitivity

Immune system
disorders
Psychiatric
disorders

Nervous system
disorders
Vascular
disorders

Common
(≥1/100 to
<1/10)

Alopecia

(***)Venous thromboembolism i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is
more frequent among hormone replacement therapy users than among non-users. For further
information, see Section 4.3 Contraindications and 4.4 Special warnings and precautions for use.

Breast Cancer Risk



An up to 2-fold increased risk of having breast cancer diagnosed is reported in women
taking combined oestrogen-progestogen therapy for more than 5 years.



Any increased risk in users of oestrogen-only therapy is substantially lower than that
seen in users of oestrogen-progestogen combinations.



The level of risk is dependent on the duration of use (see Section 4.4).



Results of the largest randomised placebo-controlled trial (WHI-study) and largest
epidemiological study (MWS) are presented.

Million Women study– Estimated additional risk of breast cancer after 5 years’ use
Age range
(years)

Additional cases per 1000
never-users of HRT over a 5
year period*

Risk ratio#

Additional cases per 1000
HRT users over 5 years
(95%CI)
Oestrogen only HRT
50-65
9-12
1.2
1-2(0-3)
Combined oestrogen-progestogen
50-65
9-12
1.7
6(5-7)
#Overall risk ratio. The risk ratio is not constant but will increase with increasing duration of
use.
Note: Since the background incidence of breast cancer differs by EU country, the number of
additional cases of breast cancer will also change proportionately.
* Taken from baseline incidence rates in developed countries.
US WHI studies - additional risk of breast cancer after 5 years’ use
Age range (yrs)

Incidence per 1000 Risk ratio & 95%CI
Additional cases per
women in placebo
1000 HRT users over
arm over 5 years
5 years (95%CI)
CEE oestrogen-only
50-79
21
0.8(0.7-1.0)
-4(-6-0)*
CEE+MPA oestrogen & progestogen‡
50-79
17
1.2(1.0-1.5)
+4(0-9)
* WHI study in women with no uterus, which did not show an increase in risk of
breast cancer.
‡When the analysis was restricted to women who had not used HRT prior to

the study there was no increased risk apparent during the first 5 years of
treatment: after 5 years the risk was higher than in non-users.
Endometrial Cancer Risk

Postmenopausal women with a uterus
The endometrial cancer risk is about 5 in every 1000 women with a uterus not using
HRT.
In women with a uterus, use of oestrogen-only HRT is not recommended because it
increases the risk of endometrial cancer (see Section 4.4).

Depending on the duration of oestrogen-only use and oestrogen dose, the
increase in risk of endometrial cancer in epidemiology studies varied from
between 5 and 55 extra cases diagnosed in every 1000 women between the
ages of 50 and 65.
Adding a progestogen to oestrogen-only therapy for at least 12 days per cycle
can prevent this increased risk. In the Million Women Study the use of five
years of combined (sequential or continuous) HRT did not increase risk of
endometrial cancer (RR of 1.0 (0.8-1.2)).
Ovarian Cancer

Use of oestrogen-only or combined oestrogen-progestogen HRT has been
associated with a slightly increased risk of having ovarian cancer diagnosed
(see Section 4.4).
A meta-analysis from 52 epidemiological studies reported an increased risk of
ovarian cancer in women currently using HRT compared to women who have
never used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years
taking 5 years of HRT, this results in about 1 extra case per 2000 users. In
women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be
diagnosed with ovarian cancer over a 5-year period.
Risk of Venous Thromboembolism
HRT is associated with a 1.3-3-fold increased relative risk of developing venous
thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The
occurrence of such an event is more likely in the first year of using HT (see Section
4.4). Results of the WHI studies are presented:
WHI Studies - Additional risk of VTE over 5 years’ use
Age range (years)

Incidence
Risk ratio and
per 1000 women in
95%CI
placebo arm over 5
years

Oral oestrogen-only*
50-59
7
Oral combined oestrogen-progestogen
50-59
4
* Study in women with no uterus.

Additional cases per
1000 HRT users over
5 years

1.2 (0.6-2.4)

1 (-3 – 10)

2.3 (1.2 – 4.3)

5 (1 - 13)

Risk of Coronary Artery Disease

The risk of coronary artery disease is slightly increased in users of combined
oestrogen-progestogen HRT over the age of 60 (see Section 4.4).
Risk of Ischaemic Stroke


The use of oestrogen-only and oestrogen - progestogen therapy is associated with an
up to 1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic
stroke is not increased during use of HRT.



This relative risk is not dependent on age or on duration of use, but as the baseline
risk is strongly age-dependent, the overall risk of stroke in women who use HRT will
increase with age, see Section 4.4.
WHI studies combined - Additional risk of ischaemic stroke* over 5 years’ use

Age range (years)

50-59

Incidence
Risk ratio and
per 1000 women in
95%CI
placebo arm over 5
years
8
1.3(1.1-1.6)

Additional cases per
1000 HRT users over
5 years
3(1-5)

* No differentiation was made between ischaemic and haemorrhagic stroke.

-

Other adverse reactions have been reported in association with oestrogen/progestogen
treatment:
skin and subcutaneous disorders: chloasma, erythema multiforme, erythema
nodosum, vascular purpura
probable dementia over the age of 65 (see Section 4.4)
dry eyes
tear film composition changes
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9

Overdose
Symptoms of over dosage with oral oestrogens are breast tenderness, nausea,
vomiting and/or metrorrhagia. Over dosage of progestogens may lead to a depressive
mood, fatigue, acne and hirsutism. If over dosage is discovered within two or three
hours and is so large that treatment seems desirable, gastric lavage can be considered.
There are no specific antidotes for over dosage and further treatment should be
symptomatic.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Progestogens and oestrogens, sequential preparations,
norethisterone and oestrogen.
ATC Code: G03FB05
Estradiol
The active ingredient, synthetic 17β-estradiol, is chemically and biologically identical
to endogenous human estradiol. It substitutes for the loss of oestrogen production in
menopausal women, and alleviates menopausal symptoms.
Norethisterone acetate
As oestrogens promote the growth of the endometrium, unopposed oestrogens
increase the risk of endometrial hyperplasia and cancer. The addition of a
progestogen greatly reduces the oestrogen-induced risk of endometrial hyperplasia in
non-hysterectomised women.

5.2

Pharmacokinetic properties
No pharmacokinetic parameters are available for Elleste Duet 1 mg. Pharmacokinetic
parameters for Elleste Duet 2 mg (2 mg estradiol + 1 mg norethisterone tablets) are
provided in the table below. The data were obtained from an open label, two way
crossover pharmacokinetic study in which treatment was administered for 7 days to
achieve steady state (n=24). Pharmacokinetic data were collected over 24 hours.

Serum unconjugated
estradiol

Serum unconjugated
estrone

mean (SD)

mean (SD)

AUC0-24h

967.8 (0.5) pg.h/ml

8366 (1.7) pg.h/ml

43.2 (0.4)
ng.h/ml

Cmax

61.6 (0.4) pg/ml

648.5 (1.5) pg/ml

11.8 (0.4) ng/ml

Cmin

19.3 (0.6) pg/ml

131.1 (2.5) pg/ml

0.5 (0.5) ng/ml

Tmax

3.4 (2.1) h

5.07 (1.8) h

0.9 (0.3) h

Estradiol

Norethisterone
mean (SD)

Readily and fully absorbed from the GI tract when given orally, peak levels are
generally observed 3-6 hours after ingestion, but by 24 hours concentrations have
returned to baseline.
Estradiol is converted to estrone and estriol primarily in the liver. These are excreted
into the bile and undergo enterohepatic recirculation and further degradation before
being excreted in the urine (90-95%) as biologically inactive glucuronide and
sulphate conjugates or in the faeces (5-10%), mostly unconjugated.
Norethisterone acetate
Norethisterone acetate is absorbed from the GI tract and its effects last for at least 24
hours. Maximum blood concentrations are generally reached 1-4 hours after
administration. Norethisterone acetate undergoes first pass effect, being transformed
to norethisterone which is then metabolised and excreted mainly in the urine as
glucuronide and sulphate conjugates.

5.

PHARMACOLOGICAL PROPERTIES

5.3

Preclinical safety data
Both estradiol and norethisterone acetate have been shown to induce adverse effects in
preclinical reproductive toxicity studies. Chiefly, estradiol showed embryotoxic effects
and induced anomalies in urogenital tract development, e.g. feministation of male
foetuses in high doses. Norethisterone acetate showed embryotoxic effects and induced
anomalies in urogenital tract development. In mice, additional anomalies in nonurogenital foetal development, including hydrocephalus and clubfoot, have been
detected.
Long-term, continuous administration of natural and synthetic oestrogens in certain
animal species increases the frequency of carcinomas of the breast, uterus, cervix,
vagina, testis, and liver. Long-term, continuous administration of norethisterone in
certain animal species increases the frequency of tumours of the hypophysis and
ovary in females, and of liver and breast in males.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core:
Lactose monohydrate,
Maize starch
Povidone 25

Talc (purified)
Magnesium stearate
Film-coating material:
Estradiol only (white) tablets:
Hydroxypropylmethyl cellulose (E464)
Titanium dioxide (E171)
Macrogol 400
Estradiol and Norethisterone Acetate only (green) tablets:
Hydroxypropylmethyl cellulose (E464)
Titanium dioxide (E171)
Macrogol 400
Quinoline yellow (E104)
Indigo carmine (E132)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
Do not store above 30°C. Store in the original package.

6.5

Nature and contents of container
Aluminium foil and UPVC blister packed in a cardboard carton.
Pack sizes: 28 film-coated tablets and 84 (3 x 28) film-coated tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER
Meda Pharmaceuticals Ltd
Skyway House
Parsonage Road

Takeley
Bishop’s Stortford
CM22 6PU

8

MARKETING AUTHORISATION NUMBER(S)
PL 15142/0063

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
Date of first authorisation: 24 March 1997
Date of latest renewal: 27 August 2007

10

DATE OF REVISION OF THE TEXT
19/04/2016

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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